phases
list | enrollmentCount
int64 | allocation
string | interventionModel
string | primaryPurpose
class label | masking
class label | healthyVolunteers
bool | sex
class label | oversightHasDmc
bool | briefSummary
string | detailedDescription
string | conditions
string | conditionsKeywords
string | protocolPdfText
string | numArms
int64 | armDescriptions
string | armGroupTypes
list | numInterventions
int64 | interventionTypes
list | interventionDescriptions
string | interventionNames
string | numLocations
int64 | locationDetails
string | target
int64 | nctid
string |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
[
4
] | 760
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the safety and efficacy of ABT-335 and rosuvastatin calcium combination therapy to monotherapy in subjects with dyslipidemia.
|
There are 3 treatment groups in the study: ABT-335 135 mg in combination with rosuvastatin 5 mg, ABT-335 135 mg monotherapy, and rosuvastatin 5 mg monotherapy. The 3 primary outcome measures only compare 2 of the treatment groups for each variable (mean percent change in HDL-C and TG comparing ABT-335 135 mg in combination with rosuvastatin 5 mg to rosuvastatin 5 mg monotherapy, and mean percent change in LDL-C comparing ABT-335 135 mg in combination with rosuvastatin 5 mg to ABT-335 135 mg monotherapy. The 6 secondary outcome measures only compare 2 of the treatment groups for each variable (mean percent change in Non-HDL-C comparing ABT-335 135 mg in combination with rosuvastatin 5 mg to ABT-335 135 mg monotherapy, mean percent change in Non-HDL-C, VLDL-C, ApoB, and Total Cholesterol comparing ABT-335 135 mg in combination with rosuvastatin 5 mg to rosuvastatin 5 mg monotherapy, and median percent change in hsCRP comparing ABT-335 135 mg in combination with rosuvastatin 5 mg to rosuvastatin 5 mg monotherapy).
|
Hypercholesterolemia Dyslipidemia
| null | 3
|
arm 1: ABT-335 135mg in combination with rosuvastatin calcium 5mg administered orally, once daily for 12 weeks arm 2: ABT-335 135mg monotherapy administered orally, once daily for 12 weeks arm 3: Rosuvastatin calcium 5mg monotherapy administered orally, once daily for 12 weeks
|
[
0,
1,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: ABT-335 135 mg in combination with rosuvastatin calcium 5 mg administered orally, once daily for 12 weeks intervention 2: ABT-335 135 mg monotherapy administered orally, once daily for 12 weeks intervention 3: Rosuvastatin calcium 5 mg monotherapy administered orally, once daily for 12 weeks
|
intervention 1: ABT-335 and rosuvastatin calcium intervention 2: ABT-335 intervention 3: rosuvastatin calcium
| 168
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
Huntsville | Alabama | United States | -86.58594 | 34.7304
Huntsville | Alabama | United States | -86.58594 | 34.7304
Ozark | Alabama | United States | -85.64049 | 31.45906
Tuscaloosa | Alabama | United States | -87.56917 | 33.20984
Chandler | Arizona | United States | -111.84125 | 33.30616
Gilbert | Arizona | United States | -111.78903 | 33.35283
Scottsdale | Arizona | United States | -111.89903 | 33.50921
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Anaheim | California | United States | -117.9145 | 33.83529
Chula Vista | California | United States | -117.0842 | 32.64005
Concord | California | United States | -122.03107 | 37.97798
Encinitas | California | United States | -117.29198 | 33.03699
Fair Oaks | California | United States | -121.27217 | 38.64463
Fresno | California | United States | -119.77237 | 36.74773
Fresno | California | United States | -119.77237 | 36.74773
Lincoln | California | United States | -121.29301 | 38.89156
Long Beach | California | United States | -118.18923 | 33.76696
Los Angeles | California | United States | -118.24368 | 34.05223
Norwalk | California | United States | -118.08173 | 33.90224
Sacramento | California | United States | -121.4944 | 38.58157
Sacramento | California | United States | -121.4944 | 38.58157
San Diego | California | United States | -117.16472 | 32.71571
West Hills | California | United States | -118.64398 | 34.19731
Aurora | Colorado | United States | -104.83192 | 39.72943
Colorado Springs | Colorado | United States | -104.82136 | 38.83388
Waterbury | Connecticut | United States | -73.0515 | 41.55815
Coral Gables | Florida | United States | -80.26838 | 25.72149
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
Holly Hill | Florida | United States | -81.03756 | 29.24359
Hollywood | Florida | United States | -80.14949 | 26.0112
Jacksonville | Florida | United States | -81.65565 | 30.33218
Jacksonville | Florida | United States | -81.65565 | 30.33218
Jupiter | Florida | United States | -80.09421 | 26.93422
Kissimmee | Florida | United States | -81.41667 | 28.30468
Largo | Florida | United States | -82.78842 | 27.90979
Melbourne | Florida | United States | -80.60811 | 28.08363
Miami | Florida | United States | -80.19366 | 25.77427
New Port Richey | Florida | United States | -82.71927 | 28.24418
New Smyrna Beach | Florida | United States | -80.927 | 29.02582
Ocala | Florida | United States | -82.14009 | 29.1872
Ocala | Florida | United States | -82.14009 | 29.1872
Orlando | Florida | United States | -81.37924 | 28.53834
Ormond Beach | Florida | United States | -81.05589 | 29.28581
Pensacola | Florida | United States | -87.21691 | 30.42131
Sarasota | Florida | United States | -82.53065 | 27.33643
Sarasota | Florida | United States | -82.53065 | 27.33643
West Palm Beach | Florida | United States | -80.05337 | 26.71534
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Winter Haven | Florida | United States | -81.73286 | 28.02224
Blue Ridge | Georgia | United States | -84.32409 | 34.86397
Decatur | Georgia | United States | -84.29631 | 33.77483
Dunwoody | Georgia | United States | -84.33465 | 33.94621
Roswell | Georgia | United States | -84.36159 | 34.02316
Roswell | Georgia | United States | -84.36159 | 34.02316
Suwanee | Georgia | United States | -84.0713 | 34.05149
Woodstock | Georgia | United States | -84.51938 | 34.10149
Arlington Heights | Illinois | United States | -87.98063 | 42.08836
Chicago | Illinois | United States | -87.65005 | 41.85003
Peoria | Illinois | United States | -89.58899 | 40.69365
Avon | Indiana | United States | -86.39972 | 39.76282
Evansville | Indiana | United States | -87.55585 | 37.97476
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Lafayette | Indiana | United States | -86.87529 | 40.4167
Newburgh | Indiana | United States | -87.40529 | 37.94449
Iowa City | Iowa | United States | -91.53017 | 41.66113
Arkansas City | Kansas | United States | -97.03837 | 37.06197
Overland Park | Kansas | United States | -94.67079 | 38.98223
Wichita | Kansas | United States | -97.33754 | 37.69224
Wichita | Kansas | United States | -97.33754 | 37.69224
Lexington | Kentucky | United States | -84.47772 | 37.98869
Louisville | Kentucky | United States | -85.75941 | 38.25424
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Slidell | Louisiana | United States | -89.78117 | 30.27519
Auburn | Maine | United States | -70.23117 | 44.09785
Scarborough | Maine | United States | -70.32172 | 43.57814
Baltimore | Maryland | United States | -76.61219 | 39.29038
Haverhill | Massachusetts | United States | -71.07728 | 42.7762
Springfield | Massachusetts | United States | -72.58981 | 42.10148
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Portage | Michigan | United States | -85.58 | 42.20115
Brooklyn Center | Minnesota | United States | -93.33273 | 45.07608
Jackson | Mississippi | United States | -90.18481 | 32.29876
Olive Branch | Mississippi | United States | -89.82953 | 34.96176
Tupelo | Mississippi | United States | -88.70464 | 34.25807
City of Saint Peters | Missouri | United States | -90.62651 | 38.80033
Kansas City | Missouri | United States | -94.57857 | 39.09973
Billings | Montana | United States | -108.50069 | 45.78329
Missoula | Montana | United States | -113.994 | 46.87215
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Concord | New Hampshire | United States | -71.53757 | 43.20814
Elizabeth | New Jersey | United States | -74.2107 | 40.66399
South Bound Brook | New Jersey | United States | -74.53154 | 40.55344
Toms River | New Jersey | United States | -74.19792 | 39.95373
Trenton | New Jersey | United States | -74.74294 | 40.21705
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Bronxville | New York | United States | -73.83208 | 40.93815
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Syracuse | New York | United States | -76.14742 | 43.04812
Williamsville | New York | United States | -78.73781 | 42.96395
Asheville | North Carolina | United States | -82.55402 | 35.60095
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Hickory | North Carolina | United States | -81.3412 | 35.73319
Morehead City | North Carolina | United States | -76.72604 | 34.72294
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Salisbury | North Carolina | United States | -80.47423 | 35.67097
Statesville | North Carolina | United States | -80.8873 | 35.78264
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Columbus | Ohio | United States | -82.99879 | 39.96118
Mogadore | Ohio | United States | -81.39789 | 41.04645
Sandusky | Ohio | United States | -82.70796 | 41.44894
Warren | Ohio | United States | -80.81842 | 41.23756
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Medford | Oregon | United States | -122.87559 | 42.32652
Carlisle | Pennsylvania | United States | -77.18887 | 40.20148
Downingtown | Pennsylvania | United States | -75.70327 | 40.0065
Feasterville | Pennsylvania | United States | -74.997 | 40.15
Harleysville | Pennsylvania | United States | -75.38712 | 40.27955
Jersey Shore | Pennsylvania | United States | -77.26442 | 41.20202
Lansdale | Pennsylvania | United States | -75.28379 | 40.2415
Melrose Park | Pennsylvania | United States | -75.13184 | 40.06178
Newtown | Pennsylvania | United States | -74.93683 | 40.22928
Penndel | Pennsylvania | United States | -74.91656 | 40.15205
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Warminster | Pennsylvania | United States | -75.09962 | 40.20678
Charleston | South Carolina | United States | -79.93275 | 32.77632
Greenville | South Carolina | United States | -82.39401 | 34.85262
Greer | South Carolina | United States | -82.22706 | 34.93873
Moncks Corner | South Carolina | United States | -80.01429 | 33.19632
Mt. Pleasant | South Carolina | United States | -79.86259 | 32.79407
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Summerville | South Carolina | United States | -80.17565 | 33.0185
Sioux Falls | South Dakota | United States | -96.70033 | 43.54997
Jackson | Tennessee | United States | -88.81395 | 35.61452
Johnson City | Tennessee | United States | -82.35347 | 36.31344
Nashville | Tennessee | United States | -86.78444 | 36.16589
Arlington | Texas | United States | -97.10807 | 32.73569
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Temple | Texas | United States | -97.34278 | 31.09823
Falls Church | Virginia | United States | -77.17109 | 38.88233
Richmond | Virginia | United States | -77.46026 | 37.55376
Richmond | Virginia | United States | -77.46026 | 37.55376
Lakewood | Washington | United States | -122.51846 | 47.17176
Madison | Wisconsin | United States | -89.40123 | 43.07305
| 0
|
NCT00463606
|
|
[
5
] | 289
|
RANDOMIZED
|
FACTORIAL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
Metoclopramide is a dopamine antagonist frequently used for the treatment of nausea, vomiting, and migraine headaches in Emergency Departments. However, little research has focused on the optimal dose of metoclopramide for treatment of nausea in the emergency department. We propose a randomized, double-blind, placebo controlled trial to investigate the optimal dose of metoclopramide for treatment of nausea.
|
The most effective dose of metoclopramide for treatment of nausea in the emergency department setting has not been thoroughly investigated. One pilot study among emergency department patients in Australia found no statistical difference between 10 mg and 0.4 milligrams/kilogram; another investigation suggests that the anti-emetic effect of 10 milligrams of metoclopramide is no more effective than placebo. In contrast, investigations focusing on chemotherapy patients and post-operative patients suggest that higher dosage metoclopramide is more effective in treating nausea and vomiting. This emergency department study will compare the anti-emetic efficacy of 10 milligrams and 20 milligrams of metoclopramide by using the visual analog scale.
In addition to evaluation of dose, we will evaluate one of the most common side affects of metoclopramide, akathisia. Akathisia is characterized by a subjective component of restlessness and an objective component in the form of the inability to remain motionless. Anti-cholinergic medications are known to reduce extrapyramidal symptoms such as akathisia when dopamine function is impaired in the basal ganglia. In fact, the use of diphenhydramine has been shown to reduce the incidence of akathisia in patients receiving a different anti-emetic, prochlorperazine. However, no research has focused on the use of anti-cholinergic medications to reduce metoclopramide induced akathisia. This investigation will assess the use of 25 mg of diphenhydramine in preventing metoclopramide induced akathisia in ED patients being treated for nausea/vomiting.
|
Nausea Extrapyramidal Symptoms
|
Metoclopramide Nausea Akathisia Emergency department
| null | 4
|
arm 1: Metoclopramide 20 mg + diphenhydramine, delivered intravenously over 15 minutes arm 2: Metoclopramide 20 mg + placebo, delivered intravenously over 15 minutes arm 3: Metoclopramide 10mg + placebo, delivered intravenously over 15 minutes arm 4: Metoclopramide 10 mg + diphenhydramine 25 mg, delivered intravenously over 15 minutes
|
[
1,
1,
1,
1
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: an anti-emetic medication intervention 2: used for prophylaxis against akathisia intervention 3: placebo intervention 4: Metoclopramide 20 mg
|
intervention 1: metoclopramide 10 mg intervention 2: Diphenhydramine 25 mg intervention 3: Placebo intervention 4: Metoclopramide 20 mg
| 1
|
The Bronx | New York | United States | -73.86641 | 40.84985
| 0
|
NCT00475306
|
[
4
] | 799
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| true
|
The purpose of this study is to investigate the efficacy and safety of several doses of the melt formulation of desmopressin in a broad population of adult patients with nocturia.
| null |
Nocturia
| null | 5
|
arm 1: Participants took a placebo 'melt' for 28 days to complete part 1 of the study. In part 2, placebo patients were randomized to one of the other 4 treatment arms based on assignments predetermined at the initial randomization, to receive active desmopressin melt for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). arm 2: Participants took desmopressin melt 10 μg for 28 days to complete part 1 of the study. Participants continued on this dose in part 2 of the study for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). arm 3: Participants took desmopressin melt 25 μg for 28 days to complete part 1 of the study. Participants continued on this dose in part 2 of the study for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). arm 4: Participants took desmopressin melt 50 μg for 28 days to complete part 1 of the study. Participants continued on this dose in part 2 of the study for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). arm 5: Participants will take desmopressin melt 100 μg for 28 days to complete part 1 of the study. Participants will continue on this dose in part 2 of the study for between 1-6 months (until the database for part 1 is locked and treatment is unblinded).
|
[
2,
0,
0,
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Oral lyophilisate of desmopressin acetate placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime in the assigned dosage: 10, 25, 50 or 100 μg intervention 2: Oral placebo placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime.
|
intervention 1: desmopressin acetate intervention 2: Placebo
| 80
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Scottsdale | Arizona | United States | -111.89903 | 33.50921
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Anaheim | California | United States | -117.9145 | 33.83529
Beverly Hills | California | United States | -118.40036 | 34.07362
Long Beach | California | United States | -118.18923 | 33.76696
Newport Beach | California | United States | -117.92895 | 33.61891
San Diego | California | United States | -117.16472 | 32.71571
Santa Rosa | California | United States | -122.71443 | 38.44047
Tarzana | California | United States | -118.55397 | 34.17334
Torrance | California | United States | -118.34063 | 33.83585
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Middlebury | Connecticut | United States | -73.12761 | 41.52787
Aventura | Florida | United States | -80.13921 | 25.95648
Clearwater | Florida | United States | -82.8001 | 27.96585
Miami | Florida | United States | -80.19366 | 25.77427
Plantation | Florida | United States | -80.23184 | 26.13421
Stuart | Florida | United States | -80.25283 | 27.19755
Tallahassee | Florida | United States | -84.28073 | 30.43826
Tampa | Florida | United States | -82.45843 | 27.94752
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Columbus | Georgia | United States | -84.98771 | 32.46098
Dunwoody | Georgia | United States | -84.33465 | 33.94621
Peoria | Illinois | United States | -89.58899 | 40.69365
Overland Park | Kansas | United States | -94.67079 | 38.98223
Metairie | Louisiana | United States | -90.15285 | 29.98409
Shreveport | Louisiana | United States | -93.75018 | 32.52515
Shreveport | Louisiana | United States | -93.75018 | 32.52515
Springfield | Massachusetts | United States | -72.58981 | 42.10148
St Louis | Missouri | United States | -90.19789 | 38.62727
Lincoln | Nebraska | United States | -96.66696 | 40.8
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Lawrenceville | New Jersey | United States | -74.7296 | 40.29733
Lawrenceville | New Jersey | United States | -74.7296 | 40.29733
Morristown | New Jersey | United States | -74.48154 | 40.79677
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Albany | New York | United States | -73.75623 | 42.65258
Carmel | New York | United States | -73.68013 | 41.43009
Garden City | New York | United States | -73.6343 | 40.72677
New York | New York | United States | -74.00597 | 40.71427
Suffern | New York | United States | -74.14959 | 41.11482
Concord | North Carolina | United States | -80.58158 | 35.40888
Greensboro | North Carolina | United States | -79.79198 | 36.07264
Wilmington | North Carolina | United States | -77.94604 | 34.23556
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Mogadore | Ohio | United States | -81.39789 | 41.04645
Bala-Cynwyd | Pennsylvania | United States | -75.23407 | 40.00761
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Reading | Pennsylvania | United States | -75.92687 | 40.33565
Greenville | South Carolina | United States | -82.39401 | 34.85262
Greer | South Carolina | United States | -82.22706 | 34.93873
Mt. Pleasant | South Carolina | United States | -79.86259 | 32.79407
Myrtle Beach | South Carolina | United States | -78.88669 | 33.68906
Kingsport | Tennessee | United States | -82.56182 | 36.54843
Nashville | Tennessee | United States | -86.78444 | 36.16589
Corpus Christi | Texas | United States | -97.39638 | 27.80058
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
Humble | Texas | United States | -95.26216 | 29.99883
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Richmond | Virginia | United States | -77.46026 | 37.55376
Virginia Beach | Virginia | United States | -75.97799 | 36.85293
Seattle | Washington | United States | -122.33207 | 47.60621
Seattle | Washington | United States | -122.33207 | 47.60621
Seattle | Washington | United States | -122.33207 | 47.60621
Kelowna | British Columbia | Canada | -119.48568 | 49.88307
Victoria | British Columbia | Canada | -123.35155 | 48.4359
Victoria | British Columbia | Canada | -123.35155 | 48.4359
Fredericton | New Brunswick | Canada | -66.66558 | 45.94541
Barrie | Ontario | Canada | -79.66634 | 44.40011
Brantford | Ontario | Canada | -80.26636 | 43.1334
Guelph | Ontario | Canada | -80.25599 | 43.54594
North Bay | Ontario | Canada | -79.46633 | 46.3168
Oakville | Ontario | Canada | -79.68292 | 43.45011
Toronto | Ontario | Canada | -79.39864 | 43.70643
| 0
|
NCT00477490
|
|
[
0
] | 101
|
RANDOMIZED
|
PARALLEL
| 4SUPPORTIVE_CARE
| 3TRIPLE
| false
| 0ALL
| false
|
Prior to surgery, a pharmacist will randomly assign participating patients to one of two groups. One group will get an injection in the knee during surgery that contains medications to limit pain and an antibiotic. A second group will get an injection in the knee during surgery that contains the same pain medications and antibiotic along with a corticosteroid to control inflammation. Corticosteroids are anti-inflammatory medications, not to be confused with muscle-building anabolic steroids you may have heard about in the news. Each patient will have an equal chance of being in either of the two groups. This study will test the safety and efficacy of methylprednisolone acetate in the treatment of pain and inflammation following total knee replacement.
|
Information collected during your office visits:
The patient will be asked for a brief medical history so that we may determine if the patient can participate in the study. A member of our research team will ask the patient a series of questions about his/her knee. The patient will be asked to answer this series of questions a total of 4 times over the course of 1 year. Also, we will record how well the patient can bend and straighten your knee at these 4 office visits. We will have the patient rate the pain in his/her knee and ask the patient if he/she is satisfied with the surgery. If the patients have any complications, those will also be recorded. The patient will also have X-rays taken of the knee at the postoperative follow-up visits. This is the normal routine following total knee replacement. The X-rays will be read by the surgeon to help determine the success of the surgery.
Injection during total knee replacement surgery:
All patients will receive an injection containing bupivicaine HCl, morphine, epinephrine, clonidine, cefuroxime, and normal saline that will be placed directly into the knee during surgery. In addition, approximately half of the patients in the study will also receive methylprednisolone acetate as part of the injection.
Information being collected during your hospital stay:
During the hospital stay, information will be gathered for this study. A physical therapist will measure how well the patient can bend and straighten the knee. The amount of pain medication that was taken at the hospital will be recorded, and the number of days spent in the hospital will also be recorded.
|
Osteoarthritis Post-traumatic; Arthrosis
|
arthroplasty replacement knee
| null | 2
|
arm 1: Patients in the active comparator group will receive intraoperative injections containing bupivacaine HCl, morphine, epinephrine, clonidine, cefuroxime, and normal saline, as per the surgeon's standard of care. arm 2: Patients in the Corticosteroid group will have the same medications as the Control Group with the addition of a corticosteroid (methylprednisolone acetate)
|
[
1,
0
] | 2
|
[
0,
0
] |
intervention 1: Same medications and doses as the active comparator, but with the addition of 40 mg of methylprednisolone acetate intervention 2: bupivacaine HCl 80 mg, morphine 4 mg, epinephrine 300 micrograms, clonidine 100 micrograms, cefuroxime 750 mg, and normal saline
|
intervention 1: methylprednisolone acetate intervention 2: active comparator
| 1
|
Lexington | Kentucky | United States | -84.47772 | 37.98869
| 0
|
NCT00492973
|
[
3
] | 48
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 2DOUBLE
| false
| 0ALL
| false
|
The study shall provide evidence for the save and efficient use of a fish oil containing lipid emulsion in parenteral nutrition of preterm infants.Safety will be assessed by monitoring hepatological and hematological laboratory parameters. Efficiency will be assessed by monitoring of inflammatory parameters.
| null |
Preterm Infants Parenteral Nutrition n-3 Fatty Acids
|
n-3 Polyunsaturated Fatty Acids (PUFA) parenteral nutrition preterm infant
| null | 2
|
arm 1: Lipidem 20 % arm 2: Lipofundin MCT/LCT 20%
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: daily i.v. infusion for up to 5 days intervention 2: daily i.v. infusion for up to 5 days
|
intervention 1: Lipofundin MCT/LCT 20 % intervention 2: Lipidem 20%
| 2
|
Munich | Bavaria | Germany | 11.57549 | 48.13743
Greifswald | N/A | Germany | 13.40244 | 54.08905
| 0
|
NCT00497289
|
[
3
] | 163
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
This is a multicenter study designed to compare the effect of exenatide plus a lifestyle modification plan versus placebo plus a lifestyle modification plan on weight loss in non-diabetic, obese subjects.
| null |
Obesity
|
exenatide obesity diabetes Amylin Lilly
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: subcutaneous injection (5mcg or 10mcg), twice a day intervention 2: subcutaneous injection (equivalent volume to active dose), twice a day
|
intervention 1: exenatide intervention 2: placebo
| 16
|
Peoria | Arizona | United States | -112.23738 | 33.5806
Tucson | Arizona | United States | -110.92648 | 32.22174
Santa Ana | California | United States | -117.86783 | 33.74557
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Topeka | Kansas | United States | -95.67804 | 39.04833
Wichita | Kansas | United States | -97.33754 | 37.69224
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
St Louis | Missouri | United States | -90.19789 | 38.62727
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Goose Creek | South Carolina | United States | -80.03259 | 32.98101
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Dallas | Texas | United States | -96.80667 | 32.78306
San Antonio | Texas | United States | -98.49363 | 29.42412
Renton | Washington | United States | -122.21707 | 47.48288
Ponce | N/A | Puerto Rico | -66.62398 | 18.01031
San Juan | N/A | Puerto Rico | -66.10572 | 18.46633
| 0
|
NCT00500370
|
[
4
] | 5
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
Primary Objective:
To determine the risk of bleeding from ASA therapy in thrombocytopenic patients who develop Acute Coronary Syndrome (ACS), and assess its effect on the overall morbidity and mortality in these patients as well as platelet functions.
|
Aspirin is known to decrease death rate by as much as 50% in patients that suffer from heart attacks. Patients with low platelet count are not given aspirin for fear of an increased risk of bleeding. Researchers want to compare the risks versus the benefits of using aspirin in this patient population.
Participants in this study who suffer chest pain will be treated with a single enteric coated aspirin 325 mg instead of the current treatment without aspirin. Participants will then be tested to confirm that they had a heart attack by EKG (a test to measure the electrical activity of the heart) and blood tests (5ml of blood) will be drawn every 8 hours to detect enzymes that are released from the heart due to the heart attack. Blood samples will also be examined for platelet number.
Participants who are found to have had a heart attack and have a platelet count of between 100,000 and 20,000 will be continued on aspirin (160 mg per day). All other standard medications for heart attacks will also be given.
Participants who are found to have had a heart attack but whose platelet number is more than 100,000 will be given the standard therapy for heart attack, including enteric coated aspirin 325 mg per day, and will no longer take part in this study. Participants who are found to have had a heart attack but whose platelet number is less than 20,000 will be not be included in the study and will be treated as deemed appropriate by their primary physician.
Participants will be examined daily and evaluated for bleeding. Blood samples (30 ml of blood) will also be drawn before or after aspirin is given and 24 hours, 72 hours and 7 days after aspirin treatment to study platelet function. Participants will be followed up on the study for 7 days. Participants will be followed up in the cardiology clinic within 1-2 weeks after discharge from the hospital, then once a month for six month. Further follow up will be every 6 month. Patients are requested to follow up with cardiology by phone at any time for any bleeding.
Participants who are not found to have had a heart attack will not receive any further aspirin treatment.
This is an investigational study. Aspirin is an FDA approved drug for treatment of heart attacks and is commercially available. Aspirin is a standard therapy for patients who have had a heart attack. Thirty patients will take part in this study. All will be enrolled at M. D. Anderson.
|
Thrombocytopenia Myocardial Infarction
|
Thrombocytopenia Platelet Function Acute Coronary Syndrome Myocardial Infarction Heart Attack Aspirin
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: 325 mg by mouth on Day 1 only, followed by 160 mg by mouth daily
|
intervention 1: Aspirin
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00501345
|
[
3
] | 22
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| true
|
The purpose of this study is to determine whether a phospholipid emulsion is effective in the treatment of chronic endotoxemia in hemodialysis patients.
|
Over 70% of dialysis patients suffer chronically from severe fatigue and tiredness. A possible inciting factor may be high levels of circulating endotoxin, which is well-established as a potent stimulator of inflammatory cytokine release.
The source of increased endotoxin in dialysis patients remains unclear, with the most popular hypotheses including back-diffusion of bacterial products from nonsterile dialysate and translocation of bacterial products across what in most dialysis patients is an edematous gut wall. This endotoxin does not appear to be associated with the dialysis procedure itself and indeed, appears to be cleared with some efficiency by the procedure. However, by the next dialysis treatment, endotoxin levels rise rapidly to levels that are in some cases significantly higher than even those measured (via EAA) in patients suffering from septic shock. Although the mechanisms by which dialysis patients tolerate these high endotoxin levels without hemodynamic collapse are not understood, high levels have been shown by The Rogosin Institute to significantly correlate with patient fatigue.
Given the potent ability of endotoxin to induce expression of inflammatory cytokines (which in turn are likely responsible for the debilitating symptoms of fatigue and malaise that afflict the majority of the dialysis population), it is logical that binding and inactivation of endotoxin may lead to improved clinical outcomes. Unfortunately, there are no products currently approved for this purpose in dialysis patients.
One approach to this problem may be to augment the endogenous systems for endotoxin inactivation. For example, it has been suggested that the various serum lipoprotein fractions may in fact be a physiologic "sink" for endotoxin (and other toxins) via binding with surface phospholipids. Therefore, dialysis patients, who as a population are characterized with hypocholesterolemia and hypolipoproteinemia, are particularly at risk for the deleterious effects of endotoxemia.
This has led to the development of "LIPIDOSE," a protein-free phospholipid emulsion. The proposed mechanism of action of this compound is via remodeling of the infused phospholipids into lipoproteins, thereby increasing lipoprotein and phospholipid content and facilitating greater endotoxin binding and neutralization. "LIPIDOSE" has undergone extensive testing in both animals and humans, and has been found to significantly increase serum phospholipid and lipoprotein concentrations, improve survival in a lethal animal model of septic peritonitis, and mitigate the symptoms of endotoxemia in healthy volunteers.
|
Fatigue End Stage Renal Disease (ESRD)
|
Fatigue Hemodialysis Endotoxemia Phospholipid Emulsion
| null | 2
|
arm 1: Dosage of 1.5 mL/kg of Lipidose over a 2-hour period. arm 2: Dosage of 1.5 mL/kg of Placebo over a 2-hour period.
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: Over the course of 2 weeks, immediately following subject's three (Monday/Wednesday/Friday (M/W/F)) normal dialysis treatments, based on subject's current weight, subject will receive 1.5 mL/kg of Lipidose over a 2-hour period. intervention 2: Over the course of 2 weeks, immediately following subject's three (M/W/F) normal dialysis treatments, based on subject's current weight, subject will receive 1.5 mL/kg of placebo over a 2-hour period.
|
intervention 1: Lipidose intervention 2: Placebo
| 1
|
New York | New York | United States | -74.00597 | 40.71427
| 0
|
NCT00506454
|
[
3
] | 35
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study was designed to evaluate the safety, pharmacokinetic profile and efficacy in Restless Legs Syndrome patients.
| null |
Restless Legs Syndrome
|
Restless Legs Syndrome
| null | 1
|
arm 1: Subjects will orally take ropinirole CR-RLS tablet(s) once daily 1-2 hours before the onset of RLS symptoms at about the same time of the day. The time of taking ropinirole must be after 16:00.Adjustment of the Ropinirole CR-RLS tablets should be completed after the Week 1 visit up to the Week 10 visit. The dose will be increased at intervals of at least one week until sufficient efficacy is obtained (use "much improved" as a guide) without safety problem. Dose escalation will start at the initial dose 0.5 mg/day to 1 mg/day; after 1 mg/day, the dose will be increased by 1 mg/day to the maximum 6 mg/day.
|
[
0
] | 1
|
[
0
] |
intervention 1: White film-coated round-shaped tablet
|
intervention 1: ropinirole controlled release (CR)-RLS
| 11
|
Fukuoka | N/A | Japan | 130.41667 | 33.6
Fukuoka | N/A | Japan | 130.41667 | 33.6
Fukuoka | N/A | Japan | 130.41667 | 33.6
Hiroshima | N/A | Japan | 132.45 | 34.4
Kanagawa | N/A | Japan | 139.91667 | 37.58333
Osaka | N/A | Japan | 135.50107 | 34.69379
Osaka | N/A | Japan | 135.50107 | 34.69379
Osaka | N/A | Japan | 135.50107 | 34.69379
Tochigi | N/A | Japan | 139.73333 | 36.38333
Tokyo | N/A | Japan | 139.69171 | 35.6895
Tokyo | N/A | Japan | 139.69171 | 35.6895
| 0
|
NCT00530790
|
[
4
] | 107
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of the study is to compare Symbicort pMDI with and without spacer in terms of steroid potency, improvement of lung function and asthma symptoms in children with asthma (6-11 years).
| null |
Asthma
|
Symbicort pMDI spacer children
| null | 2
|
arm 1: Budesonide/formoterol pMDI 40/2.25ug + spacer arm 2: Budesonide/formoterol pMDI 40/2.25 ug
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Budesonide/formoterol pMDI 40/2.25ug + spacer intervention 2: Budesonide/formoterol pMDI 40/2.25 ug
| 11
|
Budapest | N/A | Hungary | 19.04045 | 47.49835
Debrecen | N/A | Hungary | 21.62444 | 47.53167
Kaposvár | N/A | Hungary | 17.8 | 46.36667
Bialystok | N/A | Poland | 23.16433 | 53.13333
Bydgoszcz | N/A | Poland | 18.00762 | 53.1235
Bytom | N/A | Poland | 18.93282 | 50.34802
Karpacz | N/A | Poland | 15.75594 | 50.77669
Krakow | N/A | Poland | 19.93658 | 50.06143
Lodz | N/A | Poland | 19.47395 | 51.77058
Warsaw | N/A | Poland | 21.01178 | 52.22977
Moscow | N/A | Russia | 37.61556 | 55.75222
| 0
|
NCT00536913
|
[
3
] | 707
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| false
|
The primary objective of this study is to evaluate the efficacy of the combination of mometasone furoate nasal spray (MFNS) and oxymetazoline nasal spray (OXY) given together once a day in treating subjects with seasonal allergic rhinitis (SAR) in relieving symptoms including nasal congestion. The secondary objectives of this study are to evaluate the potential of the combination to produce tachyphylaxis and/or rebound congestion, and to evaluate the safety of the combination.
| null |
Seasonal Allergic Rhinitis
| null | 5
|
arm 1: Mometasone Furoate nasal spray (MFNS) with oxymetazoline nasal spray (OXY) 1 spray once daily arm 2: MFNS with OXY 3 sprays once daily arm 3: MFNS once daily arm 4: OXY twice daily arm 5: Placebo nasal spray
|
[
0,
0,
1,
1,
2
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: MFNS 2 sprays per nostril with OXY 1 spray per nostril once daily x 2 weeks. Matching placebo to MFNS given every evening (PM). intervention 2: MFNS 2 sprays per nostril with OXY 3 sprays per nostril once daily x 2 weeks. Matching placebo to MFNS given every evening. intervention 3: MFNS 2 sprays per nostril once daily x 2 weeks. Matching placebo to MFNS given every morning (AM) and every evening. intervention 4: OXY 2 sprays per nostril twice daily x 2 weeks. Matching placebo to MFNS given every morning. intervention 5: Matching placebo to MFNS given every morning and every evening x 2 weeks.
|
intervention 1: OXY combination: mometasone furoate nasal spray (MFNS) and oxymetazoline nasal spray (OXY) intervention 2: OXY combination: mometasone furoate nasal spray (MFNS) and oxymetazoline nasal spray (OXY) intervention 3: mometasone furoate nasal spray (MFNS) once daily intervention 4: oxymetazoline nasal spray (OXY) twice daily intervention 5: Placebo
| 0
| null | 0
|
NCT00552110
|
|
[
4
] | 97
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
To determine the convenience and satisfaction of new orally disintegrating tablet formulation (ODT) of lamictal in subjects with a mood disorder. This was a multicenter, open-label study in participants with a mood disorder, who reported difficulty or discomfort in swallowing the currently marketed IR compressed tablet formulation of lamotrigine and who had a person (such as a spouse, partner, companion, aid, nurse, caregiver, etc) willing to complete a Companion/Caregiver Question. Subjects were switched from the currently marketed lamotrigine IR formulation to a matching dose of lamotrigine IR orally disintegrating tablet (ODT) for 3 weeks to determine convenience and satisfaction.
| null |
Mood Disorders
|
Mood disorder
| null | 1
|
arm 1: Lamictal orally disintegrating tablet (ODT)
|
[
0
] | 1
|
[
0
] |
intervention 1: Experimental formulation
|
intervention 1: Lamotrigine
| 18
|
San Diego | California | United States | -117.16472 | 32.71571
Santa Ana | California | United States | -117.86783 | 33.74557
Jacksonville | Florida | United States | -81.65565 | 30.33218
Orange City | Florida | United States | -81.29867 | 28.94888
Winter Park | Florida | United States | -81.33924 | 28.6
Marietta | Georgia | United States | -84.54993 | 33.9526
Fairview Heights | Illinois | United States | -89.99038 | 38.58894
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Saint Charles | Missouri | United States | -90.48123 | 38.78394
Olean | New York | United States | -78.42974 | 42.07756
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cleveland | Ohio | United States | -81.69541 | 41.4995
Arlington | Texas | United States | -97.10807 | 32.73569
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
Norfolk | Virginia | United States | -76.28522 | 36.84681
Charleston | West Virginia | United States | -81.63262 | 38.34982
| 0
|
NCT00579982
|
[
3
] | 102
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 2MALE
| null |
We postulate that multiple apoptototic events are indusce through testosterone depletion and repletion with taxotere given in conjunction with androgen withdrawal.
| null |
Prostate Cancer
|
Prostate Cancer Docetaxel 03-076
| null | 2
|
arm 1: None arm 2: None
|
[
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Leuprolide LUPRON intervention 2: Starting during week 3 (day 19) of cycle 1, 7.5G applied topically daily for 3 days (applied at approximately 9p) intervention 3: 70 mg/m2 given on day o1 of each 3 week cycle
|
intervention 1: GnRh (Leuprolide) intervention 2: Testosterone Gel intervention 3: Docetaxel
| 1
|
New York | New York | United States | -74.00597 | 40.71427
| 0
|
NCT00587431
|
[
0
] | 79
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is determine if subjects with alcohol withdrawal who receive oral baclofen, plus standard benzodiazepine therapy, will experience less severe withdrawal symptoms than those who receive placebo plus standard benzodiazepine therapy.Subjects with alcohol withdrawal syndrome(AWS)who receive baclofen plus standard benzodiazepine therapy will experience fewer complications of AWS (as measured by use of additional sedatives, restraints, and/or intensive care unit \[ICU\] admissions) compared with subjects who receive placebo plus standard benzodiazepine therapy.
|
Alcohol use is ubiquitous in American society. 83% of Americans have ever consumed alcohol, 51% have in the lst month.
The average American consumes 2.18 gallons of ethanol yearly. Alcohol related morbidity and mortality are staggering problems in the USA. Symptoms of alcohol withdrawal occur because alcohol is a central nervous system depressant; abrupt withdrawal unmasks compensatory overactivity of certain parts of the nervous system, including sympathetic autonomic outflow. 5% of patients who undergo alcohol suffer from Delirium Tremors (DTs), a syndrome characterized by hallucinations, disorientation, tachycardia, hypertension, low grade fever, agitation, and diaphoresis.
DTs typically begin between 48-96 hours after the last drink and last 1 to 5 days. DTs requires hospitalization and vigorous activity in an ICU setting.
The most successful drug treatment for alcohol withdrawal has been found to be the benzodiazepines.
Symptom triggered treatment was found to be as effective as a fixed dose treatment to result in less drug being used overall, with a trend toward shorter duration of withdrawal treatment.
Baclofen is used orally for the treatment of spasticity resulting from multiple sclerosis, spinal cord injuries/diseases and intrathecally for spasticity related to cerebral palsy, spinal cord injury, and amyotrophic lateral sclerosis (ALS).
Its proposed benefit in alcohol withdrawal is that it may reduce voluntary alcohol intake, alcohol craving, and may suppress the intensity of alcohol withdrawal treatment.
|
Alcohol Withdrawal Delirium
|
Alcohol withdrawal Delirium tremors
| null | 2
|
arm 1: Standard benzodiazepine therapy plus baclofen 10 mg every 8 hours for 72 hours (9 doses) as an inpatient, or until discharge if before 72 hours. arm 2: Standard benzodiazepine therapy plus placebo every eight hous as inpatients for 72 hours or until discharge if less than 72 hours.
|
[
1,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: Baclofen 10 mg by mouth every 8 hours for 72 hours or until discharge if before 72 hours. intervention 2: Placebo intervention 3: Lorazepam was provided to all subjects (both arms of the study), as indicated by clinical condition. Standard "symptom-triggered dosing" of lorazepam for alcohol withdrawal was used. That is, the size and the frequency of the dose of lorazepam was determined by the severity of the alcohol withdrawal symptoms.
|
intervention 1: Baclofen intervention 2: Placebo intervention 3: Lorazepam
| 1
|
Duluth | Minnesota | United States | -92.10658 | 46.78327
| 0
|
NCT00597701
|
[
2,
3
] | 4
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| true
| 2MALE
| false
|
We propose oral dosing of gastrointestinal permeation enhancement technology \[GIPET\] enhanced oral acyline at 20 mg everyday for one week to determine the steady-state (multiple-dose) pharmacokinetics of oral acyline in four normal, healthy young men.
|
The purpose of this study is to test how the body responds to a new oral form of acyline given for seven days and to also look at the safety of oral acyline.
Acyline temporarily blocks the production of the hormone testosterone in healthy men. It has been tested in over 100 men in an injection form. This study will be testing acyline in a pill form for seven days.
This study may help develop an oral form of testosterone-blocker which may be useful in the treatment of diseases such as prostate cancer, premature puberty and possibly in a male contraceptive.
This study will evaluate a single dose of oral acyline given once a day for seven days and subsequent effects on Testosterone, FSH and LH blood serum concentrations.
|
Healthy
|
Male Contraception Acyline
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: 20 mg GIPET enhanced oral dose, daily for 7-days
|
intervention 1: Acyline
| 1
|
Seattle | Washington | United States | -122.33207 | 47.60621
| 0
|
NCT00603187
|
[
4
] | 82
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
The purpose of this study is to determine the safety and effectivess of a single intramuscular injection of peramivir for the treatment of subjects with acute, uncomplicated influenza.
| null |
Influenza
|
Influenza Subjects with uncomplicated acute influenza
|
Prot_SAP_000.pdf:
CLINICAL STUDY PROTOCOL
Protocol No. BCX1812-311
IND No. 76,350
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE
INFLUENZA
THE IMPROVE 1 STUDY
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy)
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza
Protocol Date: Version1.0: 24 August-2007
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35244, USA
Phone: +1 919 859 1302
Fax: +1 919 851 1416
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals,
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information
contained herein should be disclosed without prior written approval.
CONFIDENTIAL
157
157
BCX1812-311 (V1.0: 24-August-2007)
Page 2
BioCryst Pharmaceuticals, Inc.
CONFIDENTIAL
1 TITLE PAGE
Protocol Number:
BCX1812-311
Study Title:
A phase 3 m
ulticenter, random ized, double-blind,
placebo-controlled s tudy to evaluate th e effic acy and
safety of intram uscular peram ivir in subjec
ts with
uncomplicated acute influenza
IND Number:
76, 350
Investigational Product:
Peramivir (BCX1812)
Indication Studied:
Uncomplicated acute influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35233
Development Phase:
3
Sponsor Medical
Officer:
W. James Alexander, M.D., M.P.H.
Senior Vice President, Clinical and Regulatory
Operations
Chief Medical Officer
Phone: +1 919 859 1302
Fax: +1 919 851 1416
Email Address: jalexander@biocryst.com
Compliance Statement:
This study will be conducted in accordance with the
ethical principles that have their origin in the
Declaration of Helsinki and clinical research guidelines
established by the Code of Federal Regulations (Title
21, CFR Parts 50, 56, and 312) and ICH Guidelines.
Essential study documents will be archived in
accordance with applicable regulations.
Final Protocol Date:
Version 1.0: 24-August-2007
Amendment(s) Date(s):
None
158
158
159
159
BCX1812-311 (V1.0: 24-August-2007)
Page 4
BioCryst Pharmaceuticals, Inc.
CONFIDENTIAL
1.2
Clinical Study Protocol Agreement
Protocol No.
BCX1812-311
Protocol Title:
A phase 3 m
ulticenter, random ized, double-blind, placebo-
controlled study to evaluate the efficacy and safety
of
intramuscular peram ivir in subje cts with unc omplicated acute
influenza
I have caref ully read th is protoco l and agree that it contains all of the necessary
information required to conduct this study. I agree to conduct this study as
described and according to the Declaration of Helsinki, International Conference on
Harmonization Guidelines for Good Clinical Practices, and all applicable regulatory
requirements.
Investigator’s Signature
Date
Name (Print)
160
160
BCX1812-311 (V1.0: 24-August-2007)
Page 5
BioCryst Pharmaceuticals, Inc.
CONFIDENTIAL
2 SYNOPSIS
Protocol No.
BCX1812-311
Protocol Title:
A Phase 3, Multicenter, Random
ized, Double-Blind,
Placebo-Controlled Stu dy to Evaluate the Efficacy an
d
Safety of Intram
uscular Peram ivir in Subjects with
Uncomplicated Acute Influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
Investigators/Study
Sites:
Multinational
Development Phase:
3
Objectives:
Primary:
To evaluate the efficacy of peram
ivir adm inistered
intramuscularly com pared to p
lacebo on th
e tim e to
alleviation of clinica l sym ptoms in adult sub
jects with
uncomplicated acute influenza.
Secondary:
1. To evalua te the saf ety and tolera bility of pe ramivir
administered intramuscularly;
2. To evaluate seconda ry clinical outcom es in response to
treatment;
3. To evaluate changes in in
fluenza virus titer (viral
shedding) in response to treatment;
4. To assess p harmacoeconomic m easures in resp onse to
treatment
5. To assess c hanges in inf luenza vir al suscep tibility to
neuraminidase inhibitors following treatment
Number of Subjects:
Total enrollm ent: up t o 800 subjects random
ized (160
subjects in the placebo treatment group, 320 subjects in the
peramivir 150mg treatment group and 320 subjects in the
peramivir 300m g treatm ent group). The study will close
after enrollment of at least 500 subjects who have either a
positive Influenza A or B antigen te st (Rapid Antigen Test
– RAT) at screening, or who ha
ve a negative RAT at
screening but a positive influenza A or B PCR a ssay result
from a baseline nasopharyngeal swab.
Study Design:
This is a multinational, random
ized, double-blind study
comparing the efficacy and safety of two single dos
e
regimens of peramivir administered intramuscularly versus
placebo in adults with uncom
plicated acute influenza.
Each subjec t’s ass ignment to trea tment will be stra tified
according to the Rapid Antigen Test (RAT) result at
screening and current sm
oking be havior, with 80% of
subjects ce ntrally rand omized to one of
the two activ
e
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single dose regimens of peramivir (2:2:1 randomization)
Treatment Group 1: Peramivir 150mg
Treatment Group 2: Peramivir 300mg
Treatment Group 3: Placebo
Enrollment of subjects into the RAT negative s tratum will
be permitted at individual sites that have identified 3 RAT
positive su bjects a t s creening within a 10 d ay per iod,
indicating activity of influenza in the site ’s vicinity. After
identification of 3 RAT positive subjects within 10 days, a
site m ay enroll 1 RAT negative s
ubject tha t f ulfills the
inclusion/ exclusion criteria. One additional RAT negative
subject may be enrolled thereafter for each preceding RAT
positive subject that is identified.
Study drug will be adm inistered as one 2mL intramuscular
injection in each glu teal muscle (total of 4m L injected in
divided doses).
Subjects eligible for s creening will have an anterior nasal
or pharyngeal swab collected
for t esting by RAT for
influenza A and B, in accordan ce with the co mmercially
available RAT kit instructi
ons. I f the in itial RAT is
negative, th e te st shou ld be repeated with a differen
t
commercially availab le RAT kit. Subjects m
eeting the
inclusion/ exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following in a Study
Diary:
• Oral temperature measurements taken with an electronic
thermometer every 12 hours. W ith the exception of the
baseline m easurement, all tem perature m easurements
will be ob tained at least 4 hours after, or imm ediately
before, adm
inistration of oral acetaminophen
(paracetamol), aspirin, ibuprofen or other NSAID.
• Assessment of severity of each of s even sym ptoms of
influenza on a 4-point scale (0, absent; 1, m
ild; 2,
moderate; 3, severe) twice daily (AM, PM) through Day
9 following treatm ent, then once daily (AM) through
Day 14
• Assessment of subjec t’s ability to p
erform usual
activities, (rated as 0–10 on a visual analog scale) once
daily through Day 14
• Assessment of subject’s tim e lost from work or usual
activities and productivity compared to normal (rated as
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0-10 on a visual analog scal e) once daily through Day
14
• Doses of antipyretic, expe
ctorant, and/ or t hroat
lozenges taken for symptomatic relief each day through
Day 14
Anterior nose (bilateral) and posterior pharynx specim ens
(swabs) will be collected at Day 1 (pre-treatm
ent) and at
Days 3, 5, and 9, for quantitative virologic assessments. In
a subset of a m inimum of 200 subjects, an additional
virology sample will b e co llected on day 2. Specim
ens
from all subjects yielding influenza virus will also be
assessed for susceptibility to neuraminidase inhibitors (Day
1 and last specimen yielding positive result).
All virolog ic ass essments will b e p erformed by a c entral
laboratory.
At the study day 3 visit, when all subjects are evaluated for
safety and a blood draw is com
pleted for clinical
laboratory investigations, a single pharm
acokinetic (PK)
sample will also be drawn. This sin gle PK sam ple will b e
analyzed for plasm a concentrations of peram ivir (ng/mL)
and evaluated in an exposure response analysis.
At selected sites a separate sub-s tudy will be conducted to
collect limited PK sam ples for the purpose of conducting
an exposure-respons e analysis. T
his sub-stud y will be
conducted under a separate protocol, BCX1812-311PK.
Study Population:
Male and fem ale subjects, 18 y ears of age and older, with
symptoms consisten t with a diagnosis of uncomplicated
acute influenza infectio n may be screened for e nrollment.
Subject eligibility will be dependent on the presence of two
or more symptoms consistent with acute inf luenza as well
as the results obtained f rom a rapid antigen test (RAT) for
influenza A and B at screening.
Inclusion Criteria:
1. Male and non-pregnant female subjects age ≥18 years
2. A positive Influenza A or B Rapid Antigen Test (RAT)
performed with a commercially available test kit on an
adequate specimen collected from an anterior nasal or
pharyngeal swab, in accordance with the
manufacturer’s instructions. A negative initial RAT
should be repeated with a different commercially
available RAT kit. A limited number of RAT negative
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subjects may be enrolled in accordance with a defined
screening algorithm.
3. Presence of fever at time of screening of ≥38.0 ºC
(≥100.4 ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken
rectally. For subjects with a positive RAT at the time of
screening, a subject self-report of a history of fever or
feverishness within the 24 hours prior to screening will
also qualify for enrollment in the absence of
documented fever at time of screening. For subjects
with no positive RAT at screening, fever as defined
above must be documented at time of screening
4. Presence of at least one respiratory symptom (cough,
sore throat, or nasal symptoms) of any severity (mild,
moderate, or severe)
5. Presence of at least one constitutional symptom
(myalgia [muscle aches], headache, feverishness, or
fatigue) of any severity (mild, moderate, or severe)
6. Onset of symptoms no more than 48 hours before
presentation for screening
7. Written informed consent
Exclusion Criteria:
1. Women who are pregnant or breast-feeding
2. Presence of clinically significant signs of acute
respiratory distress
3. History of severe chronic obstructive pulmonary
disease (COPD) or severe persistent asthma
4. History of congestive heart failure requiring daily
pharmacotherapy with symptoms consistent with New
York Heart Association Class IV functional status
within the past 12 months
5. History of chronic renal impairment requiring
hemodialysis and/or known or suspected to have
moderate or severe renal impairment (actual or
estimated creatinine clearance <50 mL/min)
6. Current clinical evidence of active bacterial infection at
any body site that requires therapy with oral or
systemic antibiotics
7. Presence of immunocompromised status due to chronic
illness, previous organ transplant, or use of
immunosuppressive medical therapy
8. Current treatment for active viral hepatitis C
9. Presence of known HIV infection with a CD4 count
<350 cell/mm3
10. Current therapy with oral warfarin or other systemic
anticoagulant
11. Receipt of any doses of rimantadine, amantadine,
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zanamivir, or oseltamivir in the 7 days prior to
screening
12. Immunized against influenza with live attenuated virus
vaccine (FluMist®) in the previous 21 days
13. History of alcohol abuse or drug addiction within 1
year prior to admission in the study
14. Participation in a previous study of peramivir as
treatment for acute influenza or previous participation
in this study
15. Participation in a study of any investigational drug
within the last 30 days
16. Screening ECG which suggests acute ischemia or
presence of medically significant dysrhythmia.
Study Endpoints:
Primary Endpoint:
Clinical:
Time to alleviation of clinical symptoms of influenza
Secondary
Endpoint(s):
Safety
Incidence of treatm
ent-emergent adverse events and
treatment-emergent changes in clinical laboratory tests
Clinical:
Time to resum ption of subjec t’s ab ility to perf orm usual
activities
Time to resolution of fever
Incidence of influenza related complications
Virologic:
Quantitative change in influenza virus shedding, measured
by viral titer assay (TCID
50) and/or by quantitative
polymerase chain reaction (PCR) assay
Pharmacoeconomic:
Medical resource utilization (M RU), missed days of work,
and im pact of inf
luenza illn ess on subject’s work
performance and/or productivity.
Exploratory
Endpoint:
Viral Susceptibility:
Change in influenza virus susceptibility to neu raminidase
inhibitors
Investigational Product,
Dose, and Mode of
Administration:
Peramivir (BCX-1812), 75m g/mL or placebo (buffered
diluent), 2mL per injection, ad ministered intramuscularly
in the gluteal muscle, bilaterally.
Duration of Treatment:
Following treatment on day 1, study duration for individual
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subjects is expected to be up to 14 days (including all
visits).
Statistical Methods:
Descriptive statistical methods will be used to summ arize
the data from this study, with statistical testing utilized for
the p rimary and secondary efficacy endpoints. Unless
otherwise n oted, a ll s tatistical testing will be two-sided,
and will be performed using a significance (alpha) level of
0.05. For assessment of the prim ary efficacy endpoint, th e
overall sig nificance level
will be m
aintained by a
Bonferroni adjustm ent fo r the planned com
parisons
between the two active trea
tment groups and placebo.
Detailed sta tistical pro cedures will be provided in a f ull
statistical analysis plan (SAP) completed prior to database
lock and study unblinding.
Sample Size:
From previous studies of neuram
inidase treatm ent of
uncomplicated influenza it is expected that the median time
to alleviation of symptoms will be 103.3 hours for subjects
receiving placebo. Addition ally, it is expected that the
median time to alleviation for the low dose peram ivir arm
will be 69.9 hours, yielding a hazard ratio of 0. 68. Using
these assumptions, a sample si ze of 200 influenza-infected
subjects per active treatm
ent group and 100 infected
subjects in the placebo group (a total of 500 influenza-
infected su bjects) is s ufficient to provide at least 80%
power to detect a hazard ratio of 0.68 using a log-rank
statistic and α = 0.025 (SAS version 9.1.3; total accrual
time 7 months; total enrollment time 6 months). Up to 800
subjects will be enrolled to ach ieve the target number of at
least 500 subjects with diagnostic evidence (R AT or PCR)
of an acute influenza infection.
Efficacy:
The intent-to-treat infected population will include all
subjects who are random ized, received study drug, and
have proven influenza by any one of the following:
primary viral culture, PCR, or paired serology showing ≥
4-fold increase in antibody to
influenza A or B. The
primary efficacy v ariable is th e tim e to alleviation of
symptoms, defined as the time from injection of study drug
to the start of the tim
e period when each
of seven
symptoms of influenza are either absent or are present at
no more than mild severity level and remain at no worse
than this severity status for a 24 hour period.
Descriptive statistics for the primary efficacy variable will
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be tabulated by treatm ent group. Alleviation of sym ptoms
will be determined by assessment of symptoms as reported
on each su bject’s diary card. Tim
e to alle viation of
symptoms will b e sum marized for each treatm ent group.
Treatment dif ference will be
as sessed us ing a Cox
Regression model with effects for RAT result at screening,
current smoking behavior, tr eatment group, and influenza
season at random ization. Pa irwise com parisons between
each active group and placebo will be constructed from the
Cox Regression m odel. Subj ects who do not experience
alleviation of sym ptoms will be c ensored a t the date of
their last non-m issing assessment. Tim e to resum ption of
usual activities and tim
e to resolution of
f ever will be
analyzed in a similar manner.
Changes in viral titer s will be compared using the van
Elteren sta tistic con trolling f or RAT result at screen
ing,
current smoking behavior
and influenza season at
randomization. Analyses of other continuous endpoints
will be analyzed in a similar manner.
Safety:
Safety analyses will b e presen ted f or all sub jects in the
safety population, defined as all randomized subjects who
receive at least one dose of study drug. Adverse events
will be m apped to a Medica l Dictiona ry f or Regulatory
Activities (MedDRA) preferred term
and system organ
classification.
The occurrence of treatm
ent-emergent AEs will be
summarized using preferre
d term
s, system organ
classifications, and severit
y. Separate summ
aries of
treatment-emergent SAEs and treatm
ent-emergent AEs
that are related to study m edication will be generated. All
AEs will be listed f
or individua l subjec ts sho wing both
verbatim and preferred terms.
Descriptive summaries of vital signs and quantitative
clinical laboratory changes will be presented by study visit.
Frequency and percentages
of subjects with abnorm
al
laboratory test r esults will be su mmarized b y toxic ity
grade.
Concomitant m edications w ill be m
apped to a W
HO
preferred term and drug classification. The num
ber and
percent of subjects taking concomitant medications will be
summarized using preferred terms and drug classifications.
The num ber and percent of subjects experiencing each
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abnormal physical examination finding will be presented.
The number and percent of s ubjects discontinuing study as
well as the reasons for discontinuation will be summarized
by treatment group.
Protocol Date
Version 1.0: 24-August-2007
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3 TABLE OF CONTENTS
1
TITLE PAGE...................................................................................................... 2
1.1
PROTOCOL APPROVAL SIGNATURE PAGE............................................................. 3
1.2
CLINICAL STUDY PROTOCOL AGREEMENT .......................................................... 4
2
SYNOPSIS.......................................................................................................... 5
3
TABLE OF CONTENTS.................................................................................. 13
3.1
LIST OF FIGURES................................................................................................ 15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................... 16
5
INTRODUCTION ............................................................................................ 18
5.1
BACKGROUND.................................................................................................... 18
5.2
RATIONALE FOR STUDY..................................................................................... 18
5.3
NON-CLINICAL EXPERIENCE WITH PERAMIVIR.................................................. 19
5.3.1 In vitro Assays .............................................................................................. 19
5.3.2 Animal Models.............................................................................................. 20
5.4
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR.................. 20
5.5
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR................ 21
5.6 DOSE RATIONALE .................................................................................................... 22
6
STUDY OBJECTIVES..................................................................................... 23
6.1
OBJECTIVES ....................................................................................................... 23
6.1.1 Primary Objective......................................................................................... 23
6.1.2 Secondary Objective(s)................................................................................. 23
6.2
STUDY ENDPOINTS............................................................................................. 23
6.2.1 Primary Endpoint.......................................................................................... 23
6.2.2 Secondary Endpoint(s).................................................................................. 23
6.2.3 Exploratory Endpoint.................................................................................... 23
7
STUDY DESIGN ............................................................................................. 24
7.1
OVERALL STUDY DESIGN AND PLAN ................................................................. 24
8
SELECTION AND WITHDRAWAL OF SUBJECTS.................................... 25
8.1.1 Inclusion Criteria .......................................................................................... 25
8.1.2 Exclusion Criteria ......................................................................................... 26
8.1.3 Removal of Subjects from Therapy or Assessment...................................... 27
9
TREATMENTS................................................................................................ 28
9.1
TREATMENTS ADMINISTERED............................................................................ 28
9.2
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .................................................... 28
9.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................. 28
9.4
STUDY MEDICATION ACCOUNTABILITY............................................................. 29
9.5
BLINDING/UNBLINDING OF TREATMENTS.......................................................... 29
9.6
PRIOR AND CONCOMITANT THERAPIES.............................................................. 29
9.7
OVERDOSE AND TOXICITY MANAGEMENT......................................................... 29
9.8
DOSE INTERRUPTION.......................................................................................... 29
10
STUDY CONDUCT......................................................................................... 29
10.1
EVALUATIONS.................................................................................................... 30
10.1.1
Medical History ........................................................................................ 30
10.1.2
Rapid Antigen Test for Influenza ............................................................. 30
10.1.3
Physical Examination and Influenza-related Complications Assessments30
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10.1.4
Vital Signs................................................................................................. 30
10.1.5
Electrocardiogram Measurements ............................................................ 31
10.1.6
Clinical Chemistry Profiles....................................................................... 31
10.1.7
Hematology Profiles ................................................................................. 31
10.1.8
Serology for Influenza .............................................................................. 31
10.1.9
Urinalysis and Evaluation of Protein in Urine.......................................... 31
10.1.10 Urine Pregnancy Test................................................................................ 31
10.1.11 Samples for Virologic Laboratory Assessments....................................... 31
10.1.12 Subject Self Assessments.......................................................................... 32
10.1.13 Concomitant Medications......................................................................... 32
10.1.14 Adverse Events ......................................................................................... 32
10.1.15 Single Pharmacokinetic Exposure Sample ............................................... 33
10.2
SCREENING ........................................................................................................ 33
10.2.1
Informed Consent...................................................................................... 33
10.2.2
Screening/Baseline Evaluation and Enrollment........................................ 33
10.3
TREATMENT PERIOD—STUDY DAY 1................................................................ 33
10.3.1
Pre-dose Evaluations................................................................................. 34
10.4
POST-TREATMENT ASSESSMENT PERIOD........................................................... 34
10.4.1
Days 2, 3, 5, 9 and 14................................................................................ 34
11
ADVERSE EVENT MANAGEMENT............................................................ 37
11.1
DEFINITIONS ...................................................................................................... 37
11.1.1
Adverse Event........................................................................................... 37
11.1.2
Serious Adverse Event.............................................................................. 37
11.2
METHOD, FREQUENCY, AND TIME PERIOD F OR DETECTING ADVERSE EVENTS
AND REPORTING SERIOUS ADVERSE EVENTS..................................................... 38
11.2.1
Definition of Severity ............................................................................... 38
11.2.2
Definition of Relationship to Study Drug................................................. 38
11.2.3
Reporting Serious Adverse Events ........................................................... 39
11.2.4
Emergency Procedures.............................................................................. 40
12
STATISTICAL METHODS............................................................................. 40
12.1
DATA COLLECTION METHODS........................................................................... 40
12.2
STATISTICAL ANALYSIS PLAN ........................................................................... 41
12.3
SAMPLE SIZE ESTIMATES................................................................................... 41
12.4
ANALYSIS POPULATIONS ................................................................................... 41
12.4.1
Intent-To-Treat Population ....................................................................... 41
12.4.2
Intent-To-Treat Infected Population ......................................................... 41
12.4.3
Safety Population...................................................................................... 42
12.5
INTERIM AND END OF STUDY ANALYSES........................................................... 42
12.6
EFFICACY ANALYSES......................................................................................... 42
12.6.1
Primary Efficacy Endpoint ....................................................................... 42
12.6.2
Secondary Efficacy Endpoints.................................................................. 43
12.6.3
Exploratory Endpoint................................................................................ 44
12.7
SAFETY ANALYSES ............................................................................................ 44
12.8
SUB-STUDY AND PHARMACOKINETIC ANALYSIS............................................... 45
12.9
GENERAL ISSUES FOR STATISTICAL ANALYSIS .................................................. 45
12.9.1
Multiple Comparisons and Multiplicity.................................................... 45
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12.9.2
Covariates ................................................................................................. 45
12.9.3
Planned Sub-Groups ................................................................................. 45
12.9.4
Missing Data............................................................................................. 45
13
STUDY ADMINISTRATION ......................................................................... 46
13.1
REGULATORY AND ETHICAL CONSIDERATIONS ................................................. 46
13.1.1
Regulatory Authority Approvals............................................................... 46
13.1.2
Ethics Committee Approvals.................................................................... 46
13.1.3
Subject Informed Consent......................................................................... 46
13.1.4
Payment to Subjects.................................................................................. 47
13.1.5
Investigator Reporting Requirements ....................................................... 47
13.2
STUDY MONITORING.......................................................................................... 47
13.3
QUALITY ASSURANCE........................................................................................ 47
13.4
STUDY TERMINATION AND SITE CLOSURE......................................................... 48
13.5
RECORDS RETENTION ........................................................................................ 48
13.6
STUDY ORGANIZATION...................................................................................... 48
13.6.1
Data Monitoring Committee..................................................................... 48
13.7
CONFIDENTIALITY OF INFORMATION ................................................................. 48
13.8
STUDY PUBLICATION ......................................................................................... 49
14
REFERENCES ................................................................................................. 50
15
APPENDICES .................................................................................................. 52
15.1
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA
.......................................................................................................................... 52
3.1
List of Figures
Figure 1
Study Measurements and Visit Schedule...................................................... 36
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0–72
area under the curve from time 0 to 72 hours
AUC0–∞
area under the curve extrapolated from time 0 to infinity
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
Cmax
maximum plasma concentration
CK
creatine kinase
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CRF
Case Report Form
CV
coefficient of variation
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
IC50
median inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRC
influenza related complications
ITT
intent-to-treat
ITTI
intent-to-treat infected
IUD
intrauterine device
IVRS
interactive voice response system
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
NSAID
non-steroidal anti-inflammatory drug
PCR
polymerase chain reaction
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RAT
Rapid Antigen Test
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
t1/2
elimination half-life
t1/2 λz
terminal half-life
TCID50
time weighted change
f rom baseline in log
10 tissue -culture
infective dose50
TEAEs
treatment-emergent adverse events
Tmax
time to attain maximum plasma concentration
UPEP
urine protein electrophoresis
WBC
white blood cell
WHO
World Health Organization
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5 INTRODUCTION
5.1
Background
Influenza v irus is a m ember of the orthomyxovirus fam ily and cau ses an acu te v iral
disease of the respiratory tract. Typical influenza illness is characterized by abrupt onset
of fever, headache, myalgia, sore throat, and nonproductive cough.1 The illness is usually
self-limiting, with relief of symptoms occurring within 5 to 7 days. Nevertheless, it is an
important disease for several reasons,
including ease of comm
unicability, short
incubation time, rapid rate of viral mutation, morbidity with resultant loss of productivity,
risk of com plicating conditions, and increased risk of death, pa rticularly in the e lderly.
During 19 of the 23 influenza seasons
between 1972/1973 a nd 1994/1995, estim ated
influenza-associated deaths in the U nited States ranged from approxim ately 25 to m ore
than 150 per 100,000 persons above 65 years of age, accounting for more than 90% of the
deaths attributed to pneumonia and influenza.2
Presently, o nly a few m easures are availab le that can red uce th e im pact of influenza:
active immunoprophylaxis with an inactivat
ed or live attenu
ated vaccine and
chemoprophylaxis or therapy with an influe nza-specific antiviral drug. Neuram inidase
inhibitors are the current m
ainstay of an tiviral treatm ent for influenza. Mark
eted
neuraminidase inhib itors inc lude zanam ivir (Relenza®, GlaxoSm
ithKline) an d
oseltamivir (Tamiflu®, Roche-Gilead) , an oral prodrug of the activ e agent, oseltamivir
carboxylate. Influenza neuram inidase is a surface glycoprotei n that cleaves sialic acid
residues from glycoproteins and glycolipids. The enzyme is responsible for the release of
new viral p articles from infected cells and
may also ass ist in the sp reading of virus
through the mucus within the respiratory tract. The neuraminidase inhibitors represent an
important advance in the treatment of influenza with respect to activity against influenza
A and B viruses, with p roven therapeutic value in reduc ing influenza lower resp iratory
complications,3 and lower rates of antiviral drug resistance4.
The use of curren tly av ailable neu raminidase inhibitors has been lim ited by concerns
including, the degree of effectiv eness, the requirement for an inhaler device (zanamivir),
and the em ergence of resistant influenza vi rus variants in som e treated populations. 5 In
addition, there are risks of bronchospasm
w ith zanam ivir; and gastrointestinal side
effects, with oseltamivir.
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to
the armamentarium of drugs for the treatment of influenza infections due to its potential
for parenteral administration and lower frequency of dosing.
5.2
Rationale for Study
An oral formulation of peram ivir has previously been evaluated in a f ull range of safety,
tolerability, pharmacokinetic, and efficacy studies. In a m ultinational phase 3 clinical
trial conducted in 1999-2001, oral peram
ivir de monstrated antiviral activity against
influenza A and B inf
ections, and im provement in the r
elief of clin ical sym ptoms.
Because of the lim ited bioavailability of peramivir following oral administration (<5%),
it was de termined that the paren teral route of administration is m ore appropriate for the
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delivery of peram ivir. Subsequent phase
1 studies of intrave nous and intram uscular
formulations of peram ivir have confirm ed that parenteral routes of administration result
in plasma levels of drug that are as much as 100 times those achieved via the oral route.
Further details of these studies are provided below and in the Investigator Brochure.
A phase 2 random
ized, double blind, placeb
o controlled study of two single dose
regimens (150mg or 300m g) of intram uscular peramivir in subjects with uncom plicated
acute influenza infections (study B CX1812-211) was initiated in early 2007 in North
America and the UK. The study has been extended to sites in Hong Kong, Australia, New
Zealand and South Africa and is expected
to complete enrollment in m id-2007. At a
scheduled meeting on 21 May 2007, an independ ent data monitoring committee for this
study com pleted a blinded revi ew of all reported adverse
events and grade 3 and 4
clinical laboratory evaluations from the first 135 subjects random ized. Following this
blinded saf ety review the DMC provided
a written reco mmendation that the s
tudy
continue as planned.
Because of the previo
us dem onstration of significant an tiviral activ ity, th e strong
suggestion of clinical efficacy of oral pe
ramivir previously dem onstrated in acute
influenza, and the encouraging pharm
acokinetic and prelim inary safety profile of the
intramuscular formulation of pera mivir demonstrated to date, this phas e 3 study will be
conducted to evaluate the efficacy and safety profile of intram
uscular peramivir and to
determine the optimal single dose regimen.
5.3
Non-Clinical Experience with Peramivir
5.3.1 In vitro Assays
Peramivir is a selective inhibitor of vi
ral neuram inidase, with 50% inhibitory
concentrations (IC50) for bacterial and m ammalian enzymes of >300µM. 6 In an in vitro
study, 42 influenza A and 23 influenza B isolates were collected from untreated subjects
during the 1999–2000 influenza season in Canada.
7 These isolates were tested for their
susceptibility to the neuram inidase inhib itors zanam ivir, oseltam ivir carboxylate, and
peramivir using a chem
iluminescent neuram inidase assay. Inhibition of Type A
influenza neuraminidase by peram ivir was appr oximately an order of m agnitude greater
than inhibition of neuram inidase from Type B viruses. IC
50 values for the Type A
enzymes ranged from <0.1 to 1.4nM, whereas the Type B enzym es ranged from <0.1 to
11nM, with three out of four values in the
5- to 11nM range. Peram ivir was the most
potent drug against influenza A (H 3N2) viruses with a m ean IC50 of 0.60nM as well as
most potent against influenza B with a mean IC50 of 0.87nM.
In another in vitro comparison of peram
ivir, oseltam ivir, and zanam ivir, using a
neuraminidase inhibition assay with influenza A viruses, the m
edian IC 50 of pera mivir
(approximately 0.34nM) was com
parable to that of
oseltam ivir (0.45nM) and
significantly lower than zanam ivir (0.95nM). F or influenza B virus clinical isolates, the
IC50 of peramivir (1.36nM) was comparable to that of zanamivir (2.7nM) and lower than
that of oseltamivir (8.5nM).8
The potency of peram
ivir was evaluated ag
ainst five zanam ivir-resistant an d six
oseltamivir-resistant influenza viruses.9 Peramivir remained a potent inhibitor against all
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oseltamivir-resistant viruses includi ng the m utations H274Y, R292K, E119V, and
D198N, with IC 50 values ≤40nM. Peram ivir also potently inhibited (IC 50 ≤ 26nM) the
neuraminidase activity of zanamivir-resistant strains, which had the following mutations:
R292K, E119G, E119A, and E119D. Howeve
r, one zanam ivir-resistant influenza B
virus, B/Mem /96, with a m utation R152K isol ated from cell cultur e, was relatively
resistant to all neuraminidase inhibitors, including peramivir (IC50 = 400nM).
5.3.2 Animal Models
In a m ouse model of influen za infection, a single intram uscular injection of pera mivir
(10mg/kg) given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain
resulted in 100% survival in contrast to 100% mortality in a control group injected with
saline.6 In the sam e mouse m odel, treatm ent of m ice up to 72 hours after influenza
infection using peram ivir (20m g/kg) result ed in 100% survival, compared to 100%
mortality in the control group injected with vehicle.10
Peramivir has also dem onstrated activity in animal models utilizing a clinical H5 N1
isolate as th e infecting virus strain. In a mouse model, a single intramuscular dose of
peramivir (30mg/kg) injected 1 hour after inoculation with the highly pathogenic (H5N1)
A/Vietnam/1203/04 strain, resulted in a 70% survival rate that wa s similar to that seen in
mice treated with oseltam ivir given orally at 10m g/kg/day for 5 days
11. In s imilar
experiments, mice inoculated with the sam e strain of H5N1 virus tha t were then trea ted
for up to 8 days with intram
uscular peramivir exhibited 100% survival 12. This longer
duration of peram ivir treatment also prevented viral replic ation in the lungs, brain and
spleen at days 3, 6 and 9 post inoculation.
5.4
Previous Phase 3 Clinical Experience with Oral Peramivir
An oral formulation of peram
ivir has prev iously dem onstrated an tiviral activity and
preliminary clinical efficacy in ch
allenge studies in hum an volunteers, as well as in
treatment studies in patients with u ncomplicated acute inf luenza inf ections dur ing the
influenza seasons of 1999-2001. A Phase 3
multinational study (B C-01-03) of oral
peramivir was conducted. Two dos e regimens of oral peramivir, 800mg QD for 5 days,
or 800mg QD on Day 1, followed by 400mg QD for 4 days, were compared to a matched
placebo treatment group. A total of 1246 subjects were randomized to treatment at sites
in the USA, W estern and Eastern Europe, S outh America, Australia and New Zealand.
As presente d in the tab le below, th e prim ary end-point of tim e to relief of influenza
symptoms was not found to be significantly
different (p=0.17) between the three
treatment groups.13 A sub-group analysis of the time to relief of symptoms by country or
region demonstrated marked differences in
the prim ary endpoint.. In the subset of
influenza-infected subjects enrolled at sites in the US, clinically m eaningful differences
in time to relief of influenza symptoms between the placebo and the two peram ivir arms
were observed, that just m issed statistical significance (p=0.07). However, a num ber of
secondary end-points in this phase 3 study, such as tim e to overall well-being, time to
normal activity, incidence of infl
uenza rela ted com plications and quantity of viral
shedding, reached o
r approach ed statistically significant differenced between
the
peramivir and placebo treatment groups (p=0.03-0.06).
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Results of Study BC-01-03
Median Time to Relief of Influenza Symptoms (Hours)
Dose and Regimen
Overall Results (n=1246)
US Sites (n=206)
Peramivir 800mg po x 5d
89.0
70.8
Peramivir 800mg po x 1d
and 400mg po x 4d
91.7
88.8
Placebo x 5 days
104.4
106.8
p value
0.17
0.07
5.5
Previous Phase 1 Experience with Intramuscular Peramivir
Two phase one studies evaluating the safety
and pharmacokinetics of an intram uscular
formulation of pera mivir have been conduc
ted in a total of 45 he
althy volunteers
receiving peramivir.
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability
of 75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma
levels of i.m. pera
mivir generally occurre d within 30 m
inutes fol lowing injection.
Plasma pharm acokinetic param eters for i.m . peram ivir are summarized below for the
three intramuscular single dose regimens evaluated:
Dose (mg)
Cmax (ng/mL)
AUC0-∞ (hr·ng/mL)
t½a (hr)
75 i.m.
4296±812
11659±1123
19.8±7.9
150 i.m.
7612±884
23952±3804
24.3±4.1
300 i.m.
15150±2367
49649±5619
22.8±2.5
aterminal half life
In a second phase 1 study, Peram
ivir-Him-06-112, the sam e dose levels of peram ivir
were adm inistered as single i.m . injections on two consecutive days (6 subjects per
group). This double-b lind study also includ
ed a placebo arm . The pharm acokinetic
parameters of i.m . peramivir following the second day of dosing were consistent with
those seen following single doses of the drug.
The observ ations of s afety and to lerability of i. m. peram ivir in each of the 2 phas e 1
studies were unrem arkable. No serious ad
verse even ts were repo rted. The most
commonly observed ad verse events or laborato ry abnormalities were h eadache, several
reports of signs and symptom s of vasovagal reactions following injections, and transient
increases in creatine kinase. No consisten t differences in frequency of adverse events
were observed between the ac tive and placebo treatm ent groups, with the exception that
CK elevations appeared to be dose rela
ted in the peram ivir treatment groups. T he
vasovagal reactions were attri buted to the receipt of rela
tively large volum es of i.m.
injection (2 injections each of 2mL) in the fasted state.
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An ongoing phase 2 study, BCX1812-211, is
a random ized, double-blind placebo-
controlled study to evaluate the efficacy and
safety of two single d
ose reg imens of
peramivir. Up to 100 subjects per arm will receive either 150mg or 300mg of peramivir
or placebo. The prim ary endpoint of the stu
dy is the tim e to alleviation of clinical
symptoms in adult subjects with u ncomplicated acute influenza. An independent dat
a
monitoring comm ittee reviewed grouped blinde d safety data on the first 135 subjects
randomized. The study rem ains blinded. The fr equency of vasovagal reactions reported
as adverse events in this ongoing study is 2/135 (to date) which is lower than that seen in
the phase 1 volunteer studies.
5.6 Dose Rationale
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of
75mg twice daily in adults14. Oseltamivir was shown to be clinically effective in a Phase
III study of oral oseltamivir versus placebo in naturally occurring seasonal influenza, and
these data were sufficient for regulatory approval for marketing of oseltamivir. At least
75% of an oral dose of oseltam
ivir reaches the sy stemic circu lation as oseltam ivir
carboxylate. When oseltamivir is adm inistered orally at a dose of 75mg twice daily, the
serum C max of oseltam ivir carboxylate is approxim ately 348ng/m L and the AUC 0-48 is
10,876 h·ng/mL. The clinical data indicate that this level of exposure to oseltamivir was
sufficient to provide clinical improvement in uncomplicated acute influenza.
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular
doses of peram ivir are approxim ately 7600ng/mL and 24,000 h·ng/m L for the 150m g
dose and are approxim ately 15,000ng/m L and 49,000 h·ng/m L for the 300m g dose.
Previous s tudies hav e assess ed the concen
trations of the neuram
inidase inhibitor
zanamivir in nasal and pharyngeal secretions after parenteral administration of this drug. .
Within several hours after ad
ministration, the concentrati
ons in secretions wer
e
approximately 100-fold lower than in serum or plasma. In theory, relatively high levels
of a neuram inidase inh ibitor in res piratory se cretions ar e desi rable in order to rapidly
inactivate influenza virus and to delay or
prevent th e d evelopment of resistan ce in
infecting virus strains. Intramuscular doses of peramivir, including doses of 150m g and
300mg have been shown to be well tolerate
d in previous P hase 1 studies and since no
identified safety signal has been noted by an independent data monitoring committee in
the ongoing Phase 2 study, it is appropriate
for these two dose regim
ens to undergo
further evaluation in this Phase 3 study.
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6 STUDY OBJECTIVES
6.1
Objectives
6.1.1 Primary Objective
The primary objective of this study is to eval uate the efficacy of peram ivir administered
intramuscularly compared to placebo on th e time to alleviation of clinical symptoms in
adult subjects with uncomplicated influenza.
6.1.2 Secondary Objective(s)
The secondary objectives of this study are:
1. To evaluate the safety and tolerability of peramivir administered intramuscularly;
2. To evaluate secondary clinical outcomes in response to treatment;
3. To evaluate changes in
influenza virus
titer ( viral sheddi ng) in response to
treatment;
4. To assess pharmacoeconomic measures in response to treatment;
5. To assess changes in influenza viral su
sceptibility to neu raminidase inhibito rs
following treatment;
6.2
Study Endpoints
6.2.1 Primary Endpoint
Time to alleviation of clinical symptoms of influenza
6.2.2 Secondary Endpoint(s)
Secondary efficacy endpoints will include evaluations in each subject of:
1. Safety parameters, including: treatment- emergent adverse events (TEAEs)
and treatment-emergent changes in clinical laboratory tests;
2. Time to resolution of fever;
3. Time to resumption of subject’s ability to perform usual activities;
4. Incidence of influenza related complications
5. Quantitative change in influenza virus shedding measured by viral titer
assay (TCID50) and/or by quantitative polymerase chain reaction (PCR)
assay;
6. Medical resource utilization (MRU), missed days of work, and impact of
influenza illness on subject’s work performance and/or productivity.
6.2.3 Exploratory Endpoint
An exploratory endpoint will evaluate change in influenza virus susceptibility to
neuraminidase inhibitors in viral isolates recovered from subjects pre and post treatment.
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7 STUDY DESIGN
7.1
Overall Study Design and Plan
This is a multinational, random
ized, double-blind study com paring the efficacy and
safety of two single dose regim
ens of pera mivir adm inistered intramuscularly versus
placebo in adults with uncom
plicated acute influenza. Up
to 800 subjects will be
enrolled in to the s tudy. Each su bject’s as signment to trea tment will be str
atified
according to a Rapid Antigen Test (RAT) result and current smoking behavior, with 80%
of subjects centrally random ized via an Inte ractive Voice Response (IVR) system to one
of the two active single dose regimens of peramivir (2:2:1 randomization):
Treatment Group 1: Peramivir 150mg
maximum n=320
Treatment Group 2: Peramivir 300mg
maximum n=320
Treatment Group 3: Placebo
maximum n=160
Previous studies evalu ating the efficacy of
neuraminidase inh ibitors enro lled su bjects
with inf luenza-like illness on the basis of presence of
specific clinical s igns and
symptoms. These studies were conducted before
the widespread availability of rapid
influenza antigen diagnostic test kits (Rapid Antigen Tests-RAT), and typically between
50-70% of subjects enrolled we re subsequently confirm ed by viral cu lture to hav e an
active influ enza infection. The sen sitivity of comm ercially available RAT kits ranges
from 62% to 83%, depending
upon the virus sub-type.
15 In the phase 2 study of
intramuscular peram ivir (study BCX1812-211) a positive RAT test was required for
study entry. It is likely that
a number of subjects with
an influenza infection were
excluded from this study due the sensitivity of this assay.
In this ph ase 3 study a lim ited number of RA T negativ e subjects will be en rolled in
accordance with the following al gorithm to minimize false negative test results: once an
individual site has identified 3 RAT positive subjects at screening within a 10 day period,
indicating influenza activity is present in the site’s vicinity, a RAT negative subject that
meets the inclusion / ex clusion criteria m ay be enrolled. O ne additional RAT negative
subject m ay be enro lled there after for each p
receding RAT positive subjec t th at is
identified. The RAT result for each subjec
t screen ed will be reco rded on the s tudy
Interactive Voice Response System (IVRS) to manage this enrollment algorithm.
A baseline nasopharyngeal swab specimen will be sent to the central virology laboratory
for each RAT negative subject that has been randomized into the study. These specimens
will be tested for influenza A and B infection using a PCR assay. The PCR results for
these specimens will be reported to BioCryst in real time. The study will close after
enrollment of at least 500 subjects who have either a positive Influenza A or B RAT at
screening, or who have a negative RAT at screening but a positive influenza A or B PCR
assay result from a baseline nasopharyngeal swab.
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Study drug will b e ad ministered as one 2m L intramuscular injection in each g luteal
muscle (total of 4mL injected in divided doses).
At screening, subjects will have an anterior nasal or pharyngeal swab collected for testing
with a comm ercially available RAT kit for influenza A and B in accordance with the
RAT manufacturer’s instructions. If this test is positive and the subject is enrolled,
additional s pecimens will be obta ined f or isolation and c ulture of inf luenza viru s and
quantitative PCR assay. If the initial RAT is negative, th e test should be repeated with a
different commercially available RAT kit. A limited number of RA T negative subjects
may be enrolled in accordance with the screening algorithm defined above.
Enrolled subjects will record the following in a Study Diary:
•
Oral tem perature m easurements tak en w ith an electronic therm ometer every 12
hours. W ith the exception of the baseline m
easurement, all tem
perature
measurements will be obtained
at leas t 4 hours after, or imm
ediately before,
administration of oral acetaminophen (paracetamol- provided), aspirin, ibuprofen or
other NSAID.
•
Assessment of seven symptom s of influenza on a 4-point severity scale (0, absent;
1, mild; 2, moderate; 3, se vere), twice daily (A M, PM) through Day 9, then once
daily (AM) through Day 14
•
Assessment of subject’s ability to perform usual activities, (0–10 on a visual analog
scale) once daily through Day 14
•
Assessment of a subject’s tim e lost from work or usual activities and productivity
compared to normal (0-10 on a visual analogue scale) once daily through Day 14
•
Doses of antipyretic (e. g. acetaminophen/ paracetamol), expectorant, and/or throat
lozenges administered each day through Day 14.
Anterior nose (bilateral) and posterior phar ynx specimens (swabs) will be collected at
Day 1 (pre-treatment) and at Days 3, 5, and 9, for influenza viral culture and quantitative
PCR assay. In a subset of a m inimum of 200 subjects an addition al viral culture/ P CR
sample will be collecte d on Day 2. Anterior
nose (bila teral) and poster ior pha rynx
specimens (swabs) will be collected at Days 1, 3, 5, and 9 f or all subjects, and on Day 2
in the subset of 200 subjects, to assess
for potential changes
in influenza viral
susceptibility to neuraminidase inhibitors in response to treatment.
At selected sites a separate sub-study will be conducted to collect limited PK samples for
the purpose of conducting an exposure-respo
nse analysis. This sub-study will be
conducted under a separate sub-study protocol, BCX1812-311PK.
8 SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.1 Inclusion Criteria
Subjects must meet all of the following criteria for inclusion in this study:
1. Male and female subjects age ≥18 years
2. A positive Influenza A or B Rapid Antigen Test (RAT) performed with a
commercially available test kit on an adequate specimen collected from an
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anterior nasal or pharyngeal swab, in accordance with the manufacturer’s
instructions. A negative initial RAT should be repeated with a second
commercially available RAT kit. A limited number of RAT negative subjects may
be enrolled in accordance with a defined screening algorithm..
3. Presence of fever at time of screening of ≥38.0 C (≥100.4 ºF) taken orally, or
≥38.5ºC (≥101.2 F) taken rectally. For subjects who test RAT positive at the time
of screening, a subject self-report of a history of fever or feverishness within the
24 hours prior to screening will also qualify in the absence of documented fever at
time of screening. For subjects who test RAT negative at screening, fever as
described above must be documented at time of screening.
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal
symptoms) of any severity (mild, moderate, or severe)
5. Presence of at least one constitutional symptom (myalgia [muscle aches],
headache, feverishness, or fatigue) of any severity (mild, moderate, or severe)
6. Onset of illness no more than 48 hours before presentation
7. Females of child-bearing potential must have a negative urine pregnancy test
(Beta HCG) at screening/baseline AND report one of the following:
• Be surgically sterile or practice monogamy with a partner who is
surgically sterile
• Have been sexually abstinent 4 weeks prior to date of screening evaluation
and be willing to remain abstinent through 4 weeks after study drug
administration
• Use oral contraceptives or other form of hormonal birth control including
hormonal vaginal rings or transdermal patches and have been using these
for 3 months prior through 4 weeks after study drug administration
• Use an intra-uterine device (IUD), or double barrier contraception (such as
condom or diaphragm with spermicidal gel or foam) as birth control 4
weeks prior to date of screening through 4 weeks after study drug
administration
8. Provide written informed consent
8.1.2 Exclusion Criteria
Subjects to whom any of the following criteria apply will be excluded from the study:
1. Women who are pregnant or breast-feeding
2. Presence of clinically significant signs of acute respiratory distress
3. History of severe chronic obstructive pulmonary disease (COPD) or severe
persistent asthma
4. History of congestive heart failure requiring daily pharmacotherapy with
symptoms consistent with New York Heart Association Class IV functional status
within the past 12 months (section 15.1).
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5. History of chronic renal impairment requiring hemodialysis or known or
suspected to have moderate or severe renal impairment (actual or estimated
creatinine clearance <50 mL/min)
6. Clinical evidence of active bacterial infection at any body site requiring therapy
with oral or systemic antibiotics
7. Presence of immunocompromised status due to chronic illness, previous organ
transplant, or use of immunosuppressive medical therapy.
8. Current treatment of active viral hepatitis C
9. Presence of known HIV infection, with a CD4 count <350 cell/mm3
10. Current therapy with oral warfarin or other systemic anticoagulant
11. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the
7 days prior to screening
12. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the
previous 21 days
13. History of alcohol abuse or drug addiction within 1 year prior to admission in the
study
14. Participation in a previous study of peramivir as treatment for acute influenza or
previous participation in this study
15. Participation in a study of any investigational drug within the last 30 days
16. Screening ECG which suggests acute ischemia or presence of medically
significant dysrhythmia.
8.1.3 Removal of Subjects from Therapy or Assessment
All subjects are permitted to withdraw from participation in this study at any time and for
any reason, specified or unspeci fied, and without prejudice. The Investigator or sponsor
may terminate the subject’s participation in the study at any tim e for reasons including
the following:
1. Adverse event;
2. Intercurrent illness;
3. Non-compliance with study procedures;
4. Subject’s decision;
5. Administrative reasons;
6. Lack of efficacy;
7. Investigator’s opinion to protect the subject’s best interest.
Any subject who withdraws because of an adverse event will be followed until the sign(s)
or symptom(s) that constituted the adverse eve nt has/have resolved o r is dete rmined to
represent a stable medical condition.
A subject should be withdrawn fr om the trial if, in the opinion of the Investigator, it is
medically necessary, or if it is the d esire of the subject. If a subjec t does not return for a
scheduled visit, every effort should be m ade to contact the subject and determ
ine the
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subject’s medical condition.
In any circum stance, ev ery effort sho uld be m ade to
document subject outcome, if possible.
If the sub ject withdraw s consen t, n o furt her evaluations should be perfor med and no
attempts should be made to collect additional data.
9 TREATMENTS
9.1
Treatments Administered
Peramivir is an investig ational drug. Peram ivir for intramuscular injection is a small-
volume parenteral and will be supp lied as a 75 mg/mL solution in sodium citrate/ citric
acid buffer. The pH is approximately 3.0.
A m atched placebo solution of so dium citrat e/ citric acid buffer with 1.2% sod
ium
chloride at a pH of approximately 3.0 will be supplied.
9.2
Identity of Investigational Product(s)
Peramivir and placebo peramivir will be supplied in clear 2mL vials. An individual study
drug kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending
upon the treatment group), 2 syringes and 2 need les in which to draw up the solution for
intramuscular injection. All m aterials will be packaged in a labele d box container. All
study drug kits m ust be stored at 2-8 oC. Each individual study drug kit will b e labeled
with some or all of the following information as required by local regulations:
• Sponsor nam e and contact inform
ation, study protocol num
ber, kit num ber,
description of the contents of the container, instructions for the preparation of the
syringe and adm inistration of the study dr ug, conditions f or st orage, statem ent
regarding the investigationa l (clinical trial) use of the study drug and date for
retest or expiry date.
Each vial of study drug will be labeled with some or all of the following infor mation as
required by local regulations:
• Sponsor nam e, study protocol number, desc ription of the contents of the vial,
instructions for the preparation
of
the s yringe, statem ent regarding the
investigational (clinical trial) use of the study drug and lot number.
9.3
Method of Assigning Subjects to Treatment Groups
Subjects will be centrally randomized in a ratio of 2:2:1 to one of three treatment groups:
single dos e peramivir 1 50mg, single dose pera mivir 300mg or placeb o, in acco rdance
with a computer-generated random ization schedule prepared by a non-study statistician.
Subjects will be s tratified acco rding to the result of a RAT test and curren
t sm oking
behavior. Once a subject is eligible for randomization, he/she wi ll be assigned a study
drug kit nu mber that will be obta ined by stu dy staf f f rom the study inter active voice
response system (IVRS). Once a study drug kit nu mber has been assigned to a subject, it
cannot be reassigned to any other subject.
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9.4
Study Medication Accountability
The Investigator/pharmacist must maintain accurate records of the disposition of all study
drugs received from the sponsor, issued to th
e subject or directly adm inistered to the
subject (including date and time), and any drug accidentally destroyed. The sponsor will
supply a specific dru
g-accountability form . At the en
d of the study, information
describing study drug s upplies (e.g., lot num bers) and disp osition of s upplies for each
subject must be provided, signed by the Invest
igator or designee, and colle cted by the
study monitor. If any errors or irregularities in any shipment of study m edication to the
site are discovered at any time, the Project Manager must be contacted immediately.
At the end of the study, all
medication not dispensed or administered and packaging
materials will be collected with supervision of the monitor and returned to the sponsor or
destroyed on site as dictated by the appropr
iate Standard Operating P rocedure at the
participating institution.
9.5
Blinding/Unblinding of Treatments
This is a double-blind study. The treatment group assignment will not be known by the
study subjects, the investigator , the clinical staff, the CRO or Sponsor staff during the
conduct of the study.
Section 11.2.4 provides inform ation regarding the process for unblinding the treatment
assignment, if necessary, in the event of an SAE.
9.6
Prior and Concomitant Therapies
All m edications, by any route of adm
inistration, used during this study m
ust be
documented on the Case Report Form (CRF). Prescription as well as non-prescription
medications should be recorded. Medication us ed for the treatm ent of influenza-related
symptoms will be captured by the subject in the diary card provided by BioCryst.
9.7
Overdose and Toxicity Management
To date there is no experience with overdose of in tramuscular or intravenous peramivir.
If overdose occurs, subjects should receive indicated supportive therapy and evaluation of
hematologic and clinical chem istry laboratory tests should be conducted. The effec t of
hemodialysis on elimination of peramivir is unknown.
9.8
Dose Interruption
As this is a study of a single injection of
peramivir or placebo, guidelines for treatm ent
interruption for drug related SAEs or toxicities are not applicable.
10 STUDY CONDUCT
A study schedule of evaluations is presented in
Figure 1 . A detailed lis
t of the
evaluations is also provided in the following sections.
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10.1 Evaluations
All subjects enrolled in this study will undergo the following evaluations:
10.1.1 Medical History
Medical history, influenza va
ccination s tatus within th e previous 12 m
onths and
demographic data (including smoking behavior) will be recorded at Screening/Baseline.
10.1.2 Rapid Antigen Test for Influenza
At Screening/Baseline, a commercially available, rapid antigen tes t (RAT) for influenza
A and B will be performed on an adequate specimen collected by swabbing the anterior
nose or pharynx, in accordance with the RAT
manufacturer’ instructions. A negative
initial RAT should be repeated with a different commercially available RAT kit. Refer to
the Study Manual f or instructions regarding the use of the
RAT kits provided for this
study. Sites m ay use the kits provided
by the Sponsor or any other commercially
approved RAT available at their site to document a confirmed influenza infection.
A lim ited num ber of RAT negativ e subje cts will be enr olled in a ccordance with the
following algorithm: Once an ind ividual site has identified 3 RAT positive sub jects at
screening within a 10 day period, indicating that influenza activity is present in the site’s
vicinity, a RAT negative subject that m
eets the inclus ion/ exclus ion criteria m ay be
enrolled. O ne additional RAT negative subj
ect m ay be enrolled th
ereafter for each
preceding RAT positive subject that is iden
tified. The RAT result for each subject
screened will be record ed on the s tudy Inte ractive Voice response (IVR) system to
manage this enrollment algorithm.
10.1.3 Physical Examination and Influenza-related Complications Assessments
The Investigator will perform a physical ex amination at S creening/Baseline. Subject’s
weight will be recorded at Screening/Baseline.
Study personnel will be provided with an influenza-related complications (IRC) checklist
in the CRF to evalua te the subject for the presence of clinical signs and /or symptoms of
the following influenza-related complications: sinusitis, otitis, bronchitis and pneumonia.
At each follow up assessm
ent a t argeted physical exam ination will be conducted to
record the presence of influenza related complications. If the investigator determines that
the subject experiences (or is presumed to experience) an IRC as noted above, he/she will
record that assessm ent on the IR
C CRF pa ge and any m edication used to treat the
condition will be recorded on the concom
itant m edication page. Such inform
ation
describing IRC signs and/or sym ptoms should not be reported as adverse events. Any
injection site reactions noted will be recorded in the CRFs as adverse events.
10.1.4 Vital Signs
Vital signs evaluations will in clude blood press ure, pulse rate , and resp iration rate. The
investigator will record or al body tem perature at baseline. Thereafter the subject will
record oral temperature twice daily in the study diary card.
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following
the study drug injection on Day 1, then once da ily on Days 2 (for those subjects who are
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seen on day 2), 3, 5, 9, and 14.
10.1.5 Electrocardiogram Measurements
A 12-lead elec trocardiogram (ECG) will b e obtained at Screen ing/ Baselin e. I f this
baseline ECG is interpreted by the conductin
g physician as m eeting the exclusionary
criteria listed in section 8.1.2 the subject will no t be enrolled in this study. If the ECG is
interpreted as being abnorm al and does not m eet the exclusionary criteria (e.g. acute
ischemia, medically significant dysrhythmia) th en this subject m ay be enrolled, taking
into con sideration th e subjec t’s m edical history. Appropriate follow-up evaluations,
including but not limited to repeat ECGs, should be completed at subsequent study visits
as directed by the investigator.
10.1.6 Clinical Chemistry Profiles
Clinical ch emistry pro files will include a C
hemistry 20 panel (
includes sod ium,
potassium, chloride, total CO 2 [bicarbonate], creatinine, glucose, urea nitrogen, album in,
total calcium
, total m
agnesium, phosphor
us, alkaline phosphatase, alanine
aminotransferase (ALT), aspartate am
inotransferase (AST), total bilirubin,
d irect
bilirubin, lactate dehydrogenase [LDH], total protein, total creatine kinase, and uric acid)
Blood samples for clinical chem istry profiles will be collected at Screen ing/Baseline, and on
Days 3, 5 and 14.
10.1.7 Hematology Profiles
Hematology will include complete blood count (CBC) with differential.
Blood samples for he matology profiles will be collected at Screening/Baseline, and on
Days 3, Days 5 and 14.
10.1.8 Serology for Influenza
Paired blood samples for determination of antibody to influenza A and B (serology) will
be obtained with the clinical laboratory tests at Screenin g/Enrollment and at Day 14.
These specimens will be stored at the central laboratory and will be analyzed if needed to
confirm the diagnosis of influenza.
10.1.9 Urinalysis and Evaluation of Protein in Urine
Urinalysis will in clude dipstick tests for protein, glucose, ketones, blood, urobilinogen,
nitrite, pH, and spec
ific gr avity a nd m icroscopic evaluation for R
BCs and WBCs.
Samples for urinalysis will be collected at Screening/Baseline, and on Days 3, 5, and 14.
10.1.10Urine Pregnancy Test
Females of childbearing potential will be ev aluated for pregnancy at Screening/Baseline
and Day 14 using a urine pregnancy test.
10.1.11 Samples for Virologic Laboratory Assessments
An adequate spec imen will b e co llected by sw abbing the anter ior nos e (bila teral) and
posterior pharynx for virologic laboratory a ssessments including culture for the isolation
of influenza virus and/or quantitative PCR assa y at Screening/Baseline, and at Days 3, 5,
and 9. In a subset of a m inimum of 200 subjects an additio nal sample will be taken at
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Day 2. Refer to the L
aboratory Manual for instructions re garding the processing and
shipment of these specimens.
10.1.12 Subject Self Assessments
Subject self assessments will be performed beginning pre-dose on Day 1 and recorde d in
the subject’s Study Diary including the following:
• Oral temperature measurements with an electronic thermometer (provided by the
Sponsor for the study) every 12 hours. With the exception of the baseline
measurement, all temperature measurements will be obtained at least 4 hours after, or
immediately before, administration of oral acetaminophen (paracetamol, provided)
aspirin, ibuprofen or other NSAID. The times of each temperature determination will
be recorded in the Study Diary. The baseline temperature will be recorded at the
screening/Day 1 visit prior to dosing, regardless of whether the subject had recently
taken an anti-pyretic; the time of anti-pyretic use pre-treatment will be recorded in the
CRF, if applicable.
• Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction,
myalgia [muscle aches], headache, feverishness, and fatigue) on a 4-point severity
scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on
Day 1 and through Day 9, then once daily through Day 14.
• Assessment of the subject’s ability to perform usual activities using a 0–10 visual
analogue scale once daily through Day 14.
• Assessment of the subject’s time lost from work or usual activities and productivity
compared to normal using a 0-10 visual analogue scale once daily through Day 14.
The subject’s diary card will be reviewed by study staff at each visit for completion of the
record of all required ite ms, with particular emphasis on alleviation of symptoms as well
as relapse of sym ptoms. Relapse is defined as the recurrence of at leas t one respiratory
symptom and one constitutiona l sy mptom (both greater th an m ild in severity) f or 24
hours and the presence of fever (unless influenc ed by antipyretic use). Relapse can only
occur after the subject has m et the endpoint cr iteria for alleviation of symptoms. Study
staff will not attem pt to ask subjec ts to retrospectively complete missing diary card data
for any scheduled assessm ents that have not b een com pleted prio r to the c linic visit.
Study staff should, however, rem
ind the subject to com plete the diary card at all
scheduled times.
10.1.13 Concomitant Medications
All concom itant m edications used during
this study, with the exception of those
medications taken for symptomatic relief of influenza symptoms, which will be reco rded
by the subject in their diary card, must be documented on the Case Report Form (CRF).
10.1.14 Adverse Events
AEs will be assess ed from the tim e of ad ministration of stu dy medication through the
final study visit.
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10.1.15 Single Pharmacokinetic Exposure Sample
On study day 3 a single PK sample will be drawn in concert with the day 3 safety clinical
laboratory blood draw. This sample will be
sent for subsequent analys
is of the
concentration of peramivir at this time point. Data f rom this sing le PK sample will b e
combined with data from the PK s ub-study (BCX1812-311PK) to perfor m an exposure-
response analysis. This analysis will be described as part of the sub-study analysis plan..
10.2 Screening
10.2.1 Informed Consent
The nature and purpose of the study and the expectations of a participating subject will be
described to potential study subjects , their que stions will be answered, and the subjects
will th en b e asked to sign an inf
ormed c onsent docum ent. Study s ubjects will then
undergo the screening evaluation as noted in Section 10.2.2
10.2.2 Screening/Baseline Evaluation and Enrollment
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or
in the subject’s hom e, in which case all ev aluations must be conducted by appropriately
trained and qualified staff.
Clinical laboratory assessm
ents perform ed at Screenin
g are
for the purpose of
establishing a baseline. Subjects m ay be enrolled and receive treatm ent with study drug
prior to r eceiving re sults of the laboratory a ssessments (with the ex ception of urine
pregnancy test result, which must be known).
Eligible sub jects will be enrolled and ra
ndomized to blin ded study treatm ent. The
randomization will include stratification by RA T status and current s moking behavior.
The Investigator will prepare a request for blinded study drug assignment which includes
the subject’s screening number. The Investigator or designee at the clinical study center
will contact the central randomization Interactive Voice System (IVRS call center). The
IVRS call center will advise the study center of the investigational study drug kit number
that is assigned to that subject at enrollment.
Subjects that are d etermined to be ineligible will be advi sed accordingly, and the reason
for ineligibility will b e discussed. If desired by the subjec t the reason for ineligibility
may be pr ovided/discussed with their hea
lth-care provider by the Investigator or
designee.
Ineligible subjects who have been screen
ed for the study will also be entered on
the
IVRS. For such subjects, the screening num
ber assigned, subject’s date of birth and a
reason for ineligibility will be entered on to th e IVRS. All ineligible subjects must be
entered onto the IVRS within 24 hours of screening, to assis t with surve illance
analysis during the course of the study.
10.3 Treatment Period—Study Day 1
Day 1 represents the only day of study dr
ug dosing. Study drug adm inistration should
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occur as soon as possible following inform
ed consent, screening and random
ization.
Therefore, it is expec ted that the da te of Screening/ Baseline and Day 1 will usua lly be
the same date.
10.3.1 Pre-dose Evaluations
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the
subject shall complete the record of these assessments in their Study Diary prior to
dosing. The subject will be counseled regarding the expectations for recording these
assessments through Day 14.
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral
temperature) and a 12 lead ECG will be obtained prior to dosing. At Hour 0, the blinded
study drug will be administered intramuscularly (one injection in the left gluteal muscle,
and one injection in the right gluteal muscle within a period of ≤ 10 minutes.). The
calendar date and 24-hour clock time of the first and second injections will be recorded.
The following evaluations will be performed post-dose on Study Day 1:
• Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral
temperature) at 15 minutes after the study drug administration
• Record any concomitant medications
• Record any AEs
10.4 Post-Treatment Assessment Period
10.4.1 Days 2, 3, 5, 9 and 14
Study evaluations will be perform ed on Days 2 [subset], 3, 5, 9 and 14 in accordance
with the schedule of evaluations (Figure 1).
Visits may be conducted in the investigator’s o ffice or clinic, or in the subject’s home, in
which case all evaluations must be conducted by appropriately trained and qualified staff.
The Day 2 assessm ent will be con ducted in pe rson only f or the subse t of subjects who
will provide additional Day 2 viro logy samples. For all o ther study subjects, study staff
will attempt to contact the subjects on Day 2 by telephon e to confirm their com pliance
with completion of the Subject Self Assessments, to note any concom itant medications
and adverse events. Any adverse events repo
rted by the subject during this telephone
contact will be recorded on the adverse event form and verified during the visit on day 3.
At each v isit it is im portant that the sub ject’s Study Diar y record be rev iewed for
completion of daily Subject Self Assessm
ents. The subjects should be counseled as
necessary regarding self assessments and Study Diary record requirements. The subject’s
diary card will be reviewed by study staff for alleviation of symptoms as well as relapse
of symptoms. Relapse is defined as the r ecurrence of at least one resp iratory symptom
and one constitutional symptom (both greater than mild in severity) for 24 hours an d the
presence of fever (unless influenced by antipyretic use). Relapse can only occur after the
subject has met the endpoint criteria for alleviation of symptoms.
Day 3:
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The results of the CK assay a t Da y 3 will no t be m ade available to investiga tors, to
BioCryst or to any study personnel unless the C K result at Day 3 is ≥ 2000 IU/mL. A
single PK sample will be drawn as part of the safety clinical laboratory study on Day 3.
Day 14:
If a subject does not have resolution of all
influenza-related sym ptoms (defined as a
patient-recorded sym ptom score of m oderate [ 2] or seve re [ 3]), the investigato r will
schedule a follow-up assessm ent with the pati ent at Day 21 and, if required, Day 28.
These follow-up assessm ents m ay be conduc ted in person or by telephone at the
investigator’s discr etion. The subjec ts will no t be required to continu e to reco rd da ily
symptom sc ores, but w ill report th ese sco res to the inv estigator on Day 21 and, if
required, on Day 28. No protocol-m andated follow up will occur after Day 28. Further
management of the subject will be in acco
rdance with the investigator’s stan
dard
practice.
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Figure 1
Study Measurements and Visit Schedule
Treatment
Period
Assessment Day End of Study
Early Withdrawal
Screening 1
(Baseline)
Day 11
Day 22
Day 3
Day 5 (±1 day)
Day 9 (±3 day)
Day 14 (±3 day) 8
Informed Consent
X
Rapid Antigen test for Influenza A & B
X
Medical History/Physical Exam3
X
Influenza-related complications checklist3
X
X
X
X
X
X
Inclusion/Exclusion
X
Clinical Chemistries4
X
X
X
X
Hematology4
X
X
X
X
Exposure Pharmacokinetic Sample
X4
Serology (serum) Sample
X
X
Urinalysis4
X
X
X
X
Urine Pregnancy Test
X
X
Vital Signs5
X
X
X
X
X
X
X
ECG6
X
Sample (nasophar
yngeal swab) for
Influenza Virus Culture/ PCR assay and
for resistance studies
X
X
X
X
X
Study Drug Administration
X
Subject Diary Review7
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on subsequent study days may occur in subject’s home by
the investigator (all visits) or appropriately trained study center staff (Day 2, 3, 5, 9 visits).
2 Day 2 visit required only for a subset of subjects for whom additional Day 2 virology sample is required. For all other subjects, Day 2 will be a telephone contact with the subject to ensure
compliance with diary card completion, concomitant medication and adverse event review.
3 Medical history and physical exam at screening to include weight, and smoking behavior. Targeted physical examinations will be performed to complete the influenza-related complications
checklist by the appropriate medical personnel at appropriate visits.
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subject may be enrolled and begin treatment with study drug prior to receiving results.
On Day 3 an extra tube will be included with the safety blood sample for evaluation of peramivir concentrations.
5 Vital sign measures will include blood pressure, pulse rate and respiration rate. Vital signs will be recorded at Screening, pre-dose and at 15 min following the study drug administration on
Day 1, then once on remaining days as stipulated. The investigator will record oral temperature at baseline. Thereafter the subject will report oral temperature measurements twice daily in
the Study Diary
6 If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study. If the ECG is
interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, medically significant dysrhythmia) then this subject may be enrolled, taking into consideration
the subject’s medical history. Appropriate follow-up evaluations, including but not limited to repeat ECGs, should be completed at subsequent study visits as directed by the investigator.
7 Subjects record symptom assessment in Study Diary, twice dail y, beginning pr e-dose on Day 1 thr ough Day 9, then once daily through Day 14; subjects record ability to perform usual
activities once daily, beginning pre-dose on Day 1 through Day 14. Subjects record oral temperature twice daily throughout as well as all concomitant medication and adverse events
8 For any subject with unresolved influenza symptoms(moderate or severe) or unresolved adverse events, a follow up assessment (in person or by phone) will be scheduled at Day 21 and Day
28 if required
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11 ADVERSE EVENT MANAGEMENT
11.1 Definitions
11.1.1 Adverse Event
An AE is any untoward m
edical occurrence in a clinical study subject. No causal
relationship with the study drug or with the clinical study itself is implied. An AE may
be an unfavorable and unintended sign, sym ptom, syndrome, or illness that dev elops or
worsens during the clinical st
udy. Clinically relevant ab
normal results of diagnostic
procedures including abnorm
al laborator y findings (e.g., requ
iring unscheduled
diagnostic procedures or treatm ent measures, or resulting in withdrawal from the study)
are considered to be AEs.
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2).
Surgical procedures are not AEs but m ay constitute therapeutic m easures for conditions
that require surgery. The condition for which the surgery is required is an AE, if it occurs
or is detected during the study period. Planned surgical m
easures perm itted by the
clinical study protocol and the conditions(s) leading to these measures are not AEs, if the
condition(s) was (were) known befo re the start of study treatm ent. In the latter case the
condition should be reported as medical history.
Assessment of seven influenza sym ptoms (cough, sore throat, nasal obstruction, m yalgia
[muscle aches], headache, f everishness, and f atigue) will be documented in a subject’s
study diary and analy zed as a m
easure of efficacy of the study treatm
ent. These
symptoms will not b e reported as AEs unless the sym ptom(s) worsen to the exte nt that
the outcome fulfils the def inition of an SAE, which then must be recorded as such (see
Section 11.1.2). Likewise, a RAT for influenza is
required at screening in order to
determine eligibility for the study, and therefore a positive RAT is not considered an AE.
11.1.2 Serious Adverse Event
A SAE is an adverse event that results in any of the following outcomes:
• Death
• Is life-threatening (subject is at immediate risk of death at the time of the event; it
does not refer to an event that hypothetically might have caused death if it were more
severe)
• Requires in-subject hospitalization (formal admission to a hospital for medical
reasons) or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity (i.e., there is a substantial
disruption of a person’s ability to carry out normal life functions)
• Is a congenital anomaly/birth defect
• Is an important medical event
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Important medical events that may not result in death, are no t life-threatening, or do not
require hospitalization may be considered an SAE when, based upon appropriate medical
judgment, they m
ay j eopardize the subject or m
ay r equire m edical or surgical
intervention to prevent one of the outcom es listed in this definition. E xamples of such
events include allergic bronchospasm requiri
ng intensive treatm ent in an e mergency
room or at hom
e, blood dyscrasias or c
onvulsions that do not
result in subject
hospitalization, or the development of drug dependency or drug abuse.
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and
Reporting Serious Adverse Events
Reports of AEs are to be collected from the time of study drug administration through the
follow-up period ending on Day 28. The Invest igator or de signee must completely and
promptly record each AE on the appropriate
CRF. The Investig ator should attem pt, if
possible, to establish a diagnosis based on th e presenting signs and symptom s. In such
cases, the diagnosis should be docum
ented as the A
E and not the individual
sign/symptom. If a clear diagnosis cannot be established, each si gn and symptom must
be recorded individually.
The Investigator should attem pt to follo w all unresolved AEs and/or SAEs observed
during the study until they are reso lved, or for 30 days after th e subject’s last study visit,
whichever comes first.
11.2.1 Definition of Severity
All AEs will be as sessed (graded ) f or severity and class ified into on e of f our clearly
defined categories as follows:
• Mild:
(Grade 1): Transient or mild symptoms; no limitation in activity;
no intervention required. The AE does not interfere with the
participant’s normal functioning level. It may be an annoyance.
• Moderate:
(Grade 2): Symptom results in mild to moderate limitation in
activity; no or minimal intervention required. The AE produces
some impairment of functioning, but it is not hazardous to
health. It is uncomfortable or an embarrassment.
• Severe:
(Grade 3): Symptom results in significant limitation in activity;
medical intervention may be required. The AE produces
significant impairment of functioning or incapacitation.
• Life-threatening: (Grade 4): Extreme limitation in activity, significant assistance
required; significant medical intervention or therapy required;
hospitalization.
11.2.2 Definition of Relationship to Study Drug
The blinded Principal Investigator must rev iew each AE and m ake the determ ination of
relationship to study drug using the following guidelines:
Not Related:
The event can be readily explained by other factors such as the
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subject’s underlying m edical c ondition, concom itant therapy, or
accident, an d no tem poral relati onship ex ists b etween the study
drug and the event.
Unlikely:
The event d oes not follow a reason able tem poral sequ ence from
drug adm inistration and is read
ily explained by the subject’s
clinical state or by other m
odes of therapy adm inistered to the
subject.
Possibly Related:
There is so me tem poral relationship between the event an
d th e
administration of the study drug a
nd the event is unlikely to be
explained by the subject’s m edical condition, other therapies, or
accident.
Probably Related:
The event follows a reasonable tem
poral sequence from drug
administration, abates upon discontinuation of the drug, and cannot
be reasonably explained by th
e known characteristics of the
subject’s clinical state.
Definitely Related: The event follows a reason
able tem poral sequen ce from
administration of the m edication, follows a known or suspected
response pattern to the m edication, is confirm ed by im provement
upon stopping the m edication (dec hallenge), and reappears upon
repeated exposure (rechallenge,
if rechallenge is m
edically
appropriate).
11.2.3 Reporting Serious Adverse Events
Any SAE must be reported to BioCryst
or its designee within 24 hours of the
Investigator’s recognition of the SAE by fi
rst notifying the Medical Monitor at the
number listed below:
Telephone:
Europe: +44 1628 548000; North America: 1-888-724-4908
Facsimile:
Europe: +44 1628 540028; North America: 1-888-887-8097
or 1-609-734-9208
The site is required to fax a completed SAE Report Form (provided as a separate report
form) within 24 hours. All additional follow-up evaluations of the SAE must be reported
and sent by facsimile to BioCryst or its designee as soon as they are available.
The Principal Investigator or designee at each site is respons ible for submitting the IND
safety report (initial a
nd follow -up) or other safety inform
ation (e.g., revised
Investigator’s Brochure) to
the Institutional Review
Board/Independent Ethics
Committee (IRB/IEC) and for retaining a copy in their files.
If the Inv estigator becomes aware of any SA E occurring within 30 days after a s ubject
has com pleted or withdrawn from t he study, he or she should notify BioCryst or its
designee.
Any SAEs considered possibly related to treatment will be reported to the FDA and other
Regulatory Competent Authorities as applicab le via the MedW atch reporting system i n
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accordance with FDA and other ap plicable regulations. However, the Investig ator is not
obligated to actively seek reports of AEs in former study participants.
While pregnancy is not considered an AE, a ll cases of fetal drug exposure via parent as
study participant (see S ection 4.4) are to be
reported immediately to BioCryst or its
designee. Inform ation rela ted to the pregnancy m
ust be given on a “Pregnancy
Confirmation and Outcome” form that will be provided by the Sponsor or its designee.
11.2.4 Emergency Procedures
In the even t of an SAE, the Principal Inve
stigator m ay request the unblinding of the
treatment assignm ent for the subject affected
. If tim
e allows (i.e., if appropriate
treatment for the SAE is not im peded), the Principal Investigator wi ll first consult with
the Med ical Monito r r egarding the need to unblind the treatm ent assignm ent for the
subject. At all times, the clinical well-being of any subject outweighs the need to consult
with the Medical Monitor.
The Principal Investigator m
ay contact th e IVRS central random
ization center and
request the unblinding of the treatm
ent assi gnment that corresponds to the affected
subject. Th e IVRS center will record the na me of the Investigator making the request,
the date and time of the request, the reason for the request, the subject number and study
drug kit number, and whether the Medical M
onitor was consulted prior to the request
being made. The Sponsor will be informed within 24 hours if unblinding occurred.
12 STATISTICAL METHODS
Descriptive statistical methods will be used to summ arize the data from this study, with
hypothesis testing perform ed for the prim
ary and other selected efficacy endpoints.
Unless stated otherwise, the term “descriptive statistics” refers to number of subjects (n),
mean, median, standard deviation (SD), minimum, and maximum for continuous data and
frequencies and percentages for categorical da ta. The term “treatm ent group” refers to
randomized treatment assignment: peramivir 150 mg, peramivir 300 mg, or placebo. All
data collected during the study wi ll be included in data listin gs. Unless otherwise noted,
the data will be sorted first by treatm ent assignment, subject num ber, and then by date
within each subject number.
Unless specified otherwise, all statistical testing will be two-sided and will be performed
using a significance (alpha) level of 0.05.
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher.
12.1 Data Collection Methods
The data will be reco rded on the CRF appr oved by BioCryst. The Investigator must
submit a completed CRF for each subject who signs an inform
ed consent form (ICF),
regardless of duration. All documentation supporting the CRF data, such as laboratory or
hospital records, must be readily available to verify entries in the CRF.
Documents (including laborator y reports, hospital records s
ubsequent to SAEs, etc.)
transmitted to BioCryst should not carry the s
ubject’s name. This will help to ensure
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subject confidentiality.
The Investigator m ust consult the “CRF
Com pletion Manual” for com
prehensive
instruction for completion of the CRF.
12.2 Statistical Analysis Plan
A statistical analysis plan (SAP) will be cre ated prior to the review of any data. This
document will provide a m ore technical and detailed description of the proposed data
analysis methods and procedures.
12.3 Sample Size Estimates
From published resu lts, it is exp ected that th e median time to a lleviation of symptoms
will be between 103.3-116 hours for subjects receiving p lacebo. 16 , 1 7 For sam ple size
calculations the best placebo respon se (103.3 hours) will p rovide the most conserv ative
estimate of an observed hazard ratio. Additionally, it is expected that the median time to
alleviation for the lowes t dose peramivir arm will be 69.9 h ours, yielding a hazard ratio
of 0.68. Using these assum
ptions, a sa mple size of 200 infected subjects per active
treatment group and 100 infected subjects in th e placebo group is sufficient to provide at
least 80% power to detect a hazard ratio of 0.68 usi ng a log-rank statistic and α = 0.025
(SAS version 9.1.3; tota l accrual time 7 months; total enrollment time 6 months). Up to
800 subjects will b e enrolled to achieve the target num ber of at least 5 00 subjects with
diagnostic evidence (RAT or PCR) of an
acute influenza infection (200 per active
treatment; 100 receiving placebo) as described in section 12.4.2.
12.4 Analysis Populations
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected
(ITTI), and safety populations.
12.4.1 Intent-To-Treat Population
The ITT population will include all subject
s who are random ized. Subjects will be
analyzed in the treatment group to which they were randomized. The ITT population will
be used for analyses of accountability and demographics.
12.4.2 Intent-To-Treat Infected Population
The ITTI po pulation will include all subj ects who are rando mized, received study d rug,
and have proven influenza by any one of the fo llowing: culture, PCR, or paired serology
showing ≥ 4-fold increase in antibody to influe
nza A or B, and received study drug.
Subjects will be an alyzed accord ing to the treatment random ized. If a discrepancy is
noted in the final database for any subject, such that the drug differs from the randomized
treatment assignm ent, efficacy analyses m ay be repeated with the su
bjects analy zed
according to the treatm ent received. The
ITTI population will be used for prim
ary
analyses of efficacy.
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12.4.3 Safety Population
The safety population will include all subjects who received study drug. Subjects will be
analyzed according to the treatm ent received. This population will be used for all safety
analyses.
12.5 Interim and End of Study Analyses
Interim Analysis
An independent DMC will review safety data on an ongoing basi s. Safety analyses will
be presented in a manner consistent with the presentations intended for the final analysis.
End of Study Analysis
A final analysis is planned after the last su bject completes or discontinues the study, and
the resulting clinical database has been cleaned, quality checked, and locked.
12.6 Efficacy Analyses
12.6.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the time to alleviation of symptoms, defined as the time
from injection of study drug to the start of th e time period when a subject has Alleviation
of Symptoms. A subject has Alleviation of
Symptoms if all of the seven symptoms of
influenza (nasal congestion, so re throat, cough, aches and pains, fatigue (tiredness),
headache, feeling feverish) assessed on his/he
r subject diary are eith
er absent o r are
present at no m ore than m ild severity leve l and at this status for at least 21.5 hours (24
hours - 10%).
Descriptive statistics for the prim ary effi cacy endpoint will be tabulated by treatment
group. Alleviation of sym
ptoms will be d etermined by assessm ent of sym ptoms as
reported on each subject’s diary card. T ime to alle viation of sym ptoms will b e
summarized overall and for i
ndividual sym ptoms for each treatm ent group. Overall
treatment dif ferences will be assess ed using a Cox Regression m
odel with ef fects f or
RAT result at screening, current smoking behavior, treatment group, and influenza season
at randomization (if necessary). Subjects who do not experience alleviation of symptoms
will be censored at the date of their last non-missing post-baseline assessment. Pairwise
differences in tim e to alleviation of sy
mptoms am ong the treatm ent groups will be
evaluated using contrast statem ents from the final Cox m odel. In orde r to m aintain the
overall type I error in the presence of the planned comparisons between the two peramivir
treatments and placebo, a Bonfe rroni correction will be app lied to the p rimary efficacy
endpoint analysis. P -values for the planne d com parisons of each peram ivir arm to
placebo will be adjusted via a Bonferroni corr ection (i.e., if the unadjusted p-value for an
active com parison versus place bo, p, is less th an 0.05, then p
a=p*number of planned
comparisons=p*2; otherwise, p
a=p). Superiority of peram
ivir to placebo will be
established if the adjusted p-value is less than or equal to 0.05.
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12.6.2 Secondary Efficacy Endpoints
All secondary endpoints will be summ
arized using descriptive statistics by treatm
ent
group and study day/time, if appropriate. St atistical comparisons for each endpoint will
be constructed without adjustment for multiple endpoints.
The reduction in viral shedding will be assessed as the change in viral titers defined as the
time-weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL)
and will be summarized for each treatm ent group. The tim e-weighted average change
from baseline will be calculated on a by-subject basis through Day 9 using the trapezoidal
rule with a ll available post-bas eline on-tre atment data (d ata af ter initia tion of study
treatment) minus the baseline value. Specifically, the time-weighted area under the curve
for time a (ta) to time b (tb) is given by the formula
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
,
where
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
and ti represents the date of the ith viral titer
assessment and y i represents the log10 value of the i th viral titer as sessment. If there is a
baseline value and only one follow-up value, y
i then the tim e-weighted change from
baseline is defined as the difference between y i and baseline. If there is a baselin e value
and no follow-up value, the subject is exclude d from analysis. The differences between
each of the peramivir treatment groups and placebo will be evaluated using a van Elteren
Test ad justing for RAT result at screen
ing, current sm oking be havior and influenza
season at randomization (if necessary). Analyses of the PCR results will be analy zed in
a similar manner.
Subject’s ability to perform usual activities as determined from the visual analog scale
will be summarized by study visit day and treatment group. Differences between the
treatment groups will be assessed using the van Elteren Test adjusting for smoking
behavior and influenza season at randomization (if necessary). The time (days) to
resumption of a subject’s ability to perform usual activities (i.e., subject scores ability to
perform usual activities as 10) will be estimated using the method of Kaplan-Meier.
Differences between each of the peramivir treatment groups and placebo will be assessed
using the log rank statistic adjusting for RAT result at screening, current smoking
behavior and influenza season at randomization (if necessary). Subjects who do not
return to the pre-study level of performance of usual activities will be censored at the
time of their last non-missing post-baseline visual analog scale value.
Subject’s oral tem perature will be summ
arized by study visit and treatm
ent group.
Differences between the treatment groups will be assessed using the Wilcoxon Rank Sum
Test con trolling for RAT resu lt at screen ing, current sm oking behavior and influenza
season at randomization (if necessary). A subject has Resolution of Fever if he/she has a
temperature < 37.2°C (99.0°F) and no antipyretic medications have been taken for at least
12 hours. The tim e to resolution of fever will be estimated using the method of Ka plan-
Meier using temperature and sym ptom relief medication information obtained from the
subject diary data. Difference between the tr eatment groups will be assessed using the
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log rank sta tistic controlling for RAT result a t screening, current sm oking behavior and
influenza season at randomization (if necessary). Subjects who do not have resolution of
fever will be censored at the tim
e of their last non- missing post-baseline tem perature
assessment.
The MRU, MRU-related direct co sts, and indirect co sts attributable to days m issed of
work and work productivity and/or perform ance losses will be summ arized by treatment
group. Differences between each of the peramivir treatment groups and placebo group
will be evaluated using both param etric and/or non-parametric tests, as appropriate. If
necessary, bootstrapping techniques will be used to calculate confidence intervals around
the incremental differences in costs.
12.6.3 Exploratory Endpoint
Genotypic (including Hem agglutinin and Neurom inidase), phenotypic, viral culture and
PCR data will be lis ted for each sub ject. These listings will be constructed in a m anner
consistent with the F
DA June 2006 Guidance Docum
ent:“Guidance for Subm itting
Influenza R esistance D ata”.18 Ad ditionally, the num ber and percen tage of genotypic
changes from wild-type a mino acid will be summarized separately for treatm ent group,
protein type, and study visit.
12.7 Safety Analyses
AEs will be m apped to a MedDRA-pref erred term and system organ classification. The
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred
terms, system organ classifications, and severity. If a subject experiences multiple events
that m ap to a s ingle p referred term, the grea test severity and st rongest Investigator
assessment of relation to study d
rug will be assigned to the preferred term for the
appropriate sum maries. All AEs will be li
sted f or individual subje cts showing both
verbatim and preferred terms. Separate summaries of treatment-emergent SAEs and AEs
related to study drug will be generated.
Descriptive summaries of vital s igns and clinic al laboratory results will be presented by
study visit. Laboratory abnorm alities will be graded according to the DAIDS Table for
Grading Adverse Events for Adults and Pedi atrics (Publish Date: December 2004). The
number and percentage of subjects experien
cing treatm ent-emergent graded toxicities
will be summarized by treatment group. Laborator y toxicity shifts from baseline to Day
3, Day 5, and Day 14 will be summarized by treatment group.
Abnormal physical exam ination findings wi ll be presented by treatm
ent group. The
number and percent of subjects experiencing each abnormal physical examination finding
will be included.
Concomitant medications will be co ded using the WHO dictionary. The se data will be
summarized by treatment group.
Subject disposition will be presented for a
ll s ubjects. The num ber of subjects who
completed the study and discontinued from the study will be provided. The reasons for
early discontinuation also will be presented.
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12.8 Sub-Study and Pharmacokinetic Analysis
The sub-study to exam ine exposure respons e, along with the corresponding single PK
samples collected on all subjects on study day
3 will be co mpleted as part of the sub-
study. All s tatistical m ethods will be outlin ed as part of the sub-stu
dy protocol and
exposure-response analysis plan. All sub-study analyses will be reported in a separate
sub-study report.
12.9 General Issues for Statistical Analysis
12.9.1 Multiple Comparisons and Multiplicity
In order to m aintain the overall typ e I e rror in the presen ce of the plann ed comparisons
between the two peram
ivir treatm ents and pl acebo, a Bonferroni correction will be
applied to the prim ary efficacy end point an alysis. No oth er ad justments for m ultiple
comparisons are planned.
12.9.2 Covariates
Primary and secondary efficacy analyses will
be adjusted for RAT result at screen ing,
current smoking behavior and influenza season at randomization (if necessary).
12.9.3 Planned Sub-Groups
The prim ary efficacy endpoint will be summ
arized separately by stratification group
(current sm oking behavior [sm oker or non-smoker] and RAT result at screening
[negative or positive]) and by viral subtype using descriptive statistics by treatment group
and study day, if appropriate. No formal statistical testing will be utilized.
Additional analyses m ay be perform ed by count ry, if necessary, for subm ission to local
regulatory authorities.
12.9.4 Missing Data
Every effort will be m ade to obtain required data at each s cheduled evaluation from all
subjects who have been random ized. No attemp t will be m ade retrospectively to obtain
missing subject reported data (including in
fluenza symptom severity assessm
ents,
temperature, ability to perf orm usual activi ties, m issed days of work and im
pact of
influenza on subject’s work perform
ance and/or productivity)
that has not been
completed by the subject at the time of return of the subject diary to the investigative site.
In situations where it is not possible to obt ain all da ta, it m ay be necessary to im pute
missing data.
In assessing the p rimary efficacy endpoint, fo r subjects w ho withdraw or who d o no t
experience allev iation of sym ptoms, m issing data will be
censored using the date of
subject’s last non-m issing assessment of infl uenza symptoms. Missing assessm ents of
influenza symptoms conservatively will be im puted as h aving severity above absen t or
mild (as f ailures). For the subjec t diary data, the f ollowing data con ventions will be
utilized. Missing diary com pletion will be imputed as 11:59 for diary entries designated
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as m orning and 23:59 for evening and daily
reported v alues. Entr ies with va lues
exceeding the 24-hour clock will b e set to 23:59 of the day recorded. Select explo ratory
sensitivity analyses m ay be conducted to ascert ain the effect, if any, of these m
ethods.
These sensitivity analy ses are further de
scribed in the SAP. Secondary efficacy
endpoints with tim e to event da ta will be censored using the date of subject’s last non-
missing assessment of the given endpoint.
13 STUDY ADMINISTRATION
13.1 Regulatory and Ethical Considerations
13.1.1 Regulatory Authority Approvals
This study will be conducted in
com pliance with th e protoco l; GCPs, including
International Conference on Harmonization (ICH) of Te
chnical Requirem ents for
Registration of Pharm
aceuticals for Hu
man Use G
uidelines; FDA regulatory
requirements and in accordance with the ethical principles of the Declaration of Helsinki.
In addition, all applicable loca l laws and regu latory requirements relevant to the use of
new therapeutic agents in the countries involved will be adhered to.
The Investigator should submit written reports of clinical study status to their Institutional
Review Board (IRB)/ Independent E thics Committee (IEC) annually or more frequently
if requested by the IRB/ IEC. A final s
tudy notification will also be forwarded to the
IRB/IEC af ter the study is com pleted or in the event of
prem ature ter mination of the
study in accordance with the appl icable regulations. Copies of all contact with the IRB/
IEC should be m aintained in the study docum ents file. Copies of clinical study status
reports (including termination) should be provided to BioCryst.
13.1.2 Ethics Committee Approvals
Before initiation of the study at each invest
igational site, the pr otocol, the inform ed
consent form, the subject inform ation sheet, and any other relevant study documentation
will be sub mitted to th e appropriate IRB/IE C. W ritten approval of th e study m ust be
obtained before the study center can be initiated or the investigational medicinal product
is re leased to the Inv
estigator. A ny necessa ry extension s or renew als of IRB/IEC
approval must be obtained, in particular, for changes to the study such as modification of
the pro tocol, the inf ormed consent f orm, th e written inform ation provided to subjects
and/or other procedures.
The Investigator will report promptly to
the IRB/IEC any new inform
ation that m ay
adversely affect the safety of the subjects or the conduct of the study. On completion of
the study, the Investigator will prov ide the IRB/IEC with a report of the outcom e of the
study.
13.1.3 Subject Informed Consent
Signed info rmed consent m ust be obtained from each subject p rior to performing any
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study-related procedures. E
ach subject should be given both verbal and w
ritten
information describing the nature and durati
on of the clinical st
udy. The inf ormed
consent process should take place u nder conditions where the subject h as adequate time
to consider the risks and bene
fits associated with his/her
participation in the study.
Subjects will not be screened or treated
until the subjec t has signed an approved ICF
written in a language in which the subject is fluent.
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.
The informed consent should be in acco
rdance with the curren
t revision o f the
Declaration of Helsinki, current ICH and GCP guidelines, and BioCryst policy.
The Investigator must explain to potential subjects or their legal representatives the aims,
methods, reasonably anticipated benefits, a
nd potential hazards of the trial and any
discomfort it may entail. Subjects will be informed that they are free not to participate in
the trial and that they may withdraw consent to participate at any time. They will be told
that refusal to participate in the study will not prejudice future treatment. They will a lso
be told tha t their recor ds m ay be exam ined by com petent autho rities and au thorized
persons but that pe rsonal information will be tr eated as strictly confidential and will not
be publicly available. Subjects must be given the opportunity to ask questions. After this
explanation and before entry in to the trial, consent should be appropriately recorded by
means of the subject’s dated signature. The subject shoul d receive a signed and dated
copy of the ICF. The original signed infor med consent should be retained in the study
files. The Investigator shall maintain a log of all subjects who sign the ICF and indicate
if the subject was enrolled into the study or reason for non-enrollment.
13.1.4 Payment to Subjects
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC
responsible for the study at the Investigator’s site.
13.1.5 Investigator Reporting Requirements
The Investigator will provide tim ely repo rts regard ing s afety to his /her IRB/IE C as
required.
13.2 Study Monitoring
During trial conduct, BioCryst or its designee will conduct period ic monitoring visits to
ensure that the protocol and GCPs a re being followed. The monitors may review source
documents to conf irm that th e data recorded on CRFs is accurate. The investigator and
institution will allow BioCryst m
onitors or its des ignees and app ropriate regulatory
authorities direct access to source documents to perform this verification.
13.3 Quality Assurance
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits
performed by BioCryst, and/or to inspection by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the
monitoring visits and possible a udits or inspections and that sufficient tim e is devoted to
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the process.
13.4 Study Termination and Site Closure
BioCryst reserves the right to
disc ontinue the tr ial prio r to inc lusion of the in tended
number of subjects but intends only to exer
cise this r ight f or valid scientif ic or
administrative reasons. After such a deci
sion, the Investigator must contact all
participating subjects immediately after notification. As directed by BioCryst, all study
materials must be collected a nd all case report forms completed to the greatest extent
possible.
13.5 Records Retention
To enable evaluations and/or
audits from
regulatory au
thorities o r BioCryst, the
Investigator agrees to k eep records, includi ng the iden tity of all p articipating sub jects
(sufficient inf ormation to link re
cords, case report forms and hospital records), all
original signed inform ed consent form s, copies of all case report form
s and detailed
records of treatm ent disposition. The reco
rds should be retained by the Investigator
according to local regulations or as specified in the Clinical Trial Agreem ent, whichever
is longer.
If the Investigator relocates, retires, or for any reason withdraws from the study, the study
records m ay be transferred to an
acceptab le designee, such as another investigato
r,
another institution, or to BioCryst. The I
nvestigator m ust obtain BioCryst’s written
permission before disposing of any records.
13.6 Study Organization
13.6.1 Data Monitoring Committee
BioCryst will a ssemble an indep endent Data M onitoring C ommittee ( DMC) to as sess
safety parameters of the trial on a period ic, ongoing basis while the tr ial is in prog ress.
The comm ittee will include a s tatistician and th ree phys icians, tw o of whom will be
Infectious Disease specialists. Full detail s of the com position of the D MC and how the
DMC is to operate will be described in a separate DMC charter.
13.7 Confidentiality of Information
BioCryst affirms the subject’s right to prot ection against invasion of privacy. Only a
subject id entification n umber, initials and /or date of birth will id
entify subject data
retrieved by BioCryst . However, in com pliance with federal regulations, BioCryst
requires the investigato r to p ermit BioCryst ’s representatives and, when neces sary,
representatives of the FDA or
other regu latory authoritie s to review and/or copy any
medical records relevant to the study.
BioCryst will ensure that the use and disclosur e of protected health information obtained
during a research study com plies with the HIPAA Privacy Rule. Th e Rule pro vides
federal protection for the privacy of prot
ected health inf ormation by im plementing
standards to protec t an d guard ag ainst the m isuse of ind ividually id entifiable h ealth
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information of subj
ects participating in
BioCryst-sponsored Clinical Trials.
"Authorization" is required from each research subject, i.e., specified permission granted
by an individual to a covered entity for the us e or disclosure of an indi vidual's protected
health information. A valid au thorization must meet the implem entation specifications
under the HIPAA Pri
vacy Rule. Authorizat
ion m ay be com bined in the Inform
ed
Consent docum ent (approved by the IRB/IE
C) or it may be a separate docum
ent,
(approved by the IRB/IEC) or provided by the Investigator or Sponsor (without IRB/IEC
approval). It is the responsibility of the
investigator and institution to obtain such
waiver/authorization in writing f rom the appr opriate ind ividual. HIPAA authoriz ations
are required for U.S. sites only.
13.8 Study Publication
All data generated from this study are the propert y of BioCryst and shall be held in strict
confidence along with all inform
ation furnis hed by BioCryst. Independent analysis
and/or publication of these data by the Investigator or any member of his/her staff are not
permitted without prior written consent of
BioCryst. W ritten perm ission to the
Investigator will be contingen t on the review by BioCryst of the statistical ana lysis and
manuscript and will provide fo r nondisclosure of BioCryst confidential or proprietary
information. In all case s, the partie s agree to s ubmit all m anuscripts or abstracts to all
other par ties 30 days prior to su
bmission. This will e
nable all parties to pr
otect
proprietary information and to provide comme nts based on infor mation that may not yet
be available to other parties.
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oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000;
283(8): 1016-1024.
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of
oseltamivir in treatment of influenza: a randomised controlled trial. Lancet 2000;
355(9218): 1845-1850.
18. US Department of Health and Human Services, Food and Drug Administration
Center for Drug Evaluation and Reserach (CDER). Attachment to Guidance on
Antiviral Product Development- Conducting and Submitting Virology Studies to the
Agency: Guidance for Submitting Influenza Resistance Data.
http://www.fda.gov/cder/guidance/7070fnlFLU.htm
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15 APPENDICES
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina
NYHA Functional Classification of Heart Failure
Class I
No symptoms. Ordinary physical activity such as walking and climbing
stairs does not cause fatigue or dyspnea.
Class II
Symptoms with ordinary physical activity. W alking or climbing stairs
rapidly; walking uphill; walking or st air climbing after meals, in cold
weather, in wind, or when under em otional stress causes undue fatigue
or dyspnea.
Class III
Symptoms with less than ordinary
physical activity. W alking one to
two blocks on the level and clim bing more than one flight of stairs in
normal conditions causes undue fatigue or dyspnea.
Class IV
Symptoms at res t. Inab ility to carry on any ph ysical activity without
fatigue or dyspnea.
NYHA Functional Classification of Angina
Class I
Angina only with unusually strenuous activity.
Class II
Angina with slightly m ore prolonged or slightly more vigorous activity
than usual.
Class III
Angina with usual daily activity.
Class IV
Angina at rest.
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CLINICAL STUDY PROTOCOL
Protocol No. BCX1812-311
IND No. 76,350
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE
INFLUENZA
THE IMPROVE 1 STUDY
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy)
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza
Protocol Date: Version1.0: 04 September 2007
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35244, USA
Phone: +1 919 859 1302
Fax: +1 919 851 1416
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals,
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information
contained herein should be disclosed without prior written approval.
CONFIDENTIAL
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1 TITLE PAGE
Protocol Number:
BCX1812-311
Study Title:
A phase 3 m
ulticenter, random ized, double-blind,
placebo-controlled s tudy to evaluate th e effic acy and
safety of intram uscular peram ivir in subjec
ts with
uncomplicated acute influenza
IND Number:
76, 350
Investigational Product:
Peramivir (BCX1812)
Indication Studied:
Uncomplicated acute influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35233
Development Phase:
3
Sponsor Medical
Officer:
W. James Alexander, M.D., M.P.H.
Senior Vice President, Clinical Development
Chief Medical Officer
Phone: +1 919 859 1302
Fax: +1 919 851 1416
Email Address: jalexander@biocryst.com
Compliance Statement:
This study will be conducted in accordance with the
ethical principles that have their origin in the
Declaration of Helsinki and clinical research guidelines
established by the Code of Federal Regulations (Title
21, CFR Parts 50, 56, and 312) and ICH Guidelines.
Essential study documents will be archived in
accordance with applicable regulations.
Final Protocol Date:
Version 1.0: 04 September 2007
Amendment(s) Date(s):
None
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1.2
Clinical Study Protocol Agreement
Protocol No.
BCX1812-311
Protocol Title:
A phase 3 m
ulticenter, random ized, double-blind, placebo-
controlled study to evaluate the efficacy and safety
of
intramuscular peram ivir in subj ects with uncom plicated acute
influenza
I have caref ully read th is protoco l and agree that it contains all of the necessary
information required to conduct this study. I agree to conduct this study as
described and according to the Declaration of Helsinki, International Conference on
Harmonization Guidelines for Good Clinical Practices, and all applicable regulatory
requirements.
Investigator’s Signature
Date
Name (Print)
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2 SYNOPSIS
Protocol No.
BCX1812-311
Protocol Title:
A Phase 3, Multicenter, Random
ized, Double-Blind,
Placebo-Controlled Stu dy to Evaluate the Efficacy an
d
Safety of Intram
uscular Peram ivir in Subjects with
Uncomplicated Acute Influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
Investigators/Study
Sites:
Multinational
Development Phase:
3
Objectives:
Primary:
To evaluate the efficacy of peram
ivir adm inistered
intramuscularly com pared to p
lacebo on th
e tim e to
alleviation of clinica l sym ptoms in adult sub
jects with
uncomplicated acute influenza.
Secondary:
1. To evalua te the saf ety and tolera bility of pe ramivir
administered intramuscularly;
2. To evaluate seconda ry clinical outcom es in response to
treatment;
3. To evaluate changes in in
fluenza virus titer (viral
shedding) in response to treatment;
4. To assess p harmacoeconomic m easures in resp onse to
treatment
5. To assess c hanges in inf luenza vir al suscep tibility to
neuraminidase inhibitors following treatment
Number of Subjects:
Total enrollm ent: up t o 800 subjects random
ized (160
subjects in the placebo treatment group, 320 subjects in the
peramivir 150mg treatment group and 320 subjects in the
peramivir 300m g treatm ent group). The study will close
after enrollment of at least 500 subjects who have either a
positive Influenza A or B antigen te st (Rapid Antigen Test
– RAT) at screening, or who ha
ve a negative RAT at
screening but a positive influenza A or B PCR a ssay result
from a baseline nasopharyngeal swab.
Study Design:
This is a multinational, random
ized, double-blind study
comparing the efficacy and safety of two single dos
e
regimens of peramivir administered intramuscularly versus
placebo in adults with uncom
plicated acute influenza.
Each subjec t’s ass ignment to trea tment will be stra tified
according to the Rapid Antigen Test (RAT) result at
screening and current sm
oking be havior, with 80% of
subjects ce ntrally rand omized to one of
the two activ
e
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single dose regimens of peramivir (2:2:1 randomization)
Treatment Group 1: Peramivir 150mg
Treatment Group 2: Peramivir 300mg
Treatment Group 3: Placebo
Enrollment of subjects into the RAT negative s tratum will
be permitted at individual sites that have identified 3 RAT
positive su bjects a t s creening within a 10 d ay per iod,
indicating activity of influenza in the site ’s vicinity. After
identification of 3 RAT positive subjects within 10 days, a
site m ay enroll 1 RAT negative s
ubject tha t f ulfills the
inclusion/ exclusion criteria. One additional RAT negative
subject may be enrolled thereafter for each preceding RAT
positive subject that is identified.
Study drug will be adm inistered as one 2mL intramuscular
injection in each glu teal muscle (total of 4m L injected in
divided doses).
Subjects eligible for s creening will have an anterior nasal
or pharyngeal swab collected
for t esting by RAT for
influenza A and B, in accordan ce with the co mmercially
available RAT kit instructi
ons. I f the in itial RAT is
negative, th e te st shou ld be repeated with a differen
t
commercially availab le RAT kit. Subjects m
eeting the
inclusion/ exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following in a Study
Diary:
• Oral temperature measurements taken with an electronic
thermometer every 12 hours. W ith the exception of the
baseline m easurement, all tem perature m easurements
will be ob tained at least 4 hours after, or imm ediately
before, adm
inistration of oral acetaminophen
(paracetamol), aspirin, ibuprofen or other NSAID.
• Assessment of severity of each of s even sym ptoms of
influenza on a 4-point scale (0, absent; 1, m
ild; 2,
moderate; 3, severe) twice daily (AM, PM) through Day
9 following treatm ent, then once daily (AM) through
Day 14
• Assessment of subjec t’s ability to p
erform usual
activities, (rated as 0–10 on a visual analog scale) once
daily through Day 14
• Assessment of subject’s tim e lost from work or usual
activities and productivity compared to normal (rated as
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0-10 on a visual analog scal e) once daily through Day
14
• Doses of antipyretic, expe
ctorant, and/ or t hroat
lozenges taken for symptomatic relief each day through
Day 14
Anterior nose (bilateral) and posterior pharynx specim ens
(swabs) will be collected at Day 1 (pre-treatm
ent) and at
Days 3, 5, and 9, for quantitative virologic assessments. In
a subset of a m inimum of 200 subjects, an additional
virology sample will b e co llected on day 2. Specim
ens
from all subjects yielding influenza virus will also be
assessed for susceptibility to neuraminidase inhibitors (Day
1 and last specimen yielding positive result).
All virolog ic ass essments will b e p erformed by a c entral
laboratory.
At the study day 3 visit, when all subjects are evaluated for
safety and a blood draw is com
pleted for clinical
laboratory investigations, a single pharm
acokinetic (PK)
sample will also be drawn. This sin gle PK sam ple will b e
analyzed for plasm a concentrations of peram ivir (ng/mL)
and evaluated in an exposure response analysis.
At selected sites a separate sub-s tudy will be conducted to
collect limited PK sam ples for the purpose of conducting
an exposure-respons e analysis. T
his sub-stud y will be
conducted under a separate protocol, BCX1812-311PK.
Study Population:
Male and fem ale subjects, 18 y ears of age and older, with
symptoms consisten t with a diagnosis of uncomplicated
acute influenza infectio n may be screened for e nrollment.
Subject eligibility will be dependent on the presence of two
or more symptoms consistent with acute inf luenza as well
as the results obtained f rom a rapid antigen test (RAT) for
influenza A and B at screening.
Inclusion Criteria:
1. Male and non-pregnant female subjects age ≥18 years
2. A positive Influenza A or B Rapid Antigen Test (RAT)
performed with a commercially available test kit on an
adequate specimen collected from an anterior nasal or
pharyngeal swab, in accordance with the
manufacturer’s instructions. A negative initial RAT
should be repeated with a different commercially
available RAT kit. A limited number of RAT negative
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subjects may be enrolled in accordance with a defined
screening algorithm.
3. Presence of fever at time of screening of ≥38.0 ºC
(≥100.4 ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken
rectally. For subjects with a positive RAT at the time of
screening, a subject self-report of a history of fever or
feverishness within the 24 hours prior to screening will
also qualify for enrollment in the absence of
documented fever at time of screening. For subjects
with no positive RAT at screening, fever as defined
above must be documented at time of screening
4. Presence of at least one respiratory symptom (cough,
sore throat, or nasal symptoms) of any severity (mild,
moderate, or severe)
5. Presence of at least one constitutional symptom
(myalgia [muscle aches], headache, feverishness, or
fatigue) of any severity (mild, moderate, or severe)
6. Onset of symptoms no more than 48 hours before
presentation for screening
7. Written informed consent
Exclusion Criteria:
1. Women who are pregnant or breast-feeding
2. Presence of clinically significant signs of acute
respiratory distress
3. History of severe chronic obstructive pulmonary
disease (COPD) or severe persistent asthma
4. History of congestive heart failure requiring daily
pharmacotherapy with symptoms consistent with New
York Heart Association Class IV functional status
within the past 12 months
5. Screening ECG which suggests acute ischemia or
presence of medically significant dysrhythmia.
6. History of chronic renal impairment requiring
hemodialysis and/or known or suspected to have
moderate or severe renal impairment (actual or
estimated creatinine clearance <50 mL/min)
7. Current clinical evidence of active bacterial infection at
any body site that requires therapy with oral or
systemic antibiotics
8. Presence of immunocompromised status due to chronic
illness, previous organ transplant, or use of
immunosuppressive medical therapy
9. Current treatment for active viral hepatitis C
10. Presence of known HIV infection with a CD4 count
<350 cell/mm3
11. Current therapy with oral warfarin or other systemic
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anticoagulant
12. Receipt of any doses of rimantadine, amantadine,
zanamivir, or oseltamivir in the 7 days prior to
screening
13. Immunized against influenza with live attenuated virus
vaccine (FluMist®) in the previous 21 days
14. History of alcohol abuse or drug addiction within 1
year prior to admission in the study
15. Participation in a previous study of peramivir as
treatment for acute influenza or previous participation
in this study
16. Participation in a study of any investigational drug
within the last 30 days
Study Endpoints:
Primary Endpoint:
Clinical:
Time to alleviation of clinical symptoms of influenza
Secondary
Endpoint(s):
Safety
Incidence of treatm
ent-emergent adverse events and
treatment-emergent changes in clinical laboratory tests
Clinical:
Time to resum ption of subjec t’s ab ility to perf orm usual
activities
Time to resolution of fever
Incidence of influenza related complications
Virologic:
Quantitative change in influenza virus shedding, measured
by viral titer assay (TCID
50) and/or by quantitative
polymerase chain reaction (PCR) assay
Pharmacoeconomic:
Medical resource utilization (M RU), missed days of work,
and im pact of inf
luenza illn ess on subject’s work
performance and/or productivity.
Exploratory
Endpoint:
Viral Susceptibility:
Change in influenza virus susceptibility to neu raminidase
inhibitors
Investigational Product,
Dose, and Mode of
Administration:
Peramivir (BCX-1812), 75m g/mL or placebo (buffered
diluent), 2mL per injection, ad ministered intramuscularly
in the gluteal muscle, bilaterally.
Duration of Treatment:
Following treatment on day 1, study duration for individual
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subjects is expected to be up to 14 days (including all
visits).
Statistical Methods:
Descriptive statistical methods will be used to summ arize
the data from this study, with statistical testing utilized for
the p rimary and secondary efficacy endpoints. Unless
otherwise n oted, a ll s tatistical testing will be two-sided,
and will be performed using a significance (alpha) level of
0.05. For assessment of the prim ary efficacy endpoint, th e
overall sig nificance level
will be m
aintained by a
Bonferroni adjustm ent fo r the planned com
parisons
between the two active trea
tment groups and placebo.
Detailed sta tistical pro cedures will be provided in a f ull
statistical analysis plan (SAP) completed prior to database
lock and study unblinding.
Sample Size:
From previous studies of neuram
inidase treatm ent of
uncomplicated influenza it is expected that the median time
to alleviation of symptoms will be 103.3 hours for subjects
receiving placebo. Addition ally, it is expected that the
median time to alleviation for the low dose peram ivir arm
will be 69.9 hours, yielding a hazard ratio of 0. 68. Using
these assumptions, a sample si ze of 200 influenza-infected
subjects per active treatm
ent group and 100 infected
subjects in the placebo group (a total of 500 influenza-
infected su bjects) is s ufficient to provide at least 80%
power to detect a hazard ratio of 0.68 using a log-rank
statistic and α = 0.025 (SAS version 9.1.3; total accrual
time 7 months; total enrollment time 6 months). Up to 800
subjects will be enrolled to ach ieve the target number of at
least 500 subjects with diagnostic evidence (R AT or PCR)
of an acute influenza infection.
Efficacy:
The intent-to-treat infected population will include all
subjects who are random ized, received study drug, and
have proven influenza by any one of the following:
primary viral culture, PCR, or paired serology showing ≥
4-fold increase in antibody to
influenza A or B. The
primary efficacy v ariable is th e tim e to alleviation of
symptoms, defined as the time from injection of study drug
to the start of the tim
e period when each
of seven
symptoms of influenza are either absent or are present at
no more than mild severity level and remain at no worse
than this severity status for a 24 hour period.
Descriptive statistics for the primary efficacy variable will
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be tabulated by treatm ent group. Alleviation of sym ptoms
will be determined by assessment of symptoms as reported
on each su bject’s diary card. Tim
e to alle viation of
symptoms will b e sum marized for each treatm ent group.
Treatment dif ference will be
as sessed us ing a Cox
Regression model with effects for RAT result at screening,
current smoking behavior, tr eatment group, and influenza
season at random ization. Pa irwise com parisons between
each active group and placebo will be constructed from the
Cox Regression m odel. Subj ects who do not experience
alleviation of sym ptoms will be c ensored a t the date of
their last non-m issing assessment. Tim e to resum ption of
usual activities and tim
e to resolution of
f ever will be
analyzed in a similar manner.
Changes in viral titer s will be compared using the van
Elteren sta tistic con trolling f or RAT result at screen
ing,
current smoking behavior
and influenza season at
randomization. Analyses of other continuous endpoints
will be analyzed in a similar manner.
Safety:
Safety analyses will b e presen ted f or all sub jects in the
safety population, defined as all randomized subjects who
receive at least one dose of study drug. Adverse events
will be m apped to a Medica l Dictiona ry f or Regulatory
Activities (MedDRA) preferred term
and system organ
classification.
The occurrence of treatm
ent-emergent AEs will be
summarized using preferre
d term
s, system organ
classifications, and severit
y. Separate summ
aries of
treatment-emergent SAEs and treatm
ent-emergent AEs
that are related to study m edication will be generated. All
AEs will be listed f
or individua l subjec ts sho wing both
verbatim and preferred terms.
Descriptive summaries of vital signs and quantitative
clinical laboratory changes will be presented by study visit.
Frequency and percentages
of subjects with abnorm
al
laboratory test r esults will be su mmarized b y toxic ity
grade.
Concomitant m edications w ill be m
apped to a W
HO
preferred term and drug classification. The num
ber and
percent of subjects taking concomitant medications will be
summarized using preferred terms and drug classifications.
The num ber and percent of subjects experiencing each
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abnormal physical examination finding will be presented.
The number and percent of s ubjects discontinuing study as
well as the reasons for discontinuation will be summarized
by treatment group.
Protocol Date
Version 1.0: 04 September 2007
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3 TABLE OF CONTENTS
1
TITLE PAGE...................................................................................................... 2
1.1
PROTOCOL APPROVAL SIGNATURE PAGE............................................................. 3
1.2
CLINICAL STUDY PROTOCOL AGREEMENT .......................................................... 4
2
SYNOPSIS.......................................................................................................... 5
3
TABLE OF CONTENTS.................................................................................. 13
3.1
LIST OF FIGURES................................................................................................ 15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................... 16
5
INTRODUCTION ............................................................................................ 18
5.1
BACKGROUND.................................................................................................... 18
5.2
RATIONALE FOR STUDY..................................................................................... 18
5.3
NON-CLINICAL EXPERIENCE WITH PERAMIVIR.................................................. 19
5.3.1 In vitro Assays .............................................................................................. 19
5.3.2 Animal Models.............................................................................................. 20
5.4
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR.................. 20
5.5
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR................ 21
5.6 DOSE RATIONALE .................................................................................................... 22
6
STUDY OBJECTIVES..................................................................................... 23
6.1
OBJECTIVES ....................................................................................................... 23
6.1.1 Primary Objective......................................................................................... 23
6.1.2 Secondary Objective(s)................................................................................. 23
6.2
STUDY ENDPOINTS............................................................................................. 23
6.2.1 Primary Endpoint.......................................................................................... 23
6.2.2 Secondary Endpoint(s).................................................................................. 23
6.2.3 Exploratory Endpoint.................................................................................... 23
7
STUDY DESIGN ............................................................................................. 24
7.1
OVERALL STUDY DESIGN AND PLAN ................................................................. 24
8
SELECTION AND WITHDRAWAL OF SUBJECTS.................................... 25
8.1.1 Inclusion Criteria .......................................................................................... 25
8.1.2 Exclusion Criteria ......................................................................................... 26
8.1.3 Removal of Subjects from Therapy or Assessment...................................... 27
9
TREATMENTS................................................................................................ 28
9.1
TREATMENTS ADMINISTERED............................................................................ 28
9.2
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .................................................... 28
9.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................. 28
9.4
STUDY MEDICATION ACCOUNTABILITY............................................................. 29
9.5
BLINDING/UNBLINDING OF TREATMENTS.......................................................... 29
9.6
PRIOR AND CONCOMITANT THERAPIES.............................................................. 29
9.7
OVERDOSE AND TOXICITY MANAGEMENT......................................................... 29
9.8
DOSE INTERRUPTION.......................................................................................... 29
10
STUDY CONDUCT......................................................................................... 30
10.1
EVALUATIONS.................................................................................................... 30
10.1.1
Medical History ........................................................................................ 30
10.1.2
Rapid Antigen Test for Influenza ............................................................. 30
10.1.3
Physical Examination and Influenza-related Complications Assessments30
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10.1.4
Vital Signs................................................................................................. 31
10.1.5
Electrocardiogram Measurements ............................................................ 31
10.1.6
Clinical Chemistry Profiles....................................................................... 31
10.1.7
Hematology Profiles ................................................................................. 31
10.1.8
Serology for Influenza .............................................................................. 31
10.1.9
Urinalysis and Evaluation of Protein in Urine.......................................... 31
10.1.10 Urine Pregnancy Test................................................................................ 32
10.1.11 Samples for Virologic Laboratory Assessments....................................... 32
10.1.12 Subject Self Assessments.......................................................................... 32
10.1.13 Concomitant Medications......................................................................... 33
10.1.14 Adverse Events ......................................................................................... 33
10.1.15 Single Pharmacokinetic Exposure Sample ............................................... 33
10.2
SCREENING ........................................................................................................ 33
10.2.1
Informed Consent...................................................................................... 33
10.2.2
Screening/Baseline Evaluation and Enrollment........................................ 33
10.3
TREATMENT PERIOD—STUDY DAY 1................................................................ 34
10.3.1
Pre-dose Evaluations................................................................................. 34
10.4
POST-TREATMENT ASSESSMENT PERIOD........................................................... 34
10.4.1
Days 2, 3, 5, 9 and 14................................................................................ 34
10.4.2
Adverse Events Reported at Post-treatment Visits................................... 35
11
ADVERSE EVENT MANAGEMENT............................................................ 38
11.1
DEFINITIONS ...................................................................................................... 38
11.1.1
Adverse Event........................................................................................... 38
11.1.2
Serious Adverse Event.............................................................................. 38
11.2
METHOD, FREQUENCY, AND TIME PERIOD F OR DETECTING ADVERSE EVENTS
AND REPORTING SERIOUS ADVERSE EVENTS..................................................... 39
11.2.1
Definition of Severity ............................................................................... 39
11.2.2
Definition of Relationship to Study Drug................................................. 39
11.2.3
Reporting Serious Adverse Events ........................................................... 40
11.2.4
Emergency Procedures.............................................................................. 41
12
STATISTICAL METHODS............................................................................. 41
12.1
DATA COLLECTION METHODS........................................................................... 41
12.2
STATISTICAL ANALYSIS PLAN ........................................................................... 42
12.3
SAMPLE SIZE ESTIMATES................................................................................... 42
12.4
ANALYSIS POPULATIONS ................................................................................... 42
12.4.1
Intent-To-Treat Population ....................................................................... 42
12.4.2
Intent-To-Treat Infected Population ......................................................... 42
12.4.3
Safety Population...................................................................................... 43
12.5
INTERIM AND END OF STUDY ANALYSES........................................................... 43
12.6
EFFICACY ANALYSES......................................................................................... 43
12.6.1
Primary Efficacy Endpoint ....................................................................... 43
12.6.2
Secondary Efficacy Endpoints.................................................................. 44
12.6.3
Exploratory Endpoint................................................................................ 45
12.7
SAFETY ANALYSES ............................................................................................ 45
12.8
SUB-STUDY AND PHARMACOKINETIC ANALYSIS............................................... 46
12.9
GENERAL ISSUES FOR STATISTICAL ANALYSIS .................................................. 46
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12.9.1
Multiple Comparisons and Multiplicity.................................................... 46
12.9.2
Covariates ................................................................................................. 46
12.9.3
Planned Sub-Groups ................................................................................. 46
12.9.4
Missing Data............................................................................................. 46
13
STUDY ADMINISTRATION ......................................................................... 47
13.1
REGULATORY AND ETHICAL CONSIDERATIONS ................................................. 47
13.1.1
Regulatory Authority Approvals............................................................... 47
13.1.2
Ethics Committee Approvals.................................................................... 47
13.1.3
Subject Informed Consent......................................................................... 47
13.1.4
Payment to Subjects.................................................................................. 48
13.1.5
Investigator Reporting Requirements ....................................................... 48
13.2
STUDY MONITORING.......................................................................................... 48
13.3
QUALITY ASSURANCE........................................................................................ 48
13.4
STUDY TERMINATION AND SITE CLOSURE......................................................... 49
13.5
RECORDS RETENTION ........................................................................................ 49
13.6
STUDY ORGANIZATION...................................................................................... 49
13.6.1
Data Monitoring Committee..................................................................... 49
13.7
CONFIDENTIALITY OF INFORMATION ................................................................. 49
13.8
STUDY PUBLICATION ......................................................................................... 50
14
REFERENCES ................................................................................................. 51
15
APPENDICES .................................................................................................. 53
15.1
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA
.......................................................................................................................... 53
3.1
List of Figures
Figure 1
Study Measurements and Visit Schedule...................................................... 37
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0–72
area under the curve from time 0 to 72 hours
AUC0–∞
area under the curve extrapolated from time 0 to infinity
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
Cmax
maximum plasma concentration
CK
creatine kinase
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CRF
Case Report Form
CV
coefficient of variation
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
IC50
median inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRC
influenza related complications
ITT
intent-to-treat
ITTI
intent-to-treat infected
IUD
intrauterine device
IVRS
interactive voice response system
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
NSAID
non-steroidal anti-inflammatory drug
PCR
polymerase chain reaction
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RAT
Rapid Antigen Test
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
t1/2
elimination half-life
t1/2 λz
terminal half-life
TCID50
time weighted change
f rom baseline in log
10 tissue -culture
infective dose50
TEAEs
treatment-emergent adverse events
Tmax
time to attain maximum plasma concentration
UPEP
urine protein electrophoresis
WBC
white blood cell
WHO
World Health Organization
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5 INTRODUCTION
5.1
Background
Influenza v irus is a m ember of the orthomyxovirus fam ily and cau ses an acu te v iral
disease of the respiratory tract. Typical influenza illness is characterized by abrupt onset
of fever, headache, myalgia, sore throat, and nonproductive cough.1 The illness is usually
self-limiting, with relief of symptoms occurring within 5 to 7 days. Nevertheless, it is an
important disease for several reasons,
including ease of comm
unicability, short
incubation time, rapid rate of viral mutation, morbidity with resultant loss of productivity,
risk of com plicating conditions, and increased risk of death, pa rticularly in the e lderly.
During 19 of the 23 influenza seasons
between 1972/1973 a nd 1994/1995, estim ated
influenza-associated deaths in the U nited States ranged from approxim ately 25 to m ore
than 150 per 100,000 persons above 65 years of age, accounting for more than 90% of the
deaths attributed to pneumonia and influenza.2
Presently, o nly a few m easures are availab le that can red uce th e im pact of influenza:
active immunoprophylaxis with an inactivat
ed or live attenu
ated vaccine and
chemoprophylaxis or therapy with an influe nza-specific antiviral drug. Neuram inidase
inhibitors are the current m
ainstay of an tiviral treatm ent for influenza. Mark
eted
neuraminidase inhib itors inc lude zanam ivir (Relenza ®, GlaxoSm ithKline) an d
oseltamivir (Tamiflu®, Roche-Gilead) , an oral prodrug of the activ e agent, oseltamivir
carboxylate. Influenza neuram inidase is a surface glycoprotei n that cleaves sialic acid
residues from glycoproteins and glycolipids. The enzyme is responsible for the release of
new viral p articles from infected cells and
may also ass ist in the sp reading of virus
through the mucus within the respiratory tract. The neuraminidase inhibitors represent an
important advance in the treatment of influenza with respect to activity against influenza
A and B viruses, with p roven therapeutic value in reduc ing influenza lower resp iratory
complications,3 and lower rates of antiviral drug resistance4.
The use of curren tly av ailable neu raminidase inhibitors has been lim ited by concerns
including, the degree of effectiv eness, the requirement for an inhaler device (zanamivir),
and the em ergence of resistant influenza vi rus variants in som e treated populations. 5 In
addition, there are risks of bronchospasm
w ith zanam ivir; and gastrointestinal side
effects, with oseltamivir.
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to
the armamentarium of drugs for the treatment of influenza infections due to its potential
for parenteral administration and lower frequency of dosing.
5.2
Rationale for Study
An oral formulation of peram ivir has previously been evaluated in a f ull range of safety,
tolerability, pharmacokinetic, and efficacy studies. In a m ultinational phase 3 clinical
trial conducted in 1999-2001, oral peram
ivir de monstrated antiviral activity against
influenza A and B inf
ections, and im provement in the r
elief of clin ical sym ptoms.
Because of the lim ited bioavailability of peramivir following oral administration (<5%),
it was de termined that the paren teral route of administration is m ore appropriate for the
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delivery of peram ivir. Subsequent phase
1 studies of intrave nous and intram uscular
formulations of peram ivir have confirm ed that parenteral routes of administration result
in plasma levels of drug that are as much as 100 times those achieved via the oral route.
Further details of these studies are provided below and in the Investigator Brochure.
A phase 2 random
ized, double blind, placeb
o controlled study of two single dose
regimens (150mg or 300m g) of intram uscular peramivir in subjects with uncom plicated
acute influenza infections (study B CX1812-211) was initiated in early 2007 in North
America and the UK. The study has been extended to sites in Hong Kong, Australia, New
Zealand and South Africa and is expected
to complete enrollment in m id-2007. At a
scheduled meeting on 21 May 2007, an independ ent data monitoring committee for this
study com pleted a blinded revi ew of all reported adverse
events and grade 3 and 4
clinical laboratory evaluations from the first 135 subjects random ized. Following this
blinded saf ety review the DMC provided
a written reco mmendation that the s
tudy
continue as planned.
Because of the previo
us dem onstration of significant an tiviral activ ity, th e strong
suggestion of clinical efficacy of oral pe
ramivir previously dem onstrated in acute
influenza, and the encouraging pharm
acokinetic and prelim inary safety profile of the
intramuscular formulation of pera mivir demonstrated to date, this phas e 3 study will be
conducted to evaluate the efficacy and safety profile of intram
uscular peramivir and to
determine the optimal single dose regimen.
5.3
Non-Clinical Experience with Peramivir
5.3.1 In vitro Assays
Peramivir is a selective inhibitor of vi
ral neuram inidase, with 50% inhibitory
concentrations (IC50) for bacterial and m ammalian enzymes of >300µM. 6 In an in vitro
study, 42 influenza A and 23 influenza B isolates were collected from untreated subjects
during the 1999–2000 influenza season in Canada.
7 These isolates were tested for their
susceptibility to the neuram inidase inhib itors zanam ivir, oseltam ivir carboxylate, and
peramivir using a chem
iluminescent neuram inidase assay. Inhibition of Type A
influenza neuraminidase by peram ivir was appr oximately an order of m agnitude greater
than inhibition of neuram inidase from Type B viruses. IC
50 values for the Type A
enzymes ranged from <0.1 to 1.4nM, whereas the Type B enzym es ranged from <0.1 to
11nM, with three out of four values in the
5- to 11nM range. Peram ivir was the most
potent drug against influenza A (H 3N2) viruses with a m ean IC50 of 0.60nM as well as
most potent against influenza B with a mean IC50 of 0.87nM.
In another in vitro comparison of peram
ivir, oseltam ivir, and zanam ivir, using a
neuraminidase inhibition assay with influenza A viruses, the m
edian IC 50 of pera mivir
(approximately 0.34nM) was com
parable to that of
oseltam ivir (0.45nM) and
significantly lower than zanam ivir (0.95nM). F or influenza B virus clinical isolates, the
IC50 of peramivir (1.36nM) was comparable to that of zanamivir (2.7nM) and lower than
that of oseltamivir (8.5nM).8
The potency of peram
ivir was evaluated ag
ainst five zanam ivir-resistant an d six
oseltamivir-resistant influenza viruses.9 Peramivir remained a potent inhibitor against all
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oseltamivir-resistant viruses includi ng the m utations H274Y, R292K, E119V, and
D198N, with IC 50 values ≤40nM. Peram ivir also potently inhibited (IC 50 ≤ 26nM) the
neuraminidase activity of zanamivir-resistant strains, which had the following mutations:
R292K, E119G, E119A, and E119D. Howeve
r, one zanam ivir-resistant influenza B
virus, B/Mem /96, with a m utation R152K isol ated from cell cultur e, was relatively
resistant to all neuraminidase inhibitors, including peramivir (IC50 = 400nM).
5.3.2 Animal Models
In a m ouse model of influen za infection, a single intram uscular injection of pera mivir
(10mg/kg) given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain
resulted in 100% survival in contrast to 100% mortality in a control group injected with
saline.6 In the sam e mouse m odel, treatm ent of m ice up to 72 hours after influenza
infection using peram ivir (20m g/kg) result ed in 100% survival, compared to 100%
mortality in the control group injected with vehicle.10
Peramivir has also dem onstrated activity in animal models utilizing a clinical H5 N1
isolate as th e infecting virus strain. In a mouse model, a single intramuscular dose of
peramivir (30mg/kg) injected 1 hour after inoculation with the highly pathogenic (H5N1)
A/Vietnam/1203/04 strain, resulted in a 70% survival rate that wa s similar to that seen in
mice treated with oseltam ivir given orally at 10m g/kg/day for 5 days
11. In s imilar
experiments, mice inoculated with the sam e strain of H5N1 virus tha t were then trea ted
for up to 8 days with intram
uscular peramivir exhibited 100% survival 12. This longer
duration of peram ivir treatment also prevented viral replic ation in the lungs, brain and
spleen at days 3, 6 and 9 post inoculation.
5.4
Previous Phase 3 Clinical Experience with Oral Peramivir
An oral formulation of peram
ivir has prev iously dem onstrated an tiviral activity and
preliminary clinical efficacy in ch
allenge studies in hum an volunteers, as well as in
treatment studies in patients with u ncomplicated acute inf luenza inf ections dur ing the
influenza seasons of 1999-2001. A Phase 3
multinational study (B C-01-03) of oral
peramivir was conducted. Two dos e regimens of oral peramivir, 800mg QD for 5 days,
or 800mg QD on Day 1, followed by 400mg QD for 4 days, were compared to a matched
placebo treatment group. A total of 1246 subjects were randomized to treatment at sites
in the USA, W estern and Eastern Europe, S outh America, Australia and New Zealand.
As presente d in the tab le below, th e prim ary end-point of tim e to relief of influenza
symptoms was not found to be significantly
different (p=0.17) between the three
treatment groups.13 A sub-group analysis of the time to relief of symptoms by country or
region demonstrated marked differences in
the prim ary endpoint.. In the subset of
influenza-infected subjects enrolled at sites in the US, clinically m eaningful differences
in time to relief of influenza symptoms between the placebo and the two peram ivir arms
were observed, that just m issed statistical significance (p=0.07). However, a num ber of
secondary end-points in this phase 3 study, such as tim e to overall well-being, time to
normal activity, incidence of infl
uenza rela ted com plications and quantity of viral
shedding, reached o
r approach ed statistically significant differenced between
the
peramivir and placebo treatment groups (p=0.03-0.06).
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Results of Study BC-01-03
Median Time to Relief of Influenza Symptoms (Hours)
Dose and Regimen
Overall Results (n=1246)
US Sites (n=206)
Peramivir 800mg po x 5d
89.0
70.8
Peramivir 800mg po x 1d
and 400mg po x 4d
91.7
88.8
Placebo x 5 days
104.4
106.8
p value
0.17
0.07
5.5
Previous Phase 1 Experience with Intramuscular Peramivir
Two phase one studies evaluating the safety
and pharmacokinetics of an intram uscular
formulation of pera mivir have been conduc
ted in a total of 45 he
althy volunteers
receiving peramivir.
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability
of 75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma
levels of i.m. pera
mivir generally occurre d within 30 m
inutes fol lowing injection.
Plasma pharm acokinetic param eters for i.m . peram ivir are summarized below for the
three intramuscular single dose regimens evaluated:
Dose (mg)
Cmax (ng/mL)
AUC0-∞ (hr·ng/mL)
t½a (hr)
75 i.m.
4296±812
11659±1123
19.8±7.9
150 i.m.
7612±884
23952±3804
24.3±4.1
300 i.m.
15150±2367
49649±5619
22.8±2.5
aterminal half life
In a second phase 1 study, Peram
ivir-Him-06-112, the sam e dose levels of peram ivir
were adm inistered as single i.m . injections on two consecutive days (6 subjects per
group). This double-b lind study also includ
ed a placebo arm . The pharm acokinetic
parameters of i.m . peramivir following the second day of dosing were consistent with
those seen following single doses of the drug.
The observ ations of s afety and to lerability of i. m. peram ivir in each of the 2 phas e 1
studies were unrem arkable. No serious ad
verse even ts were repo rted. The most
commonly observed ad verse events or laborato ry abnormalities were h eadache, several
reports of signs and symptom s of vasovagal reactions following injections, and transient
increases in creatine kinase. No consisten t differences in frequency of adverse events
were observed between the ac tive and placebo treatm ent groups, with the exception that
CK elevations appeared to be dose rela
ted in the peram ivir treatment groups. T he
vasovagal reactions were attri buted to the receipt of rela
tively large volum es of i.m.
injection (2 injections each of 2mL) in the fasted state.
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An ongoing phase 2 study, BCX1812-211, is
a random ized, double-blind placebo-
controlled study to evaluate the efficacy and
safety of two single d
ose reg imens of
peramivir. Up to 100 subjects per arm will receive either 150mg or 300mg of peramivir
or placebo. The prim ary endpoint of the stu
dy is the tim e to alleviation of clinical
symptoms in adult subjects with u ncomplicated acute influenza. An independent dat
a
monitoring comm ittee reviewed grouped blinde d safety data on the first 135 subjects
randomized. The study rem ains blinded. The fr equency of vasovagal reactions reported
as adverse events in this ongoing study is 2/135 (to date) which is lower than that seen in
the phase 1 volunteer studies.
5.6 Dose Rationale
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of
75mg twice daily in adults14. Oseltamivir was shown to be clinically effective in a Phase
III study of oral oseltamivir versus placebo in naturally occurring seasonal influenza, and
these data were sufficient for regulatory approval for marketing of oseltamivir. At least
75% of an oral dose of oseltam
ivir reaches the sy stemic circu lation as oseltam ivir
carboxylate. When oseltamivir is adm inistered orally at a dose of 75mg twice daily, the
serum C max of oseltam ivir carboxylate is approxim ately 348ng/m L and the AUC 0-48 is
10,876 h·ng/mL. The clinical data indicate that this level of exposure to oseltamivir was
sufficient to provide clinical improvement in uncomplicated acute influenza.
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular
doses of peram ivir are approxim ately 7600ng/mL and 24,000 h·ng/m L for the 150m g
dose and are approxim ately 15,000ng/m L and 49,000 h·ng/m L for the 300m g dose.
Previous s tudies hav e assess ed the concen
trations of the neuram
inidase inhibitor
zanamivir in nasal and pharyngeal secretions after parenteral administration of this drug. .
Within several hours after ad
ministration, the concentrati
ons in secretions wer
e
approximately 100-fold lower than in serum or plasma. In theory, relatively high levels
of a neuram inidase inh ibitor in res piratory se cretions ar e desi rable in order to rapidly
inactivate influenza virus and to delay or
prevent th e d evelopment of resistan ce in
infecting virus strains. Intramuscular doses of peramivir, including doses of 150m g and
300mg have been shown to be well tolerate
d in previous P hase 1 studies and since no
identified safety signal has been noted by an independent data monitoring committee in
the ongoing Phase 2 study, it is appropriate
for these two dose regim
ens to undergo
further evaluation in this Phase 3 study.
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6 STUDY OBJECTIVES
6.1
Objectives
6.1.1 Primary Objective
The primary objective of this study is to eval uate the efficacy of peram ivir administered
intramuscularly compared to placebo on th e time to alleviation of clinical symptoms in
adult subjects with uncomplicated influenza.
6.1.2 Secondary Objective(s)
The secondary objectives of this study are:
1. To evaluate the safety and tolerability of peramivir administered intramuscularly;
2. To evaluate secondary clinical outcomes in response to treatment;
3. To evaluate changes in
influenza virus
titer ( viral sheddi ng) in response to
treatment;
4. To assess pharmacoeconomic measures in response to treatment;
5. To assess changes in influenza viral su
sceptibility to neu raminidase inhibito rs
following treatment;
6.2
Study Endpoints
6.2.1 Primary Endpoint
Time to alleviation of clinical symptoms of influenza
6.2.2 Secondary Endpoint(s)
Secondary efficacy endpoints will include evaluations in each subject of:
1. Safety parameters, including: treatment- emergent adverse events (TEAEs)
and treatment-emergent changes in clinical laboratory tests;
2. Time to resolution of fever;
3. Time to resumption of subject’s ability to perform usual activities;
4. Incidence of influenza related complications
5. Quantitative change in influenza virus shedding measured by viral titer
assay (TCID50) and/or by quantitative polymerase chain reaction (PCR)
assay;
6. Medical resource utilization (MRU), missed days of work, and impact of
influenza illness on subject’s work performance and/or productivity.
6.2.3 Exploratory Endpoint
An exploratory endpoint will evaluate change in influenza virus susceptibility to
neuraminidase inhibitors in viral isolates recovered from subjects pre and post treatment.
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7 STUDY DESIGN
7.1
Overall Study Design and Plan
This is a multinational, random
ized, double-blind study com paring the efficacy and
safety of two single dose regim
ens of pera mivir adm inistered intramuscularly versus
placebo in adults with uncom
plicated acute influenza. Up
to 800 subjects will be
enrolled in to the s tudy. Each su bject’s as signment to trea tment will be str
atified
according to a Rapid Antigen Test (RAT) result and current smoking behavior, with 80%
of subjects centrally random ized via an Inte ractive Voice Response (IVR) system to one
of the two active single dose regimens of peramivir (2:2:1 randomization):
Treatment Group 1: Peramivir 150mg
maximum n=320
Treatment Group 2: Peramivir 300mg
maximum n=320
Treatment Group 3: Placebo
maximum n=160
Previous studies evalu ating the efficacy of
neuraminidase inh ibitors enro lled su bjects
with inf luenza-like illness on the basis of presence of
specific clinical signs and
symptoms. These studies were conducted before
the widespread availability of rapid
influenza antigen diagnostic test kits (Rapid Antigen Tests-RAT), and typically between
50-70% of subjects enrolled we re subsequently confirm ed by viral cu lture to hav e an
active influ enza infection. The sen sitivity of comm ercially available RAT kits ranges
from 62% to 83%, depending
upon the virus sub-type.
15 In the phase 2 study of
intramuscular peram ivir (study BCX1812-211) a positive RAT test was required for
study entry. It is likely that
a number of subjects with
an influenza infection were
excluded from this study due the sensitivity of this assay.
In this ph ase 3 study a lim ited number of RA T negativ e subjects will be en rolled in
accordance with the following al gorithm to minimize false negative test results: once an
individual site has identified 3 RAT positive subjects at screening within a 10 day period,
indicating influenza activity is present in the site’s vicinity, a RAT negative subject that
meets the inclusion / ex clusion criteria m ay be enrolled. O ne additional RAT negative
subject m ay be enro lled there after for each p
receding RAT positive subjec t th at is
identified. The RAT result for each subjec
t screen ed will be reco rded on the s tudy
Interactive Voice Response System (IVRS) to manage this enrollment algorithm.
A baseline nasopharyngeal swab specimen will be sent to the central virology laboratory
for each RAT negative subject that has been randomized into the study. These specimens
will be tested for influenza A and B infection using a PCR assay. The PCR results for
these specimens will be reported to BioCryst in real time. The study will close after
enrollment of at least 500 subjects who have either a positive Influenza A or B RAT at
screening, or who have a negative RAT at screening but a positive influenza A or B PCR
assay result from a baseline nasopharyngeal swab.
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Study drug will b e ad ministered as one 2m L intramuscular injection in each g luteal
muscle (total of 4mL injected in divided doses).
At screening, subjects will have an anterior nasal or pharyngeal swab collected for testing
with a comm ercially available RAT kit for influenza A and B in accordance with the
RAT manufacturer’s instructions. If this test is positive and the subject is enrolled,
additional s pecimens will be obta ined f or isolation and c ulture of inf luenza viru s and
quantitative PCR assay. If the initial RAT is negative, th e test should be repeated with a
different commercially available RAT kit. A limited number of RA T negative subjects
may be enrolled in accordance with the screening algorithm defined above.
Enrolled subjects will record the following in a Study Diary:
•
Oral tem perature m easurements tak en w ith an electronic therm ometer every 12
hours. W ith the exception of the baseline m
easurement, all tem
perature
measurements will be obtained
at leas t 4 hours after, or imm
ediately before,
administration of oral acetaminophen (paracetamol- provided), aspirin, ibuprofen or
other NSAID.
•
Assessment of seven symptom s of influenza on a 4-point severity scale (0, absent;
1, mild; 2, moderate; 3, se vere), twice daily (A M, PM) through Day 9, then once
daily (AM) through Day 14
•
Assessment of subject’s ability to perform usual activities, (0–10 on a visual analog
scale) once daily through Day 14
•
Assessment of a subject’s tim e lost from work or usual activities and productivity
compared to normal (0-10 on a visual analogue scale) once daily through Day 14
•
Doses of antipyretic (e. g. acetaminophen/ paracetamol), expectorant, and/or throat
lozenges administered each day through Day 14.
Anterior nose (bilateral) and posterior phar ynx specimens (swabs) will be collected at
Day 1 (pre-treatment) and at Days 3, 5, and 9, for influenza viral culture and quantitative
PCR assay. In a subset of a m inimum of 200 subjects an addition al viral culture/ P CR
sample will be collecte d on Day 2. Anterior
nose (bila teral) and poster ior pha rynx
specimens (swabs) will be collected at Days 1, 3, 5, and 9 f or all subjects, and on Day 2
in the subset of 200 subjects, to assess
for potential changes
in influenza viral
susceptibility to neuraminidase inhibitors in response to treatment.
At selected sites a separate sub-study will be conducted to collect limited PK samples for
the purpose of conducting an exposure-respo
nse analysis. This sub-study will be
conducted under a separate sub-study protocol, BCX1812-311PK.
8 SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.1 Inclusion Criteria
Subjects must meet all of the following criteria for inclusion in this study:
1. Male and female subjects age ≥18 years
2. A positive Influenza A or B Rapid Antigen Test (RAT) performed with a
commercially available test kit on an adequate specimen collected from an
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anterior nasal or pharyngeal swab, in accordance with the manufacturer’s
instructions. A negative initial RAT should be repeated with a second
commercially available RAT kit. A limited number of RAT negative subjects may
be enrolled in accordance with a defined screening algorithm..
3. Presence of fever at time of screening of ≥38.0 C (≥100.4 ºF) taken orally, or
≥38.5ºC (≥101.2 F) taken rectally. For subjects who test RAT positive at the time
of screening, a subject self-report of a history of fever or feverishness within the
24 hours prior to screening will also qualify in the absence of documented fever at
time of screening. For subjects who test RAT negative at screening, fever as
described above must be documented at time of screening.
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal
symptoms) of any severity (mild, moderate, or severe)
5. Presence of at least one constitutional symptom (myalgia [muscle aches],
headache, feverishness, or fatigue) of any severity (mild, moderate, or severe)
6. Onset of illness no more than 48 hours before presentation
7. Females of child-bearing potential must have a negative urine pregnancy test
(Beta HCG) at screening/baseline AND report one of the following:
• Be surgically sterile or practice monogamy with a partner who is
surgically sterile
• Have been sexually abstinent 4 weeks prior to date of screening evaluation
and be willing to remain abstinent through 4 weeks after study drug
administration
• Use oral contraceptives or other form of hormonal birth control including
hormonal vaginal rings or transdermal patches and have been using these
for 3 months prior through 4 weeks after study drug administration
• Use an intra-uterine device (IUD), or double barrier contraception (such as
condom or diaphragm with spermicidal gel or foam) as birth control 4
weeks prior to date of screening through 4 weeks after study drug
administration
8. Provide written informed consent
8.1.2 Exclusion Criteria
Subjects to whom any of the following criteria apply will be excluded from the study:
1. Women who are pregnant or breast-feeding
2. Presence of clinically significant signs of acute respiratory distress
3. History of severe chronic obstructive pulmonary disease (COPD) or severe
persistent asthma
4. History of congestive heart failure requiring daily pharmacotherapy with
symptoms consistent with New York Heart Association Class IV functional status
within the past 12 months (section 15.1).
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5. Screening ECG which suggests acute ischemia or presence of medically
significant dysrhythmia.
6. History of chronic renal impairment requiring hemodialysis or known or
suspected to have moderate or severe renal impairment (actual or estimated
creatinine clearance <50 mL/min)
7. Clinical evidence of active bacterial infection at any body site requiring therapy
with oral or systemic antibiotics
8. Presence of immunocompromised status due to chronic illness, previous organ
transplant, or use of immunosuppressive medical therapy.
9. Current treatment of active viral hepatitis C
10. Presence of known HIV infection, with a CD4 count <350 cell/mm3
11. Current therapy with oral warfarin or other systemic anticoagulant
12. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the
7 days prior to screening
13. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the
previous 21 days
14. History of alcohol abuse or drug addiction within 1 year prior to admission in the
study
15. Participation in a previous study of peramivir as treatment for acute influenza or
previous participation in this study
16. Participation in a study of any investigational drug within the last 30 days
8.1.3 Removal of Subjects from Therapy or Assessment
All subjects are permitted to withdraw from participation in this study at any time and for
any reason, specified or unspeci fied, and without prejudice. The Investigator or sponsor
may terminate the subject’s participation in the study at any tim e for reasons including
the following:
1. Adverse event;
2. Intercurrent illness;
3. Non-compliance with study procedures;
4. Subject’s decision;
5. Administrative reasons;
6. Lack of efficacy;
7. Investigator’s opinion to protect the subject’s best interest.
Any subject who withdraws because of an adverse event will be followed until the sign(s)
or symptom(s) that constituted the adverse eve nt has/have resolved o r is dete rmined to
represent a stable medical condition.
A subject should be withdrawn fr om the trial if, in the opinion of the Investigator, it is
medically necessary, or if it is the d esire of the subject. If a subjec t does not return for a
scheduled visit, every effort should be m ade to contact the subject and determ
ine the
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subject’s medical condition.
In any circum stance, ev ery effort sho uld be m ade to
document subject outcome, if possible.
If the sub ject withdraw s consen t, n o furt her evaluations should be perfor med and no
attempts should be made to collect additional data.
9 TREATMENTS
9.1
Treatments Administered
Peramivir is an investig ational drug. Peram ivir for intramuscular injection is a small-
volume parenteral and will be supp lied as a 75 mg/mL solution in sodium citrate/ citric
acid buffer. The pH is approximately 3.0.
A m atched placebo solution of so dium citrat e/ citric acid buffer with 1.2% sod
ium
chloride at a pH of approximately 3.0 will be supplied.
9.2
Identity of Investigational Product(s)
Peramivir and placebo peramivir will be supplied in clear 2mL vials. An individual study
drug kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending
upon the treatment group), 2 syringes and 2 need les in which to draw up the solution for
intramuscular injection. All m aterials will be packaged in a labele d box container. All
study drug kits m ust be stored at 2-8 oC. Each individual study drug kit will b e labeled
with some or all of the following information as required by local regulations:
• Sponsor nam e and contact inform
ation, study protocol num
ber, kit num ber,
description of the contents of the container, instructions for the preparation of the
syringe and adm inistration of the study dr ug, conditions f or st orage, statem ent
regarding the investigationa l (clinical trial) use of the study drug and date for
retest or expiry date.
Each vial of study drug will be labeled with some or all of the following infor mation as
required by local regulations:
• Sponsor nam e, study protocol number, desc ription of the contents of the vial,
instructions for the preparation
of
the s yringe, statem ent regarding the
investigational (clinical trial) use of the study drug and lot number.
9.3
Method of Assigning Subjects to Treatment Groups
Subjects will be centrally randomized in a ratio of 2:2:1 to one of three treatment groups:
single dos e peramivir 1 50mg, single dose pera mivir 300mg or placeb o, in acco rdance
with a computer-generated random ization schedule prepared by a non-study statistician.
Subjects will be s tratified acco rding to the result of a RAT test and curren
t sm oking
behavior. Once a subject is eligible for randomization, he/she wi ll be assigned a study
drug kit nu mber that will be obta ined by stu dy staf f f rom the study inter active voice
response system (IVRS). Once a study drug kit nu mber has been assigned to a subject, it
cannot be reassigned to any other subject.
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9.4
Study Medication Accountability
The Investigator/pharmacist must maintain accurate records of the disposition of all study
drugs received from the sponsor, issued to th
e subject or directly adm inistered to the
subject (including date and time), and any drug accidentally destroyed. The sponsor will
supply a specific dru
g-accountability form . At the en
d of the study, information
describing study drug s upplies (e.g., lot num bers) and disp osition of s upplies for each
subject must be provided, signed by the Invest
igator or designee, and collected by the
study monitor. If any errors or irregularities in any shipment of study m edication to the
site are discovered at any time, the Project Manager must be contacted immediately.
At the end of the study, all
medication not dispensed or administered and packaging
materials will be collected with supervision of the monitor and returned to the sponsor or
destroyed on site as dictated by the appropr
iate Standard Operating P rocedure at the
participating institution.
9.5
Blinding/Unblinding of Treatments
This is a double-blind study. The treatment group assignment will not be known by the
study subjects, the investigator , the clinical staff, the CRO or Sponsor staff during the
conduct of the study.
Section 11.2.4 provides inform ation regarding the process for unblinding the treatment
assignment, if necessary, in the event of an SAE.
9.6
Prior and Concomitant Therapies
All m edications, by any route of adm
inistration, used during this study m
ust be
documented on the Case Report Form (CRF). Prescription as well as non-prescription
medications should be recorded. Medication us ed for the treatm ent of influenza-related
symptoms will be captured by the subject in the diary card provided by BioCryst.
9.7
Overdose and Toxicity Management
To date there is no experience with overdose of in tramuscular or intravenous peramivir.
If overdose occurs, subjects should receive indicated supportive therapy and evaluation of
hematologic and clinical chem istry laboratory tests should be conducted. The effec t of
hemodialysis on elimination of peramivir is unknown.
9.8
Dose Interruption
As this is a study of a single injection of
peramivir or placebo, guidelines for treatm ent
interruption for drug related SAEs or toxicities are not applicable.
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10 STUDY CONDUCT
A study schedule of evaluations is presented in
Figure 1 . A detailed lis
t of the
evaluations is also provided in the following sections.
10.1 Evaluations
All subjects enrolled in this study will undergo the following evaluations:
10.1.1 Medical History
Medical history, influenza va
ccination s tatus within th e previous 12 m
onths and
demographic data (including smoking behavior) will be recorded at Screening/Baseline.
10.1.2 Rapid Antigen Test for Influenza
At Screening/Baseline, a commercially available, rapid antigen tes t (RAT) for influenza
A and B will be performed on an adequate specimen collected by swabbing the anterior
nose or pharynx, in accordance with the RAT
manufacturer’ instructions. A negative
initial RAT should be repeated with a different commercially available RAT kit. Refer to
the Study Manual f or instructions regarding the use of the
RAT kits provided for this
study. Sites m ay use the kits provided
by the Sponsor or any other commercially
approved RAT available at their site to document a confirmed influenza infection.
A lim ited num ber of RAT negativ e subje cts will be enr olled in a ccordance with the
following algorithm: Once an ind ividual site has identified 3 RAT positive sub jects at
screening within a 10 day period, indicating that influenza activity is present in the site’s
vicinity, a RAT negative subject that m
eets the inclus ion/ exclus ion criteria m ay be
enrolled. O ne additional RAT negative subj
ect m ay be enrolled th
ereafter for each
preceding RAT positive subject that is iden
tified. The RAT result for each subject
screened will be record ed on the s tudy Inte ractive Voice response (IVR) system to
manage this enrollment algorithm.
10.1.3 Physical Examination and Influenza-related Complications Assessments
The Investigator will perform a physical ex amination at S creening/Baseline. Subject’s
weight will be recorded at Screening/Baseline.
Study personnel will be provided with an influenza-related complications (IRC) checklist
in the CRF to evalua te the subject for the presence of clinical signs and /or symptoms of
the following influenza-related complications: sinusitis, otitis, bronchitis and pneumonia.
At each follow up assessm
ent a t argeted physical exam ination will be conducted to
record the presence of influenza related complications. If the investigator determines that
the subject experiences (or is presumed to experience) an IRC as noted above, he/she will
record that assessm ent on the IR
C CRF pa ge and any m edication used to treat the
condition will be reco rded on the concom itant medication page. The investigato r will
promptly provide appropriate treatm
ent fo r any suspected or proven IRC, as such
treatment will not affect the efficacy assessments. Such information describing IRC signs
and/or symptoms should not be reported as adverse events. Any inj ection site reactions
noted will be recorded in the CRFs as adverse events.
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10.1.4 Vital Signs
Vital signs evaluations will in clude blood press ure, pulse rate , and resp iration rate. The
investigator will record or al body tem perature at baseline. Thereafter the subject will
record oral temperature twice daily in the study diary card.
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following
the study drug injection on Day 1, then once da ily on Days 2 (for those subjects who are
seen on day 2), 3, 5, 9, and 14.
10.1.5 Electrocardiogram Measurements
A 12-lead elec trocardiogram (ECG) will be
obtained a t Screen ing/ Baseline. The
principal investigator will be re sponsible for interpretation of the Screening ECG. This
interpretation may be performed by the investigator or he/she may delegate this action to
another physician and the investigator wi
ll acknowledge the interp
retation. If this
baseline ECG is interpreted as meeting the exclusionary criteria listed in section 8.1.2 the
subject will not be enrolled in this study. If the ECG is interpreted as being abnormal but
does not meet the exclusionary criteria,
the subject m ay be enrolled unless other
exclusion criteria apply. The principal investigator is responsible to ensure that such an
enrolled subject be inform ed of the nature of the abnorm al ECG and that any m edically
indicated repeat ECG examinations and/or referral of the subject for further evaluation is
made either during subject' s participation in the study or imm ediately after the subject' s
discharge from the study.
10.1.6 Clinical Chemistry Profiles
Clinical ch emistry pro files will include a C
hemistry 20 panel (
includes sod ium,
potassium, chloride, total CO 2 [bicarbonate], creatinine, glucose, urea nitrogen, album in,
total calcium
, total m
agnesium, phosphor
us, alkaline phosphatase, alanine
aminotransferase (ALT), aspartate am
inotransferase (AST), total bilirubin,
d irect
bilirubin, lactate dehydrogenase [LDH], total protein, total creatine kinase, and uric acid)
Blood samples for clinical chem istry profiles will be collected at Screen ing/Baseline, and on
Days 3, 5 and 14.
10.1.7 Hematology Profiles
Hematology will include complete blood count (CBC) with differential.
Blood samples for he matology profiles will be collected at Screening/Baseline, and on
Days 3, Days 5 and 14.
10.1.8 Serology for Influenza
Paired blood samples for determination of antibody to influenza A and B (serology) will
be obtained with the clinical laboratory tests at Screenin g/Enrollment and at Day 14.
These specimens will be stored at the central laboratory and will be analyzed if needed to
confirm the diagnosis of influenza.
10.1.9 Urinalysis and Evaluation of Protein in Urine
Urinalysis will in clude dipstick tests for protein, glucose, ketones, blood, urobilinogen,
nitrite, pH, and spec
ific gr avity a nd m icroscopic evaluation for R
BCs and WBCs.
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Samples for urinalysis will be collected at Screening/Baseline, and on Days 3, 5, and 14.
10.1.10Urine Pregnancy Test
Females of childbearing potential will be ev aluated for pregnancy at Screening/Baseline
and Day 14 using a urine pregnancy test.
10.1.11 Samples for Virologic Laboratory Assessments
An adequate spec imen will b e co llected by sw abbing the anter ior nos e (bila teral) and
posterior pharynx for virologic laboratory a ssessments including culture for the isolation
of influenza virus and/or quantitative PCR assa y at Screening/Baseline, and at Days 3, 5,
and 9. In a subset of a m inimum of 200 subjects an additio nal sample will be taken at
Day 2. Refer to the L
aboratory Manual for instructions re garding the processing and
shipment of these specimens.
10.1.12 Subject Self Assessments
Subject self assessments will be performed beginning pre-dose on Day 1 and recorde d in
the subject’s Study Diary including the following:
• Oral temperature measurements with an electronic thermometer (provided by the
Sponsor for the study) every 12 hours. With the exception of the baseline
measurement, all temperature measurements will be obtained at least 4 hours after, or
immediately before, administration of oral acetaminophen (paracetamol, provided)
aspirin, ibuprofen or other NSAID. The times of each temperature determination will
be recorded in the Study Diary. The baseline temperature will be recorded at the
screening/Day 1 visit prior to dosing, regardless of whether the subject had recently
taken an anti-pyretic; the time of anti-pyretic use pre-treatment will be recorded in the
CRF, if applicable.
• Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction,
myalgia [muscle aches], headache, feverishness, and fatigue) on a 4-point severity
scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on
Day 1 and through Day 9, then once daily through Day 14.
• Assessment of the subject’s ability to perform usual activities using a 0–10 visual
analogue scale once daily through Day 14.
• Assessment of the subject’s time lost from work or usual activities and productivity
compared to normal using a 0-10 visual analogue scale once daily through Day 14.
The subject’s diary card will be reviewed by study staff at each visit for completion of the
record of all required ite ms, with particular emphasis on alleviation of symptoms as well
as relapse of sym ptoms. Relapse is defined as the recurrence of at leas t one respiratory
symptom and one constitutiona l sy mptom (both greater th an m ild in severity) f or 24
hours and the presence of fever (unless influenc ed by antipyretic use). Relapse can only
occur after the subject has m et the endpoint cr iteria for alleviation of symptoms. Study
staff will not attem pt to ask subjec ts to retrospectively complete missing diary card data
for any scheduled assessm ents that have not b een com pleted prio r to the c linic visit.
Study staff should, however, rem
ind the subject to com plete the diary card at all
scheduled times.
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10.1.13 Concomitant Medications
All concom itant m edications used during
this study, with the exception of those
medications taken for symptomatic relief of influenza symptoms, which will be reco rded
by the subject in their diary card, must be documented on the Case Report Form (CRF).
10.1.14 Adverse Events
AEs will be assess ed from the tim e of ad ministration of stu dy medication through the
final study visit.
10.1.15 Single Pharmacokinetic Exposure Sample
On study day 3 a single PK sample will be drawn in concert with the day 3 safety clinical
laboratory blood draw. This sample will be
sent for subsequent analys
is of the
concentration of peramivir at this time point. Data f rom this sing le PK sample will b e
combined with data from the PK s ub-study (BCX1812-311PK) to perfor m an exposure-
response analysis. This analysis will be described as part of the sub-study analysis plan..
10.2 Screening
10.2.1 Informed Consent
The nature and purpose of the study and the expectations of a participating subject will be
described to potential study subjects , their que stions will be answered, and the subjects
will th en b e asked to sign an inf
ormed c onsent docum ent. Study s ubjects will then
undergo the screening evaluation as noted in Section 10.2.2
10.2.2 Screening/Baseline Evaluation and Enrollment
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or
in the subject’s hom e, in which case all ev aluations must be conducted by appropriately
trained and qualified staff.
Clinical laboratory assessm
ents perform ed at Screenin
g are
for the purpose of
establishing a baseline. Subjects m ay be enrolled and receive treatm ent with study drug
prior to r eceiving re sults of the laboratory a ssessments (with the ex ception of urine
pregnancy test result, which must be known).
Eligible sub jects will be enrolled and ra
ndomized to blin ded study treatm ent. The
randomization will include stratification by RA T status and current s moking behavior.
The Investigator will prepare a request for blinded study drug assignment which includes
the subject’s screening number. The Investigator or designee at the clinical study center
will contact the central randomization Interactive Voice System (IVRS call center). The
IVRS call center will advise the study center of the investigational study drug kit number
that is assigned to that subject at enrollment.
Subjects that are d etermined to be ineligible will be advi sed accordingly, and the reason
for ineligibility will b e discussed. If desired by the subjec t the reason for ineligibility
may be pr ovided/discussed with their hea
lth-care provider by the Investigator or
designee.
Ineligible subjects who have been screen
ed for the study will also be entered on
the
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IVRS. For such subjects, the screening num
ber assigned, subject’s date of birth and a
reason for ineligibility will be entered on to th e IVRS. All ineligible subjects must be
entered onto the IVRS within 24 hours of screening, to assis t with surve illance
analysis during the course of the study.
10.3 Treatment Period—Study Day 1
Day 1 represents the only day of study dr
ug dosing. Study drug adm inistration should
occur as soon as possible following inform
ed consent, screening and random
ization.
Therefore, it is expec ted that the da te of Screening/ Baseline and Day 1 will usua lly be
the same date.
10.3.1 Pre-dose Evaluations
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the
subject shall complete the record of these assessments in their Study Diary prior to
dosing. The subject will be counseled regarding the expectations for recording these
assessments through Day 14.
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral
temperature) and a 12 lead ECG will be obtained prior to dosing. At Hour 0, the blinded
study drug will be administered intramuscularly (one injection in the left gluteal muscle,
and one injection in the right gluteal muscle within a period of ≤ 10 minutes.). The
calendar date and 24-hour clock time of the first and second injections will be recorded.
The following evaluations will be performed post-dose on Study Day 1:
• Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral
temperature) at 15 minutes after the study drug administration
• Record any concomitant medications
• Record any AEs
10.4 Post-Treatment Assessment Period
10.4.1 Days 2, 3, 5, 9 and 14
Study evaluations will be performed on Days 2 [subset of subjects only], 3, 5, 9 and 14 in
accordance with the schedule of evaluations (Figure 1). Subjects with persistent moderate
or severe influenza symptoms at day 14 will also complete a Day 21 visit.
Visits may be conducted in the investigator’s o ffice or clinic, or in the subject’s home, in
which case all evaluations must be conducted by appropriately trained and qualified staff.
The Day 2 assessment will be conducted in clinic or by study staff only for the subset o f
subjects who will provide additional Day 2 virology samples. For all other study subjects,
study staff will attem pt to contact the subjec ts on Day 2 by telephone to confirm
their
compliance with com pletion of the Subject Self Assessments, to note any concom itant
medications and adverse events. A ny adverse events reported by the subject during this
telephone contact will be recorded on the adverse event form and verified during the visit
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on day 3.
At each v isit it is im portant that the sub ject’s Study Diar y record be rev iewed for
completion of daily Subject Self Assessm
ents. The subjects should be counseled as
necessary regarding self assessments and Study Diary record requirements. The subject’s
diary card will be reviewed by study staff for alleviation of symptoms as well as relapse
of symptoms. Relapse is defined as the r ecurrence of at least one resp iratory symptom
and one constitutional symptom (both greater than mild in severity) for 24 hours an d the
presence of fever (unless influenced by antipyretic use). Relapse can only occur after the
subject has met the endpoint criteria for alleviation of symptoms.
Day 3:
The results of the serum CK result obtained a
t Day 3 will not be m
ade available to
investigators, to BioCryst or to any study personnel, unless the CK result at Day 3 is
≥
2000 IU/mL. A single PK sa mple will be obt ained on Day 3 at the sam e time as the
clinical laboratory blood specimen is obtained.
Day 14:
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven
symptoms assessed) of either m oderate or se vere intensity at th e Day 14 visit th en the
subject must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required
at day 28 (± 3 days) If a subject reports m oderate or severe influenza symptoms then the
investigator will record the intensity of each of the influenza symptoms on a visit specific
CRF page at the day 21 and day 28 visits. A
fter day 14 the subjec t will not re cord
symptoms in a diary.
Day 21 (if applicable):
The day 21 visit is to be completed only if the subject reports sym ptoms of influenza of
moderate or severe intensity at day 14. The investigator will make a clinical judgment as
to the appropriate medical course of action for such subjects at the Day 2 1 visit and such
action(s) will be re corded on the Day 21 CRF page. The investigator will re
call the
subject for a further study visit at day 28 (± 3 days) if m oderate or severe symptom(s) of
influenza persist at Day 21.
Day 28 (if applicable):
The day 28 visit is to be completed only if the subject reports sym ptoms of influenza of
moderate or severe intensity at day 21. The investigator will make a clinical judgment as
to the appropriate m edical course of action
for such subjects at this visit and such
action(s) will be recorded on the Da y 28 CR F page. No further follow-up visits beyond
day 28 are to be form ally scheduled unless in the clinical judgm ent of the investigator
further follow-up is required. The investigat
or will use his/her
clinical judgm ent to
manage the subject, referring the subject, if appropriate, for further care.
10.4.2 Adverse Events Reported at Post-treatment Visits
In this stud y, symptoms of influenza will be considered separately from adverse e vents
reported during the post-treatment period. Accordingly, adverse events that have onset in
the post-treatment period will be assessed and followed as specified in 11.2. Specifically,
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the inves tigator shou ld attem pt to f ollow all unresolved AEs and/or SAEs observed
during the study until they are resolved, or ar e judged medically stable, or are otherwise
medically explained.
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Figure 1
Study Measurements and Visit Schedule
Treatment
Period
Assessment Day End of Study
Early Withdrawal
Screening 1
(Baseline)
Day 11
Day 22
Day 3
Day 5 (±1 day)
Day 9 (±3 day)
Day 14 (±3 day) 8
Informed Consent
X
Rapid Antigen test for Influenza A & B
X
Medical History/Physical Exam3
X
Influenza-related complications checklist3
X
X
X
X
X
X
Inclusion/Exclusion
X
Clinical Chemistries4
X
X
X
X
Hematology4
X
X
X
X
Exposure Pharmacokinetic Sample
X4
Serology (serum) Sample
X
X
Urinalysis4
X
X
X
X
Urine Pregnancy Test
X
X
Vital Signs5
X
X
X
X
X
X
X
ECG6
X
Sample (nasopharyngeal swab) for
Influenza Virus Culture/ PCR assay and
for resistance studies
X
X
X
X
X
Study Drug Administration
X
Subject Diary Review7
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on subsequent study days may occur in subject’s home by
the investigator (all visits) or appropriately trained study center staff (Day 2, 3, 5, 9 visits).
2 Day 2 visit required only for a subset of subjects for whom additional Day 2 virology sample is required. For all other subjects, Day 2 will be a telephone contact with the subject to ensure
compliance with diary card completion, concomitant medication and adverse event review.
3 Medical history and physical exam at screening to include weight, and smoking behavior. Targeted physical examinations will be performed to complete the influenza-related complications
checklist by the appropriate medical personnel at appropriate visits.
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subject may be enrolled and begin treatment with study drug prior to receiving results.
On Day 3 an extra tube will be included with the safety blood sample for evaluation of peramivir concentrations.
5 Vital sign measures will include blood pressure, pulse rate and respiration rate. Vital signs will be recorded at Screening, pre-dose and at 15 min following the study drug administration on
Day 1, then once on remaining days as stipulated. The investigator will record oral temperature at baseline. Thereafter the subject will report oral temperature measurements twice daily in
the Study Diary
6 If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study. If the ECG is
interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, medically significant dysrhythmia) then this subject may be enrolled If the conditions
highlighted in section 10.1.5 are met for the subject.
7 Subjects record symptom assessment in Study Diary, twice dail y, beginning pr e-dose on Day 1 through Day 9, then once daily through Day 1 4; subjects record ability to perform usual
activities once daily, beginning pre-dose on Day 1 through Day 14. Subjects record oral temperature twice daily throughout as well as all concomitant medication and adverse events
8 For any subjec t with unresolved moderate or severe intensity influenza sym ptoms a follow up assess ment will be schedul ed at Day 21 ( ± 3 day s) and Day 28 (± 3 day s) if r equired
(See Section 10.4.1).
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11 ADVERSE EVENT MANAGEMENT
11.1 Definitions
11.1.1 Adverse Event
An AE is any untoward m
edical occurrence in a clinical study subject. No causal
relationship with the study drug or with the clinical study itself is implied. An AE may
be an unfavorable and unintended sign, sym ptom, syndrome, or illness that dev elops or
worsens during the clinical st
udy. Clinically relevant ab
normal results of diagnostic
procedures including abnorm
al laborator y findings (e.g., requ
iring unscheduled
diagnostic procedures or treatm ent measures, or resulting in withdrawal from the study)
are considered to be AEs.
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2).
Surgical procedures are not AEs but m ay constitute therapeutic m easures for conditions
that require surgery. The condition for which the surgery is required is an AE, if it occurs
or is detected during the study period. Planned surgical m
easures perm itted by the
clinical study protocol and the conditions(s) leading to these measures are not AEs, if the
condition(s) was (were) known befo re the start of study treatm ent. In the latter case the
condition should be reported as medical history.
Assessment of seven influenza sym ptoms (cough, sore throat, nasal obstruction, m yalgia
[muscle aches], headache, f everishness, and f atigue) will be documented in a subject’s
study diary and analy zed as a m
easure of efficacy of the study treatm
ent. These
symptoms will not b e reported as AEs unless the sym ptom(s) worsen to the exte nt that
the outcome fulfils the def inition of an SAE, which then must be recorded as such (see
Section 11.1.2). Likewise, a RAT for influenza is
required at screening in order to
determine eligibility for the study, and therefore a positive RAT is not considered an AE.
11.1.2 Serious Adverse Event
A SAE is an adverse event that results in any of the following outcomes:
• Death
• Is life-threatening (subject is at immediate risk of death at the time of the event; it
does not refer to an event that hypothetically might have caused death if it were more
severe)
• Requires in-subject hospitalization (formal admission to a hospital for medical
reasons) or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity (i.e., there is a substantial
disruption of a person’s ability to carry out normal life functions)
• Is a congenital anomaly/birth defect
• Is an important medical event
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Important medical events that may not result in death, are no t life-threatening, or do not
require hospitalization may be considered an SAE when, based upon appropriate medical
judgment, they m
ay j eopardize the subject or m
ay r equire m edical or surgical
intervention to prevent one of the outcom es listed in this definition. E xamples of such
events include allergic bronchospasm requiri
ng intensive treatm ent in an e mergency
room or at hom
e, blood dyscrasias or c
onvulsions that do not
result in subject
hospitalization, or the development of drug dependency or drug abuse.
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and
Reporting Serious Adverse Events
Reports of AEs are to be collected from the time of study drug administration through the
follow-up period ending on Day 14. The Invest igator or de signee must completely and
promptly record each AE on the appropriate
CRF. The Investig ator should attem pt, if
possible, to establish a diagnosis based on th e presenting signs and symptom s. In such
cases, the diagnosis should be docum
ented as the A
E and not the individual
sign/symptom. If a clear diagnosis cannot be established, each si gn and symptom must
be recorded individually.
The Investigator should attem pt to follo w all unresolved AEs and/or SAEs observed
during the study until they are resolved, or ar e judged medically stable, or are otherwise
medically explained.
11.2.1 Definition of Severity
All AEs will be as sessed (graded ) f or severity and class ified into on e of f our clearly
defined categories as follows:
• Mild:
(Grade 1): Transient or mild symptoms; no limitation in activity;
no intervention required. The AE does not interfere with the
participant’s normal functioning level. It may be an annoyance.
• Moderate:
(Grade 2): Symptom results in mild to moderate limitation in
activity; no or minimal intervention required. The AE produces
some impairment of functioning, but it is not hazardous to
health. It is uncomfortable or an embarrassment.
• Severe:
(Grade 3): Symptom results in significant limitation in activity;
medical intervention may be required. The AE produces
significant impairment of functioning or incapacitation.
• Life-threatening: (Grade 4): Extreme limitation in activity, significant assistance
required; significant medical intervention or therapy required;
hospitalization.
11.2.2 Definition of Relationship to Study Drug
The blinded Principal Investigator must rev iew each AE and m ake the determ ination of
relationship to study drug using the following guidelines:
Not Related:
The event can be readily explained by other factors such as the
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subject’s underlying m edical c ondition, concom itant therapy, or
accident, an d no tem poral relati onship ex ists b etween the study
drug and the event.
Unlikely:
The event d oes not follow a reason able tem poral sequ ence from
drug adm inistration and is read
ily explained by the subject’s
clinical state or by other m
odes of therapy adm inistered to the
subject.
Possibly Related:
There is so me tem poral relationship between the event an
d th e
administration of the study drug a
nd the event is unlikely to be
explained by the subject’s m edical condition, other therapies, or
accident.
Probably Related:
The event follows a reasonable tem
poral sequence from drug
administration, abates upon discontinuation of the drug, and cannot
be reasonably explained by th
e known characteristics of the
subject’s clinical state.
Definitely Related: The event follows a reason
able tem poral sequen ce from
administration of the m edication, follows a known or suspected
response pattern to the m edication, is confirm ed by im provement
upon stopping the m edication (dec hallenge), and reappears upon
repeated exposure (rechallenge,
if rechallenge is m
edically
appropriate).
11.2.3 Reporting Serious Adverse Events
Any SAE must be reported to BioCryst
or its designee within 24 hours of the
Investigator’s recognition of the SAE by fi
rst notifying the Medical Monitor at the
number listed below:
Telephone:
Europe: +44 1628 548000; North America: 1-888-724-4908
Facsimile:
Europe: +44 1628 540028; North America: 1-888-887-8097
or 1-609-734-9208
The site is required to fax a completed SAE Report Form (provided as a separate report
form) within 24 hours. All additional follow-up evaluations of the SAE must be reported
and sent by facsimile to BioCryst or its designee as soon as they are available.
The Principal Investigator or designee at each site is respons ible for submitting the IND
safety report (initial a
nd follow -up) or other safety inform
ation (e.g., revised
Investigator’s Brochure) to
the Institutional Review
Board/Independent Ethics
Committee (IRB/IEC) and for retaining a copy in their files.
If the Inv estigator becomes aware of any SA E occurring within 30 days after a s ubject
has com pleted or withdrawn from t he study, he or she should notify BioCryst or its
designee.
Any SAEs considered possibly related to treatment will be reported to the FDA and other
Regulatory Competent Authorities as applicab le via the MedW atch reporting system i n
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accordance with FDA and other ap plicable regulations. However, the Investig ator is not
obligated to actively seek reports of AEs in former study participants.
While pregnancy is not considered an AE, a ll cases of fetal drug exposure via parent as
study participant (see S ection 4.4) are to be
reported immediately to BioCryst or its
designee. Inform ation rela ted to the pregnancy m
ust be given on a “Pregnancy
Confirmation and Outcome” form that will be provided by the Sponsor or its designee.
11.2.4 Emergency Procedures
In the even t of an SAE, the Principal Inve
stigator m ay request the unblinding of the
treatment assignm ent for the subject affected
. If tim
e allows (i.e., if appropriate
treatment for the SAE is not im peded), the Principal Investigator wi ll first consult with
the Med ical Monito r r egarding the need to unblind the treatm ent assignm ent for the
subject. At all times, the clinical well-being of any subject outweighs the need to consult
with the Medical Monitor.
The Principal Investigator m
ay contact th e IVRS central random
ization center and
request the unblinding of the treatm
ent assi gnment that corresponds to the affected
subject. Th e IVRS center will record the na me of the Investigator making the request,
the date and time of the request, the reason for the request, the subject number and study
drug kit number, and whether the Medical M
onitor was consulted prior to the request
being made. The Sponsor will be informed within 24 hours if unblinding occurred.
12 STATISTICAL METHODS
Descriptive statistical methods will be used to summ arize the data from this study, with
hypothesis testing perform ed for the prim
ary and other selected efficacy endpoints.
Unless stated otherwise, the term “descriptive statistics” refers to number of subjects (n),
mean, median, standard deviation (SD), minimum, and maximum for continuous data and
frequencies and percentages for categorical da ta. The term “treatm ent group” refers to
randomized treatment assignment: peramivir 150 mg, peramivir 300 mg, or placebo. All
data collected during the study wi ll be included in data listin gs. Unless otherwise noted,
the data will be sorted first by treatm ent assignment, subject num ber, and then by date
within each subject number.
Unless specified otherwise, all statistical testing will be two-sided and will be performed
using a significance (alpha) level of 0.05.
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher.
12.1 Data Collection Methods
The data will be reco rded on the CRF appr oved by BioCryst. The Investigator must
submit a completed CRF for each subject who signs an inform
ed consent form (ICF),
regardless of duration. All documentation supporting the CRF data, such as laboratory or
hospital records, must be readily available to verify entries in the CRF.
Documents (including laborator y reports, hospital records s
ubsequent to SAEs, etc.)
transmitted to BioCryst should not carry the s
ubject’s name. This will help to ensure
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subject confidentiality.
12.2 Statistical Analysis Plan
A statistical analysis plan (SAP) will be cre ated prior to the review of any data. This
document will provide a m ore technical and detailed description of the proposed data
analysis methods and procedures.
12.3 Sample Size Estimates
From published resu lts, it is exp ected that th e median time to a lleviation of symptoms
will be between 103.3-116 hours for subjects receiving p lacebo. 16 , 1 7 For sam ple size
calculations the best placebo respon se (103.3 hours) will p rovide the most conserv ative
estimate of an observed hazard ratio. Additionally, it is expected that the median time to
alleviation for the lowes t dose peramivir arm will be 69.9 h ours, yielding a hazard ratio
of 0.68. Using these assum
ptions, a sa mple size of 200 infected subjects per active
treatment group and 100 infected subjects in th e placebo group is sufficient to provide at
least 80% power to detect a hazard ratio of 0.68 usi ng a log-rank statistic and α = 0.025
(SAS version 9.1.3; tota l accrual time 7 months; total enrollment time 6 months). Up to
800 subjects will b e enrolled to achieve the target num ber of at least 5 00 subjects with
diagnostic evidence (RAT or PCR) of an
acute influenza infection (200 per active
treatment; 100 receiving placebo) as described in section 12.4.2.
12.4 Analysis Populations
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected
(ITTI), and safety populations.
12.4.1 Intent-To-Treat Population
The ITT population will include all subject
s who are random ized. Subjects will be
analyzed in the treatment group to which they were randomized. The ITT population will
be used for analyses of accountability and demographics.
12.4.2 Intent-To-Treat Infected Population
The ITTI po pulation will include all subj ects who are rando mized, received study d rug,
and have proven influenza by any one of the fo llowing: culture, PCR, or paired serology
showing ≥ 4-fold increase in antibody to influe
nza A or B, and received study drug.
Subjects will be an alyzed accord ing to the treatment random ized. If a discrepancy is
noted in the final database for any subject, such that the drug differs from the randomized
treatment assignm ent, efficacy analyses m ay be repeated with the su
bjects analy zed
according to the treatm ent received. The
ITTI population will be used for prim
ary
analyses of efficacy.
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12.4.3 Safety Population
The safety population will include all subjects who received study drug. Subjects will be
analyzed according to the treatm ent received. This population will be used for all safety
analyses.
12.5 Interim and End of Study Analyses
Interim Analysis
An independent DMC will review safety data on an ongoing basi s. Safety analyses will
be presented in a manner consistent with the presentations intended for the final analysis.
End of Study Analysis
A final analysis is planned after the last su bject completes or discontinues the study, and
the resulting clinical database has been cleaned, quality checked, and locked.
12.6 Efficacy Analyses
12.6.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the time to alleviation of symptoms, defined as the time
from injection of study drug to the start of th e time period when a subject has Alleviation
of Symptoms. A subject has Alleviation of
Symptoms if all of the seven symptoms of
influenza (nasal congestion, so re throat, cough, aches and pains, fatigue (tiredness),
headache, feeling feverish) assessed on his/he
r subject diary are eith
er absent o r are
present at no m ore than m ild severity leve l and at this status for at least 21.5 hours (24
hours - 10%).
Descriptive statistics for the prim ary effi cacy endpoint will be tabulated by treatment
group. Alleviation of sym
ptoms will be d etermined by assessm ent of sym ptoms as
reported on each subject’s diary card. T ime to alle viation of sym ptoms will b e
summarized overall and for i
ndividual sym ptoms for each treatm ent group. Overall
treatment dif ferences will be assess ed using a Cox Regression m
odel with ef fects f or
RAT result at screening, current smoking behavior, treatment group, and influenza season
at randomization (if necessary). Subjects who do not experience alleviation of symptoms
will be censored at the date of their last non-missing post-baseline assessment. Pairwise
differences in tim e to alleviation of sy
mptoms am ong the treatm ent groups will be
evaluated using contrast statem ents from the final Cox m odel. In orde r to m aintain the
overall type I error in the presence of the planned comparisons between the two peramivir
treatments and placebo, a Bonfe rroni correction will be app lied to the p rimary efficacy
endpoint analysis. P -values for the planne d com parisons of each peram ivir arm to
placebo will be adjusted via a Bonferroni corr ection (i.e., if the unadjusted p-value for an
active com parison versus place bo, p, is less th an 0.05, then p
a=p*number of planned
comparisons=p*2; otherwise, p
a=p). Superiority of peram
ivir to placebo will be
established if the adjusted p-value is less than or equal to 0.05.
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12.6.2 Secondary Efficacy Endpoints
All secondary endpoints will be summ
arized using descriptive statistics by treatm
ent
group and study day/time, if appropriate. St atistical comparisons for each endpoint will
be constructed without adjustment for multiple endpoints.
The reduction in viral shedding will be assessed as the change in viral titers defined as the
time-weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL)
and will be summarized for each treatm ent group. The tim e-weighted average change
from baseline will be calculated on a by-subject basis through Day 9 using the trapezoidal
rule with a ll available post-bas eline on-tre atment data (d ata af ter initia tion of study
treatment) minus the baseline value. Specifically, the time-weighted area under the curve
for time a (ta) to time b (tb) is given by the formula
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
,
where
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
and ti represents the date of the ith viral titer
assessment and y i represents the log10 value of the i th viral titer as sessment. If there is a
baseline value and only one follow-up value, y
i then the tim e-weighted change from
baseline is defined as the difference between y i and baseline. If there is a baselin e value
and no follow-up value, the subject is exclude d from analysis. The differences between
each of the peramivir treatment groups and placebo will be evaluated using a van Elteren
Test ad justing for RAT result at screen
ing, current sm oking be havior and influenza
season at randomization (if necessary). Analyses of the PCR results will be analy zed in
a similar manner.
Subject’s ability to perform usual activities as determined from the visual analog scale
will be summarized by study visit day and treatment group. Differences between the
treatment groups will be assessed using the van Elteren Test adjusting for smoking
behavior and influenza season at randomization (if necessary). The time (days) to
resumption of a subject’s ability to perform usual activities (i.e., subject scores ability to
perform usual activities as 10) will be estimated using the method of Kaplan-Meier.
Differences between each of the peramivir treatment groups and placebo will be assessed
using the log rank statistic adjusting for RAT result at screening, current smoking
behavior and influenza season at randomization (if necessary). Subjects who do not
return to the pre-study level of performance of usual activities will be censored at the
time of their last non-missing post-baseline visual analog scale value.
Subject’s oral tem perature will be summ
arized by study visit and treatm
ent group.
Differences between the treatment groups will be assessed using the Wilcoxon Rank Sum
Test con trolling for RAT resu lt at screen ing, current sm oking behavior and influenza
season at randomization (if necessary). A subject has Resolution of Fever if he/she has a
temperature < 37.2°C (99.0°F) and no antipyretic medications have been taken for at least
12 hours. The tim e to resolution of fever will be estimated using the method of Ka plan-
Meier using temperature and sym ptom relief medication information obtained from the
subject diary data. Difference between the tr eatment groups will be assessed using the
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log rank sta tistic controlling for RAT result a t screening, current sm oking behavior and
influenza season at randomization (if necessary). Subjects who do not have resolution of
fever will be censored at the tim
e of their last non- missing post-baseline tem perature
assessment.
The MRU, MRU-related direct co sts, and indirect co sts attributable to days m issed of
work and work productivity and/or perform ance losses will be summ arized by treatment
group. Differences between each of the peramivir treatment groups and placebo group
will be evaluated using both param etric and/or non-parametric tests, as appropriate. If
necessary, bootstrapping techniques will be used to calculate confidence intervals around
the incremental differences in costs.
12.6.3 Exploratory Endpoint
Genotypic (including Hem agglutinin and Neurom inidase), phenotypic, viral culture and
PCR data will be lis ted for each sub ject. These listings will be constructed in a m anner
consistent with the F
DA June 2006 Guidance Docum
ent:“Guidance for Subm itting
Influenza R esistance D ata”.18 Ad ditionally, the num ber and percen tage of genotypic
changes from wild-type a mino acid will be summarized separately for treatm ent group,
protein type, and study visit.
12.7 Safety Analyses
AEs will be m apped to a MedDRA-pref erred term and system organ classification. The
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred
terms, system organ classifications, and severity. If a subject experiences multiple events
that m ap to a s ingle p referred term, the grea test severity and st rongest Investigator
assessment of relation to study d
rug will be assigned to the preferred term for the
appropriate sum maries. All AEs will be li
sted f or individual subje cts showing both
verbatim and preferred terms. Separate summaries of treatment-emergent SAEs and AEs
related to study drug will be generated.
Descriptive summaries of vital s igns and clinic al laboratory results will be presented by
study visit. Laboratory abnorm alities will be graded according to the DAIDS Table for
Grading Adverse Events for Adults and Pedi atrics (Publish Date: December 2004). The
number and percentage of subjects experien
cing treatm ent-emergent graded toxicities
will be summarized by treatment group. Laborator y toxicity shifts from baseline to Day
3, Day 5, and Day 14 will be summarized by treatment group.
Abnormal physical exam ination findings wi ll be presented by treatm
ent group. The
number and percent of subjects experiencing each abnormal physical examination finding
will be included.
Concomitant medications will be co ded using the WHO dictionary. The se data will be
summarized by treatment group.
Subject disposition will be presented for a
ll s ubjects. The num ber of subjects who
completed the study and discontinued from the study will be provided. The reasons for
early discontinuation also will be presented.
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12.8 Sub-Study and Pharmacokinetic Analysis
The sub-study to exam ine exposure respons e, along with the corresponding single PK
samples collected on all subjects on study day
3 will be co mpleted as part of the sub-
study. All s tatistical m ethods will be outlin ed as part of the sub-stu
dy protocol and
exposure-response analysis plan. All sub-study analyses will be reported in a separate
sub-study report.
12.9 General Issues for Statistical Analysis
12.9.1 Multiple Comparisons and Multiplicity
In order to m aintain the overall typ e I e rror in the presen ce of the plann ed comparisons
between the two peram
ivir treatm ents and pl acebo, a Bonferroni correction will be
applied to the prim ary efficacy end point an alysis. No oth er ad justments for m ultiple
comparisons are planned.
12.9.2 Covariates
Primary and secondary efficacy analyses will
be adjusted for RAT result at screen ing,
current smoking behavior and influenza season at randomization (if necessary).
12.9.3 Planned Sub-Groups
The prim ary efficacy endpoint will be summ
arized separately by stratification group
(current sm oking behavior [sm oker or non-smoker] and RAT result at screening
[negative or positive]) and by viral subtype using descriptive statistics by treatment group
and study day, if appropriate. No formal statistical testing will be utilized.
Additional analyses m ay be perform ed by count ry, if necessary, for subm ission to local
regulatory authorities.
12.9.4 Missing Data
Every effort will be m ade to obtain required data at each s cheduled evaluation from all
subjects who have been random ized. No attemp t will be m ade retrospectively to obtain
missing subject reported data (including in
fluenza symptom severity assessm
ents,
temperature, ability to perf orm usual activi ties, m issed days of work and im
pact of
influenza on subject’s work perform
ance and/or productivity)
that has not been
completed by the subject at the time of return of the subject diary to the investigative site.
In situations where it is not possible to obt ain all da ta, it m ay be necessary to im pute
missing data.
In assessing the p rimary efficacy endpoint, fo r subjects w ho withdraw or who d o no t
experience allev iation of sym ptoms, m issing data will be
censored using the date of
subject’s last non-m issing assessment of infl uenza symptoms. Missing assessm ents of
influenza symptoms conservatively will be im puted as h aving severity above absen t or
mild (as f ailures). For the subjec t diary data, the f ollowing data con ventions will be
utilized. Missing diary com pletion will be imputed as 11:59 for diary entries designated
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as m orning and 23:59 for evening and daily
reported v alues. Entr ies with va lues
exceeding the 24-hour clock will b e set to 23:59 of the day recorded. Select explo ratory
sensitivity analyses m ay be conducted to ascert ain the effect, if any, of these m
ethods.
These sensitivity analy ses are further de
scribed in the SAP. Secondary efficacy
endpoints with tim e to event da ta will be censored using the date of subject’s last non-
missing assessment of the given endpoint.
13 STUDY ADMINISTRATION
13.1 Regulatory and Ethical Considerations
13.1.1 Regulatory Authority Approvals
This study will be conducted in
com pliance with th e protoco l; GCPs, including
International Conference on Harmonization (ICH) of Te
chnical Requirem ents for
Registration of Pharm
aceuticals for Hu
man Use G
uidelines; FDA regulatory
requirements and in accordance with the ethical principles of the Declaration of Helsinki.
In addition, all applicable loca l laws and regu latory requirements relevant to the use of
new therapeutic agents in the countries involved will be adhered to.
The Investigator should submit written reports of clinical study status to their Institutional
Review Board (IRB)/ Independent E thics Committee (IEC) annually or more frequently
if requested by the IRB/ IEC. A final s
tudy notification will also be forwarded to the
IRB/IEC af ter the study is com pleted or in the event of
prem ature ter mination of the
study in accordance with the appl icable regulations. Copies of all contact with the IRB/
IEC should be m aintained in the study docum ents file. Copies of clinical study status
reports (including termination) should be provided to BioCryst.
13.1.2 Ethics Committee Approvals
Before initiation of the study at each invest
igational site, the pr otocol, the inform ed
consent form, the subject inform ation sheet, and any other relevant study documentation
will be sub mitted to th e appropriate IRB/IE C. W ritten approval of th e study m ust be
obtained before the study center can be initiated or the investigational medicinal product
is re leased to the Inv
estigator. A ny necessa ry extension s or renew als of IRB/IEC
approval must be obtained, in particular, for changes to the study such as modification of
the pro tocol, the inf ormed consent f orm, th e written inform ation provided to subjects
and/or other procedures.
The Investigator will report promptly to
the IRB/IEC any new inform
ation that m ay
adversely affect the safety of the subjects or the conduct of the study. On completion of
the study, the Investigator will prov ide the IRB/IEC with a report of the outcom e of the
study.
13.1.3 Subject Informed Consent
Signed info rmed consent m ust be obtained from each subject p rior to performing any
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study-related procedures. E
ach subject should be given both verbal and w
ritten
information describing the nature and durati
on of the clinical st
udy. The inf ormed
consent process should take place u nder conditions where the subject h as adequate time
to consider the risks and bene
fits associated with his/her
participation in the study.
Subjects will not be screened or treated
until the subjec t has signed an approved ICF
written in a language in which the subject is fluent.
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.
The informed consent should be in acco
rdance with the curren
t revision o f the
Declaration of Helsinki, current ICH and GCP guidelines, and BioCryst policy.
The Investigator must explain to potential subjects or their legal representatives the aims,
methods, reasonably anticipated benefits, a
nd potential hazards of the trial and any
discomfort it may entail. Subjects will be informed that they are free not to participate in
the trial and that they may withdraw consent to participate at any time. They will be told
that refusal to participate in the study will not prejudice future treatment. They will a lso
be told tha t their recor ds m ay be exam ined by com petent autho rities and au thorized
persons but that pe rsonal information will be tr eated as strictly confidential and will not
be publicly available. Subjects must be given the opportunity to ask questions. After this
explanation and before entry in to the trial, consent should be appropriately recorded by
means of the subject’s dated signature. The subject shoul d receive a signed and dated
copy of the ICF. The original signed infor med consent should be retained in the study
files. The Investigator shall maintain a log of all subjects who sign the ICF and indicate
if the subject was enrolled into the study or reason for non-enrollment.
13.1.4 Payment to Subjects
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC
responsible for the study at the Investigator’s site.
13.1.5 Investigator Reporting Requirements
The Investigator will provide tim ely repo rts regard ing s afety to his /her IRB/IE C as
required.
13.2 Study Monitoring
During trial conduct, BioCryst or its designee will conduct period ic monitoring visits to
ensure that the protocol and GCPs a re being followed. The monitors may review source
documents to conf irm that th e data recorded on CRFs is accurate. The investigator and
institution will allow BioCryst m
onitors or its des ignees and app ropriate regulatory
authorities direct access to source documents to perform this verification.
13.3 Quality Assurance
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits
performed by BioCryst, and/or to inspection by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the
monitoring visits and possible a udits or inspections and that sufficient tim e is devoted to
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the process.
13.4 Study Termination and Site Closure
BioCryst reserves the right to
disc ontinue the tr ial prio r to inc lusion of the in tended
number of subjects but intends only to exer
cise this r ight f or valid scientif ic or
administrative reasons. After such a deci
sion, the Investigator must contact all
participating subjects immediately after notification. As directed by BioCryst, all study
materials must be collected a nd all case report forms completed to the greatest extent
possible.
13.5 Records Retention
To enable evaluations and/or
audits from
regulatory au
thorities o r BioCryst, the
Investigator agrees to k eep records, includi ng the iden tity of all p articipating sub jects
(sufficient inf ormation to link re
cords, case report forms and hospital records), all
original signed inform ed consent form s, copies of all case report form
s and detailed
records of treatm ent disposition. The reco
rds should be retained by the Investigator
according to local regulations or as specified in the Clinical Trial Agreem ent, whichever
is longer.
If the Investigator relocates, retires, or for any reason withdraws from the study, the study
records m ay be transferred to an
acceptab le designee, such as another investigato
r,
another institution, or to BioCryst. The I
nvestigator m ust obtain BioCryst’s written
permission before disposing of any records.
13.6 Study Organization
13.6.1 Data Monitoring Committee
BioCryst will a ssemble an indep endent Data M onitoring C ommittee ( DMC) to as sess
safety parameters of the trial on a period ic, ongoing basis while the tr ial is in prog ress.
The comm ittee will include a s tatistician and th ree phys icians, tw o of whom will be
Infectious Disease specialists. Full detail s of the com position of the D MC and how the
DMC is to operate will be described in a separate DMC charter.
13.7 Confidentiality of Information
BioCryst affirms the subject’s right to prot ection against invasion of privacy. Only a
subject id entification n umber, initials and /or date of birth will id
entify subject data
retrieved by BioCryst . However, in com pliance with federal regulations, BioCryst
requires the investigato r to p ermit BioCryst ’s representatives and, when neces sary,
representatives of the FDA or
other regu latory authoritie s to review and/or copy any
medical records relevant to the study.
BioCryst will ensure that the use and disclosur e of protected health information obtained
during a research study com plies with the HIPAA Privacy Rule. Th e Rule pro vides
federal protection for the privacy of prot
ected health inf ormation by im plementing
standards to protec t an d guard ag ainst the m isuse of ind ividually id entifiable h ealth
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information of subj
ects participating in
BioCryst-sponsored Clinical Trials.
"Authorization" is required from each research subject, i.e., specified permission granted
by an individual to a covered entity for the us e or disclosure of an indi vidual's protected
health information. A valid au thorization must meet the implem entation specifications
under the HIPAA Pri
vacy Rule. Authorizat
ion m ay be com bined in the Inform
ed
Consent docum ent (approved by the IRB/IE
C) or it may be a separate docum
ent,
(approved by the IRB/IEC) or provided by the Investigator or Sponsor (without IRB/IEC
approval). It is the responsibility of the
investigator and institution to obtain such
waiver/authorization in writing f rom the appr opriate ind ividual. HIPAA authoriz ations
are required for U.S. sites only.
13.8 Study Publication
All data generated from this study are the propert y of BioCryst and shall be held in strict
confidence along with all inform
ation furnis hed by BioCryst. Independent analysis
and/or publication of these data by the Investigator or any member of his/her staff are not
permitted without prior written consent of
BioCryst. W ritten perm ission to the
Investigator will be contingen t on the review by BioCryst of the statistical ana lysis and
manuscript and will provide fo r nondisclosure of BioCryst confidential or proprietary
information. In all case s, the partie s agree to s ubmit all m anuscripts or abstracts to all
other par ties 30 days prior to su
bmission. This will e
nable all parties to pr
otect
proprietary information and to provide comme nts based on infor mation that may not yet
be available to other parties.
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14 REFERENCES
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282.
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality
associated with influenza and respiratory syncytial virus in the United States. JAMA
2003;289(2):179–186.
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment
on influenza-related lower respiratory tract complications and hospitalizations. Arch
Intern Med 2003;163(14):1667–1672.
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral
neuraminidase inhibitor oseltamivir in experimental human influenza: randomized
controlled trials for prevention and treatment. JAMA 1999;282(13):1240–1246.
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant
influenza A viruses in children treated with oseltamivir: descriptive study. Lancet
2004;364(9436):759–765.
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-
influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir.
Antimicrob Agents Chemother 2001;45(4):1162–1167.
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus
isolates to different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147.
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir,
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and
neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother
2001;45(12):3403–3408.
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine
combinations exert additive and synergistic anti-influenza virus effects in MDCK
cells. Antimicrob Agents Chemother 2004;48(12):4855–4863.
10. BioCryst Pharmaceuticals. Unpublished data.
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S.
Injectable peramivir promotes survival in mice and ferrets infected with highly
pathogenic avian influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San
Francisco
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA.
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival
against lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03.
14. Tamiflu® Package Insert. Roche Pharmaceuticals. Rev. December 2005.
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product
information sheets
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16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the
oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000;
283(8): 1016-1024.
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of
oseltamivir in treatment of influenza: a randomised controlled trial. Lancet 2000;
355(9218): 1845-1850.
18. US Department of Health and Human Services, Food and Drug Administration
Center for Drug Evaluation and Reserach (CDER). Attachment to Guidance on
Antiviral Product Development- Conducting and Submitting Virology Studies to the
Agency: Guidance for Submitting Influenza Resistance Data.
http://www.fda.gov/cder/guidance/7070fnlFLU.htm
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15 APPENDICES
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina
NYHA Functional Classification of Heart Failure
Class I
No symptoms. Ordinary physical activity such as walking and climbing
stairs does not cause fatigue or dyspnea.
Class II
Symptoms with ordinary physical activity. W alking or climbing stairs
rapidly; walking uphill; walking or st air climbing after meals, in cold
weather, in wind, or when under em otional stress causes undue fatigue
or dyspnea.
Class III
Symptoms with less than ordinary
physical activity. W alking one to
two blocks on the level and clim bing more than one flight of stairs in
normal conditions causes undue fatigue or dyspnea.
Class IV
Symptoms at res t. Inab ility to carry on any ph ysical activity without
fatigue or dyspnea.
NYHA Functional Classification of Angina
Class I
Angina only with unusually strenuous activity.
Class II
Angina with slightly m ore prolonged or slightly more vigorous activity
than usual.
Class III
Angina with usual daily activity.
Class IV
Angina at rest.
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CLINICAL STUDY PROTOCOL
Protocol No. BCX1812-311
IND No. 76,350
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE
INFLUENZA
THE IMPROVE I STUDY
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy)
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza
Protocol Date(s):
Version 1.0: 04 September 2007
Version 2.0: 05 October 2007
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35244, USA
Phone: +1 919 859 1302
Fax: +1 919 851 1416
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals,
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information
contained herein should be disclosed without prior written approval.
CONFIDENTIAL
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1
TITLE PAGE
Protocol Number:
BCX1812-311
Study Title:
A phase 3 multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of
intramuscular peramivir in subjects with uncomplicated acute
influenza
IND Number:
76, 350
Investigational Product:
Peramivir (BCX1812)
Indication Studied:
Uncomplicated acute influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35233
Development Phase:
3
Sponsor Medical Officer:
W. James Alexander, M.D., M.P.H.
Senior Vice President, Clinical Development
Chief Medical Officer
Phone: +1 919 859 1302
Fax: +1 919 851 1416
Email Address: jalexander@biocryst.com
Compliance Statement:
This study will be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki
and clinical research guidelines established by the Code of
Federal Regulations (Title 21, CFR Parts 50, 56, and 312)
and ICH Guidelines. Essential study documents will be
archived in accordance with applicable regulations.
Final Protocol Date:
Version 1.0: 04 September 2007
Amendment(s) Date(s):
Version 2.0: 05 October 2007
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1.2
Clinical Study Protocol Agreement
Protocol No.
BCX1812-311
Protocol Title:
A phase 3 multicenter, random ized, double-blind, placebo-controlled
study to evaluate the effic acy and safety of intramuscular peramivir in
subjects with uncomplicated acute influenza
I have carefully read this protocol and agree that it contains all of the necessary information
required to conduct this study. I agree to c onduct this study as described and according t o
the Decl aration of Helsinki, Internationa l Conference on Har monization Guidelines for
Good Clinical Practices, and all applicable regulatory requirements.
Investigator’s Signature
Date
Name (Print)
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2
SYNOPSIS
Protocol No.
BCX1812-311
Protocol Title:
A phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of
intramuscular peramivir in subjects with uncomplicated acute
influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
Investigators/Study Sites:
Multinational
Development Phase:
3
Objectives:
Primary:
To evaluate the efficacy of peramivir administered
intramuscularly compared to placebo on the time to alleviation
of clinical symptoms in adult subjects with uncomplicated acute
influenza.
Secondary:
1.
To evaluate the safety and tolerability of peramivir
administered intramuscularly
2.
To evaluate secondary clinical outcomes in response to
treatment
3.
To evaluate changes in influenza virus titer in
nasopharyngeal samples (viral shedding) in response to
treatment
Exploratory:
1. To assess pharmacoeconomic measures as response to
treatment
2. To assess changes in influenza viral susceptibility to
neuraminidase inhibitors following treatment
Number of Subjects:
Total enrollment: a total of 750 evaluable subjects will be
randomized to treatment (150 subjects in the placebo treatment
group, 300 subjects in the peramivir 150mg treatment group and
300 subjects in the peramivir 300mg treatment group).
An evaluable subject is one who is randomized, receives study
drug, and has confirmed acute influenza by primary viral culture
or PCR. A positive Rapid Antigen Test (RAT) at screening will
be required for enrollment. Because results of clinic-based RAT
tests may not precisely indicate presence of influenza infection,
it is expected that at least 850 subjects will be randomized to
treatment to ensure that 750 evaluable subjects are treated.
Study Design:
This is a multinational, randomized, double-blind study
comparing the efficacy and safety of two single dose regimens
of peramivir administered intramuscularly versus placebo in
adults with uncomplicated acute influenza.
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Each subject’s assignment to treatment will be stratified
according to body mass index (BMI). Two BMI strata are
planned: Normal-Overweight (≤ 29.9 kg/m2), and Obese (≥ 30.0
kg/m2). The number of subjects enrolled who have a BMI ≤ 29.9
kg/m2 (Normal-Overweight) will be at least 75% of the total
enrollment. The number of subjects enrolled who have a BMI ≥
30.0 kg/m2 (Obese) will be ≤ 25% of total enrollment.
All subjects will be centrally randomized to one of three
treatment groups according to BMI strata in a ratio of 2:2:1 such
that 80% of subjects are randomized to one of the two single
dose regimens of peramivir.
Treatment Group 1: Peramivir 150mg
Treatment Group 2: Peramivir 300mg
Treatment Group 3: Placebo
Study drug will be administered as bilateral 2mL intramuscular
injections (total of 4mL injected in equally divided doses).
Procedures for gluteal intramuscular injection, with a
recommended needle length appropriate to the physical
characteristics of the subject, are provided in the study drug
administration manual.
Subjects eligible for screening will have an anterior nasal swab
collected for testing by rapid antigen testing (RAT) for influenza
A and B, in accordance with the commercially available RAT
kit instructions. If the initial RAT is negative, the test should be
repeated within one hour. Subjects meeting the
inclusion/exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following information in a
Study Diary:
• Assessment of the presence and severity of each of seven
symptoms of influenza on a 4-point scale (0, absent; 1, mild;
2, moderate; 3, severe) twice daily (AM, PM) through Day 9
following treatment, then once daily (AM) through Day 14
• Oral temperature measurements taken with an electronic
thermometer every 12 hours. With the exception of the
baseline measurement, all temperature measurements will be
obtained at least 4 hours after, or immediately before,
administration of oral acetaminophen (paracetamol) or other
anti-pyretic medications.
• Assessment of subject’s time lost from work or usual
activities and rating of productivity compared to normal
(rated as 0-10 on a visual analog scale) once daily through
Day 14
• Doses of antipyretic, expectorant, and/or throat lozenges
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taken for symptomatic relief each day through Day 14
Anterior nose (bilateral) and posterior pharynx specimens
(swabs) will be collected at Day 1 (pre-treatment) and at Days 3,
5, and 9, for quantitative virologic assessments. Specimens from
all subjects yielding influenza virus will also be assessed for
susceptibility to neuraminidase inhibitors (Day 1 and last
specimen yielding positive result on culture) as well as other
virologic assessments (e.g. PCR, genotypic testing)
All virologic assessments will be performed by a central
laboratory.
Two samples for pharmacokinetic (PK) testing for plasma levels
of peramivir will be obtained from all subjects randomized. The
first PK sample will be obtained between 30 and 60 minutes
following study drug administration in all subjects. The second
PK sample will be obtained at the day 3 visit in all subjects. The
data from these PK samples will be utilized in a population
exposure-response analysis.
At selected sites a separate sub-study will be conducted to
collect additional PK samples between treatment and Day 3 for
the purpose of conducting a separate exposure-response
analysis. This sub-study will be conducted under a separate
protocol, BCX1812-311PK.
Study Population:
Male and female subjects, 18 years of age and older, with
symptoms consistent with a diagnosis of uncomplicated acute
influenza infection may be screened for enrollment. Subject
eligibility will require the presence of two or more symptoms
consistent with acute influenza as well as positive results
obtained from a rapid antigen test (RAT) for influenza A or B at
screening.
Inclusion Criteria:
1. Male and non-pregnant female subjects age ≥18 years.
2. A positive Influenza A or B Rapid Antigen Test (RAT)
performed with a commercially available test kit on an
adequate anterior nasal specimen, in accordance with the
manufacturer’s instructions. A negative initial RAT should
be repeated within one-hour.
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4
ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. A
subject self-report of a history of fever or feverishness
within the 24 hours prior to screening will also qualify for
enrollment in the absence of documented fever at the time of
screening.
4. Presence of at least one respiratory symptom (cough, sore
throat, or nasal symptoms) of at least moderate severity.
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5. Presence of at least one constitutional symptom (myalgia
[aches and pains], headache, feverishness, or fatigue) of at
least moderate severity.
6. Onset of symptoms no more than 48 hours before
presentation for screening.
7. Written informed consent.
Exclusion Criteria:
1. Women who are pregnant or breast-feeding.
2. Presence of clinically significant signs of acute respiratory
distress.
3. History of severe chronic obstructive pulmonary disease
(COPD) or severe persistent asthma.
4. History of congestive heart failure requiring daily
pharmacotherapy with symptoms consistent with New York
Heart Association Class III or IV functional status within the
past 12 months.
5. Screening ECG which suggests acute ischemia or presence
of medically significant dysrhythmia.
6. History of chronic renal impairment requiring hemodialysis
and/or known or suspected to have moderate or severe renal
impairment (actual or estimated creatinine clearance <50
mL/min).
7. Clinical evidence of worsening of any chronic medical
condition (temporally associated with the onset of symptoms
of influenza) which, in the investigator’s opinion, indicates
that such finding(s) could represent complications of
influenza.
8. Current clinical evidence, including clinical signs and/or
symptoms consistent with otitis, bronchitis, sinusitis and/or
pneumonia, or active bacterial infection at any body site that
requires therapy with oral or systemic antibiotics.
9. Presence of immunocompromised status due to chronic
illness, previous organ transplant, or use of
immunosuppressive medical therapy which would include
oral or systemic treatment with > 10 mg prednisone or
equivalent on a daily basis within 30 days of screening.
10. Currently receiving treatment for viral hepatitis B or viral
hepatitis C.
11. Presence of known HIV infection with a CD4 count <350
cell/mm3.
12. Current therapy with oral warfarin or other systemic
anticoagulant.
13. Receipt of any doses of rimantadine, amantadine, zanamivir,
or oseltamivir in the 7 days prior to screening.
14. Immunized against influenza with live attenuated virus
vaccine (FluMist®) in the previous 21 days.
15. Immunized against influenza with inactivated virus vaccine
within the previous 14 days.
16. Receipt of any intramuscular injection within the previous
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14 days.
17. History of alcohol abuse or drug addiction within 1 year
prior to admission in the study.
18. Participation in a previous study of intramuscular or
intravenous peramivir or previous participation in this study
19. Participation in a study of any investigational drug or device
within the last 30 days.
Study Endpoints:
Primary Endpoint:
Clinical:
Time to alleviation of clinical symptoms of influenza.
Secondary Endpoint(s):
Safety:
Incidence of treatment-emergent adverse events and treatment-
emergent changes in clinical laboratory tests.
Clinical:
Time to resolution of fever.
Incidence of influenza related complications.
Virologic:
Quantitative change in influenza virus shedding, measured by
viral titer assay (TCID50).
Exploratory Endpoint(s):
Pharmacoeconomic:
Medical resource utilization (MRU), missed days of work, and
impact of influenza illness on subject’s work performance
and/or productivity.
Virologic:
Quantitative change in influenza virus shedding, measured by
PCR.
Change in influenza virus susceptibility to neuraminidase
inhibitors.
Investigational Product, Dose, and Mode of Administration:
Peramivir (BCX-1812), 75mg/mL, 2mL per injection, administered as bilateral injections.
Reference Therapy, Dose, and Mode of Administration:
Matching Placebo (buffered diluent), 2mL per injection administered as bilateral injections.
Duration of Treatment:
Following treatment on day 1, study duration for all subjects is
expected to be up to 14 days (including all visits). Presence of
unresolved adverse events and/or treatment-emergent laboratory
findings at the Day 14 visit, or persistent or recurrent symptoms
of influenza (of the seven symptoms assessed) of either
moderate or severe intensity at the Day 14 visit, will require
additional follow up.
Statistical Methods:
Study Hypothesis:
The null hypothesis (H0) for this study is that the time to
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alleviation of influenza symptoms is the same for subjects
treated with placebo and for subjects treated with peramivir
150mg (H01) or peramivir 300mg (H02).
The alternative hypothesis (H1) is that subjects treated with
peramivir 150mg (H11) or peramivir 300mg (H12) have an
improvement in time to alleviation of influenza symptoms over
those treated with placebo.
Sample Size:
From preliminary results of a phase 2 study evaluating peramivir
treatment of uncomplicated influenza, it is expected that the
median time to alleviation of symptoms will be 137.0 hours
(95% CI: 115.9, 165.8) for subjects receiving placebo
treatment. Additionally, it is expected that the median time to
alleviation for the 150 mg dose peramivir arm will be reduced
by 30% compared to placebo (see table below) yielding a hazard
ratio of 0.70.
Median Time To Alleviation of Symptoms (Hours)
Placebo
Peramivir 150mg
Difference (hours)
145.0
101.5
43.5
140.0
98.0
42.0
135.0
94.5
40.5
130.0
91.0
39.0
125.0
87.5
37.5
120.0
84.0
36.0
115.0
80.5
34.5
110.0
77.0
33.0
105.0
73.5
31.5
100.0
70.0
30.0
Using these assumptions, a sample size of 300 evaluable
subjects per active treatment group and 150 evaluable subjects
in the placebo group (a total of 750 evaluable subjects) is
sufficient to provide at least 90% power to detect a hazard ratio
of 0.70 using a log-rank statistic and α = 0.025 (SAS version
9.1.3; total accrual time 7 months; total enrollment time 6
months).
Efficacy:
The intent-to-treat infected population (ITTI) will include all
subjects who are randomized, received study drug, and have
confirmed influenza by primary viral culture or PCR. The
primary efficacy variable is the time to alleviation of symptoms,
defined as the time from injection of study drug to the start of
the time period when each of seven symptoms of influenza are
either absent or are present at no more than mild severity level
and remain at no worse than this severity status for a 21.5 hour
(24 hours – 10%) period.
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Descriptive statistics for the primary efficacy variable will be
tabulated by treatment group. Alleviation of symptoms will be
determined by assessment of symptoms as reported on each
subject’s diary card. Time to alleviation of symptoms will be
summarized for each treatment group. Treatment difference will
be assessed using a Cox Regression model with effects for BMI
at screening, influenza type by PCR at screening, treatment
group, and, if necessary, influenza season at randomization.
Pairwise comparisons between each active group and placebo
will be constructed from the Cox Regression model. Subjects
who do not experience alleviation of symptoms will be censored
at the date of their last non-missing assessment. Time to
resolution of fever will be analyzed in a similar manner.
Efficacy analyses will be repeated for a Per-Protocol Infected
population (PPI). This population will include those subjects in
the ITTI population who received an adequate intramuscular
injection. Details of this population will be described in the
statistical analysis plan. The PPI population analysis will be
used as supportive to the primary analysis with the ITTI.
Changes in influenza virus TCID50 (viral titers from
nasopharyngeal specimens) will be compared using the van
Elteren statistic controlling for BMI at screening, influenza type
by PCR, and, if necessary, for influenza season at
randomization. Analyses of other continuous endpoints will be
analyzed in a similar manner.
The number and percentage of subjects experiencing influenza
related complications (IRC) will be summarized by
complication preferred term and treatment group. The
difference between the treatment groups will be assessed using a
logistic regression model with factors for treatment group, BMI
at screening, influenza type by PCR, and influenza season at
randomization (if necessary). Pairwise differences between the
treatment groups will be evaluated using contrasts from the final
logistic regression model.
Safety:
Safety analyses will be presented for all subjects in the safety
population, defined as all randomized subjects who receive at
least one dose of study drug. Adverse events will be mapped to
a Medical Dictionary for Regulatory Activities (MedDRA)
preferred term and system organ classification.
The occurrence of treatment-emergent AEs will be summarized
using preferred terms, system organ classifications, and severity.
Separate summaries of treatment-emergent SAEs and treatment-
emergent AEs that are related to study medication will be
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generated. All AEs will be listed for individual subjects
showing both verbatim and preferred terms.
Descriptive summaries of vital signs and quantitative clinical
laboratory changes will be presented by study visit. Frequency
and percentages of subjects with abnormal laboratory test results
will be summarized by toxicity grade.
Concomitant medications will be mapped to a WHO preferred
term and drug classification. The number and percent of
subjects taking concomitant medications will be summarized
using preferred terms and drug classifications. The number and
percent of subjects experiencing each abnormal physical
examination finding will be presented.
The number and percent of subjects discontinuing study as well
as the reasons for discontinuation will be summarized by
treatment group.
Date of Protocol:
Version 1.0: 04-September-2007
Amendment (Dates):
Version 2.0: 05-October-2007
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3
TABLE OF CONTENTS
1 TITLE
PAGE .................................................................................................................2
1.1 P
ROTOCOL APPROVAL SIGNATURE PAGE ......................................................................3
1.2 C
LINICAL STUDY PROTOCOL AGREEMENT ....................................................................4
2 SYNOPSIS
.....................................................................................................................5
3 TABLE
OF CONTENTS .............................................................................................13
3.1 L
IST OF FIGURES...........................................................................................................15
3.2 L
IST OF TABLES............................................................................................................15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................16
5 INTRODUCTION
........................................................................................................18
5.1 B
ACKGROUND...............................................................................................................18
5.2 R
ATIONALE FOR STUDY................................................................................................18
5.3 N
ON-CLINICAL EXPERIENCE WITH PERAMIVIR............................................................19
5.3.1
In vitro Assays..........................................................................................................19
5.3.2 Anim
al Models.........................................................................................................19
5.4 P
REVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR...........................20
5.5 P
REVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR ........................20
5.6 P
HASE 2 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR..........................................21
5.7 DOSE RATIONALE ................................................................................................................23
6 STUDY
OBJECTIVES ................................................................................................24
6.1 O
BJECTIVES ..................................................................................................................24
6.1.1 Prim
ary Objective ....................................................................................................24
6.1.2 Secondary
Objective(s) ............................................................................................24
6.1.3 Explorator
y Objective(s)..........................................................................................24
6.2 S
TUDY ENDPOINTS .......................................................................................................24
6.2.1 Prim
ary Endpoint .....................................................................................................24
6.2.2 Secondary
Endpoint(s).............................................................................................24
6.2.3 Explorator
y Endpoints .............................................................................................25
7 STUDY
DESIGN.........................................................................................................25
7.1 O
VERALL STUDY DESIGN AND PLAN ...........................................................................25
8
SELECTION AND WITHDRAWAL OF SUBJECTS................................................26
8.1.1 Inclusion
Criteria......................................................................................................26
8.1.2 Exclusion
Criteria.....................................................................................................27
8.1.3
Removal of Subjects from Therapy or Assessment .................................................27
9 TREATMENTS
............................................................................................................28
9.1 T
REATMENTS ADMINISTERED ......................................................................................28
9.2 I
DENTITY OF INVESTIGATIONAL PRODUCT(S)..............................................................28
9.3 M
ETHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................29
9.4 S
TUDY MEDICATION ACCOUNTABILITY ......................................................................29
9.5 B
LINDING/UNBLINDING OF TREATMENTS....................................................................29
9.6 P
RIOR AND CONCOMITANT THERAPIES........................................................................30
9.7 O
VERDOSE AND TOXICITY MANAGEMENT...................................................................30
9.8 D
OSE INTERRUPTION ....................................................................................................30
10 STUDY
CONDUCT ....................................................................................................30
10.1 E
VALUATIONS...............................................................................................................30
10.1.1 Medical
History ...................................................................................................30
10.1.2
Rapid Antigen Test for Influenza ........................................................................30
10.1.3
Physical Examination and Influenza-related Complications Assessments..........31
10.1.4 Vital
Signs ...........................................................................................................31
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10.1.5 Electrocardiogram
Measurements .......................................................................31
10.1.6 Clinical
Laboratories............................................................................................31
10.1.7
Urine Pregnancy Test...........................................................................................32
10.1.8 Serology
for Influenza .........................................................................................32
10.1.9
Samples for Virologic Laboratory Assessments..................................................32
10.1.10
Subject Self Assessments.....................................................................................32
10.1.11 Concom
itant Medications....................................................................................33
10.1.12 Adverse
Events ....................................................................................................33
10.1.13
Pharmacokinetic Exposure Samples....................................................................33
10.2 S
CREENING PERIOD ......................................................................................................33
10.2.1 Inform
ed Consent ................................................................................................33
10.2.2
Screening/Baseline Evaluation and Enrollment...................................................33
10.3 T
REATMENT PERIOD—STUDY DAY 1 ..........................................................................34
10.3.1 Pre-dose
Evaluations-Study Day 1 ......................................................................34
10.3.2 Post-dose
Evaluations-Study Day 1.....................................................................34
10.4 P
OST-TREATMENT ASSESSMENT PERIOD.....................................................................35
10.4.1
Days 2, 3, 5, 9 and 14 ..........................................................................................35
10.4.2
Adverse Events Reported at Post-treatment Visits ..............................................36
11
ADVERSE EVENT MANAGEMENT........................................................................39
11.1 D
EFINITIONS .................................................................................................................39
11.1.1 Adverse
Event......................................................................................................39
11.1.2
Serious Adverse Event.........................................................................................39
11.2 M
ETHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING ADVERSE EVENTS AND
REPORTING SERIOUS ADVERSE EVENTS ......................................................................40
11.2.1 Definition
of Severity ..........................................................................................40
11.2.2
Definition of Relationship to Study Drug............................................................41
11.2.3
Reporting Serious Adverse Events ......................................................................41
11.2.4 E
mergency Procedures ........................................................................................42
12 STATISTICAL
METHODS ........................................................................................42
12.1 D
ATA COLLECTION METHODS .....................................................................................42
12.2 S
TATISTICAL ANALYSIS PLAN......................................................................................43
12.3 S
TUDY HYPOTHESIS .....................................................................................................43
12.4 S
AMPLE SIZE ESTIMATES .............................................................................................43
12.5 A
NALYSIS POPULATIONS..............................................................................................44
12.6 I
NTERIM AND END OF STUDY ANALYSES.....................................................................45
12.7 E
FFICACY ANALYSES ...................................................................................................45
12.7.1
Primary Efficacy Endpoint ..................................................................................45
12.7.2
Secondary Efficacy Endpoints.............................................................................45
12.7.3 Explorator
y Endpoint...........................................................................................46
12.8 S
AFETY ANALYSES.......................................................................................................47
12.9 S
UB-STUDY AND PHARMACOKINETIC ANALYSIS.........................................................47
12.10 G
ENERAL ISSUES FOR STATISTICAL ANALYSIS............................................................47
12.10.1
Multiple Comparisons and Multiplicity...............................................................47
12.10.2 Covariates
............................................................................................................48
12.10.3 Planned
Sub-Groups ............................................................................................48
12.10.4 Missing
Data........................................................................................................48
13 STUDY
ADMINISTRATION.....................................................................................48
13.1 R
EGULATORY AND ETHICAL CONSIDERATIONS...........................................................48
13.1.1
Regulatory Authority Approvals .........................................................................48
13.1.2
Ethics Committee Approvals...............................................................................49
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13.1.3
Subject Informed Consent ...................................................................................49
13.1.4
Payment to Subjects.............................................................................................50
13.1.5 Investigator
Reporting Requirements ..................................................................50
13.2 S
TUDY MONITORING ....................................................................................................50
13.3 Q
UALITY ASSURANCE ..................................................................................................50
13.4 S
TUDY TERMINATION AND SITE CLOSURE...................................................................50
13.5 R
ECORDS RETENTION...................................................................................................50
13.6 S
TUDY ORGANIZATION.................................................................................................51
13.6.1
Data Monitoring Committee................................................................................51
13.7 C
ONFIDENTIALITY OF INFORMATION ...........................................................................51
13.8 S
TUDY PUBLICATION....................................................................................................51
14 REFERENCES
.............................................................................................................52
15 APPENDICE
S..............................................................................................................54
15.1 NYHA
FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA......54
15.2 C
RITERIA FOR SEVERE COPD AND SEVERE ASTHMA..................................................55
3.1
List of Figures
Figure 1
Study Measurements and Visit Schedule.................................................................37
3.2
List of Tables
Table 1
Results of study BC-01-03.......................................................................................20
Table 2
Pharmacokinetic parameters from study Him-06-111. ............................................21
Table 3
Summary of Efficacy from BCX1812-211. .............................................................22
Table 4
Summary of Safety from BCX1812-211. ................................................................23
Table 5
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio)..........44
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0–72
area under the curve from time 0 to 72 hours
AUC0–∞
area under the curve extrapolated from time 0 to infinity
BMI
Body Mass Index in kg/m2
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CIOMS
Council for International Organizations of Medical sciences
Cmax
maximum plasma concentration
CK
creatine kinase
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CRF
Case Report Form
CV
coefficient of variation
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
IC50
median inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRC
influenza related complications
ITT
intent-to-treat
ITTI
intent-to-treat infected
IUD
intrauterine device
IVRS
interactive voice response system
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
NSAID
non-steroidal anti-inflammatory drug
PCR
polymerase chain reaction
RAT
Rapid Antigen Test
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
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SD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Event
t1/2
elimination half-life
t1/2 λz
terminal half-life
TCID50
tissue-culture infective dose50
TEAEs
treatment-emergent adverse events
Tmax
time to attain maximum plasma concentration
WBC
white blood cell
WHO
World Health Organization
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5
INTRODUCTION
5.1
Background
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of the
respiratory tract. Typical influenza illness is characterized by abrupt onset of fever, headache,
myalgia, sore throat, and nonproductive cough.1 The illness is usually self-limiting, with relief of
symptoms occurring within 5 to 7 days. Nevertheless, it is an important disease for several
reasons, including ease of communicability, short incubation time, rapid rate of viral mutation,
morbidity with resultant loss of productivity, risk of complicating conditions, and increased risk
of death, particularly in the elderly. During 19 of the 23 influenza seasons between 1972/1973
and 1994/1995, estimated influenza-associated deaths in the United States ranged from
approximately 25 to more than 150 per 100,000 persons above 65 years of age, accounting for
more than 90% of the deaths attributed to pneumonia and influenza.2
Presently, only a few measures are available that can reduce the impact of influenza: active
immunoprophylaxis with an inactivated or live attenuated vaccine and chemoprophylaxis or
therapy with an influenza-specific antiviral drug. Neuraminidase inhibitors are the current
mainstay of antiviral treatment for influenza. Marketed neuraminidase inhibitors include
zanamivir (Relenza®, GlaxoSmithKline) and oseltamivir (Tamiflu®, Roche-Gilead), an oral
prodrug of the active agent, oseltamivir carboxylate. Influenza neuraminidase is a surface
glycoprotein that cleaves sialic acid residues from glycoproteins and glycolipids. The enzyme is
responsible for the release of new viral particles from infected cells and may also assist in the
spreading of virus through the mucus within the respiratory tract. The neuraminidase inhibitors
represent an important advance in the treatment of influenza with respect to activity against
influenza A and B viruses, with proven therapeutic value in reducing influenza lower respiratory
complications,3 and lower rates of antiviral drug resistance4.
The use of currently available neuraminidase inhibitors has been limited by concerns including,
the degree of effectiveness, the requirement for an inhaler device (zanamivir), and the emergence
of resistant influenza virus variants in some treated populations.5 In addition, there are risks of
bronchospasm with zanamivir; and gastrointestinal side effects, with oseltamivir.
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to the
armamentarium of drugs for the treatment of influenza infections due to its potential for
parenteral administration and lower frequency of dosing.
5.2
Rationale for Study
An oral formulation of peramivir has previously been evaluated in a full range of safety,
tolerability, pharmacokinetic, and efficacy studies. In a multinational phase 3 clinical trial
conducted in 1999-2001, oral peramivir demonstrated antiviral activity against influenza A and B
infections, and improvement in the relief of clinical symptoms. Because of the limited
bioavailability of peramivir following oral administration (<5%), it was determined that the
parenteral route of administration is more appropriate for the delivery of peramivir. Subsequent
phase 1 studies of intravenous and intramuscular formulations of peramivir have confirmed that
parenteral routes of administration result in plasma levels of drug that are as much as 100 times
those achieved via the oral route. Further details of these studies are provided below and in the
Investigator Brochure.
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Because of the previous demonstration of significant antiviral activity, the strong suggestion of
clinical efficacy of oral peramivir previously demonstrated in acute influenza, and the
encouraging pharmacokinetic and preliminary safety profile of the intramuscular formulation of
peramivir demonstrated to date, this phase 3 study will be conducted to evaluate the efficacy and
safety profile of intramuscular peramivir and to determine the optimal single dose regimen.
5.3
Non-Clinical Experience with Peramivir
5.3.1
In vitro Assays
Peramivir is a selective inhibitor of viral neuraminidase, with 50% inhibitory concentrations
(IC50) for bacterial and mammalian enzymes of >300µM.6 In an in vitro study, 42 influenza A and
23 influenza B isolates were collected from untreated subjects during the 1999–2000 influenza
season in Canada.7 These isolates were tested for their susceptibility to the neuraminidase
inhibitors zanamivir, oseltamivir carboxylate, and peramivir using a chemiluminescent
neuraminidase assay. Inhibition of Type A influenza neuraminidase by peramivir was
approximately an order of magnitude greater than inhibition of neuraminidase from Type B
viruses. IC50 values for the Type A enzymes ranged from <0.1 to 1.4nM, whereas the Type B
enzymes ranged from <0.1 to 11nM, with three out of four values in the 5- to 11nM range.
Peramivir was the most potent drug against influenza A (H3N2) viruses with a mean IC50 of
0.60nM as well as most potent against influenza B with a mean IC50 of 0.87nM.
In another in vitro comparison of peramivir, oseltamivir, and zanamivir, using a neuraminidase
inhibition assay with influenza A viruses, the median IC50 of peramivir (approximately 0.34nM)
was comparable to that of oseltamivir (0.45nM) and significantly lower than zanamivir (0.95nM).
For influenza B virus clinical isolates, the median IC50 of peramivir (1.36nM) was comparable to
that of zanamivir (2.7nM) and lower than that of oseltamivir (8.5nM).8
The potency of peramivir was evaluated against five zanamivir-resistant and six oseltamivir-
resistant influenza viruses.9 Peramivir remained a potent inhibitor against all oseltamivir-resistant
viruses including the mutations H274Y, R292K, E119V, and D198N, with IC50 values ≤40nM.
Peramivir also potently inhibited (IC50 ≤ 26nM) the neuraminidase activity of zanamivir-resistant
strains, which had the following mutations: R292K, E119G, E119A, and E119D. However, one
zanamivir-resistant influenza B virus, B/Mem/96, with a mutation R152K isolated from cell
culture, was relatively resistant to all neuraminidase inhibitors, including peramivir (IC50 =
400nM).
5.3.2
Animal Models
In a mouse model of influenza infection, a single intramuscular injection of peramivir (10mg/kg)
given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain resulted in 100%
survival in contrast to 100% mortality in a control group injected with saline.6 In the same mouse
model, treatment of mice up to 72 hours after influenza infection using peramivir (20mg/kg)
resulted in 100% survival, compared to 100% mortality in the control group injected with
vehicle.10
Peramivir has also demonstrated activity in animal models utilizing a clinical H5N1 isolate as the
infecting virus strain. In a mouse model, a single intramuscular dose of peramivir (30mg/kg)
injected 1 hour after inoculation with the highly pathogenic (H5N1) A/Vietnam/1203/04 strain,
resulted in a 70% survival rate that was similar to that seen in mice treated with oseltamivir given
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orally at 10mg/kg/day for 5 days11. In similar experiments, mice inoculated with the same strain
of H5N1 virus that were then treated for up to 8 days with intramuscular peramivir exhibited
100% survival12. This longer duration of peramivir treatment also prevented viral replication in
the lungs, brain and spleen at days 3, 6 and 9 post inoculation.
5.4
Previous Phase 3 Clinical Experience with Oral Peramivir
An oral formulation of peramivir has previously demonstrated antiviral activity and preliminary
clinical efficacy in challenge studies in human volunteers, as well as in treatment studies in
patients with uncomplicated acute influenza infections during the influenza seasons of 1999-
2001. A Phase 3 multinational study (BC-01-03) of oral peramivir was conducted. Two dose
regimens of oral peramivir, 800mg QD for 5 days, or 800mg QD on Day 1, followed by 400mg
QD for 4 days, were compared to a matched placebo treatment group. A total of 1246 subjects
were randomized to treatment at sites in the USA, Western and Eastern Europe, South America,
Australia and New Zealand. As presented in the Table 1 below, the primary end-point of time to
relief of influenza symptoms in 694 subjects with confirmed influenza was not found to be
significantly different (p=0.17) between the three treatment groups.13 A sub-group analysis of the
time to relief of symptoms by country or region demonstrated marked differences in the primary
endpoint.. In the subset of influenza-infected subjects enrolled at sites in the US, clinically
meaningful differences in time to relief of influenza symptoms between the placebo and the two
peramivir arms were observed, however statistical significance (p=0.07) was not achieved.
However, a number of secondary endpoints in this phase 3 study, such as time to overall well-
being, time to normal activity, incidence of influenza related complications and quantity of viral
shedding, achieved or approached statistically significant differences between the peramivir and
placebo treatment groups (p=0.03-0.06).
Table 1
Results of study BC-01-03
Median Time to Relief of Influenza Symptoms (Hours)
Dose and Regimen
Overall Results
(n=694)
US Sites
(n=198)
Peramivir 800mg po x 5d
89.0
70.8
Peramivir 800mg po x 1d
and 400mg po x 4d
91.7
88.8
Placebo x 5 days
104.4
106.8
p value
0.17
0.07
5.5
Previous Phase 1 Experience with Intramuscular Peramivir
Two phase 1studies evaluating the safety and pharmacokinetics of an intramuscular formulation
of peramivir have been conducted in a total of 45 healthy volunteers receiving peramivir.
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability of
75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma levels of
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i.m. peramivir generally occurred within 30 minutes following injection. Plasma
pharmacokinetic parameters for i.m. peramivir are summarized in Table 2 below for the three
intramuscular single dose regimens evaluated.
Table 2
Pharmacokinetic parameters from study Him-06-111.
Dose (mg)
Cmax (ng/mL)
AUC0-∞ (hr·ng/mL)
t½a (hr)
75 i.m.
4296 ± 812
11659 ± 1123
19.8 ± 7.9
150 i.m.
7612 ± 884
23952 ± 3804
24.3 ± 4.1
300 i.m.
15150 ± 2367
49649 ± 5619
22.8 ± 2.5
aterminal half life
In a second phase 1 study, Peramivir-Him-06-112, the same dose levels of peramivir were
administered as single i.m. injections on two consecutive days (6 subjects per group). This
double-blind study also included a placebo arm. The pharmacokinetic parameters of i.m.
peramivir following the second day of dosing were consistent with those seen following single
doses of the drug.
The observations of safety and tolerability of i.m. peramivir in each of the 2 phase 1 studies were
unremarkable. No serious adverse events were reported. The most commonly observed adverse
events or laboratory abnormalities were headache, several reports of signs and symptoms of
vasovagal reactions following injections, and transient increases in creatine kinase. No consistent
differences in frequency of adverse events were observed between the active and placebo
treatment groups, with the exception that CK elevations appeared to be dose related in the
peramivir treatment groups. The vasovagal reactions were attributed to the receipt of relatively
large volumes of i.m. injection (2 injections each of 2mL) in the fasted state.
5.6
Phase 2 Experience with Intramuscular Peramivir
A phase 2 study BCX1812-211 was completed in 2007. This study was a randomized, double-
blind placebo- controlled study to evaluate the efficacy and safety of two single dose regimens of
peramivir. A total of 344 subjects were enrolled into this study with 115 subjects randomized to
Placebo; 114 subjects randomized to peramivir 150 mg; and 114 subjects randomized to
peramivir 300 mg. The primary endpoint of the study was the time to alleviation of clinical
symptoms in adult subjects with uncomplicated acute influenza. Based on preliminary data, the
primary endpoint of time to alleviation of clinical symptoms in BCX1812-211 did not achieve
statistical significance in the pre-planned ITTI study population (Table 3). Based on pre-planned
and post hoc analyses, it appeared that a majority of subjects within this phase 2 study did not
receive an adequate intramuscular injection.
In phase 1 studies (Hi
m-06-111 and Him-06-112) of i.m . per amivir, significant increases in
creatine kinase (CK) were observed at Day 3 compared with Baseline (Day 1) in all subjects who
received active study drug or placebo. CK is a well established marker of muscle damage, and it
was hypothesized that CK increase may act as a surrogate marker of an adequate i.m. injection.
Within the phase 2 study, an increase in CK between Baseline (Day 1) and Day 3 was not
observed in a majority of subjects. In the phase 1 studies study drug was administered with a 1½
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inch needle. In the phase 2 study a shorter needle (1 inch) was supplied with the study drug, with
guidance that a longer needle (1½ inch) should be used for larger subjects. Based on the observed
lack of CK increases at Day 3 compared to baseline, the Sponsor hypothesized that the needle
used for injection failed to penetrate muscle and deliver intramuscular study medication in many
subjects.
A sub group of subjects was identified in which a Day 3 CK increase of at least 50U/L was
observed over baseline. Within this adequate intramuscular injection sub-group, notable
improvements in the time to alleviation of symptoms were observed for both peramivir dose
groups: 44.6 hours for peramivir 150 mg treatment and 64.8 hours for the peramivir 300 mg
treatment (Table 3). These efficacy data support the further development of peramivir as a single
dose, intramuscular treatment for acute influenza.
Table 3
Summary of Efficacy from BCX1812-211.
Placebo
Peramivir
150mg
Peramivir
300mg
Intent-to-Treat Infected Population1 (n=313)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=107
137.0
115.9-163.8
n=104
114.1
95.2-145.5
22.9
n=102
115.9
77.8-136.6
21.1
Adequate Injection Population2 (n=101)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=40
152.2
103.8-183.9
n=32
107.6
76.8-175.1
44.6
n=29
87.4
40.8-163.8
64.8
1: Intent-to-Treat Infected Population: PCR+ for either Influenza A and/or Influenza B at
baseline/screening visit.
2: Adequate Injection Population: ITTI subjects in who study drug reached target muscle tissue,
as evidenced by an increase in serum CK levels of ≥ 50 U/L over baseline at the Day 3 study
visit.
An independent data monitoring committee reviewed grouped blinded safety data throughout
study BCX1812-211. In the overall safety population (n=342), doses of peramivir 150 mg and
300 mg were both found to be well tolerated and no safety concerns were identified by the DMC.
The three treatment groups were similar with respect to the frequency and severity of adverse
events. Two serious adverse events were reported in the study, and neither was considered by the
investigator to be related to treatment. One SAE (pyelonephritis) occurred 5-days after study
treatment in a subject who received placebo, and one SAE (meningitis, resulting in death)
occurred 10-days after study treatment in a subject who received 300 mg of peramivir. There
were no meaningful differences among the three treatment groups with respect to the frequency
or severity of graded laboratory toxicities. A summary of the adverse events and graded toxicities,
together with a list of the most frequently reported adverse events, is presented in Table 4.
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Table 4
Summary of Safety from BCX1812-211.
Safety Parameters
Placebo
(N=114)
Peramivir 150 mg
(N=113)
Peramivir 300 mg
(N=115)
Any Clinical Adverse Event
49 (43%)
43 (38%)
44 (38%)
Any Graded Laboratory Toxicity
99 (87%)
93 (82%)
92 (80%)
Any Serious Adverse Event
1 (<1%)
0
1 (<1%)
Most Frequent Adverse Events
Assessed as Study Drug-Related
Diarrhea
Nausea
Vasovagal Reaction
5 (4%)
7 (6%)
4 (4%)
5 (4%)
7 (6%)
2 (2%)
6 (5%)
9 (8%)
0
5.7 Dose Rationale
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 75mg
twice daily in adults14. Oseltamivir was shown to be clinically effective in a phase 3 study of oral
oseltamivir versus placebo in naturally occurring seasonal influenza, and these data were
sufficient for regulatory approval for marketing of oseltamivir. At least 75% of an oral dose of
oseltamivir reaches the systemic circulation as oseltamivir carboxylate. When oseltamivir is
administered orally at a dose of 75mg twice daily, the serum Cmax of oseltamivir carboxylate is
approximately 348ng/mL and the AUC0-48 is 10,876 h·ng/mL. The clinical data indicate that this
level of exposure to oseltamivir was sufficient to provide clinical improvement in uncomplicated
acute influenza.
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular doses of
peramivir are approximately 7600ng/mL and 24,000 h·ng/mL for the 150mg dose and are
approximately 15,000ng/mL and 49,000 h·ng/mL for the 300mg dose. Previous studies have
assessed the concentrations of the neuraminidase inhibitor zanamivir in nasal and pharyngeal
secretions after parenteral administration of this drug. . Within several hours after administration,
the concentrations in secretions were approximately 100-fold lower than in serum or plasma. In
theory, relatively high levels of a neuraminidase inhibitor in respiratory secretions are desirable in
order to rapidly inactivate influenza virus and to delay or prevent the development of resistance in
infecting virus strains. Intramuscular doses of peramivir, including doses of 150mg and 300mg
have been shown to be well tolerated in previous Phase 1 studies. In the completed Phase 2
study, both doses of peramivir (150 mg and 300 mg) were well tolerated and no safety concerns
were apparent. Therefore, it is appropriate for these two dose regimens to undergo further
evaluation in this Phase 3 study.
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6
STUDY OBJECTIVES
6.1
Objectives
6.1.1
Primary Objective
To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the
time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza.
6.1.2
Secondary Objective(s)
The secondary objectives of this study are:
1. To evaluate the safety and tolerability of peramivir administered intramuscularly,
2. To evaluate secondary clinical outcomes in response to treatment,
3. To evaluate changes in influenza virus titer in nasopharyngeal samples (viral shedding) in
response to treatment.
6.1.3
Exploratory Objective(s)
The following exploratory objectives have been identified for this study.
1. To assess pharmacoeconomic measures as response to treatment.
2. To assess changes in influenza viral susceptibility to neuraminidase inhibitors following
treatment.
6.2
Study Endpoints
6.2.1
Primary Endpoint
The primary clinical endpoint is the time to alleviation of clinical symptoms of influenza for each
subject.
6.2.2
Secondary Endpoint(s)
Secondary safety, clinical, and virologic endpoints will include evaluations in each subject of:
Safety:
Incidence of treatment-emergent adverse events and treatment-emergent changes
in clinical laboratory tests.
Clinical:
Time to resolution of fever; Incidence of influenza related complications.
Virologic:
Quantitative change in influenza virus shedding, measured by viral titer assay
(TCID50).
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6.2.3
Exploratory Endpoints
Pharmacoeconomic and virologic evaluations in each subject for exploratory endpoints will also
be assessed and include:
Pharmacoeconomic:
Medical resource utilization (MRU), missed days of work, and impact of
influenza illness on subject’s work performance and/or productivity.
Virologic:
Quantitative change in influenza virus shedding, measured by PCR;
Change in influenza virus susceptibility to neuraminidase inhibitors.
7
STUDY DESIGN
7.1
Overall Study Design and Plan
This is a multinational, randomized, double-blind study comparing the efficacy and safety of two
single dose regimens of peramivir administered intramuscularly versus placebo in adults with
uncomplicated acute influenza.
Each subject’s assignment to treatment will be stratified according to body mass index (BMI).
Two BMI strata are planned: Normal-Overweight (≤ 29.9 kg/m2), and Obese (≥ 30.0 kg/m2). The
number of subjects enrolled who have a BMI ≤ 29.9 kg/m2 (Normal-Overweight) will be at least
75% of the total enrollment. The number of subjects enrolled who have a BMI ≥ 30.0 kg/m2
(Obese) will be ≤ 25% of total enrollment. All subjects will be centrally randomized to one of
three treatment groups in a ratio of 2:2:1 such that 80% of subjects are randomized to one of the
two single dose regimens of peramivir.
Treatment Group 1: Peramivir 150mg
Treatment Group 2: Peramivir 300mg
Treatment Group 3: Placebo
Study drug will be administered as bilateral 2mL intramuscular injections (total of 4mL injected
in equally divided doses). Procedures for intramuscular injection, with a recommended needle
length appropriate to the physical characteristics of the subject, are provided in the study drug
administration manual.
Subjects eligible for screening will have an anterior nasal swab collected for testing by RAT for
influenza A and B, in accordance with the commercially available RAT kit instructions. If the
initial RAT is negative, the test should be repeated within one hour. Subjects meeting the
inclusion/ exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following information in a Study Diary.
•
Assessment of the presence and severity of each of seven symptoms of influenza on a
4-point scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily (AM, PM) through
Day 9 following treatment, then once daily (AM) through Day 14.
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•
Oral temperature measurements will be taken with an electronic thermometer every 12
hours. With the exception of the baseline measurement, all temperature measurements
will be obtained at least 4 hours after, or immediately before, administration of oral
acetaminophen (paracetamol) or other antipyretic medication.
•
Assessment of subject’s time lost from work or usual activities and rating of productivity
compared to normal (rated as 0-10 on a visual analog scale) once daily through Day 14
•
Doses of antipy retic, expectorant, and/or th roat lozenges taken for s ymptomatic relief
each day through Day 14
Anterior nose (bilateral) and posterior pharynx specimens (swabs) will be collected at Day 1 (pre-
treatment) and at Days 3, 5, and 9, for quantitative virologic assessments. Specimens from all
subjects yielding influenza virus will also be assessed for susceptibility to neuraminidase
inhibitors (Day 1 and last specimen yielding positive result) as well as other virologic
assessments (e.g. PCR, genotypic testing). All virologic assessments will be performed by a
central laboratory.
Two samples for pharmacokinetic (PK) testing for plasma levels of peramivir will be obtained
from all subjects randomized. The first PK sample will be obtained between 30 and 60 minutes
following study drug administration in all subjects. The second PK sample will be obtained at the
day 3 visit in all subjects. The data from these PK samples will be utilized in a population
exposure-response analysis.
At selected sites a separate sub-study will be conducted to collect additional PK samples between
treatment and Day 3 for the purpose of conducting a separate exposure-response analysis. This
sub-study will be conducted under a separate protocol, BCX1812-311PK. Study drug will be
administered as bilateral 2mL intramuscular injections (total of 4mL injected in divided doses).
Procedures for intramuscular injection, with a recommended needle length appropriate to the size
and weight of the subject, are provided in the study drug administration manual.
8
SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.1
Inclusion Criteria
Subjects must meet all of the following criteria for inclusion in this study:
1. Male and non-pregnant female subjects age ≥18 years.
2. A positive Influenza A or B Rapid Antigen Test (RAT) performed with a commercially
available test kit on an adequate anterior nasal specimen, in accordance with the
manufacturer’s instructions. A negative initial RAT should be repeated within one hour.
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC
(≥101.2 ºF) taken rectally. A subject self-report of a history of fever or feverishness
within the 24 hours prior to screening will also qualify for enrollment in the absence of
documented fever at the time of screening.
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of
at least moderate severity.
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5. Presence of at least one constitutional symptom (myalgia [aches and pains], headache,
feverishness, or fatigue) of at least moderate severity.
6. Onset of symptoms no more than 48 hours before presentation for screening.
7. Written informed consent.
8.1.2
Exclusion Criteria
Subjects to whom any of the following criteria apply will be excluded from the study:
1. Women who are pregnant or breast-feeding.
2. Presence of clinically significant signs of acute respiratory distress
3. History of severe chronic obstructive pulmonary disease (COPD) or severe persistent
asthma. (See Section 15.2).
4. History of congestive heart failure requiring daily pharmacotherapy with symptoms
consistent with New York Heart Association Class III or IV functional status within the
past 12 months. (See Section 15.1).
5. Screening ECG which suggests acute ischemia or presence of medically significant
dysrhythmia.
6. History of chronic renal impairment requiring hemodialysis and/or known or suspected to
have moderate or severe renal impairment (actual or estimated creatinine clearance <50
mL/min).
7. Clinical evidence of worsening of any chronic medical condition (temporally associated
with the onset of symptoms of influenza) which, in the investigator’s opinion, indicates
that such finding(s) could represent complications of influenza.
8. Current clinical evidence, including clinical signs and/or symptoms consistent with otitis,
bronchitis, sinusitis and/or pneumonia, or active bacterial infection at any body site that
requires therapy with oral or systemic antibiotics.
9. Presence of immunocompromised status due to chronic illness, previous organ transplant,
or use of immunosuppressive medical therapy which would include oral or systemic
treatment with > 10 mg prednisone or equivalent on a daily basis within 30 days of
screening.
10. Currently receiving treatment for viral hepatitis B or viral hepatitis C.
11. Presence of known HIV infection with a CD4 count <350 cell/mm3.
12. Current therapy with oral warfarin or other systemic anticoagulant.
13. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the 7 days
prior to screening.
14. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the
previous 21 days.
15. Immunized against influenza with inactivated virus vaccine within the previous 14 days.
16. Receipt of any intramuscular injection within the previous 14 days.
17. History of alcohol abuse or drug addiction within 1 year prior to admission in the study.
18. Participation in a previous study of intramuscular or intravenous peramivir or previous
participation in this study.
19. Participation in a study of any investigational drug or device within the last 30 days.
8.1.3
Removal of Subjects from Therapy or Assessment
All subjects are permitted to withdraw fro m participation in this study at any ti me and for any
reason, specified or
unspecified, and without prejudice. T he Investigator or sp onsor m ay
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terminate the subject’s participation in the study at any time for reasons including the following:
1. Adverse event;
2. Intercurrent illness;
3. Non-compliance with study procedures;
4. Subject’s decision;
5. Administrative reasons;
6. Lack of efficacy;
7. Investigator’s opinion to protect the subject’s best interest.
Any subject who withdraws because of an adve
rse event will be followe d until the sign(s) or
symptom(s) that constituted the adverse event has/ha ve resolved or is determ ined to represent a
stable medical condition.
A subject should be with drawn from the trial if, in the opinion of the Investigator, it is medically
necessary, or if it is the desire of the subject.
If a subject does not return for a scheduled visit,
every effort should be made to contact the subject and determine the subject’s medical condition.
In any circumstance, every effort should be made to document subject outcome, if possible.
If the subject withdraws consent, no fu rther ev aluations should b e perfo rmed and no attempts
should be made to collect additional data.
9
TREATMENTS
9.1
Treatments Administered
Peramivir is an investigational drug. Peramivir for intramuscular injection is a small-volume
parenteral and will be supplied as a 75mg/mL solution in sodium citrate/ citric acid buffer. The
pH is approximately 3.0.
A matched placebo solution of sodium citrate/ citric acid buffer with 1.2% sodium chloride at a
pH of approximately 3.0 will be supplied.
The gluteal site of injection and the syringe needle length are to be recorded in the subjects CRF.
Procedures for intramuscular injection, with a recommended needle length appropriate to the
physical characteristics of the subject, are provided in the study drug administration manual.
9.2
Identity of Investigational Product(s)
Peramivir and placebo peramivir will be supplied in clear 2mL vials. An individual study drug
kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending upon the
treatment group), 2 syringes and 2 needles in which to draw up the solution for intramuscular
injection. All materials will be packaged in a labeled box container. All study drug kits must be
stored at 2-8oC.
Each individual study drug kit will be labeled with some or all of the following information as
required by local regulations:
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•
Sponsor name and contact information, study protocol number, kit number, description of
the contents of the container, instructions for the preparation of the syringe and
administration of the study drug, conditions for storage, statement regarding the
investigational (clinical trial) use of the study drug and date for retest or expiry date.
Each vial of study drug will be labeled with some or all of the following information as required
by local regulations:
•
Sponsor name, study protocol number, description of the contents of the vial, instructions
for the preparation of the syringe, statement regarding the investigational (clinical trial)
use of the study drug and lot number.
9.3
Method of Assigning Subjects to Treatment Groups
Subjects will be centrally randomized according to BMI strata in a ratio of 2:2:1 to one of three
treatment groups: single dose peramivir 150mg, single dose peramivir 300mg or placebo, in
accordance with a computer-generated randomization schedule prepared by a non-study
statistician. Eighty percent (80%) of subjects will be randomized to treatment with one of the two
single dose regimens of peramivir, 20% will be randomized to treatment with placebo.
Each subject’s assignment to treatment will be stratified according to body mass index (BMI).
Two BMI strata are planned: Normal-Overweight (≤ 29.9 kg/m2), and Obese (≥ 30.0 kg/m2). The
number of subjects enrolled who have a BMI ≤ 29.9 kg/m2 (Normal-Overweight) will be at least
75% of the total enrollment. The number of subjects enrolled who have a BMI ≥ 30.0 kg/m2
(Obese) will be ≤ 25% of total enrollment.
Once a subject is eligible for randomization, he/she will be assigned a study drug kit number that
will be obtained by study staff from the study interactive voice response system (IVRS). Once a
study drug kit number has been assigned to a subject, it cannot be reassigned to any other subject.
9.4
Study Medication Accountability
The Investigator/pharmacist must maintain accurate records of the disposition of all study drugs
received from the sponsor, issued to the subject or directly administered to the subject (including
date and time), and any drug accidentally destroyed. The sponsor will supply a specific drug-
accountability form. At the end of the study, information describing study drug supplies (e.g., lot
numbers) and disposition of supplies for each subject must be provided, signed by the
Investigator or designee, and collected by the study monitor. If any errors or irregularities in any
shipment of study medication to the site are discovered at any time, the Project Manager must be
contacted immediately.
At the end of the study, all medication not dispensed or administered and packaging materials
will be collected with supervision of the monitor and returned to the sponsor or destroyed on site
as dictated by the appropriate Standard Operating Procedure at the participating institution.
9.5
Blinding/Unblinding of Treatments
This is a double-blind study. The treatment group assignment will not be known by the study
subjects, the investigator, the clinical staff, the CRO or Sponsor staff during the conduct of the
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study.
Section 11.2.4 provides information regarding the process for unblinding the treatment
assignment, if necessary, in the event of an SAE.
9.6
Prior and Concomitant Therapies
All medications, by any route of administration, used during this study must be documented on
the Case Report Form (CRF). Prescription as well as non-prescription medications should be
recorded. Medication used for the treatment of influenza-related symptoms will be captured by
the subject in the diary card provided by BioCryst.
9.7
Overdose and Toxicity Management
To date there is no experience with overdose of intramuscular or intravenous peramivir. If
overdose occurs, subjects should receive indicated supportive therapy and evaluation of
hematologic and clinical chemistry laboratory tests should be conducted. The effect of
hemodialysis on elimination of peramivir is unknown.
9.8
Dose Interruption
As this is a study of a single injection of peramivir or placebo, guidelines for treatment
interruption for drug related SAEs or toxicities are not applicable.
10 STUDY CONDUCT
A study schedule of evaluations is presented in Figure 1. A detailed list of the evaluations an
visits is also provided in the following sections.
10.1 Evaluations
All subjects enrolled in this study will undergo the following evaluations:
10.1.1 Medical History
Medical history, influenza vaccination status within the previous 12 months and demographic
data (including smoking behavior) will be recorded at Screening/Baseline.
10.1.2 Rapid Antigen Test for Influenza
At Screening/Baseline, a commercially available, rapid antigen test (RAT) for influenza A and B
will be performed on an adequate specimen collected by swabbing the anterior nose in
accordance with the RAT manufacturer’ instructions. A negative initial RAT should be repeated
within one hour. Refer to the Study Manual for instructions regarding the use of the RAT kits
provided for this study. Sites may use the kits provided by the Sponsor or any other
commercially approved RAT available at their site to document a confirmed influenza infection.
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10.1.3 Physical Examination and Influenza-related Complications Assessments
The Investigator will perform a physical examination at Screening/Baseline. Subject’s height and
weight, and BMI will be recorded at Screening/Baseline in the subjects CRF.
Study personnel will be provided with an influenza-related complications (IRC) checklist in the
CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following
influenza-related complications: sinusitis, otitis, bronchitis and pneumonia. Note that subjects
with clinical signs and/or symptoms consistent with otitis, bronchitis, sinusitis, and/or pneumonia
at screening are not eligible for enrollment in this study (See Section 8.1.2: exclusion criteria
number 8).
A targeted physical examination will be conducted at each visit to record the presence/absence of
influenza related complications (IRC). If the investigator determines that the subject experiences
(or is presumed to experience) an IRC as noted above, he/she will record that assessment on the
IRC CRF page and any medication used to treat the condition will be recorded on the
concomitant medication page. The investigator will promptly provide appropriate treatment for
any suspected or proven IRC. Such information describing IRC signs and/or symptoms should
not be reported as adverse events. Any injection site reactions noted will be recorded in the CRFs
as adverse events.
10.1.4 Vital Signs
Vital signs evaluations will include blood pressure, pulse rate, and respiration rate. The
investigator will record oral body temperature at baseline. Thereafter the subject will record oral
temperature twice daily in the study diary card.
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following the
study drug injection on Day 1, then once daily on Days 3, 5, 9, and 14.
10.1.5 Electrocardiogram Measurements
A 12-lead electrocardiogram (ECG) will be obtained at Screening/Baseline. The principal
investigator will be responsible for interpretation of the Screening ECG. This interpretation may
be performed by the investigator or he/she may delegate this action to another physician and the
investigator will acknowledge the interpretation. If this baseline ECG is interpreted as meeting
the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study. If the
ECG is interpreted as being abnormal but does not meet the exclusionary criteria, the subject may
be enrolled unless other exclusion criteria apply. The principal investigator is responsible to
ensure that such an enrolled subject be informed of the nature of the abnormal ECG and that any
medically indicated repeat ECG examinations and/or referral of the subject for further evaluation
is made either during subject's participation in the study or immediately after the subject's
discharge from the study.
10.1.6 Clinical Laboratories
Clinical chemistry profiles will include a Chemistry 20 panel (includes sodium, potassium,
chloride, total CO2 [bicarbonate], creatinine, glucose, urea nitrogen, albumin, total calcium, total
magnesium, phosphorus, alkaline phosphatase, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), total bilirubin, direct bilirubin, lactate dehydrogenase [LDH], total
protein, total creatine kinase, and uric acid).
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Hematology will include complete blood count (CBC) with differential.
Urinalysis will include dipstick tests for protein, glucose, ketones, blood, urobilinogen, nitrite,
pH, and specific gravity and microscopic evaluation for RBCs and WBCs.
Clinical laboratory studies (clinical chemistries, hematology, and urinalysis) will be completed at
Screening/Baseline, and on Days 3, 5 and 14.
10.1.7 Urine Pregnancy Test
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and Day
14 using a urine pregnancy test.
10.1.8 Serology for Influenza
Paired blood samples for determination of antibody to influenza A and B (serology) will be
obtained with the clinical laboratory tests at Screening/Enrollment and at Day 14. These
specimens will be stored at the central laboratory and will be analyzed if needed to confirm the
diagnosis of influenza.
10.1.9 Samples for Virologic Laboratory Assessments
An adequate specimen will be collected by swabbing the anterior nose (bilateral) and posterior
pharynx for virologic laboratory assessments including culture for the isolation of influenza virus
and/or quantitative PCR assay at Screening/Baseline, and at Days 3, 5, and 9. Refer to the
Laboratory Manual for instructions regarding the processing and shipment of these specimens.
10.1.10 Subject Self Assessments
Subject self assessments will be performed beginning pre-dose on Day 1 and recorded in the
subject’s Study Diary including the following:
•
Oral temperature measurements with an electronic thermometer (provided by the Sponsor for
the study) every 12 hours. With the exception of the baseline measurement, all temperature
measurements will be obtained at least 4 hours after, or immediately before, administration of
oral acetaminophen (paracetamol, provided) or other anti-pyretic medications. The times of
each temperature determination will be recorded in the Study Diary. The baseline
temperature will be recorded at the screening/Day 1 visit prior to dosing, regardless of
whether the subject had recently taken an anti-pyretic; the time of anti-pyretic use pre-
treatment will be recorded in the CRF, if applicable.
•
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia
[aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent;
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 and through Day 9,
then once daily through Day 14.
•
Assessment of the subject’s time lost from work or usual activities and productivity compared
to normal using a 0-10 visual analogue scale once daily through Day 14.
The subject’s diary card will be reviewed by study staff at each visit for completion of the record
of all required items, with particular emphasis on alleviation of symptoms as well as relapse of
symptoms. Relapse is defined as the recurrence of at least one respiratory symptom and one
constitutional symptom (both greater than mild in severity) for 24 hours and the presence of fever
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(unless influenced by antipyretic use). Relapse can only occur after the subject has met the
endpoint criteria for alleviation of symptoms. Study staff will not attempt to ask subjects to
retrospectively complete missing diary card data for any scheduled assessments that have not
been completed prior to the clinic visit. Study staff should, however, remind the subject to
complete the diary card at all scheduled times.
10.1.11 Concomitant Medications
All concomitant medications used during this study, with the exception of those medications
taken for symptomatic relief of influenza symptoms, which will be recorded by the subject in
their diary card, must be documented on the Case Report Form (CRF).
10.1.12 Adverse Events
AEs will be assessed from the time of administration of study medication through the final study
visit.
10.1.13 Pharmacokinetic Exposure Samples
All subjects will have two pharmacokinetic (PK) samples drawn to assess peramivir drug levels.
The first PK sample will be drawn on day 1 between 30 and 60 minutes following study drug
administration in all subjects. The second PK sample will be drawn at the day 3 visit in all
subjects. The sample will be drawn at the same time as the blood draw is completed for clinical
laboratory investigations. The 30-60 minute sample (treatment day 1) and the day 3 PK sample
will be analyzed for plasma concentrations of peramivir (ng/mL) and evaluated in a population
exposure response analysis.
At selected sites a separate sub-study will also be conducted to collect additional PK samples for
the purpose of conducting an exposure-response analysis. This sub-study will be conducted
under a separate protocol, BCX1812-311PK. Data from these two PK samples in all subjects will
be combined with data from the PK sub-study (BCX1812-311PK) to perform a population based
exposure-response analysis. This analysis will be described as part of the sub-study analysis plan.
All PK samples will be processed at a central bioanalytical laboratory. Refer to the instructions
provided regarding the processing and shipment of these PK samples.
10.2 Screening Period
10.2.1 Informed Consent
The nature and purpose of the study and the expectations of a participating subject will be
described to potential study subjects, their questions will be answered, and the subjects will then
be asked to sign an informed consent document. Study subjects will then undergo the screening
evaluation as noted in Section 10.2.2
10.2.2 Screening/Baseline Evaluation and Enrollment
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or in the
subject’s home, in which case all evaluations must be conducted by appropriately trained and
qualified staff.
Clinical laboratory assessments performed at Screening are for the purpose of establishing a
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baseline. Subjects may be enrolled and receive treatment with study drug prior to receiving
results of the laboratory assessments (with the exception of urine pregnancy test result, which
must be known).
Eligible subjects will be enrolled and randomized to blinded study treatment. The randomization
will be stratified by BMI: Normal-Overweight (BMI ≤ 29.9 kg/m2) and Obese (BMI ≥ 30.0
kg/m2). The Investigator will prepare a request for blinded study drug assignment which includes
the subject’s screening number. The Investigator or designee at the clinical study center will
contact the central randomization Interactive Voice System (IVRS call center). The IVRS call
center will advise the study center of the investigational study drug kit number that is assigned to
that subject at enrollment.
Subjects that are determined to be ineligible will be advised accordingly, and the reason for
ineligibility will be discussed. If desired by the subject the reason for ineligibility may be
provided and/or discussed with their health-care provider by the Investigator or designee.
Ineligible subjects who have been screened for the study will also be entered on the IVRS. For
such subjects, the screening number assigned, subject’s date of birth and a reason for ineligibility
will be entered on to the IVRS. All ineligible subjects must be entered onto the IVRS within
24 hours of screening, to assist with surveillance analysis during the course of the study.
10.3 Treatment Period—Study Day 1
Day 1 represents the only day of study drug dosing. Study drug administration should occur as
soon as possible following informed consent, screening and randomization. Therefore, it is
expected that the date of Screening/ Baseline and Day 1 will usually be the same date.
10.3.1 Pre-dose Evaluations-Study Day 1
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the subject
shall complete the record of these assessments in their Study Diary prior to dosing. The subject
will be counseled regarding the expectations for recording these assessments through Day 14.
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) and a
12 lead ECG will be obtained prior to dosing.
10.3.2 Post-dose Evaluations-Study Day 1
The blinded study drug will be administered (hour 0) as bilateral intramuscular injections within a
period of ≤ 10 minutes. The calendar date and 24-hour clock time of the first and second
injections will be recorded. The gluteal site of injection and the syringe needle length are also to
be recorded in the subjects CRF. Sites are instructed to follow procedures for intramuscular
injection, with a recommended needle length appropriate to the physical characteristics of the
subject, provided in the study drug administration manual.
The following evaluations will be performed post-dose on Study Day 1:
•
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) 15
minutes following the second intramuscular injection of blinded study drug; record the exact
24-hour clock time of the vital sign measurements in the subjects CRF.
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•
Draw a PK sample between 30 and 60 minutes following the second intramuscular injection
of blinded study drug; record the exact 24-hour clock time of the blood draw.
•
Record any concomitant medications.
•
Record any AEs.
10.4 Post-Treatment Assessment Period
10.4.1 Days 2, 3, 5, 9 and 14
Study evaluations will be performed on Days 2, 3, 5, 9 and 14 in accordance with the schedule of
evaluations (Figure 1). Subjects with persistent moderate or severe influenza symptoms at day 14
will also complete a Day 21 visit, and if required a Day 28 visit.
Visits may be conducted in the investigator’s office or clinic, or in the subject’s home, in which
case all evaluations must be conducted by appropriately trained and qualified staff.
Study staff will attempt to contact the subjects on Day 2 by telephone to confirm their compliance
with completion of the Subject Self Assessments, to note any concomitant medications and
adverse events. Any adverse events reported by the subject during this telephone contact will be
recorded on the adverse event form and verified during the visit on day 3.
At each visit it is important that the subject’s Study Diary record be reviewed for completion of
daily Subject Self Assessments. The subjects should be counseled as necessary regarding self
assessments and Study Diary record requirements. The subject’s diary card will be reviewed by
study staff for alleviation of symptoms as well as relapse of symptoms. Relapse is defined as the
recurrence of at least one respiratory symptom and one constitutional symptom (both greater than
mild in severity) for 24 hours and the presence of fever (unless influenced by antipyretic use).
Relapse can only occur after the subject has met the endpoint criteria for alleviation of symptoms.
Day 3:
The second PK sample for all subjects will be obtained on Day 3 at the same time as the clinical
laboratory blood specimen is obtained. The exact 24-hour clock time of the blood draw will be
recorded in the subjects CRF.
Day 14:
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven
symptoms assessed) of either moderate or severe intensity at the Day 14 visit then the subject
must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required at day 28 (± 3
days) If a subject reports moderate or severe influenza symptoms then the investigator will
record the intensity of each of the influenza symptoms on a visit specific CRF page at the day 21
and day 28 visits. After day 14 the subject will not record symptoms in a diary.
Day 21 (if applicable):
The day 21 visit is to be completed only if the subject reports symptoms of influenza of moderate
or severe intensity at day 14. The investigator will make a clinical judgment as to the appropriate
medical course of action for such subjects at the Day 21 visit and such action(s) will be recorded
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on the Day 21 CRF page. The investigator will recall the subject for a further study visit at day 28
(± 3 days) if moderate or severe symptom(s) of influenza persist at Day 21.
Day 28 (if applicable):
The day 28 visit is to be completed only if the subject reports symptoms of influenza of moderate
or severe intensity at day 21. The investigator will make a clinical judgment as to the appropriate
medical course of action for such subjects at this visit and such action(s) will be recorded on the
Day 28 CRF page. No further follow-up visits beyond day 28 are to be formally scheduled unless
in the clinical judgment of the investigator further follow-up is required. The investigator will use
his/her clinical judgment to manage the subject, referring the subject, if appropriate, for further
medical care.
10.4.2 Adverse Events Reported at Post-treatment Visits
In this study, symptoms of influenza will be considered separately from adverse events reported
during the post-treatment period. Accordingly, adverse events that have onset in the post-
treatment period will be assessed and followed as specified in 11.2. Specifically, the investigator
should attempt to follow all unresolved AEs and/or SAEs observed during the study until they are
resolved, or are judged medically stable, or are otherwise medically explained.
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Figure 1
Study Measurements and Visit Schedule
Treatment
Period
Assessment Day
End of Study
Early Withdrawal
Assessments
Screening 1
(Baseline)
Day 11
Day 22
Day 3
Day 5
(±1 day)
Day 9
(±3 day)
Day 14
(±3 day) 8
Informed Consent
X
Rapid Antigen test for
Influenza A & B
X
Medical History/Physical Exam
X
Influenza-related complications
checklist3
X
X
X
X
X
Inclusion/Exclusion
X
Clinical Chemistries4
X
X
X
X
Hematology4
X
X
X
X
Exposure Pharmacokinetic Sample
X
X4
Serology (serum) Sample
X
X
Urinalysis4
X
X
X
X
Urine Pregnancy Test
X
X
Vital Signs5
X
X
X
X
X
X
ECG6
X
Sample (nasopharyngeal swab) for
Influenza Virus Culture/ PCR assay
and for resistance studies
X
X
X
X
Study Drug Administration
X
Subject Diary Review7
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Study Measurements and Visit Schedule Figure Legend on Next Page
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Study Measurements and Visit Schedule Figure Legend
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on
subsequent study days may occur in subject’s home by the investigator (all visits) or appropriately trained study center staff (Day 3, 5, 9
visits).
2 Day 2 will be a telephone contact with the subject to ensure compliance with diary card completion, concomitant medication and adverse
event review.
3 A targeted physical examination will be conducted at each visit to record the presence/absence of influenza related complications.
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subject may be enrolled and begin
treatment with study drug prior to receiving results. A PK sample will be drawn 30-60 minutes following the second treatment
administration injection. On Day 3 an extra tube will be included with the safety blood sample to collect the second PK sample for
evaluation of peramivir concentrations.
5 Vital sign measures will include blood pressure, pulse rate and respiration rate. Vital signs will be recorded at Screening, pre-dose and at
15 min following the study drug administration on Day 1, then once on remaining days as stipulated. The investigator will record oral
temperature at baseline. Thereafter the subject will report oral temperature measurements twice daily in the Study Diary
6 If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will
not be enrolled in this study. If the ECG is interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia,
medically significant dysrhythmia) then this subject may be enrolled If the conditions highlighted in section 10.1.5 are met for the subject.
7 Subjects record symptom assessment in Study Diary, twice daily, beginning pre-dose on Day 1 through Day 9, then once daily through
Day 14. Subjects record time lost from work or usual activities and rating of productivity compared to normal once daily through Day 14.
Subjects record oral temperature twice daily throughout as well as all concomitant medication and adverse events.
8 For any subject with unresolved moderate or severe intensity influenza symptoms a follow up assessment will be scheduled at Day 21 (±
3 days) and Day 28 (± 3 days) if required (See Section 10.4.1).
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11 ADVERSE EVENT MANAGEMENT
11.1 Definitions
11.1.1 Adverse Event
An AE is any untoward medical occurrence in a clinical study subject. No causal relationship
with the study drug or with the clinical study itself is implied. An AE may be an unfavorable and
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical
study. Clinically relevant abnormal results of diagnostic procedures including abnormal
laboratory findings (e.g., requiring unscheduled diagnostic procedures or treatment measures, or
resulting in withdrawal from the study) are considered to be AEs.
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2).
Surgical procedures are not AEs but may constitute therapeutic measures for conditions that
require surgery. The condition for which the surgery is required is an AE, if it occurs or is
detected during the study period. Planned surgical measures permitted by the clinical study
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was
(were) known before the start of study treatment. In the latter case the condition should be
reported as medical history.
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia [aches
and pains], headache, feverishness, and fatigue) will be documented in a subject’s study diary and
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as
AEs unless the symptom(s) worsen to the extent that the outcome fulfils the definition of an SAE,
which then must be recorded as such (see Section 11.1.2). Likewise, a RAT for influenza is
required at screening in order to determine eligibility for the study, and therefore a positive RAT
is not considered an AE.
11.1.2 Serious Adverse Event
A SAE is an adverse event that results in any of the following outcomes:
•
Death
•
Is life-threatening (subject is at immediate risk of death at the time of the event; it does not
refer to an event that hypothetically might have caused death if it were more severe)
•
Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or
prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity (i.e., there is a substantial disruption
of a person’s ability to carry out normal life functions)
•
Is a congenital anomaly/birth defect
•
Is an important medical event
Important medical events that may not result in death, are not life-threatening, or do not require
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they
may jeopardize the subject or may require medical or surgical intervention to prevent one of the
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outcomes listed in this definition. Examples of such events include allergic bronchospasm
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions
that do not result in subject hospitalization, or the development of drug dependency or drug
abuse.
In addition Suspected Unexpected Serious Adverse Reactions (SUSAR) may also be reported to
competent authorities where this type of reporting is required (e.g. European Union Directives).
See section 11.2.3.
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and Reporting
Serious Adverse Events
Reports of AEs are to be collected from the time of study drug administration through the
follow-up period ending on Day 14. The Investigator or designee must completely and promptly
record each AE on the appropriate CRF. The Investigator should attempt, if possible, to establish
a diagnosis based on the presenting signs and symptoms. In such cases, the diagnosis should be
documented as the AE and not the individual sign/symptom. If a clear diagnosis cannot be
established, each sign and symptom must be recorded individually.
The Investigator should attempt to follow all unresolved AEs and/or SAEs observed during the
study until they are resolved, or are judged medically stable, or are otherwise medically
explained.
11.2.1 Definition of Severity
All AEs will be assessed (graded) for severity and classified into one of four clearly defined
categories as follows:
•
Mild:
(Grade 1): Transient or mild symptoms; no limitation in activity; no
intervention required. The AE does not interfere with the participant’s
normal functioning level. It may be an annoyance.
•
Moderate:
(Grade 2): Symptom results in mild to moderate limitation in activity;
no or minimal intervention required. The AE produces some
impairment of functioning, but it is not hazardous to health. It is
uncomfortable or an embarrassment.
•
Severe:
(Grade 3): Symptom results in significant limitation in activity;
medical intervention may be required. The AE produces significant
impairment of functioning or incapacitation.
•
Life-threatening:
(Grade 4): Extreme limitation in activity, significant assistance
required; significant medical intervention or therapy required;
hospitalization.
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11.2.2 Definition of Relationship to Study Drug
The blinded Principal Investigator must review each AE and make the determination of
relationship to study drug using the following guidelines:
Not Related:
The event can be readily explained by other factors such as the subject’s
underlying medical condition, concomitant therapy, or accident, and no
temporal relationship exists between the study drug and the event.
Unlikely:
The event does not follow a reasonable temporal sequence from drug
administration and is readily explained by the subject’s clinical state or
by other modes of therapy administered to the subject.
Possibly Related:
There is some temporal relationship between the event and the
administration of the study drug and the event is unlikely to be explained
by the subject’s medical condition, other therapies, or accident.
Probably Related:
The event follows a reasonable temporal sequence from drug
administration, abates upon discontinuation of the drug, and cannot be
reasonably explained by the known characteristics of the subject’s
clinical state.
Definitely Related:
The event follows a reasonable temporal sequence from administration
of the medication, follows a known or suspected response pattern to the
medication, is confirmed by improvement upon stopping the medication
(dechallenge), and reappears upon repeated exposure (rechallenge, if
rechallenge is medically appropriate).
11.2.3 Reporting Serious Adverse Events
Any SAE / SUSAR (Suspected Unexpected Serious Adverse Reaction) must be reported to
BioCryst or its designee within 24 hours of the Investigator’s recognition of the SAE by first
notifying the Medical Monitor at the number listed below:
Telephone:
Europe: +44 1628 548000;
North America: 1-888-724-4908
Facsimile:
Europe: +44 1628 540028;
North America: 1-888-887-8097
or 1-609-734-9208
In addition to the telephone numbers listed above, local country-specific toll free numbers may be
provided within the study reference manual.
The site is required to fax a completed SAE / SUSAR Report Form (provided as a separate report
form) within 24 hours. All additional follow-up evaluations of the SAE / SUSAR must be
reported and sent by facsimile to BioCryst or its designee as soon as they are available.
The Principal Investigator or designee at each site is responsible for submitting the IND safety
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) to
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and for retaining a copy
in their files.
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If the Investigator becomes aware of any SAE / SUSAR occurring within 30 days after a subject
has completed or withdrawn from the study, he or she should notify BioCryst or its designee.
Any SAEs / SUSARs considered possibly related to treatment will be reported to the FDA and
other Regulatory Competent Authorities as applicable via the MedWatch / CIOMS reporting
system in accordance with FDA and other applicable regulations. However, the Investigator is not
obligated to actively seek reports of AEs in former study participants.
While pregnancy is not considered an AE, all cases of fetal drug exposure via parent as study
participant (see Section 4.4) are to be reported immediately to BioCryst or its designee.
Information related to the pregnancy must be given on a “Pregnancy Confirmation and Outcome”
form that will be provided by the Sponsor or its designee.
11.2.4 Emergency Procedures
In the event of an SAE / SUSAR, the Principal Investigator may request the unblinding of the
treatment assignment for the subject affected. If time allows (i.e., if appropriate treatment for the
SAE is not impeded), the Principal Investigator will first consult with the Medical Monitor
regarding the need to unblind the treatment assignment for the subject. At all times, the clinical
well-being of any subject outweighs the need to consult with the Medical Monitor.
The Principal Investigator may contact the IVRS central randomization center and request the
unblinding of the treatment assignment that corresponds to the affected subject. The IVRS center
will record the name of the Investigator making the request, the date and time of the request, the
subject number and date of birth. The Sponsor will be informed within 24 hours if unblinding
occurred.
12 STATISTICAL METHODS
Descriptive statistical methods will be used to summarize the data from this study, with
hypothesis testing performed for the primary and other selected efficacy endpoints. Unless stated
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median,
standard deviation (SD), minimum, and maximum for continuous data and frequencies and
percentages for categorical data. The term “treatment group” refers to randomized treatment
assignment: peramivir 150 mg, peramivir 300 mg, or placebo. All data collected during the study
will be included in data listings. Unless otherwise noted, the data will be sorted first by treatment
assignment, subject number, and then by date within each subject number.
Unless specified otherwise, all statistical testing will be two-sided and will be performed using a
significance (alpha) level of 0.05.
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher.
12.1 Data Collection Methods
The data will be recorded on the CRF approved by BioCryst. The Investigator must submit a
completed CRF for each subject who signs an informed consent form (ICF), regardless of
duration. All documentation supporting the CRF data, such as laboratory or hospital records,
must be readily available to verify entries in the CRF.
Documents (including laboratory reports, hospital records subsequent to SAEs, etc.) transmitted
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to BioCryst should not carry the subject’s name. This will help to ensure subject confidentiality.
12.2 Statistical Analysis Plan
A statistical analysis plan (SAP) will be created and approved prior to the review of any data.
This document will provide a more technical and detailed description of the proposed data
analysis methods and procedures.
12.3 Study Hypothesis
The primary hypothesis for evaluating the primary objective may be stated as follows:
The null hypothesis (H0) is that the time to alleviation of influenza symptoms is the same for
subjects treated with placebo and for subjects treated with peramivir 150mg (H01) or peramivir
300mg (H02).
The alternative hypothesis (H1) is that subjects treated with peramivir 150mg (H11) or peramivir
300mg (H12) have an improvement in time to alleviation of influenza symptoms over those
treated with placebo.
12.4 Sample Size Estimates
A total of 750 evaluable subjects randomized in a 2:2:1 (300 subjects treated with peramivir
150mg: 300 subjects treated with peramivir 300 mg: 150 subjects treated with placebo) are
estimated for this phase 3 study. Because results of clinic-based RAT tests may not precisely
indicate presence of influenza infection, it is expected that at least 850 subjects will be
randomized to treatment to ensure that 750 evaluable subjects are treated.
From preliminary results of a phase 2 study evaluating peramivir treatment of uncomplicated
influenza, it is expected that the median time to alleviation of symptoms will be 137.0 hours (95%
CI: 115.9, 165.8) for subjects receiving placebo treatment. Additionally, it is expected that the
median time to alleviation for the 150 mg dose peramivir arm will be reduced by 30% compared
to placebo (Table 5) yielding a hazard ratio of 0.70.
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Table 5
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio).
Median Time To Alleviation of Symptoms (Hours)
Placebo
Peramivir 150mg
Difference (hours)
145.0
101.5
43.5
140.0
98.0
42.0
135.0
94.5
40.5
130.0
91.0
39.0
125.0
87.5
37.5
120.0
84.0
36.0
115.0
80.5
34.5
110.0
77.0
33.0
105.0
73.5
31.5
100.0
70.0
30.0
Using these assumptions, a sample size of 300 evaluable subjects per active treatment group and
150 evaluable subjects in the placebo group (a total of 750 evaluable subjects) is sufficient to
provide at least 90% power to detect a hazard ratio of 0.70 using a log-rank statistic and
α = 0.025 (SAS version 9.1.3; total accrual time 7 months; total enrollment time 6 months).
12.5 Analysis Populations
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected (ITTI),
per-protocol infected (PPI), and safety populations. Additional analysis populations may be
defined to evaluate study results. Any additional analysis populations will be defined in the SAP.
Intent-To-Treat Population: The ITT population will include all subjects who are randomized.
Subjects will be analyzed in the treatment group to which they were randomized. The ITT
population will be used for analyses of accountability and demographics.
Intent-To-Treat Infected Population: The ITTI population will include all subjects who are
randomized, received study drug, and have confirmed influenza by culture or PCR. Subjects will
be analyzed according to the treatment randomized. If a discrepancy is noted in the final database
for any subject, such that the drug differs from the randomized treatment assignment, efficacy
analyses may be repeated with the subjects analyzed according to the treatment received. The
ITTI population will be used for primary analyses of efficacy.
Per-Protocol Infected: The PPI population includes all subjects in the ITTI population who
receive an adequate intramuscular injection. The definition of an adequate intramuscular injection
will be further described in the SAP. The PPI population will be used as supportive of the primary
analyses for efficacy completed with the ITTI population.
Safety Population: The safety population will include all subjects who received study drug.
Subjects will be analyzed according to the treatment received. This population will be used for
all safety analyses.
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12.6 Interim and End of Study Analyses
Interim Analysis
An independent DMC will review safety data on an ongoing basis. Safety analyses will be
presented in a manner consistent with the presentations intended for the final analysis.
End of Study Analysis
A final analysis is planned after the last subject completes or discontinues the study, and the
resulting clinical database has been cleaned, quality checked, and locked.
12.7 Efficacy Analyses
12.7.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the time to alleviation of symptoms, defined as the time from
injection of study drug to the start of the time period when a subject has Alleviation of
Symptoms. A subject has Alleviation of Symptoms if all of the seven symptoms of influenza
(nasal congestion, sore throat, cough, aches and pains, fatigue (tiredness), headache, feeling
feverish) assessed on his/her subject diary are either absent or are present at no more than mild
severity level and at this status for at least 21.5 hours (24 hours - 10%).
Descriptive statistics for the primary efficacy endpoint will be tabulated by treatment group.
Alleviation of symptoms will be determined by assessment of symptoms as reported on each
subject’s diary card. Time to alleviation of symptoms will be summarized overall and for
individual symptoms for each treatment group. Overall treatment differences will be assessed
using a Cox Regression model with effects for BMI at screening, influenza type by PCR,
treatment group, and influenza season at randomization (if necessary). Subjects who do not
experience alleviation of symptoms will be censored at the date of their last non-missing post-
baseline assessment. Pairwise differences in time to alleviation of symptoms among the
treatment groups will be evaluated using contrast statements from the final Cox model. In order to
maintain the overall type I error in the presence of the planned comparisons between the two
peramivir treatments and placebo, a Bonferroni correction will be applied to the primary efficacy
endpoint analysis. P-values for the planned comparisons of each peramivir arm to placebo will be
adjusted via a Bonferroni correction (i.e., if the unadjusted p-value for an active comparison
versus placebo, p, is less than 0.05, then pa=p*number of planned comparisons=p*2; otherwise,
pa=p). Superiority of peramivir to placebo will be established if the adjusted p-value is less than
or equal to 0.05.
12.7.2 Secondary Efficacy Endpoints
All secondary endpoints will be summarized using descriptive statistics by treatment group, and
study day/time, if appropriate. Statistical comparisons for each endpoint will be constructed
without adjustment for multiple endpoints.
The reduction in viral shedding will be assessed as the change in viral titers defined as the time-
weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and will be
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summarized for each treatment group. The time-weighted average change from baseline will be
calculated on a by-subject basis through Day 9 using the trapezoidal rule with all available post-
baseline on-treatment data (data after initiation of study treatment) minus the baseline value.
Specifically, the time-weighted area under the curve for time a (ta) to time b (tb) is given by the
formula
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
,
where
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
and ti represents the date of the ith viral titer
assessment and yi represents the log10 value of the ith viral titer assessment. If there is a baseline
value and only one follow-up value, yi then the time-weighted change from baseline is defined as
the difference between yi and baseline. If there is a baseline value and no follow-up value, the
subject is excluded from analysis. The differences between each of the peramivir treatment
groups and placebo will be evaluated using a van Elteren Test adjusting for BMI at screening,
influenza type by PCR, and influenza season at randomization (if necessary). Analyses of the
PCR results will be analyzed in a similar manner.
Subject’s oral temperature will be summarized by study visit and treatment group. Differences
between the treatment groups will be assessed using the Wilcoxon Rank Sum Test controlling for
BMI at screening, influenza type by PCR, and influenza season at randomization (if necessary).
A subject has Resolution of Fever if he/she has a temperature < 37.2°C (99.0°F) and no
antipyretic medications have been taken for at least 12 hours. The time to resolution of fever will
be estimated using the method of Kaplan-Meier using temperature and symptom relief medication
information obtained from the subject diary data. Difference between the treatment groups will
be assessed using the log rank statistic controlling for BMI at screening, influenza type by PCR,
and influenza season at randomization (if necessary). Subjects who do not have resolution of
fever will be censored at the time of their last non-missing post-baseline temperature assessment.
The number and percentage of subjects experiencing influenza related complications will be
summarized by complication preferred term and treatment group. The difference between the
treatment groups will be assessed a logistic regression model with factors for treatment group,
BMI at screening, influenza type by PCR, and influenza season at randomization (if necessary).
Pairwise differences between the treatment groups will be evaluated using contrasts from the final
logistic regression model.
12.7.3 Exploratory Endpoint
The MRU, MRU-related direct costs, and indirect costs attributable to days missed of work and
work productivity and/or performance losses will be summarized by treatment group and BMI.
Methods for describing differences between treatment groups will be presented in the SAP.
Genotypic (including Hemagglutinin and Neuraminidase), phenotypic, viral culture and PCR data
will be listed for each subject. These listings will be constructed in a manner consistent with the
FDA June 2006 Guidance Document: “Guidance for Submitting Influenza Resistance Data”.18
Additionally, the number and percentage of genotypic changes from wild-type amino acid will be
summarized separately for treatment group, protein type, and study visit.
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12.8 Safety Analyses
AEs will be mapped to a MedDRA-preferred term and system organ classification. The
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred terms,
system organ classifications, and severity. If a subject experiences multiple events that map to a
single preferred term, the greatest severity and strongest Investigator assessment of relation to
study drug will be assigned to the preferred term for the appropriate summaries. All AEs will be
listed for individual subjects showing both verbatim and preferred terms. Separate summaries of
treatment-emergent SAEs and AEs related to study drug will be generated.
Descriptive summaries of vital signs and clinical laboratory results will be presented by study
visit. Laboratory abnormalities will be graded according to the DAIDS Table for Grading
Adverse Events for Adults and Pediatrics (Publish Date: December 2004). The number and
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by
treatment group. Laboratory toxicity shifts from baseline to Day 3, Day 5, and Day 14 will be
summarized by treatment group.
Abnormal physical examination findings will be presented by treatment group. The number and
percent of subjects experiencing each abnormal physical examination finding will be included.
Concomitant medications will be coded using the WHO dictionary. These data will be
summarized by treatment group.
Subject disposition will be presented for all subjects. The number of subjects who completed the
study and discontinued from the study will be provided. The reasons for early discontinuation
also will be presented.
12.9 Sub-Study and Pharmacokinetic Analysis
A sub-study to collect pharmacokinetic samples in up to 60 peramivir treated subjects to examine
exposure response will be conducted at selected sites. The data from the sub-study will be
combined with the two PK samples (collected on all subjects at 30-60 minutes following
administration of study drug and on study day 3) to perform a population exposure-response
analysis. All analyses related to exposure-response will be completed as part of the sub-study. All
statistical methods will be outlined as part of the sub-study protocol and exposure-response
analysis plan. All sub-study analyses, and exposure-response analyses from PK samples obtained
in this study and a companion study BCX1812-312, will be reported in a separate sub-study
report.
12.10
General Issues for Statistical Analysis
12.10.1
Multiple Comparisons and Multiplicity
In order to maintain the overall type I error in the presence of the planned comparisons between
the two peramivir treatments and placebo, a Bonferroni correction will be applied to the primary
efficacy endpoint analysis. No other adjustments for multiple comparisons are planned.
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12.10.2
Covariates
Primary and secondary efficacy analyses will be adjusted for BMI at screening, influenza type by
PCR, and influenza season at randomization (if necessary).
12.10.3
Planned Sub-Groups
The primary efficacy endpoint will be summarized separately by BMI, influenza season at
randomization (if necessary), and by viral subtype by PCR using descriptive statistics by
treatment group and study day, if appropriate. No formal statistical testing will be utilized.
Additional analyses may be performed by country, if necessary, for submission to local
regulatory authorities.
12.10.4
Missing Data
Every effort will be made to obtain required data at each scheduled evaluation from all subjects
who have been randomized. No attempt will be made retrospectively to obtain missing subject
reported data (including influenza symptom severity assessments, temperature, ability to perform
usual activities, missed days of work and impact of influenza on subject’s work performance
and/or productivity) that has not been completed by the subject at the time of return of the subject
diary to the investigative site. In situations where it is not possible to obtain all data, it may be
necessary to impute missing data.
In assessing the primary efficacy endpoint, for subjects who withdraw or who do not experience
alleviation of symptoms, missing data will be censored using the date of subject’s last non-
missing assessment of influenza symptoms. Missing assessments of influenza symptoms
conservatively will be imputed as having severity above absent or mild (as failures). For the
subject diary data, the following data conventions will be utilized. Missing diary completion will
be imputed as 11:59 for diary entries designated as morning and 23:59 for evening and daily
reported values. Entries with values exceeding the 24-hour clock will be set to 23:59 of the day
recorded. Select exploratory sensitivity analyses may be conducted to ascertain the effect, if any,
of these methods. These sensitivity analyses are further described in the SAP. Secondary
efficacy endpoints with time to event data will be censored using the date of subject’s last non-
missing assessment of the given endpoint.
13 STUDY ADMINISTRATION
13.1 Regulatory and Ethical Considerations
13.1.1 Regulatory Authority Approvals
This study will be conducted in compliance with the protocol; GCPs, including International
Conference on Harmonization (ICH) of Technical Requirements for Registration of
Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements and in accordance
with the ethical principles of the Declaration of Helsinki. In addition, all applicable local laws
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and regulatory requirements relevant to the use of new therapeutic agents in the countries
involved will be adhered to.
The Investigator should submit written reports of clinical study status to their Institutional
Review Board (IRB)/ Independent Ethics Committee (IEC) annually or more frequently if
requested by the IRB/ IEC. A final study notification will also be forwarded to the IRB/IEC after
the study is completed or in the event of premature termination of the study in accordance with
the applicable regulations. Copies of all contact with the IRB/ IEC should be maintained in the
study documents file. Copies of clinical study status reports (including termination) should be
provided to BioCryst.
13.1.2 Ethics Committee Approvals
Before initiation of the study at each investigational site, the protocol, the informed consent form,
the subject information sheet, and any other relevant study documentation will be submitted to
the appropriate IRB/IEC. Written approval of the study must be obtained before the study center
can be initiated or the investigational medicinal product is released to the Investigator. Any
necessary extensions or renewals of IRB/IEC approval must be obtained, in particular, for
changes to the study such as modification of the protocol, the informed consent form, the written
information provided to subjects and/or other procedures.
The Investigator will report promptly to the IRB/IEC any new information that may adversely
affect the safety of the subjects or the conduct of the study. On completion of the study, the
Investigator will provide the IRB/IEC with a report of the outcome of the study.
13.1.3 Subject Informed Consent
Signed informed consent must be obtained from each subject prior to performing any study-
related procedures. Each subject should be given both verbal and written information describing
the nature and duration of the clinical study. The informed consent process should take place
under conditions where the subject has adequate time to consider the risks and benefits associated
with his/her participation in the study. Subjects will not be screened or treated until the subject
has signed an approved ICF written in a language in which the subject is fluent.
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC. The
informed consent should be in accordance with the current revision of the Declaration of
Helsinki, current ICH and GCP guidelines, and BioCryst policy.
The Investigator must explain to potential subjects or their legal representatives the aims,
methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it
may entail. Subjects will be informed that they are free not to participate in the trial and that they
may withdraw consent to participate at any time. They will be told that refusal to participate in
the study will not prejudice future treatment. They will also be told that their records may be
examined by competent authorities and authorized persons but that personal information will be
treated as strictly confidential and will not be publicly available. Subjects must be given the
opportunity to ask questions. After this explanation and before entry into the trial, consent should
be appropriately recorded by means of the subject’s dated signature. The subject should receive a
signed and dated copy of the ICF. The original signed informed consent should be retained in the
study files. The Investigator shall maintain a log of all subjects who sign the ICF and indicate if
the subject was enrolled into the study or reason for non-enrollment.
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13.1.4 Payment to Subjects
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC
responsible for the study at the Investigator’s site.
13.1.5 Investigator Reporting Requirements
The Investigator will provide timely reports regarding safety to his/her IRB/IEC as required.
13.2 Study Monitoring
During trial conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure
that the protocol and GCPs are being followed. The monitors may review source documents to
confirm that the data recorded on CRFs is accurate. The investigator and institution will allow
BioCryst monitors or its designees and appropriate regulatory authorities direct access to source
documents to perform this verification.
13.3 Quality Assurance
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits
performed by BioCryst, and/or to inspection by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the
monitoring visits and possible audits or inspections and that sufficient time is devoted to the
process.
13.4 Study Termination and Site Closure
BioCryst reserves the right to discontinue the trial prior to inclusion of the intended number of
subjects but intends only to exercise this right for valid scientific or administrative reasons. After
such a decision, the Investigator must contact all participating subjects immediately after
notification. As directed by BioCryst, all study materials must be collected and all case report
forms completed to the greatest extent possible.
13.5 Records Retention
To enable evaluations and/or audits from regulatory authorities or BioCryst, the Investigator
agrees to keep records, including the identity of all participating subjects (sufficient information
to link records, case report forms and hospital records), all original signed informed consent
forms, copies of all case report forms and detailed records of treatment disposition. The records
should be retained by the Investigator according to local regulations or as specified in the Clinical
Trial Agreement, whichever is longer.
If the Investigator relocates, retires, or for any reason withdraws from the study, the study records
may be transferred to an acceptable designee, such as another investigator, another institution, or
to BioCryst. The Investigator must obtain BioCryst’s written permission before disposing of any
records.
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13.6 Study Organization
13.6.1 Data Monitoring Committee
BioCryst will assemble an independent Data Monitoring Committee (DMC) to assess safety
parameters of the trial on a periodic, ongoing basis while the trial is in progress. The committee
will include a statistician and three physicians, two of whom will be Infectious Disease / Clinical
Virology specialists. Full details of the composition of the DMC and how the DMC is to operate
will be described in a separate DMC charter.
13.7 Confidentiality of Information
BioCryst affirms the subject’s right to protection against invasion of privacy. Only a subject
identification number, initials and/or date of birth will identify subject data retrieved by BioCryst.
However, in compliance with federal regulations, BioCryst requires the investigator to permit
BioCryst’s representatives and, when necessary, representatives of the FDA or other regulatory
authorities to review and/or copy any medical records relevant to the study.
BioCryst will ensure that the use and disclosure of protected health information obtained during a
research study complies with the HIPAA Privacy Rule, where this rule is applicable. The Rule
provides federal protection for the privacy of protected health information by implementing
standards to protect and guard against the misuse of individually identifiable health information
of subjects participating in BioCryst-sponsored Clinical Trials. "Authorization" is required from
each research subject, i.e., specified permission granted by an individual to a covered entity for
the use or disclosure of an individual's protected health information. A valid authorization must
meet the implementation specifications under the HIPAA Privacy Rule. Authorization may be
combined in the Informed Consent document (approved by the IRB/IEC) or it may be a separate
document, (approved by the IRB/IEC) or provided by the Investigator or Sponsor (without
IRB/IEC approval). It is the responsibility of the investigator and institution to obtain such
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are
required for U.S. sites only.
13.8 Study Publication
All data generated from this study are the property of BioCryst and shall be held in strict
confidence along with all information furnished by BioCryst. Independent analysis and/or
publication of these data by the Investigator or any member of his/her staff are not permitted
without prior written consent of BioCryst. Written permission to the Investigator will be
contingent on the review by BioCryst of the statistical analysis and manuscript and will provide
for nondisclosure of BioCryst confidential or proprietary information. In all cases, the parties
agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This
will enable all parties to protect proprietary information and to provide comments based on
information that may not yet be available to other parties.
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14 REFERENCES
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282.
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality associated with
influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179–186.
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment on
influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med
2003;163(14):1667–1672.
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral neuraminidase
inhibitor oseltamivir in experimental human influenza: randomized controlled trials for
prevention and treatment. JAMA 1999;282(13):1240–1246.
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant influenza
A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759–
765.
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-influenza
virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents
Chemother 2001;45(4):1162–1167.
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to
different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147.
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir,
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase
inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45(12):3403–3408.
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine
combinations exert additive and synergistic anti-influenza virus effects in MDCK cells.
Antimicrob Agents Chemother 2004;48(12):4855–4863.
10. BioCryst Pharmaceuticals. Unpublished data.
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. Injectable
peramivir promotes survival in mice and ferrets infected with highly pathogenic avian
influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San Francisco
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA.
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival against
lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03.
14. Tamiflu® Package Insert. Roche Pharmaceuticals. Rev. December 2005.
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product
information sheets
16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the oral
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283(8): 1016-
1024.
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of oseltamivir in
treatment of influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-1850.
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18. US Department of Health and Human Services, Food and Drug Administration Center for
Drug Evaluation and Reserach (CDER). Attachment to Guidance on Antiviral Product
Development- Conducting and Submitting Virology Studies to the Agency: Guidance for
Submitting Influenza Resistance Data. http://www.fda.gov/cder/guidance/7070fnlFLU.htm
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15 APPENDICES
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina
NYHA Functional Classification of Heart Failure
Class I
No symptoms. Ordinary physical activity such as walking and climbing stairs
does not cause fatigue or dyspnea.
Class II
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly;
walking uphill; walking or stair climbing after meals, in cold weather, in wind,
or when under emotional stress causes undue fatigue or dyspnea.
Class III
Symptoms w ith less than ordinary phy
sical activity. Walking one to two
blocks on t he level and clim bing m ore th an one flight of stai rs in norm al
conditions causes undue fatigue or dyspnea.
Class IV
Symptoms at rest. Inability to carry on any physical activity without fatigue or
dyspnea.
NYHA Functional Classification of Angina
Class I
Angina only with unusually strenuous activity.
Class II
Angina with slightl y more prolonged o r slightly more vigorous activit y than
usual.
Class III
Angina with usual daily activity.
Class IV
Angina at rest.
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15.2 Criteria for Severe COPD and Severe Asthma
The following guidelines are provided to assist in the evaluation of subjects who have a medical
history for Chronic Obstructive Pulmonary Disease (COPD) and/or Asthma. Subjects with severe
COPD or severe persistent Asthma are to be excluded from this study. (See section 8.1.2,
exclusion criteria number 3).
Classification of Asthma from National Asthma and Education and Prevention Program
For Adults and Children (> 5 yrs) who
can use a spirometer or peak flow meter
Classification
Days with
Symptoms
Nights with
Symptoms
FEV1 or PEF
% Predicted Normal
PEF Variability
(%)
Severe persistent
Continual
Frequent
≤ 60
> 30
Moderate Persistent
Daily
> 1/ week
> 60 - < 80
> 30
Mild Persistent
> 2 / week
but < 1
times / day
> 2/ month
≥ 80
20 – 30
Mild Intermittent
≤ 2 / week
< 2 / month
≥ 80
< 20
FEV1: percentage predicted value for forced expiratory volume in 1 second.
PEF: percentage of personal best for peak expiratory flow.
Extracted from: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart,
Lung, and Blood Institute, National Asthma Education and Prevention Program. HHS/NIH 2007
Spirometric Classification of COPD Severity based upon Post-Bronchodilator FEV1
(GOLD Criteria)
Stage
Characteristics
Mild COPD
FEV1/FVC < 70%
FEV1 ≥ 80% predicted
Moderate COPD
FEV1/FVC < 70%
50 % ≤ FEV1 < 80% predicted
Severe COPD
FEV1/FVC < 70%
30 % ≤ FEV1 < 50% predicted
Very Severe COPD
FEV1/FVC < 70%
FEV1 < 30% predicted or FEV1 < 50%
predicted plus chronic respiratory failure
FEV1: percentage predicted value for forced expiratory volume in one second.
FVC: forced vital capacity
Extracted from: Rabe KF, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease (GOLD Executive Summary). Am. J. Respir. Crit. Care Med. 2007:176;532-555.
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CLINICAL STUDY PROTOCOL
Protocol No. BCX1812-311
IND No. 76,350
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE
INFLUENZA
THE IMPROVE I STUDY
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy)
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza
Protocol Date(s):
Version 1.0: 04 September 2007
Version 2.0: 05 October 2007
Version 3.0 20 November 2007
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35244, USA
Phone: +1 919 859 1302
Fax: +1 919 851 1416
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals,
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information
contained herein should be disclosed without prior written approval.
CONFIDENTIAL
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1
TITLE PAGE
Protocol Number:
BCX1812-311
Study Title:
A phase 3 multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of
intramuscular peramivir in subjects with uncomplicated acute
influenza.
IND Number:
76, 350
Investigational Product:
Peramivir (BCX1812)
Indication Studied:
Uncomplicated acute influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35233
Development Phase:
3
Sponsor Medical Officer:
W. James Alexander, M.D., M.P.H.
Senior Vice President, Clinical Development
Chief Medical Officer
Phone: +1 919 859 1302
Fax: +1 919 851 1416
Email Address: jalexander@biocryst.com
Compliance Statement:
This study will be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki
and clinical research guidelines established by the Code of
Federal Regulations (Title 21, CFR Parts 50, 56, and 312)
and ICH Guidelines. Essential study documents will be
archived in accordance with applicable regulations.
Final Protocol Date:
Version 1.0: 04 September 2007
Amendment(s) Date(s):
Version 2.0: 05 October 2007
Version 3.0: 20 November 2007
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1.2
Clinical Study Protocol Agreement
Protocol No.
BCX1812-311
Protocol Title:
A phase 3 multicenter, random ized, double-blind, placebo-controlled
study to evaluate the effic acy and safety of intramuscular peramivir in
subjects with uncomplicated acute influenza
I have carefully read this protocol and agree that it contains all of the necessary information
required to conduct this study. I agree to c onduct this study as described and according t o
the Decl aration of Helsinki, Internationa l Conference on Har monization Guidelines for
Good Clinical Practices, and all applicable regulatory requirements.
Investigator’s Signature
Date
Name (Print)
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2
SYNOPSIS
Protocol No.
BCX1812-311
Protocol Title:
A phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of
intramuscular peramivir in subjects with uncomplicated acute
influenza.
Sponsor:
BioCryst Pharmaceuticals, Inc.
Investigators/Study Sites:
Multinational
Development Phase:
3
Objectives:
Primary:
To evaluate the efficacy of peramivir administered
intramuscularly compared to placebo on the time to alleviation
of clinical symptoms in adult subjects with uncomplicated acute
influenza A.
Secondary:
1.
To evaluate the safety and tolerability of peramivir
administered intramuscularly
2.
To evaluate secondary clinical outcomes in response to
treatment
3.
To evaluate changes in influenza virus titer in
nasopharyngeal samples (viral shedding) in response to
treatment
Exploratory:
1. To assess pharmacoeconomic measures as response to
treatment
2. To assess changes in influenza viral susceptibility to
neuraminidase inhibitors following treatment
Number of Subjects:
Total enrollment: up to a total of 750 evaluable subjects will be
randomized to treatment (150 subjects in the placebo treatment
group, 300 subjects in the peramivir 300mg treatment group and
300 subjects in the peramivir 600mg treatment group).
An evaluable subject is one who is randomized, receives study
drug, and has confirmed acute influenza A by primary viral
culture or PCR. A positive Rapid Antigen Test (RAT) for
influenza A at screening will be required for enrollment.
Because results of clinic-based RAT tests may not precisely
indicate presence of influenza infection, it is expected that at
least 850 subjects will be randomized to treatment to ensure that
750 evaluable subjects are treated.
Study Design:
This is a multinational, randomized, double-blind study
comparing the efficacy and safety of two single dose regimens
of peramivir administered intramuscularly versus placebo in
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adults with uncomplicated acute influenza.
Each subject’s assignment to treatment will be stratified
according to smoking status.
All subjects will be centrally randomized to one of three
treatment groups according to smoking status strata in a ratio of
2:2:1 such that 80% of subjects are randomized to one of the two
single dose regimens of peramivir.
Treatment Group 1: Peramivir 300mg
Treatment Group 2: Peramivir 600mg
Treatment Group 3: Placebo
Study drug will be administered as bilateral 4mL intramuscular
injections (total of 8mL injected in equally divided doses).
Procedures for gluteal intramuscular injection, with a
recommended needle length appropriate to the physical
characteristics of the subject, are provided in the study drug
administration manual.
Subjects eligible for screening will have an anterior nasal swab
collected for testing by rapid antigen testing (RAT) for influenza
A, in accordance with the commercially available RAT kit
instructions. If the initial RAT is negative, the test should be
repeated within one hour. Subjects meeting the
inclusion/exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following information in a
Study Diary:
• Assessment of the presence and severity of each of seven
symptoms of influenza on a 4-point scale (0, absent; 1, mild;
2, moderate; 3, severe) twice daily (AM, PM) through Day 9
following treatment, then once daily (AM) through Day 14
• Oral temperature measurements taken with an electronic
thermometer every 12 hours. With the exception of the
baseline measurement, all temperature measurements will be
obtained at least 4 hours after, or immediately before,
administration of oral acetaminophen (paracetamol) or other
anti-pyretic medications.
• Assessment of subject’s time lost from work or usual
activities and rating of productivity compared to normal
(rated as 0-10 on a visual analog scale) once daily through
Day 14
• Doses of antipyretic, expectorant, and/or throat lozenges
taken for symptomatic relief each day through Day 14
Anterior nose (bilateral) and posterior pharynx specimens
(swabs) will be collected at Day 1 (pre-treatment) and at Days 3,
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5, and 9, for quantitative virologic assessments. Specimens from
all subjects yielding influenza virus will also be assessed for
susceptibility to neuraminidase inhibitors (Day 1 and last
specimen yielding positive result on culture) as well as other
virologic assessments (e.g. PCR, genotypic testing)
All virologic assessments will be performed by a central
laboratory.
Two samples for pharmacokinetic (PK) testing for plasma levels
of peramivir will be obtained from all subjects randomized. The
first PK sample will be obtained between 30 and 60 minutes
following study drug administration in all subjects. The second
PK sample will be obtained at the day 3 visit in all subjects. The
data from these PK samples will be utilized in a population
exposure-response analysis.
At selected sites a separate sub-study will be conducted to
collect additional PK samples between treatment and Day 3 for
the purpose of conducting a separate exposure-response
analysis. This sub-study will be conducted under a separate
protocol, BCX1812-311PK.
Study Population:
Male and female subjects, 18 years of age and older, with
symptoms consistent with a diagnosis of uncomplicated acute
influenza infection may be screened for enrollment. Subject
eligibility will require the presence of two or more symptoms of
at least moderate severity consistent with acute influenza as well
as positive results obtained from a rapid antigen test (RAT) for
influenza A at screening.
Inclusion Criteria:
1. Male and non-pregnant female subjects age ≥18 years.
2. A positive Influenza A Rapid Antigen Test (RAT)
performed with a commercially available test kit on an
adequate anterior nasal specimen, in accordance with the
manufacturer’s instructions. A negative initial RAT should
be repeated within one-hour. Subjects with a positive
influenza B or mixed A and B RAT will be excluded.
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4
ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. A
subject self-report of a history of fever or feverishness
within the 24 hours prior to screening will also qualify for
enrollment in the absence of documented fever at the time of
screening.
4. Presence of at least one respiratory symptom (cough, sore
throat, or nasal symptoms) of at least moderate severity.
5. Presence of at least one constitutional symptom (myalgia
[aches and pains], headache, feverishness, or fatigue) of at
least moderate severity.
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6. Onset of symptoms no more than 48 hours before
presentation for screening.
7. Written informed consent.
Exclusion Criteria:
1. Women who are pregnant or breast-feeding.
2. Presence of clinically significant signs of acute respiratory
distress.
3. History of severe chronic obstructive pulmonary disease
(COPD) or severe persistent asthma.
4. History of congestive heart failure requiring daily
pharmacotherapy with symptoms consistent with New York
Heart Association Class III or IV functional status within the
past 12 months.
5. Screening ECG which suggests acute ischemia or presence
of medically significant dysrhythmia.
6. History of chronic renal impairment requiring hemodialysis
and/or known or suspected to have moderate or severe renal
impairment (actual or estimated creatinine clearance <50
mL/min).
7. Clinical evidence of worsening of any chronic medical
condition (temporally associated with the onset of symptoms
of influenza) which, in the investigator’s opinion, indicates
that such finding(s) could represent complications of
influenza.
8. Current clinical evidence, including clinical signs and/or
symptoms consistent with otitis, bronchitis, sinusitis and/or
pneumonia, or active bacterial infection at any body site that
requires therapy with oral or systemic antibiotics.
9. Presence of immunocompromised status due to chronic
illness, previous organ transplant, or use of
immunosuppressive medical therapy which would include
oral or systemic treatment with > 10 mg prednisone or
equivalent on a daily basis within 30 days of screening.
10. Currently receiving treatment for viral hepatitis B or viral
hepatitis C.
11. Presence of known HIV infection with a CD4 count <350
cell/mm3.
12. Current therapy with oral warfarin or other systemic
anticoagulant.
13. Receipt of any doses of rimantadine, amantadine, zanamivir,
or oseltamivir in the 7 days prior to screening.
14. Immunized against influenza with live attenuated virus
vaccine (FluMist®) in the previous 21 days.
15. Immunized against influenza with inactivated virus vaccine
within the previous 14 days.
16. Receipt of any intramuscular injection within the previous
14 days.
17. History of alcohol abuse or drug addiction within 1 year
prior to admission in the study.
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18. Participation in a previous study of intramuscular or
intravenous peramivir or previous participation in this study
19. Participation in a study of any investigational drug or device
within the last 30 days.
Study Endpoints:
Primary Endpoint:
Clinical:
Time to alleviation of clinical symptoms of influenza.
Secondary Endpoint(s):
Safety:
Incidence of treatment-emergent adverse events and treatment-
emergent changes in clinical laboratory tests.
Clinical:
Time to resolution of fever.
Incidence of influenza related complications.
Virologic:
Quantitative change in influenza virus shedding, measured by
viral titer assay (TCID50).
Exploratory Endpoint(s):
Pharmacoeconomic:
Medical resource utilization (MRU), missed days of work, and
impact of influenza illness on subject’s work performance
and/or productivity.
Virologic:
Quantitative change in influenza virus shedding, measured by
PCR.
Change in influenza virus susceptibility to neuraminidase
inhibitors.
Investigational Product, Dose, and Mode of Administration:
Peramivir (BCX-1812), 7 5mg/mL, 4mL (300m g) per injection, adm inistered as bilateral
injections.
Reference Therapy, Dose, and Mode of Administration:
Matching Placebo (buffered diluent), 4mL per injection administered as bilateral injections.
Duration of Treatment:
Following treatment on day 1, study duration for all subjects is
expected to be up to 14 days (including all visits). Presence of
unresolved adverse events and/or treatment-emergent laboratory
findings at the Day 14 visit, or persistent or recurrent symptoms
of influenza (of the seven symptoms assessed) of either
moderate or severe intensity at the Day 14 visit, will require
additional follow up.
Statistical Methods:
Study Hypothesis:
The null hypothesis (H0) for this study is that the time to
alleviation of influenza symptoms is the same for subjects
treated with placebo and for subjects treated with peramivir
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300mg (H01) or peramivir 600mg (H02).
The alternative hypothesis (H1) is that subjects treated with
peramivir 300mg (H11) or peramivir 600mg (H12) have an
improvement in time to alleviation of influenza symptoms over
those treated with placebo.
Sample Size:
From preliminary results of a phase 2 study evaluating peramivir
treatment of uncomplicated influenza, it is expected that the
median time to alleviation of symptoms will be 137.0 hours
(95% CI: 115.9, 165.8) for subjects receiving placebo
treatment. Additionally, it is expected that the median time to
alleviation for the 150 mg dose peramivir arm will be reduced
by 30% compared to placebo (see table below) yielding a hazard
ratio of 0.70.
Median Time To Alleviation of Symptoms (Hours)
Placebo
Peramivir 150mg
Difference (hours)
145.0
101.5
43.5
140.0
98.0
42.0
135.0
94.5
40.5
130.0
91.0
39.0
125.0
87.5
37.5
120.0
84.0
36.0
115.0
80.5
34.5
110.0
77.0
33.0
105.0
73.5
31.5
100.0
70.0
30.0
Using these assumptions, a sample size of 300 evaluable
subjects per active treatment group and 150 evaluable subjects
in the placebo group (a total of 750 evaluable subjects) is
sufficient to provide at least 90% power to detect a hazard ratio
of 0.70 using a log-rank statistic and α = 0.025 (SAS version
9.1.3; total accrual time 7 months; total enrollment time 6
months).
Efficacy:
The intent-to-treat infected population (ITTI) will include all
subjects who are randomized, received study drug, and have
confirmed influenza A by primary viral culture or PCR. The
primary efficacy variable is the time to alleviation of symptoms,
defined as the time from injection of study drug to the start of
the time period when each of seven symptoms of influenza are
either absent or are present at no more than mild severity level
and remain at no worse than this severity status for a 21.5 hour
(24 hours – 10%) period.
Descriptive statistics for the primary efficacy variable will be
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tabulated by treatment group. Alleviation of symptoms will be
determined by assessment of symptoms as reported on each
subject’s diary card. Time to alleviation of symptoms will be
summarized for each treatment group. Treatment differences
between each active group and placebo will be assessed using a
Wilcoxon-Gehan statistic stratified by smoking status at
screening. Subjects who do not experience alleviation of
symptoms will be censored at the date of their last non-missing
assessment. The overall significance level will be maintained by
utilization of Hochberg’s method for the planned comparisons
between the two active treatments and placebo. Time to
resolution of fever will be analyzed in a similar manner without
the adjustment for multiple comparisons.
Efficacy analyses will be repeated for a Per-Protocol Infected
population (PPI). This population will include those subjects in
the ITTI population who received an adequate intramuscular
injection. Details of this population will be described in the
statistical analysis plan. The PPI population analysis will be
used as supportive to the primary analysis with the ITTI.
Changes in influenza virus TCID50 (viral titers from
nasopharyngeal specimens) will be compared using the van
Elteren statistic controlling for smoking status at screening.
Analyses of other continuous endpoints will be analyzed in a
similar manner.
The number and percentage of subjects experiencing influenza
related complications (IRC) will be summarized by
complication preferred term and treatment group. The
difference between the treatment groups will be assessed using a
logistic regression model with factors for treatment group and
smoking status at screening. Pairwise differences between the
treatment groups will be evaluated using contrasts from the final
logistic regression model.
Safety:
Safety analyses will be presented for all subjects in the safety
population, defined as all randomized subjects who receive at
least one dose of study drug. Adverse events will be mapped to
a Medical Dictionary for Regulatory Activities (MedDRA)
preferred term and system organ classification.
The occurrence of treatment-emergent AEs will be summarized
using preferred terms, system organ classifications, and severity.
Separate summaries of treatment-emergent SAEs and treatment-
emergent AEs that are related to study medication will be
generated. All AEs will be listed for individual subjects
showing both verbatim and preferred terms.
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Descriptive summaries of vital signs and quantitative clinical
laboratory changes will be presented by study visit. Frequency
and percentages of subjects with abnormal laboratory test results
will be summarized by toxicity grade.
Concomitant medications will be mapped to a WHO preferred
term and drug classification. The number and percent of
subjects taking concomitant medications will be summarized
using preferred terms and drug classifications. The number and
percent of subjects experiencing each abnormal physical
examination finding will be presented.
The number and percent of subjects discontinuing study as well
as the reasons for discontinuation will be summarized by
treatment group.
Date of Protocol:
Version 1.0: 04-September-2007
Amendment (Dates):
Version 2.0: 05-October-2007
Version 3.0: 20-November-2007
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3
TABLE OF CONTENTS
1
TITLE PAGE...............................................................................................................................2
1.1
PROTOCOL APPROVAL SIGNATURE PAGE......................................................................................3
1.2
CLINICAL STUDY PROTOCOL AGREEMENT....................................................................................4
2
SYNOPSIS...................................................................................................................................5
3
TABLE OF CONTENTS...........................................................................................................13
3.1
LIST OF FIGURES .........................................................................................................................15
3.2
LIST OF TABLES ..........................................................................................................................15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................................16
5
INTRODUCTION......................................................................................................................18
5.1
BACKGROUND.............................................................................................................................18
5.2
RATIONALE FOR STUDY ..............................................................................................................18
5.3
NON-CLINICAL EXPERIENCE WITH PERAMIVIR...........................................................................19
5.3.1
In vitro Assays.......................................................................................................................19
5.3.2
Animal Models......................................................................................................................19
5.4
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR...........................................20
5.5
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR.........................................20
5.6
PHASE 2 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR .........................................................22
5.7 DOSE RATIONALE................................................................................................................................25
6
STUDY OBJECTIVES..............................................................................................................26
6.1
OBJECTIVES ................................................................................................................................26
6.1.1
Primary Objective..................................................................................................................26
6.1.2
Secondary Objective(s) .........................................................................................................26
6.1.3
Exploratory Objective(s) .......................................................................................................26
6.2
STUDY ENDPOINTS......................................................................................................................26
6.2.1
Primary Endpoint...................................................................................................................26
6.2.2
Secondary Endpoint(s) ..........................................................................................................26
6.2.3
Exploratory Endpoints...........................................................................................................27
7
STUDY DESIGN.......................................................................................................................27
7.1
OVERALL STUDY DESIGN AND PLAN ..........................................................................................27
8
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................................28
8.1.1
Inclusion Criteria...................................................................................................................28
8.1.2
Exclusion Criteria..................................................................................................................29
8.1.3
Removal of Subjects from Therapy or Assessment...............................................................30
9
TREATMENTS .........................................................................................................................30
9.1
TREATMENTS ADMINISTERED.....................................................................................................30
9.2
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .............................................................................30
9.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................31
9.4
STUDY MEDICATION ACCOUNTABILITY......................................................................................31
9.5
BLINDING/UNBLINDING OF TREATMENTS...................................................................................31
9.6
PRIOR AND CONCOMITANT THERAPIES.......................................................................................32
9.7
OVERDOSE AND TOXICITY MANAGEMENT..................................................................................32
9.8
DOSE INTERRUPTION...................................................................................................................32
10
STUDY CONDUCT..................................................................................................................32
10.1
EVALUATIONS.............................................................................................................................32
10.1.1
Informed Consent .............................................................................................................32
10.1.2
Medical History ................................................................................................................32
10.1.3
Rapid Antigen Test for Influenza .....................................................................................32
10.1.4
Physical Examination and Influenza-related Complications Assessments .......................33
10.1.5
Vital Signs ........................................................................................................................33
10.1.6
Electrocardiogram Measurements ....................................................................................33
10.1.7
Clinical Laboratories ........................................................................................................33
10.1.8
Urine Pregnancy Test .......................................................................................................34
10.1.9
Serology for Influenza ......................................................................................................34
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10.1.10
Samples for Virologic Laboratory Assessments...............................................................34
10.1.11
Subject Self Assessments..................................................................................................34
10.1.12
Concomitant Medications.................................................................................................35
10.1.13
Adverse Events.................................................................................................................35
10.1.14
Pharmacokinetic Exposure Samples.................................................................................35
10.2
SCREENING PERIOD.....................................................................................................................35
10.2.1
Informed Consent .............................................................................................................35
10.2.2
Screening/Baseline Evaluation and Enrollment................................................................35
10.3
TREATMENT PERIOD—STUDY DAY 1 .........................................................................................36
10.3.1
Pre-dose Evaluations-Study Day 1 ...................................................................................36
10.3.2
Post-dose Evaluations-Study Day 1..................................................................................36
10.4
POST-TREATMENT ASSESSMENT PERIOD....................................................................................37
10.4.1
Days 2, 3, 5, 9 and 14 .......................................................................................................37
10.4.2
Adverse Events Reported at Post-treatment Visits ...........................................................38
11
ADVERSE EVENT MANAGEMENT......................................................................................41
11.1
DEFINITIONS ...............................................................................................................................41
11.1.1
Adverse Event...................................................................................................................41
11.1.2
Serious Adverse Event......................................................................................................41
11.2
METHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING ADVERSE EVENTS AND REPORTING
SERIOUS ADVERSE EVENTS ........................................................................................................42
11.2.1
Definition of Severity .......................................................................................................42
11.2.2
Definition of Relationship to Study Drug.........................................................................43
11.2.3
Reporting Serious Adverse Events ...................................................................................43
11.2.4
Emergency Procedures .....................................................................................................44
12
STATISTICAL METHODS ......................................................................................................44
12.1
DATA COLLECTION METHODS ....................................................................................................44
12.2
STATISTICAL ANALYSIS PLAN ....................................................................................................45
12.3
STUDY HYPOTHESIS....................................................................................................................45
12.4
SAMPLE SIZE ESTIMATES............................................................................................................45
12.5
ANALYSIS POPULATIONS ............................................................................................................46
12.6
INTERIM AND END OF STUDY ANALYSES....................................................................................47
12.7
EFFICACY ANALYSES..................................................................................................................47
12.7.1
Primary Efficacy Endpoint ...............................................................................................47
12.7.2
Secondary Efficacy Endpoints..........................................................................................47
12.7.3
Exploratory Endpoints......................................................................................................48
12.8
SAFETY ANALYSES .....................................................................................................................48
12.9
SUB-STUDY AND PHARMACOKINETIC ANALYSIS........................................................................49
12.10
GENERAL ISSUES FOR STATISTICAL ANALYSIS ...........................................................................49
12.10.1
Multiple Comparisons and Multiplicity............................................................................49
12.10.2
Covariates.........................................................................................................................49
12.10.3
Planned Sub-Groups.........................................................................................................49
12.10.4
Missing Data.....................................................................................................................50
13
STUDY ADMINISTRATION...................................................................................................50
13.1
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................................................50
13.1.1
Regulatory Authority Approvals.......................................................................................50
13.1.2
Ethics Committee Approvals............................................................................................51
13.1.3
Subject Informed Consent ................................................................................................51
13.1.4
Payment to Subjects..........................................................................................................51
13.1.5
Investigator Reporting Requirements ...............................................................................51
13.2
STUDY MONITORING...................................................................................................................52
13.3
QUALITY ASSURANCE.................................................................................................................52
13.4
STUDY TERMINATION AND SITE CLOSURE..................................................................................52
13.5
RECORDS RETENTION .................................................................................................................52
13.6
STUDY ORGANIZATION...............................................................................................................52
13.6.1
Data Monitoring Committee.............................................................................................52
13.7
CONFIDENTIALITY OF INFORMATION ..........................................................................................53
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13.8
STUDY PUBLICATION ..................................................................................................................53
14
REFERENCES...........................................................................................................................54
15
APPENDICES ...........................................................................................................................56
15.1
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA ......................56
15.2
CRITERIA FOR SEVERE COPD AND SEVERE ASTHMA .................................................................57
3.1
List of Figures
Figure 1
Study Measurements and Visit Schedule.................................................................39
3.2
List of Tables
Table 1
Results of study BC-01-03.......................................................................................20
Table 2
Pharmacokinetic parameters from study Him-06-111. ............................................21
Table 3
Summary of Efficacy from BCX1812-211. .............................................................24
Table 4
Summary of Safety from BCX1812-211. ................................................................25
Table 5
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio)..........46
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0–72
area under the curve from time 0 to 72 hours
AUC0–∞
area under the curve extrapolated from time 0 to infinity
BMI
Body Mass Index in kg/m2
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CIOMS
Council for International Organizations of Medical sciences
Cmax
maximum plasma concentration
CK
creatine kinase
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CRF
Case Report Form
CV
coefficient of variation
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
IC50
median inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRC
influenza related complications
ITT
intent-to-treat
ITTI
intent-to-treat infected
IUD
intrauterine device
IVRS
interactive voice response system
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
NSAID
non-steroidal anti-inflammatory drug
PCR
polymerase chain reaction
RAT
Rapid Antigen Test
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
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SD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Event
t1/2
elimination half-life
t1/2 λz
terminal half-life
TCID50
tissue-culture infective dose50
TEAEs
treatment-emergent adverse events
Tmax
time to attain maximum plasma concentration
UPEP
Urine protein electrophoresis
WBC
white blood cell
WHO
World Health Organization
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5
INTRODUCTION
5.1
Background
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of the
respiratory tract. Typical influenza illness is characterized by abrupt onset of fever, headache,
myalgia, sore throat, and nonproductive cough.1 The illness is usually self-limiting, with relief of
symptoms occurring within 5 to 7 days. Nevertheless, it is an important disease for several
reasons, including ease of communicability, short incubation time, rapid rate of viral mutation,
morbidity with resultant loss of productivity, risk of complicating conditions, and increased risk
of death, particularly in the elderly. During 19 of the 23 influenza seasons between 1972/1973
and 1994/1995, estimated influenza-associated deaths in the United States ranged from
approximately 25 to more than 150 per 100,000 persons above 65 years of age, accounting for
more than 90% of the deaths attributed to pneumonia and influenza.2
Presently, only a few measures are available that can reduce the impact of influenza: active
immunoprophylaxis with an inactivated or live attenuated vaccine and chemoprophylaxis or
therapy with an influenza-specific antiviral drug. Neuraminidase inhibitors are the current
mainstay of antiviral treatment for influenza. Marketed neuraminidase inhibitors include
zanamivir (Relenza®, GlaxoSmithKline) and oseltamivir (Tamiflu®, Roche-Gilead), an oral
prodrug of the active agent, oseltamivir carboxylate. Influenza neuraminidase is a surface
glycoprotein that cleaves sialic acid residues from glycoproteins and glycolipids. The enzyme is
responsible for the release of new viral particles from infected cells and may also assist in the
spreading of virus through the mucus within the respiratory tract. The neuraminidase inhibitors
represent an important advance in the treatment of influenza with respect to activity against
influenza A and B viruses, with proven therapeutic value in reducing influenza lower respiratory
complications,3 and lower rates of antiviral drug resistance4.
The use of currently available neuraminidase inhibitors has been limited by concerns including,
the degree of effectiveness, the requirement for an inhaler device (zanamivir), and the emergence
of resistant influenza virus variants in some treated populations.5 In addition, there are risks of
bronchospasm with zanamivir; and gastrointestinal side effects, with oseltamivir.
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to the
armamentarium of drugs for the treatment of influenza infections due to its potential for
parenteral administration and lower frequency of dosing.
5.2
Rationale for Study
An oral formulation of peramivir has previously been evaluated in a full range of safety,
tolerability, pharmacokinetic, and efficacy studies. In a multinational phase 3 clinical trial
conducted in 1999-2001, oral peramivir demonstrated antiviral activity against influenza A and B
infections, and improvement in the relief of clinical symptoms. Because of the limited
bioavailability of peramivir following oral administration (<5%), it was determined that the
parenteral route of administration is more appropriate for the delivery of peramivir. Subsequent
phase 1 studies of intravenous and intramuscular formulations of peramivir have confirmed that
parenteral routes of administration result in plasma levels of drug that are as much as 100 times
those achieved via the oral route. In a phase 2 study of intramuscular peramivir in subjects with
acute uncomplicated influenza, subjects who received a single injection of 150mg or 300mg
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peramivir had clinically meaningful reductions in the time to alleviation of symptoms of
influenza, compared to subjects who received a placebo injection. Further details of these studies
are provided below and in the Investigator Brochure.
Because of the previous demonstration of clinical efficacy of intramuscular peramivir in acute
influenza in the phase 2 study, and the encouraging pharmacokinetic and preliminary safety
profile of the intramuscular formulation of peramivir demonstrated to date, this phase 3 study will
be conducted to evaluate the efficacy and safety profile of intramuscular peramivir and to
determine the optimal single dose regimen.
5.3
Non-Clinical Experience with Peramivir
5.3.1
In vitro Assays
Peramivir is a selective inhibitor of viral neuraminidase, with 50% inhibitory concentrations
(IC50) for bacterial and mammalian enzymes of >300µM.6 In an in vitro study, 42 influenza A and
23 influenza B isolates were collected from untreated subjects during the 1999–2000 influenza
season in Canada.7 These isolates were tested for their susceptibility to the neuraminidase
inhibitors zanamivir, oseltamivir carboxylate, and peramivir using a chemiluminescent
neuraminidase assay. Inhibition of Type A influenza neuraminidase by peramivir was
approximately an order of magnitude greater than inhibition of neuraminidase from Type B
viruses. IC50 values for the Type A enzymes ranged from <0.1 to 1.4nM, whereas the Type B
enzymes ranged from <0.1 to 11nM, with three out of four values in the 5- to 11nM range.
Peramivir was the most potent drug against influenza A (H3N2) viruses with a mean IC50 of
0.60nM as well as most potent against influenza B with a mean IC50 of 0.87nM.
In another in vitro comparison of peramivir, oseltamivir, and zanamivir, using a neuraminidase
inhibition assay with influenza A viruses, the median IC50 of peramivir (approximately 0.34nM)
was comparable to that of oseltamivir (0.45nM) and significantly lower than zanamivir (0.95nM).
For influenza B virus clinical isolates, the median IC50 of peramivir (1.36nM) was comparable to
that of zanamivir (2.7nM) and lower than that of oseltamivir (8.5nM).8
The potency of peramivir was evaluated against five zanamivir-resistant and six oseltamivir-
resistant influenza viruses.9 Peramivir remained a potent inhibitor against all oseltamivir-resistant
viruses including the mutations H274Y, R292K, E119V, and D198N, with IC50 values ≤40nM.
Peramivir also potently inhibited (IC50 ≤ 26nM) the neuraminidase activity of zanamivir-resistant
strains, which had the following mutations: R292K, E119G, E119A, and E119D. However, one
zanamivir-resistant influenza B virus, B/Mem/96, with a mutation R152K isolated from cell
culture, was relatively resistant to all neuraminidase inhibitors, including peramivir (IC50 =
400nM).
5.3.2
Animal Models
In a mouse model of influenza infection, a single intramuscular injection of peramivir (10mg/kg)
given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain resulted in 100%
survival in contrast to 100% mortality in a control group injected with saline.6 In the same mouse
model, treatment of mice up to 72 hours after influenza infection using peramivir (20mg/kg)
resulted in 100% survival, compared to 100% mortality in the control group injected with
vehicle.10
Peramivir has also demonstrated activity in animal models utilizing a clinical H5N1 isolate as the
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infecting virus strain. In a mouse model, a single intramuscular dose of peramivir (30mg/kg)
injected 1 hour after inoculation with the highly pathogenic (H5N1) A/Vietnam/1203/04 strain,
resulted in a 70% survival rate that was similar to that seen in mice treated with oseltamivir given
orally at 10mg/kg/day for 5 days11. In similar experiments, mice inoculated with the same strain
of H5N1 virus that were then treated for up to 8 days with intramuscular peramivir exhibited
100% survival12. This longer duration of peramivir treatment also prevented viral replication in
the lungs, brain and spleen at days 3, 6 and 9 post inoculation.
5.4
Previous Phase 3 Clinical Experience with Oral Peramivir
An oral formulation of peramivir has previously demonstrated antiviral activity and preliminary
clinical efficacy in challenge studies in human volunteers, as well as in treatment studies in
patients with uncomplicated acute influenza infections during the influenza seasons of 1999-
2001. A Phase 3 multinational study (BC-01-03) of oral peramivir was conducted. Two dose
regimens of oral peramivir, 800mg QD for 5 days, or 800mg QD on Day 1, followed by 400mg
QD for 4 days, were compared to a matched placebo treatment group. A total of 1246 subjects
were randomized to treatment at sites in the USA, Western and Eastern Europe, South America,
Australia and New Zealand. As presented in the Table 1 below, the primary end-point of time to
relief of influenza symptoms in 694 subjects with confirmed influenza was not found to be
significantly different (p=0.17) between the three treatment groups.13 A sub-group analysis of the
time to relief of symptoms by country or region demonstrated marked differences in the primary
endpoint.. In the subset of influenza-infected subjects enrolled at sites in the US, clinically
meaningful differences in time to relief of influenza symptoms between the placebo and the two
peramivir arms were observed, however statistical significance (p=0.07) was not achieved.
However, a number of secondary endpoints in this phase 3 study, such as time to overall well-
being, time to normal activity, incidence of influenza related complications and quantity of viral
shedding, achieved or approached statistically significant differences between the peramivir and
placebo treatment groups (p=0.03-0.06).
Table 1
Results of study BC-01-03
Median Time to Relief of Influenza Symptoms (Hours)
Dose and Regimen
Overall Results
(n=694)
US Sites
(n=198)
Peramivir 800mg po x 5d
89.0
70.8
Peramivir 800mg po x 1d
and 400mg po x 4d
91.7
88.8
Placebo x 5 days
104.4
106.8
p value
0.17
0.07
5.5
Previous Phase 1 Experience with Intramuscular Peramivir
Two phase 1studies evaluating the safety and pharmacokinetics of an intramuscular formulation
of peramivir have been conducted in a total of 45 healthy volunteers receiving peramivir. An
additional phase 1 study has recently been initiated to evaluate the pharmacokinetics and
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tolerability of higher single doses (up to 600 mg) of intramuscular peramivir.
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability of
75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma levels of
i.m. peramivir generally occurred within 30 minutes following injection. Plasma
pharmacokinetic parameters for i.m. peramivir are summarized in Table 2 below for the three
intramuscular single dose regimens evaluated.
Table 2
Pharmacokinetic parameters from study Him-06-111.
Dose (mg)
Cmax (ng/mL)
AUC0-∞ (hr·ng/mL)
t½a (hr)
75 i.m.
4296 ± 812
11659 ± 1123
19.8 ± 7.9
150 i.m.
7612 ± 884
23952 ± 3804
24.3 ± 4.1
300 i.m.
15150 ± 2367
49649 ± 5619
22.8 ± 2.5
aterminal half life
In a second phase 1 study, Peramivir-Him-06-112, the same dose levels of peramivir were
administered as single i.m. injections on two consecutive days (6 subjects per group). This
double-blind study also included a placebo arm. The pharmacokinetic parameters of i.m.
peramivir following the second day of dosing were consistent with those seen following single
doses of the drug.
An additional phase 1 study, BCX1812- 117, was initiated to evaluate the effect of needle length
adjustment according to gender and bod
y m ass index on the pharm acokinetics and s afety of
peramivir fo llowing vent rogluteal int ramuscular injection, and dors
ogluteal intram uscular
injection in a subgroup o f subjects. Interim data are available for the first 40 subjects who
received single peram ivir doses of
600 m g, co nsisting of directly
obse rved tolerabilit y
assessments, safety laboratory studies, reporte d adverse even ts, and pharmacokinetic data.
Clinical laboratory results obtained 72 hours after dosing showed no abnorm alities with reg ards
to hematology or urinary analytes and the only chemistry analytes outside normal ranges (CK and
AST) were related to receipt of intramuscular injection.
A majority of the first 40 subjects treated com plained of acute pain immediately after injection at
the ventrogluteal site and a num ber of these subj ects reported that the pain w as also assoc iated
with muscle cramping. Some subjects reported radiation of pain to the lower extremities. In most
instances, these reactions abated after 15-30 minutes.
This protocol also evaluated the acute tolerab ility of doses of 450 m g and 600 mg of perami vir
administered at the dors
ogluteal site. Direct
observations deter mined that the use of the
dorsogluteal injection site resulted in an acute tolerability profile of the 600 mg dose of peramivir
that was i mproved com pared to that observed w
ith ventrogl uteal site injections. However, a
number of th ese subjects also experienced acute pain and discomfort and some reported muscle
cramping in the gluteal area which persisted for up to 30 minutes.
In summary, this study confirmed that the intram uscular injection of peram ivir results in acute
pain and discomfort after gluteal injection in the majority of subjects in whom total doses of up to
600mg are adm inistered. In some subjects, the ac
ute pain at the injection site
may also b e
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associated with muscle cramping. Based on these findings, the dorsogluteal site will be util ized
in future trials.
The safety data for i.m. peramivir administered as single doses ranging from 75 mg to 600mg at
the dorsogluteal injection site in each of the 3 phase 1 studies conducted to date have been
unremarkable. No serious adverse events were reported. The most commonly observed adverse
events or laboratory abnormalities were injection site pain or discomfort, headache, and transient
increases in muscle enzymes (CK). There have been several reports of signs and symptoms of
self-limited vasovagal reactions following injections.. No consistent differences in frequency of
adverse events or laboratory toxicities were observed between the active and placebo treatment
groups in the controlled phase 1studies, with the exception that CK elevations appeared to be
dose related in the peramivir treatment groups.
5.6
Phase 2 Experience with Intramuscular Peramivir
A phase 2 study BCX1812-211 was completed in 2007. This study was a randomized, double-
blind placebo- controlled study to evaluate the efficacy and safety of two single dose regimens of
peramivir. A total of 344 subjects were enrolled into this study with 115 subjects randomized to
Placebo; 114 subjects randomized to peramivir 150 mg; and 114 subjects randomized to
peramivir 300 mg. The primary endpoint of the study was the time to alleviation of clinical
symptoms in adult subjects with uncomplicated acute influenza. Based on preliminary data, the
primary endpoint of time to alleviation of clinical symptoms in BCX1812-211 did not achieve
statistical significance in the pre-planned ITTI study population (Table 3).. Based on pre-planned
and post hoc analyses, it appeared that a majority of subjects within this phase 2 study did not
receive an adequate intramuscular injection.
In phase 1 studies (Hi
m-06-111 and Him-06-112) of i.m . per amivir, significant increases in
creatine kinase (CK) were observed at Day 3 compared with Baseline (Day 1) in all subjects who
received active study drug or placebo. CK is a well established marker of muscle damage, and it
was hypothesized that CK increase may act as a surrogate marker of an adequate i.m. injection.
Within the phase 2 study, an increase in CK between Baseline (Day 1) and Day 3 was not
observed in a majority of subjects. In the phase 1 studies study drug was administered with a 1½
inch needle. In the phase 2 study a shorter needle (1 inch) was supplied with the study drug, with
guidance that a longer needle (1½ inch) should be used for larger subjects. Based on the observed
lack of CK increases at Day 3 compared to baseline, the Sponsor hypothesized that the needle
used for injection failed to penetrate muscle and deliver intramuscular study medication in many
subjects.
A sub group of subjects was identified in which a Day 3 CK increase of at least 50U/L was
observed over baseline. Within this adequate intramuscular injection sub-group, notable
improvements in the time to alleviation of symptoms were observed for both peramivir dose
groups: 44.6 hours for peramivir 150 mg treatment and 64.8 hours for the peramivir 300 mg
treatment
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Table 3). A further sub-group analysis suggested that in subjects with an influenza B infection
confirmed by PCR a single dose of peramivir had marginal activity (Table 3). These efficacy data
support the further development of peramivir as a single dose, intramuscular treatment for acute
influenza.
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Table 3
Summary of Efficacy from BCX1812-211.
Placebo
Peramivir
150mg
Peramivir
300mg
Intent-to-Treat Infected Population1 (n=313)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=107
137.0
115.9-163.8
n=104
114.1
95.2-145.5
22.9
n=102
115.9
77.8-136.6
21.1
Adequate Injection Population2 (n=101)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=40
152.2
103.8-183.9
n=32
107.6
76.8-175.1
44.6
n=29
87.4
40.8-163.8
64.8
ITTI Influenza A infected population (n=247)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=83
138.4
117.0-173.4
n=85
115.7
92.2-145.5
22.7
n=79
115.9
51.1-195.9
22.5
ITTI Influenza B infected population (n=66)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=24
117.1
100.3-162.3
n=19
100.8
68.2-162.0
16.3
n=23
123.3
67.5-178.7
-6.2
1: Intent-to-Treat Infected Population: PCR+ for either Influenza A and/or Influenza B at
baseline/screening visit.
2: Adequate Injection Population: ITTI subjects in who study drug reached target muscle tissue,
as evidenced by an increase in serum CK levels of ≥ 50 U/L over baseline at the Day 3 study
visit.
An independent data monitoring committee reviewed grouped blinded safety data throughout
study BCX1812-211. In the overall safety population (n=342), doses of peramivir 150 mg and
300 mg were both found to be well tolerated and no safety concerns were identified by the DMC.
The three treatment groups were similar with respect to the frequency and severity of adverse
events. Two serious adverse events were reported in the study, and neither was considered by the
investigator to be related to treatment. One SAE (pyelonephritis) occurred 5-days after study
treatment in a subject who received placebo, and one SAE (meningitis, resulting in death)
occurred 10-days after study treatment in a subject who received 300 mg of peramivir. There
were no meaningful differences among the three treatment groups with respect to the frequency
or severity of graded laboratory toxicities. A summary of the adverse events and graded toxicities,
together with a list of the most frequently reported adverse events, is presented in Table 4.
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Table 4
Summary of Safety from BCX1812-211.
Safety Parameters
Placebo
(N=114)
Peramivir 150 mg
(N=113)
Peramivir 300 mg
(N=115)
Any Clinical Adverse Event
49 (43%)
43 (38%)
44 (38%)
Any Graded Laboratory Toxicity
99 (87%)
93 (82%)
92 (80%)
Any Serious Adverse Event
1 (<1%)
0
1 (<1%)
Most Frequent Adverse Events
Assessed as Study Drug-Related
Diarrhea
Nausea
Vasovagal Reaction
5 (4%)
7 (6%)
4 (4%)
5 (4%)
7 (6%)
2 (2%)
6 (5%)
9 (8%)
0
5.7 Dose Rationale
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 75mg
twice daily in adults14. Oseltamivir was shown to be clinically effective in a phase 3 study of oral
oseltamivir versus placebo in naturally occurring seasonal influenza, and these data were
sufficient for regulatory approval for marketing of oseltamivir. At least 75% of an oral dose of
oseltamivir reaches the systemic circulation as oseltamivir carboxylate. When oseltamivir is
administered orally at a dose of 75mg twice daily, the serum Cmax of oseltamivir carboxylate is
approximately 348ng/mL and the AUC0-48 is 10,876 h·ng/mL. The clinical data indicate that this
level of exposure to oseltamivir was sufficient to provide clinical improvement in uncomplicated
acute influenza.
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular doses of
peramivir are approximately 7600ng/mL and 24,000 h·ng/mL for the 150mg dose and are
approximately 15,000ng/mL and 49,000 h·ng/mL for the 300mg dose. Previous studies have
assessed the concentrations of the neuraminidase inhibitor zanamivir in nasal and pharyngeal
secretions after parenteral administration of this drug. . Within several hours after administration,
the concentrations in secretions were approximately 100-fold lower than in serum or plasma. In
theory, relatively high levels of a neuraminidase inhibitor in respiratory secretions are desirable in
order to rapidly inactivate influenza virus and to delay or prevent the development of resistance in
infecting virus strains. Intramuscular doses of peramivir, including doses of 300mg and 600mg
have been shown to be well tolerated in previous Phase 1 studies. In the completed Phase 2
study, both doses of peramivir (150 mg and 300 mg) were well tolerated and no safety concerns
were apparent. As evidence of a dose response between the 150mg and 300mg doses was
observed in the phase 2 study, it is possible that a higher dose of 600mg of peramivir may further
improve the treatment response observed in study 211. Therefore, it is appropriate to evaluate
two dose regimens of 300mg and 600mg to undergo further evaluation in this Phase 3 study.
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6
STUDY OBJECTIVES
6.1
Objectives
6.1.1
Primary Objective
To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the
time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza.
6.1.2
Secondary Objective(s)
The secondary objectives of this study are:
1. To evaluate the safety and tolerability of peramivir administered intramuscularly,
2. To evaluate secondary clinical outcomes in response to treatment,
3. To evaluate changes in influenza virus titer in nasopharyngeal samples (viral shedding) in
response to treatment.
6.1.3
Exploratory Objective(s)
The following exploratory objectives have been identified for this study.
1. To assess pharmacoeconomic measures as response to treatment.
2. To assess changes in influenza viral susceptibility to neuraminidase inhibitors following
treatment.
6.2
Study Endpoints
6.2.1
Primary Endpoint
The primary clinical endpoint is the time to alleviation of clinical symptoms of influenza in
subjects with influenza A.
6.2.2
Secondary Endpoint(s)
Secondary safety, clinical, and virologic endpoints will include evaluations in each subject of:
Safety:
Incidence of treatment-emergent adverse events and treatment-emergent changes
in clinical laboratory tests.
Clinical:
Time to resolution of fever; Incidence of influenza related complications.
Virologic:
Quantitative change in influenza virus shedding, measured by viral titer assay
(TCID50).
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6.2.3
Exploratory Endpoints
Pharmacoeconomic and virologic evaluations in each subject for exploratory endpoints will also
be assessed and include:
Pharmacoeconomic:
Medical resource utilization (MRU), missed days of work, and impact of
influenza illness on subject’s work performance and/or productivity.
Virologic:
Quantitative change in influenza virus shedding, measured by PCR;
Change in influenza virus susceptibility to neuraminidase inhibitors.
7
STUDY DESIGN
7.1
Overall Study Design and Plan
This is a multinational, randomized, double-blind study comparing the efficacy and safety of two
single dose regimens of peramivir administered intramuscularly versus placebo in adults with
uncomplicated acute influenza.
Up to a total of 750 evaluable subjects will be randomized to treatment (150 subjects in the
placebo treatment group, 300 subjects in the peramivir 300mg treatment group and 300 subjects
in the peramivir 600mg treatment group).
Each subject’s assignment to treatment will be stratified according to smoking status. All subjects
will be centrally randomized to one of three treatment groups in a ratio of 2:2:1 such that 80% of
subjects are randomized to one of the two single dose regimens of peramivir.
Treatment Group 1: Peramivir 300mg
Treatment Group 2: Peramivir 600mg
Treatment Group 3: Placebo
Study drug will be administered as bilateral 4mL intramuscular injections (total of 8mL injected
in equally divided doses). Procedures for intramuscular injection, with a recommended needle
length appropriate to the physical characteristics of the subject, are provided in the study drug
administration manual.
Subjects eligible for screening will have an anterior nasal swab collected for testing by RAT for
influenza A and B, in accordance with the commercially available RAT kit instructions. If the
initial RAT is negative, the test should be repeated within one hour. Subjects meeting the
inclusion/ exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following information in a Study Diary.
•
Assessment of the presence and severity of each of seven symptoms of influenza on a
4-point scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily (AM, PM) through
Day 9 following treatment, then once daily (AM) through Day 14.
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•
Oral temperature measurements will be taken with an electronic thermometer every 12
hours. With the exception of the baseline measurement, all temperature measurements
will be obtained at least 4 hours after, or immediately before, administration of oral
acetaminophen (paracetamol) or other antipyretic medication.
•
Assessment of subject’s time lost from work or usual activities and rating of productivity
compared to normal (rated as 0-10 on a visual analog scale) once daily through Day 14
•
Doses of antipy retic, expectorant, and/or th roat lozenges taken for s ymptomatic relief
each day through Day 14
Anterior nose (bilateral) and posterior pharynx specimens (swabs) will be collected at Day 1 (pre-
treatment) and at Days 3, 5, and 9, for quantitative virologic assessments. Specimens from all
subjects yielding influenza virus will also be assessed for susceptibility to neuraminidase
inhibitors (Day 1 and last specimen yielding positive result) as well as other virologic
assessments (e.g. PCR, genotypic testing). All virologic assessments will be performed by a
central laboratory.
Two samples for pharmacokinetic (PK) testing for plasma levels of peramivir will be obtained
from all subjects randomized. The first PK sample will be obtained between 30 and 60 minutes
following study drug administration in all subjects. The second PK sample will be obtained at the
day 3 visit in all subjects. The data from these PK samples will be utilized in a population
exposure-response analysis.
At selected sites a separate sub-study will be conducted to collect additional PK samples between
treatment and Day 3 for the purpose of conducting a separate exposure-response analysis. This
sub-study will be conducted under a separate protocol, BCX1812-311PK.
Study drug will be administered as bilateral 2mL intramuscular injections (total of 4mL injected
in divided doses). Procedures for intramuscular injection, with a recommended needle length
appropriate to the size and weight of the subject, are provided in the study drug administration
manual.
8
SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.1
Inclusion Criteria
Subjects must meet all of the following criteria for inclusion in this study:
1. Male and non-pregnant female subjects age ≥18 years.
2. A positive Influenza A Rapid Antigen Test (RAT) performed with a commercially
available test kit on an adequate anterior nasal specimen, in accordance with the
manufacturer’s instructions. A negative initial RAT should be repeated within one hour.
Subjects with a positive influenza B or mixed A and B RAT will be excluded.
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC
(≥101.2 ºF) taken rectally. A subject self-report of a history of fever or feverishness
within the 24 hours prior to screening will also qualify for enrollment in the absence of
documented fever at the time of screening.
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4. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of
at least moderate severity.
5. Presence of at least one constitutional symptom (myalgia [aches and pains], headache,
feverishness, or fatigue) of at least moderate severity.
6. Onset of symptoms no more than 48 hours before presentation for screening.
7. Written informed consent.
8.1.2
Exclusion Criteria
Subjects to whom any of the following criteria apply will be excluded from the study:
1. Women who are pregnant or breast-feeding.
2. Presence of clinically significant signs of acute respiratory distress
3. History of severe chronic obstructive pulmonary disease (COPD) or severe persistent
asthma. (See Section 15.2).
4. History of congestive heart failure requiring daily pharmacotherapy with symptoms
consistent with New York Heart Association Class III or IV functional status within the
past 12 months. (See Section 15.1).
5. Screening ECG which suggests acute ischemia or presence of medically significant
dysrhythmia.
6. History of chronic renal impairment requiring hemodialysis and/or known or suspected to
have moderate or severe renal impairment (actual or estimated creatinine clearance <50
mL/min).
7. Clinical evidence of worsening of any chronic medical condition (temporally associated
with the onset of symptoms of influenza) which, in the investigator’s opinion, indicates
that such finding(s) could represent complications of influenza.
8. Current clinical evidence, including clinical signs and/or symptoms consistent with otitis,
bronchitis, sinusitis and/or pneumonia, or active bacterial infection at any body site that
requires therapy with oral or systemic antibiotics.
9. Presence of immunocompromised status due to chronic illness, previous organ transplant,
or use of immunosuppressive medical therapy which would include oral or systemic
treatment with > 10 mg prednisone or equivalent on a daily basis within 30 days of
screening.
10. Currently receiving treatment for viral hepatitis B or viral hepatitis C.
11. Presence of known HIV infection with a CD4 count <350 cell/mm3.
12. Current therapy with oral warfarin or other systemic anticoagulant.
13. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the 7 days
prior to screening.
14. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the
previous 21 days.
15. Immunized against influenza with inactivated virus vaccine within the previous 14 days.
16. Receipt of any intramuscular injection within the previous 14 days.
17. History of alcohol abuse or drug addiction within 1 year prior to admission in the study.
18. Participation in a previous study of intramuscular or intravenous peramivir or previous
participation in this study.
19. Participation in a study of any investigational drug or device within the last 30 days.
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8.1.3
Removal of Subjects from Therapy or Assessment
All subjects are permitted to withdraw fro m participation in this study at any ti me and for any
reason, specified or
unspecified, and without prejudice. T he Investigator or sp onsor m ay
terminate the subject’s participation in the study at any time for reasons including the following:
1. Adverse event;
2. Intercurrent illness;
3. Non-compliance with study procedures;
4. Subject’s decision;
5. Administrative reasons;
6. Lack of efficacy;
7. Investigator’s opinion to protect the subject’s best interest.
Any subject who withdraws because of an adve
rse event will be followe d until the sign(s) or
symptom(s) that constituted the adverse event has/ha ve resolved or is determ ined to represent a
stable medical condition.
A subject should be with drawn from the trial if, in the opinion of the Investigator, it is medically
necessary, or if it is the desire of the subject.
If a subject does not return for a scheduled visit,
every effort should be made to contact the subject and determine the subject’s medical condition.
In any circumstance, every effort should be made to document subject outcome, if possible.
If the subject withdraws consent, no fu rther ev aluations should b e perfo rmed and no attempts
should be made to collect additional data.
9
TREATMENTS
9.1
Treatments Administered
Peramivir is an investigational drug. Peramivir for intramuscular injection is a small-volume
parenteral and will be supplied as a 75mg/mL solution in sodium citrate/ citric acid buffer. The
pH is approximately 3.0.
A matched placebo solution of sodium citrate/ citric acid buffer with 1.2% sodium chloride at a
pH of approximately 3.0 will be supplied.
The gluteal site of injection and the syringe needle length are to be recorded in the subjects CRF.
Procedures for intramuscular injection, with a recommended needle length appropriate to the
physical characteristics of the subject, are provided in the study drug administration manual.
9.2
Identity of Investigational Product(s)
Peramivir and placebo peramivir will be supplied in clear 2mL vials. An individual study drug
kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending upon the
treatment group). Syringes and needles will be provided in which to draw up the solution for
intramuscular injection. All study drug kits must be stored at 2-8oC.
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Each individual study drug kit will be labeled with some or all of the following information as
required by local regulations:
•
Sponsor name and contact information, study protocol number, kit number, description of
the contents of the container, instructions for the preparation of the syringe and
administration of the study drug, conditions for storage, statement regarding the
investigational (clinical trial) use of the study drug and date for retest or expiry date.
Each vial of study drug will be labeled with some or all of the following information as required
by local regulations:
•
Sponsor name, study protocol number, description of the contents of the vial, instructions
for the preparation of the syringe, statement regarding the investigational (clinical trial)
use of the study drug and lot number.
9.3
Method of Assigning Subjects to Treatment Groups
Subjects will be centrally randomized according in a ratio of 2:2:1 to one of three treatment
groups: single dose peramivir 300mg, single dose peramivir 600mg or placebo, in accordance
with a computer-generated randomization schedule prepared by a non-study statistician. Eighty
percent (80%) of subjects will be randomized to treatment with one of the two single dose
regimens of peramivir, 20% will be randomized to treatment with placebo.
Each subject’s assignment to treatment will be stratified according to smoking status.
Once a subject is eligible for randomization, he/she will be assigned two study drug kit numbers
that will be obtained by study staff from the study interactive voice response system (IVRS).
Once a study drug kit number has been assigned to a subject, it cannot be reassigned to any other
subject.
9.4
Study Medication Accountability
The Investigator/pharmacist must maintain accurate records of the disposition of all study drugs
received from the sponsor, issued to the subject or directly administered to the subject (including
date and time), and any drug accidentally destroyed. The sponsor will supply a specific drug-
accountability form. At the end of the study, information describing study drug supplies (e.g., lot
numbers) and disposition of supplies for each subject must be provided, signed by the
Investigator or designee, and collected by the study monitor. If any errors or irregularities in any
shipment of study medication to the site are discovered at any time, the Project Manager must be
contacted immediately.
At the end of the study, all medication not dispensed or administered and packaging materials
will be collected with supervision of the monitor and returned to the sponsor or destroyed on site
as dictated by the appropriate Standard Operating Procedure at the participating institution.
9.5
Blinding/Unblinding of Treatments
This is a double-blind study. The treatment group assignment will not be known by the study
subjects, the investigator, the clinical staff, the CRO or Sponsor staff during the conduct of the
study.
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Section 11.2.4 provides information regarding the process for unblinding the treatment
assignment, if necessary, in the event of an SAE.
9.6
Prior and Concomitant Therapies
All medications, by any route of administration, used during this study must be documented on
the Case Report Form (CRF). Prescription as well as non-prescription medications should be
recorded. Medication used for the treatment of influenza-related symptoms will be captured by
the subject in the diary card provided by BioCryst.
9.7
Overdose and Toxicity Management
To date there is no experience with overdose of intramuscular or intravenous peramivir. If
overdose occurs, subjects should receive indicated supportive therapy and evaluation of
hematologic and clinical chemistry laboratory tests should be conducted. The effect of
hemodialysis on elimination of peramivir is unknown.
9.8
Dose Interruption
As this is a study of a single dose of peramivir or placebo, guidelines for treatment interruption
for drug related SAEs or toxicities are not applicable.
10 STUDY CONDUCT
A study schedule of evaluations is presented in Figure 1. A detailed list of the evaluations and
visits is also provided in the following sections.
10.1 Evaluations
All subjects enrolled in this study will undergo the following evaluations:
10.1.1 Informed Consent
Prior to any study-related procedure subjects will be administered informed consent. For further
discussion of consent see section 10.2.1.
10.1.2 Medical History
Medical history, influenza vaccination status within the previous 12 months and demographic
data (including smoking behavior) will be recorded at Screening/Baseline.
10.1.3 Rapid Antigen Test for Influenza
At Screening/Baseline, a commercially available, rapid antigen test (RAT) for influenza A will be
performed on an adequate specimen collected by swabbing the anterior nose in accordance with
the RAT manufacturer’ instructions. A negative initial RAT should be repeated within one hour.
Subjects with a positive influenza B or mixed A and B RAT will be excluded. Refer to the Study
Manual for instructions regarding the use of the RAT kits provided for this study. Sites may use
the kits provided by the Sponsor or any other commercially approved RAT available at their site
to document a confirmed influenza infection.
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10.1.4 Physical Examination and Influenza-related Complications Assessments
The Investigator will perform a physical examination at Screening/Baseline. Subject’s height and
weight, and BMI will be recorded at Screening/Baseline in the subjects CRF.
Study personnel will be provided with an influenza-related complications (IRC) checklist in the
CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following
influenza-related complications: sinusitis, otitis, bronchitis and pneumonia. Note that subjects
with clinical signs and/or symptoms consistent with otitis, bronchitis, sinusitis, and/or pneumonia
at screening are not eligible for enrollment in this study (See Section 8.1.2: exclusion criteria
number 8).
A targeted physical examination will be conducted at each visit to record the presence/absence of
influenza related complications (IRC). If the investigator determines that the subject experiences
(or is presumed to experience) an IRC as noted above, he/she will record that assessment on the
IRC CRF page and any medication used to treat the condition will be recorded on the
concomitant medication page. The investigator will promptly provide appropriate treatment for
any suspected or proven IRC. Such information describing IRC signs and/or symptoms should
not be reported as adverse events. Any injection site reactions noted will be recorded in the CRFs
as adverse events.
10.1.5 Vital Signs
Vital signs evaluations will include blood pressure, pulse rate, and respiration rate. The
investigator will record oral or rectal body temperature at baseline. Thereafter the subject will
record oral temperature twice daily in the study diary card.
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following the
study drug injection on Day 1, then once daily on Days 3, 5, 9, and 14.
10.1.6 Electrocardiogram Measurements
A 12-lead electrocardiogram (ECG) will be obtained at Screening/Baseline. The principal
investigator will be responsible for interpretation of the Screening ECG. This interpretation may
be performed by the investigator or he/she may delegate this action to another physician and the
investigator will acknowledge the interpretation. If this baseline ECG is interpreted as meeting
the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study. If the
ECG is interpreted as being abnormal but does not meet the exclusionary criteria, the subject may
be enrolled unless other exclusion criteria apply. The principal investigator is responsible to
ensure that such an enrolled subject be informed of the nature of the abnormal ECG and that any
medically indicated repeat ECG examinations and/or referral of the subject for further evaluation
is made either during subject's participation in the study or immediately after the subject's
discharge from the study.
10.1.7 Clinical Laboratories
Clinical chemistry profiles will include a Chemistry 20 panel (includes sodium, potassium,
chloride, total CO2 [bicarbonate], creatinine, glucose, urea nitrogen, albumin, total calcium, total
magnesium, phosphorus, alkaline phosphatase, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), total bilirubin, direct bilirubin, lactate dehydrogenase [LDH], total
protein, total creatine kinase, and uric acid).
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Hematology will include complete blood count (CBC) with differential.
Urinalysis will include dipstick tests for protein, glucose, ketones, blood, urobilinogen, nitrite,
pH, and specific gravity and microscopic evaluation for RBCs and WBCs. For any subject with a
Day 3 positive test for urine protein by dipstick test of 2+ or higher, who had a Baseline/ Day 1
protein dipstick of <2+, a 24 hour urine collection for assessment of protein and a simultaneous
assessment by UPEP on the same specimen will be obtained.
Clinical laboratory studies (clinical chemistries, hematology, and urinalysis) will be completed at
Screening/Baseline, and on Days 3, 5 and 14.
10.1.8 Urine Pregnancy Test
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and Day
14 using a urine pregnancy test.
10.1.9 Serology for Influenza
Paired blood samples for determination of antibody to influenza A and B (serology) will be
obtained with the clinical laboratory tests at Screening/Enrollment and at Day 14. These
specimens will be stored at the central laboratory and will be analyzed if needed to confirm the
diagnosis of influenza.
10.1.10 Samples for Virologic Laboratory Assessments
An adequate specimen will be collected by swabbing the anterior nose (bilateral) and posterior
pharynx for virologic laboratory assessments including culture for the isolation of influenza virus
and/or quantitative PCR assay at Screening/Baseline, and at Days 3, 5, and 9. Refer to the
Laboratory Manual for instructions regarding the processing and shipment of these specimens.
10.1.11 Subject Self Assessments
Subject self assessments will be performed beginning pre-dose on Day 1 and recorded in the
subject’s Study Diary including the following:
•
Oral temperature measurements with an electronic thermometer (provided by the Sponsor for
the study) every 12 hours. With the exception of the baseline measurement, all temperature
measurements will be obtained at least 4 hours after, or immediately before, administration of
oral acetaminophen (paracetamol, provided) or other anti-pyretic medications. The times of
each temperature determination will be recorded in the Study Diary. The baseline
temperature will be recorded at the screening/Day 1 visit prior to dosing, regardless of
whether the subject had recently taken an anti-pyretic; the time of anti-pyretic use pre-
treatment will be recorded in the CRF, if applicable.
•
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia
[aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent;
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 and through Day 9,
then once daily through Day 14.
•
Assessment of the subject’s time lost from work or usual activities and productivity compared
to normal using a 0-10 visual analogue scale once daily through Day 14.
The subject’s diary card will be reviewed by study staff at each visit for completion of the record
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of all required items, with particular emphasis on alleviation of symptoms as well as relapse of
symptoms. Relapse is defined as the recurrence of at least one respiratory symptom and one
constitutional symptom (both greater than mild in severity) for 24 hours and the presence of fever
(unless influenced by antipyretic use). Relapse can only occur after the subject has met the
endpoint criteria for alleviation of symptoms. Study staff will not attempt to ask subjects to
retrospectively complete missing diary card data for any scheduled assessments that have not
been completed prior to the clinic visit. Study staff should, however, remind the subject to
complete the diary card at all scheduled times.
10.1.12 Concomitant Medications
All concomitant medications used during this study, with the exception of those medications
taken for symptomatic relief of influenza symptoms, which will be recorded by the subject in
their diary card, must be documented on the Case Report Form (CRF).
10.1.13 Adverse Events
AEs will be assessed from the time of administration of study medication through the final study
visit.
10.1.14 Pharmacokinetic Exposure Samples
All subjects will have two pharmacokinetic (PK) samples drawn to assess peramivir drug levels.
The first PK sample will be drawn on day 1 between 30 and 60 minutes following study drug
administration in all subjects. The second PK sample will be drawn at the day 3 visit in all
subjects. The sample will be drawn at the same time as the blood draw is completed for clinical
laboratory investigations. The 30-60 minute sample (treatment day 1) and the day 3 PK sample
will be analyzed for plasma concentrations of peramivir (ng/mL) and evaluated in a population
exposure response analysis.
At selected sites a separate sub-study will also be conducted to collect additional PK samples for
the purpose of conducting an exposure-response analysis. This sub-study will be conducted
under a separate protocol, BCX1812-311PK. Data from these two PK samples in all subjects will
be combined with data from the PK sub-study (BCX1812-311PK) to perform a population based
exposure-response analysis. This analysis will be described as part of the sub-study analysis plan.
All PK samples will be processed at a central bioanalytical laboratory. Refer to the instructions
provided regarding the processing and shipment of these PK samples.
10.2 Screening Period
10.2.1 Informed Consent
The nature and purpose of the study and the expectations of a participating subject will be
described to potential study subjects, their questions will be answered, and the subjects will then
be asked to sign an informed consent document. Study subjects will then undergo the screening
evaluation as noted in Section 10.2.2
10.2.2 Screening/Baseline Evaluation and Enrollment
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or in the
subject’s home, in which case all evaluations must be conducted by appropriately trained and
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qualified staff.
Clinical laboratory assessments performed at Screening are for the purpose of establishing a
baseline. Subjects may be enrolled and receive treatment with study drug prior to receiving
results of the laboratory assessments (with the exception of urine pregnancy test result, which
must be known).
Eligible subjects will be enrolled and randomized to blinded study treatment. The randomization
will be stratified by smoking status. The Investigator will prepare a request for blinded study
drug assignment which includes the subject’s screening number. The Investigator or designee at
the clinical study center will contact the central randomization Interactive Voice System (IVRS
call center). The IVRS call center will advise the study center of the two investigational study
drug kit numbers that are assigned to that subject at enrollment.
Subjects that are determined to be ineligible will be advised accordingly, and the reason for
ineligibility will be discussed. If desired by the subject the reason for ineligibility may be
provided and/or discussed with their health-care provider by the Investigator or designee.
Ineligible subjects who have been screened for the study will also be entered on the IVRS. For
such subjects, the screening number assigned, subject’s date of birth and a reason for ineligibility
will be entered on to the IVRS. All ineligible subjects must be entered onto the IVRS within
24 hours of screening, to assist with surveillance analysis during the course of the study.
10.3 Treatment Period—Study Day 1
Day 1 represents the only day of study drug dosing. Study drug administration should occur as
soon as possible following informed consent, screening and randomization. Therefore, it is
expected that the date of Screening/ Baseline and Day 1 will usually be the same date.
10.3.1 Pre-dose Evaluations-Study Day 1
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the subject
shall complete the record of these assessments in their Study Diary prior to dosing. The subject
will be counseled regarding the expectations for recording these assessments through Day 14.
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) and a
12 lead ECG will be obtained prior to dosing.
A nasopharyngeal swab for influenza culture/ PCR assay will be obtained prior to dosing.
10.3.2 Post-dose Evaluations-Study Day 1
The blinded study drug will be administered (hour 0) as bilateral intramuscular injections within a
period of ≤ 10 minutes. The calendar date and 24-hour clock time of the first and second
injections will be recorded. The gluteal site of injection and the syringe needle length are also to
be recorded in the subjects CRF. Sites are instructed to follow procedures for intramuscular
injection, with a recommended needle length appropriate to the physical characteristics of the
subject, provided in the study drug administration manual.
The following evaluations will be performed post-dose on Study Day 1:
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•
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) 15
minutes following the second intramuscular injection of blinded study drug; record the exact
24-hour clock time of the vital sign measurements in the subjects CRF.
•
Draw a PK sample between 30 and 60 minutes following the second intramuscular injection
of blinded study drug; record the exact 24-hour clock time of the blood draw.
•
Record any concomitant medications.
•
Record any AEs.
10.4 Post-Treatment Assessment Period
10.4.1 Days 2, 3, 5, 9 and 14
Study evaluations will be performed on Days 2, 3, 5, 9 and 14 in accordance with the schedule of
evaluations (Figure 1). Subjects with persistent moderate or severe influenza symptoms at day 14
will also complete a Day 21 visit, and if required a Day 28 visit.
Visits may be conducted in the investigator’s office or clinic, or in the subject’s home, in which
case all evaluations must be conducted by appropriately trained and qualified staff.
Study staff will attempt to contact the subjects on Day 2 by telephone to confirm their compliance
with completion of the Subject Self Assessments, to note any concomitant medications and
adverse events. Any adverse events reported by the subject during this telephone contact will be
recorded on the adverse event form and verified during the visit on day 3.
For any subject with a Day 3 positive test for urine protein by dipstick test of 2+ or higher, who
had a Baseline/ Day 1 protein dipstick of <2+, a 24 hour urine collection for assessment of
protein and a simultaneous assessment by UPEP on the same specimen will be obtained.
At each visit it is important that the subject’s Study Diary record be reviewed for completion of
daily Subject Self Assessments. The subjects should be counseled as necessary regarding self
assessments and Study Diary record requirements. The subject’s diary card will be reviewed by
study staff for alleviation of symptoms as well as relapse of symptoms. Relapse is defined as the
recurrence of at least one respiratory symptom and one constitutional symptom (both greater than
mild in severity) for 24 hours and the presence of fever (unless influenced by antipyretic use).
Relapse can only occur after the subject has met the endpoint criteria for alleviation of symptoms.
Day 3:
The second PK sample for all subjects will be obtained on Day 3 at the same time as the clinical
laboratory blood specimen is obtained. The exact 24-hour clock time of the blood draw will be
recorded in the subjects CRF.
Day 14:
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven
symptoms assessed) of either moderate or severe intensity at the Day 14 visit then the subject
must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required at day 28 (± 3
days) If a subject reports moderate or severe influenza symptoms then the investigator will
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record the intensity of each of the influenza symptoms on a visit specific CRF page at the day 21
and day 28 visits. After day 14 the subject will not record symptoms in a diary.
Day 21 (if applicable):
The day 21 visit is to be completed only if the subject reports symptoms of influenza of moderate
or severe intensity at day 14. The investigator will make a clinical judgment as to the appropriate
medical course of action for such subjects at the Day 21 visit and such action(s) will be recorded
on the Day 21 CRF page. The investigator will recall the subject for a further study visit at day 28
(± 3 days) if moderate or severe symptom(s) of influenza persist at Day 21.
Day 28 (if applicable):
The day 28 visit is to be completed only if the subject reports symptoms of influenza of moderate
or severe intensity at day 21. The investigator will make a clinical judgment as to the appropriate
medical course of action for such subjects at this visit and such action(s) will be recorded on the
Day 28 CRF page. No further follow-up visits beyond day 28 are to be formally scheduled unless
in the clinical judgment of the investigator further follow-up is required. The investigator will use
his/her clinical judgment to manage the subject, referring the subject, if appropriate, for further
medical care.
10.4.2 Adverse Events Reported at Post-treatment Visits
In this study, symptoms of influenza will be considered separately from adverse events reported
during the post-treatment period. Accordingly, adverse events that have onset in the post-
treatment period will be assessed and followed as specified in 11.2. Specifically, the investigator
should attempt to follow all unresolved AEs and/or SAEs observed during the study until they are
resolved, or are judged medically stable, or are otherwise medically explained.
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Figure 1
Study Measurements and Visit Schedule
Treatment
Period
Assessment Day
End of Study
Early Withdrawal
Assessments
Screening 1
(Baseline)
Day 11
Day 22
Day 3
Day 5
(±1 day)
Day 9
(±3 day)
Day 14
(±3 day) 8
Informed Consent
X
Rapid Antigen test for
Influenza A
X
Medical History/Physical Exam
X
Influenza-related complications
checklist3
X
X
X
X
X
Inclusion/Exclusion
X
Clinical Chemistries4
X
X
X
X
Hematology4
X
X
X
X
Exposure Pharmacokinetic Sample9
X
X4
Serology (serum) Sample
X
X
Urinalysis10
X
X4
X
X
Urine Pregnancy Test
X
X
Vital Signs5
X
X
X
X
X
X
ECG6
X
Sample (nasopharyngeal swab) for
Influenza Virus Culture/ PCR assay
and for resistance studies
X
X
X
X
Study Drug Administration
X
Subject Diary Review7
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Study Measurements and Visit Schedule Figure Legend on Next Page
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Study Measurements and Visit Schedule Figure Legend
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on
subsequent study days may occur in subject’s home by the investigator (all visits) or appropriately trained study center staff (Day 3, 5, 9
visits).
2 Day 2 will be a telephone contact with the subject to ensure compliance with diary card completion, concomitant medication and adverse
event review.
3 A targeted physical examination will be conducted at each visit to record the presence/absence of influenza related complications.
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subject may be enrolled
and begin treatment with study drug prior to receiving results. A PK sample will be drawn 30-60 minutes following the second
treatment administration injection. On Day 3 an extra tube will be included with the safety blood sample to collect the second
PK sample for evaluation of peramivir concentrations. For any subject with a Day 3 positive test for urine protein by dipstick test of 2+
or higher, who had a Baseline/ Day 1 protein dipstick of <2+, a 24 hour urine collection for assessment of protein and a simultaneous
assessment by UPEP on the same specimen will be obtained.
5 Vital sign measures will include blood pressure, pulse rate and respiration rate. Vital signs will be recorded at Screening, pre-dose and at
15 min following the study drug administration on Day 1, then once on remaining days as stipulated. The investigator will record oral
temperature at baseline. Thereafter the subject will report oral temperature measurements twice daily in the Study Diary
6 If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will
not be enrolled in this study. If the ECG is interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia,
medically significant dysrhythmia) then this subject may be enrolled If the conditions highlighted in section 10.1.5 are met for the subject.
7 Subjects record symptom assessment in Study Diary, twice daily, beginning pre-dose on Day 1 through Day 9, then once daily through
Day 14. Subjects record time lost from work or usual activities and rating of productivity compared to normal once daily through Day 14.
Subjects record oral temperature twice daily throughout as well as all influenza related medications.
8 For any subject with unresolved moderate or severe intensity influenza symptoms a follow up assessment will be scheduled at Day 21 (±
3 days) and Day 28 (± 3 days) if required (See Section 10.4.1).
9 A PK sample will be drawn 30-60 minutes following the second treatment injection on Day 1, and on Day 3..
10.For any subject with a Day 3 positive test for urine protein by dipstick test of 2+ or higher, who had a Baseline/ Day 1 protein dipstick of
<2+, a 24 hour urine collection for assessment of protein and a simultaneous assessment by UPEP on the same specimen will be obtained.
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11 ADVERSE EVENT MANAGEMENT
11.1 Definitions
11.1.1 Adverse Event
An AE is any untoward medical occurrence in a clinical study subject. No causal relationship
with the study drug or with the clinical study itself is implied. An AE may be an unfavorable and
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical
study. Clinically relevant abnormal results of diagnostic procedures including abnormal
laboratory findings (e.g., requiring unscheduled diagnostic procedures or treatment measures, or
resulting in withdrawal from the study) are considered to be AEs.
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2).
Surgical procedures are not AEs but may constitute therapeutic measures for conditions that
require surgery. The condition for which the surgery is required is an AE, if it occurs or is
detected during the study period. Planned surgical measures permitted by the clinical study
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was
(were) known before the start of study treatment. In the latter case the condition should be
reported as medical history.
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia [aches
and pains], headache, feverishness, and fatigue) will be documented in a subject’s study diary and
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as
AEs unless the symptom(s) worsen to the extent that the outcome fulfils the definition of an SAE,
which then must be recorded as such (see Section 11.1.2). Likewise, a RAT for influenza is
required at screening in order to determine eligibility for the study, and therefore a positive RAT
is not considered an AE.
11.1.2 Serious Adverse Event
A SAE is an adverse event that results in any of the following outcomes:
•
Death
•
Is life-threatening (subject is at immediate risk of death at the time of the event; it does not
refer to an event that hypothetically might have caused death if it were more severe)
•
Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or
prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity (i.e., there is a substantial disruption
of a person’s ability to carry out normal life functions)
•
Is a congenital anomaly/birth defect
•
Is an important medical event
Important medical events that may not result in death, are not life-threatening, or do not require
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they
may jeopardize the subject or may require medical or surgical intervention to prevent one of the
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outcomes listed in this definition. Examples of such events include allergic bronchospasm
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions
that do not result in subject hospitalization, or the development of drug dependency or drug
abuse.
In addition Suspected Unexpected Serious Adverse Reactions (SUSAR) may also be reported to
competent authorities where this type of reporting is required (e.g. European Union Directives).
See section 11.2.3.
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and Reporting
Serious Adverse Events
Reports of AEs are to be collected from the time of study drug administration through the
follow-up period ending on Day 14. The Investigator or designee must completely and promptly
record each AE on the appropriate CRF. The Investigator should attempt, if possible, to establish
a diagnosis based on the presenting signs and symptoms. In such cases, the diagnosis should be
documented as the AE and not the individual sign/symptom. If a clear diagnosis cannot be
established, each sign and symptom must be recorded individually.
The Investigator should attempt to follow all unresolved AEs and/or SAEs observed during the
study until they are resolved, or are judged medically stable, or are otherwise medically
explained.
11.2.1 Definition of Severity
All AEs will be assessed (graded) for severity and classified into one of four clearly defined
categories as follows:
•
Mild:
(Grade 1): Transient or mild symptoms; no limitation in activity; no
intervention required. The AE does not interfere with the participant’s
normal functioning level. It may be an annoyance.
•
Moderate:
(Grade 2): Symptom results in mild to moderate limitation in activity;
no or minimal intervention required. The AE produces some
impairment of functioning, but it is not hazardous to health. It is
uncomfortable or an embarrassment.
•
Severe:
(Grade 3): Symptom results in significant limitation in activity;
medical intervention may be required. The AE produces significant
impairment of functioning or incapacitation.
•
Life-threatening:
(Grade 4): Extreme limitation in activity, significant assistance
required; significant medical intervention or therapy required;
hospitalization.
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11.2.2 Definition of Relationship to Study Drug
The blinded Principal Investigator must review each AE and make the determination of
relationship to study drug using the following guidelines:
Not Related:
The event can be readily explained by other factors such as the subject’s
underlying medical condition, concomitant therapy, or accident, and no
temporal relationship exists between the study drug and the event.
Unlikely:
The event does not follow a reasonable temporal sequence from drug
administration and is readily explained by the subject’s clinical state or
by other modes of therapy administered to the subject.
Possibly Related:
There is some temporal relationship between the event and the
administration of the study drug and the event is unlikely to be explained
by the subject’s medical condition, other therapies, or accident.
Probably Related:
The event follows a reasonable temporal sequence from drug
administration, abates upon discontinuation of the drug, and cannot be
reasonably explained by the known characteristics of the subject’s
clinical state.
Definitely Related:
The event follows a reasonable temporal sequence from administration
of the medication, follows a known or suspected response pattern to the
medication, is confirmed by improvement upon stopping the medication
(dechallenge), and reappears upon repeated exposure (rechallenge, if
rechallenge is medically appropriate).
11.2.3 Reporting Serious Adverse Events
Any SAE / SUSAR (Suspected Unexpected Serious Adverse Reaction) must be reported to
BioCryst or its designee within 24 hours of the Investigator’s recognition of the SAE by first
notifying the Medical Monitor at the number listed below:
Telephone:
Europe: +44 1628 548000;
North America: 1-888-724-4908
Facsimile:
Europe: +44 1628 540028;
North America: 1-888-887-8097
or 1-609-734-9208
In addition to the telephone numbers listed above, local country-specific toll free numbers may be
provided within the study reference manual.
The site is required to fax a completed SAE / SUSAR Report Form (provided as a separate report
form) within 24 hours. All additional follow-up evaluations of the SAE / SUSAR must be
reported and sent by facsimile to BioCryst or its designee as soon as they are available.
The Principal Investigator or designee at each site is responsible for submitting the IND safety
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) to
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and for retaining a copy
in their files.
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If the Investigator becomes aware of any SAE / SUSAR occurring within 30 days after a subject
has completed or withdrawn from the study, he or she should notify BioCryst or its designee.
Any SAEs / SUSARs considered possibly related to treatment will be reported to the FDA and
other Regulatory Competent Authorities as applicable via the MedWatch / CIOMS reporting
system in accordance with FDA and other applicable regulations. However, the Investigator is not
obligated to actively seek reports of AEs in former study participants.
While pregnancy is not considered an AE, all cases of fetal drug exposure via parent as study
participant (see Section 4.4) are to be reported immediately to BioCryst or its designee.
Information related to the pregnancy must be given on a “Pregnancy Confirmation and Outcome”
form that will be provided by the Sponsor or its designee.
11.2.4 Emergency Procedures
In the event of an SAE / SUSAR, the Principal Investigator may request the unblinding of the
treatment assignment for the subject affected. If time allows (i.e., if appropriate treatment for the
SAE is not impeded), the Principal Investigator will first consult with the Medical Monitor
regarding the need to unblind the treatment assignment for the subject. At all times, the clinical
well-being of any subject outweighs the need to consult with the Medical Monitor.
The Principal Investigator may contact the IVRS central randomization center and request the
unblinding of the treatment assignment that corresponds to the affected subject. The IVRS center
will record the name of the Investigator making the request, the date and time of the request, the
subject number and date of birth. The Sponsor will be informed within 24 hours if unblinding
occurred.
12 STATISTICAL METHODS
Descriptive statistical methods will be used to summarize the data from this study, with
hypothesis testing performed for the primary and other selected efficacy endpoints. Unless stated
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median,
standard deviation (SD), minimum, and maximum for continuous data and frequencies and
percentages for categorical data. The term “treatment group” refers to randomized treatment
assignment: peramivir 300 mg, peramivir 600 mg, or placebo. All data collected during the study
will be included in data listings. Unless otherwise noted, the data will be sorted first by treatment
assignment, subject number, and then by date within each subject number.
Unless specified otherwise, all statistical testing will be two-sided and will be performed using a
significance (alpha) level of 0.05.
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher.
12.1 Data Collection Methods
The data will be recorded on the CRF approved by BioCryst. The Investigator must submit a
completed CRF for each subject who signs an informed consent form (ICF), regardless of
duration. All documentation supporting the CRF data, such as laboratory or hospital records,
must be readily available to verify entries in the CRF.
Documents (including laboratory reports, hospital records subsequent to SAEs, etc.) transmitted
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to BioCryst should not carry the subject’s name. This will help to ensure subject confidentiality.
12.2 Statistical Analysis Plan
A statistical analysis plan (SAP) will be created and approved prior to the review of any data.
This document will provide a more technical and detailed description of the proposed data
analysis methods and procedures.
12.3 Study Hypothesis
The primary hypothesis for evaluating the primary objective may be stated as follows:
The null hypothesis (H0) is that the time to alleviation of influenza symptoms is the same for
subjects treated with placebo and for subjects treated with peramivir 300mg (H01) or peramivir
600mg (H02).
The alternative hypothesis (H1) is that subjects treated with peramivir 300mg (H11) or peramivir
600mg (H12) have an improvement in time to alleviation of influenza symptoms over those
treated with placebo.
12.4 Sample Size Estimates
Up to a total of 750 evaluable subjects randomized in a 2:2:1 (300 subjects treated with peramivir
300mg: 300 subjects treated with peramivir 600 mg: 150 subjects treated with placebo) are
estimated for this phase 3 study. Because results of clinic-based RAT tests may not precisely
indicate presence of influenza infection, it is expected that at least 850 subjects will be
randomized to treatment to ensure that 750 evaluable subjects are treated.
From preliminary results of a phase 2 study evaluating peramivir treatment of uncomplicated
influenza, it is expected that the median time to alleviation of symptoms will be 137.0 hours (95%
CI: 115.9, 165.8) for subjects receiving placebo treatment. Additionally, it is expected that the
median time to alleviation for the 150 mg dose peramivir arm will be reduced by 30% compared
to placebo (Table 5) yielding a hazard ratio of 0.70.
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Table 5
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio).
Median Time To Alleviation of Symptoms (Hours)
Placebo
Peramivir 150mg
Difference (hours)
145.0
101.5
43.5
140.0
98.0
42.0
135.0
94.5
40.5
130.0
91.0
39.0
125.0
87.5
37.5
120.0
84.0
36.0
115.0
80.5
34.5
110.0
77.0
33.0
105.0
73.5
31.5
100.0
70.0
30.0
Using these assumptions, a sample size of 300 evaluable subjects per active treatment group and
150 evaluable subjects in the placebo group (a total of 750 evaluable subjects) is sufficient to
provide at least 90% power to detect a hazard ratio of 0.70 using a log-rank statistic and
α = 0.025 (SAS version 9.1.3; total accrual time 7 months; total enrollment time 6 months).
12.5 Analysis Populations
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected (ITTI),
per-protocol infected (PPI), and safety populations. Additional analysis populations may be
defined to evaluate study results. Any additional analysis populations will be defined in the SAP.
Intent-To-Treat Population: The ITT population will include all subjects who are randomized.
Subjects will be analyzed in the treatment group to which they were randomized. The ITT
population will be used for analyses of accountability and demographics.
Intent-To-Treat Infected Population: The ITTI population will include all subjects who are
randomized, received study drug, and have confirmed influenza A by culture or PCR. Subjects
will be analyzed according to the treatment randomized. If a discrepancy is noted in the final
database for any subject, such that the drug differs from the randomized treatment assignment,
efficacy analyses may be repeated with the subjects analyzed according to the treatment received.
The ITTI population will be used for primary analyses of efficacy.
Per-Protocol Infected: The PPI population includes all subjects in the ITTI population who
receive an adequate intramuscular injection. The definition of an adequate intramuscular injection
will be further described in the SAP. The PPI population will be used as supportive of the primary
analyses for efficacy completed with the ITTI population.
Safety Population: The safety population will include all subjects who received study drug.
Subjects will be analyzed according to the treatment received. This population will be used for
all safety analyses.
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12.6 Interim and End of Study Analyses
Interim Analysis
An independent DMC will review safety data on an ongoing basis. Safety analyses will be
presented in a manner consistent with the presentations intended for the final analysis.
End of Study Analysis
A final analysis is planned after the last subject completes or discontinues the study, and the
resulting clinical database has been cleaned, quality checked, and locked.
12.7 Efficacy Analyses
12.7.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the time to alleviation of symptoms of influenza in subjects
diagnosed with influenza A, defined as the time from injection of study drug to the start of the
time period when a subject has Alleviation of Symptoms. A subject has Alleviation of Symptoms
if all of the seven symptoms of influenza (nasal congestion, sore throat, cough, aches and pains,
fatigue (tiredness), headache, feeling feverish) assessed on his/her subject diary are either absent
or are present at no more than mild severity level and at this status for at least 21.5 hours (24
hours - 10%).
Descriptive statistics for the primary efficacy variable will be tabulated by treatment group.
Alleviation of symptoms will be determined by assessment of symptoms as reported on each
subject’s diary card. Time to alleviation of symptoms will be summarized for each treatment
group. Treatment comparisons between each active group and placebo will be assessed using a
Wilcoxon-Gehan19 statistic stratified by smoking status at screening Pairwise comparisons
between each active group and placebo will be assessed using a Wilcoxon-Gehan test.. Subjects
who do not experience alleviation of symptoms will be censored at the date of their last non-
missing post-baseline assessment. For assessment of the primary efficacy endpoint, the overall
significance level will be maintained by utilization of Hochberg’s20 method for the planned
comparisons between the two active treatments and placebo.
12.7.2 Secondary Efficacy Endpoints
All secondary endpoints will be summarized using descriptive statistics by treatment group, and
study day/time, if appropriate. Statistical comparisons for each endpoint will be constructed
without adjustment for multiple endpoints.
The reduction in viral shedding will be assessed as the change in viral titers defined as the time-
weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and will be
summarized for each treatment group. The time-weighted average change from baseline will be
calculated on a by-subject basis through Day 9 using the trapezoidal rule with all available post-
baseline on-treatment data (data after initiation of study treatment) minus the baseline value.
Specifically, the time-weighted area under the curve for time a (ta) to time b (tb) is given by the
formula
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)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
,
where
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
and ti represents the date of the ith viral titer
assessment and yi represents the log10 value of the ith viral titer assessment. If there is a baseline
value and only one follow-up value, yi then the time-weighted change from baseline is defined as
the difference between yi and baseline. If there is a baseline value and no follow-up value, the
subject is excluded from analysis. The differences between each of the peramivir treatment
groups and placebo will be evaluated using a van Elteren Test adjusting for smoking status at
screening. Analyses of the PCR results will be analyzed in a similar manner.
Subject’s oral temperature will be summarized by study visit and treatment group. Differences
between the treatment groups will be assessed using the van Elteren test controlling for smoking
status at screening. A subject has Resolution of Fever if he/she has a temperature < 37.2°C
(99.0°F) and no antipyretic medications have been taken for at least 12 hours. The time to
resolution of fever will be estimated using the method of Kaplan-Meier using temperature and
symptom relief medication information obtained from the subject diary data. Differences
between the treatment groups will be assessed using the Wilcoxon-Gehan statistic controlling for
smoking status at screening. Subjects who do not have resolution of fever will be censored at the
time of their last non-missing post-baseline temperature assessment.
The number and percentage of subjects experiencing influenza related complications will be
summarized by complication preferred term and treatment group. The difference between the
treatment groups will be assessed a logistic regression model with factors for treatment group and
smoking status at screening. Pairwise differences between the treatment groups will be evaluated
using contrasts from the final logistic regression model.
12.7.3 Exploratory Endpoints
The MRU, MRU-related direct costs, and indirect costs attributable to days missed of work and
work productivity and/or performance losses will be summarized by treatment group and
smoking status. Methods for describing differences between treatment groups will be presented
in the SAP.
Genotypic (including Hemagglutinin and Neuraminidase), phenotypic, viral culture and PCR data
will be listed for each subject. These listings will be constructed in a manner consistent with the
FDA June 2006 Guidance Document: “Guidance for Submitting Influenza Resistance Data”.18
Additionally, the number and percentage of genotypic changes from wild-type amino acid will be
summarized separately for treatment group, protein type, and study visit.
12.8 Safety Analyses
AEs will be mapped to a MedDRA-preferred term and system organ classification. The
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred terms,
system organ classifications, and severity. If a subject experiences multiple events that map to a
single preferred term, the greatest severity and strongest Investigator assessment of relation to
study drug will be assigned to the preferred term for the appropriate summaries. All AEs will be
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listed for individual subjects showing both verbatim and preferred terms. Separate summaries of
treatment-emergent SAEs and AEs related to study drug will be generated.
Descriptive summaries of vital signs and clinical laboratory results will be presented by study
visit. Laboratory abnormalities will be graded according to the DAIDS Table for Grading
Adverse Events for Adults and Pediatrics (Publish Date: December 2004). The number and
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by
treatment group. Laboratory toxicity shifts from baseline to Day 3, Day 5, and Day 14 will be
summarized by treatment group.
Abnormal physical examination findings will be presented by treatment group. The number and
percent of subjects experiencing each abnormal physical examination finding will be included.
Concomitant medications will be coded using the WHO dictionary. These data will be
summarized by treatment group.
Subject disposition will be presented for all subjects. The number of subjects who completed the
study and discontinued from the study will be provided. The reasons for early discontinuation
also will be presented.
12.9 Sub-Study and Pharmacokinetic Analysis
A sub-study to collect pharmacokinetic samples in up to 60 peramivir treated subjects to examine
exposure response will be conducted at selected sites. The data from the sub-study will be
combined with the two PK samples (collected on all subjects at 30-60 minutes following
administration of study drug and on study day 3) to perform a population exposure-response
analysis. All analyses related to exposure-response will be completed as part of the sub-study. All
statistical methods will be outlined as part of the sub-study protocol and exposure-response
analysis plan. All sub-study analyses, and exposure-response analyses from PK samples obtained
in this study and a companion study BCX1812-312, will be reported in a separate sub-study
report.
12.10
General Issues for Statistical Analysis
12.10.1
Multiple Comparisons and Multiplicity
In order to maintain the overall type I error in the presence of the planned comparisons between
the two peramivir treatments and placebo, Hochberg’s method will be applied to the primary
efficacy endpoint analysis. No other adjustments for multiple comparisons are planned.
12.10.2
Covariates
Primary and secondary efficacy analyses will be adjusted for smoking status at screening.
12.10.3
Planned Sub-Groups
The primary efficacy endpoint will be summarized separately by smoking status at screening
using descriptive statistics by treatment group and study day, if appropriate. No formal statistical
testing will be utilized.
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Additional analyses may be performed by country, if necessary, for submission to local
regulatory authorities.
12.10.4
Missing Data
Every effort will be made to obtain required data at each scheduled evaluation from all subjects
who have been randomized. No attempt will be made retrospectively to obtain missing subject
reported data (including influenza symptom severity assessments, temperature, ability to perform
usual activities, missed days of work and impact of influenza on subject’s work performance
and/or productivity) that has not been completed by the subject at the time of return of the subject
diary to the investigative site. In situations where it is not possible to obtain all data, it may be
necessary to impute missing data.
In assessing the primary efficacy endpoint, for subjects who withdraw or who do not experience
alleviation of symptoms, missing data will be censored using the date of subject’s last non-
missing assessment of influenza symptoms. Missing assessments of influenza symptoms
conservatively will be imputed as having severity above absent or mild (as failures). For the
subject diary data, the following data conventions will be utilized. Missing diary completion will
be imputed as 11:59 for diary entries designated as morning and 23:59 for evening and daily
reported values. Select exploratory sensitivity analyses may be conducted to ascertain the effect,
if any, of these methods. These sensitivity analyses are further described in the SAP. Secondary
efficacy endpoints with time to event data will be censored using the date of subject’s last non-
missing assessment of the given endpoint.
13 STUDY ADMINISTRATION
13.1 Regulatory and Ethical Considerations
13.1.1 Regulatory Authority Approvals
This study will be conducted in compliance with the protocol; GCPs, including International
Conference on Harmonization (ICH) of Technical Requirements for Registration of
Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements and in accordance
with the ethical principles of the Declaration of Helsinki. In addition, all applicable local laws
and regulatory requirements relevant to the use of new therapeutic agents in the countries
involved will be adhered to.
The Investigator should submit written reports of clinical study status to their Institutional
Review Board (IRB)/ Independent Ethics Committee (IEC) annually or more frequently if
requested by the IRB/ IEC. A final study notification will also be forwarded to the IRB/IEC after
the study is completed or in the event of premature termination of the study in accordance with
the applicable regulations. Copies of all contact with the IRB/ IEC should be maintained in the
study documents file. Copies of clinical study status reports (including termination) should be
provided to BioCryst.
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13.1.2 Ethics Committee Approvals
Before initiation of the study at each investigational site, the protocol, the informed consent form,
the subject information sheet, and any other relevant study documentation will be submitted to
the appropriate IRB/IEC. Written approval of the study must be obtained before the study center
can be initiated or the investigational medicinal product is released to the Investigator. Any
necessary extensions or renewals of IRB/IEC approval must be obtained, in particular, for
changes to the study such as modification of the protocol, the informed consent form, the written
information provided to subjects and/or other procedures.
The Investigator will report promptly to the IRB/IEC any new information that may adversely
affect the safety of the subjects or the conduct of the study. On completion of the study, the
Investigator will provide the IRB/IEC with a report of the outcome of the study.
13.1.3 Subject Informed Consent
Signed informed consent must be obtained from each subject prior to performing any study-
related procedures. Each subject should be given both verbal and written information describing
the nature and duration of the clinical study. The informed consent process should take place
under conditions where the subject has adequate time to consider the risks and benefits associated
with his/her participation in the study. Subjects will not be screened or treated until the subject
has signed an approved ICF written in a language in which the subject is fluent.
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC. The
informed consent should be in accordance with the current revision of the Declaration of
Helsinki, current ICH and GCP guidelines, and BioCryst policy.
The Investigator must explain to potential subjects or their legal representatives the aims,
methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it
may entail. Subjects will be informed that they are free not to participate in the trial and that they
may withdraw consent to participate at any time. They will be told that refusal to participate in
the study will not prejudice future treatment. They will also be told that their records may be
examined by competent authorities and authorized persons but that personal information will be
treated as strictly confidential and will not be publicly available. Subjects must be given the
opportunity to ask questions. After this explanation and before entry into the trial, consent should
be appropriately recorded by means of the subject’s dated signature. The subject should receive a
signed and dated copy of the ICF. The original signed informed consent should be retained in the
study files. The Investigator shall maintain a log of all subjects who sign the ICF and indicate if
the subject was enrolled into the study or reason for non-enrollment.
13.1.4 Payment to Subjects
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC
responsible for the study at the Investigator’s site.
13.1.5 Investigator Reporting Requirements
The Investigator will provide timely reports regarding safety to his/her IRB/IEC as required.
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13.2 Study Monitoring
During trial conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure
that the protocol and GCPs are being followed. The monitors may review source documents to
confirm that the data recorded on CRFs is accurate. The investigator and institution will allow
BioCryst monitors or its designees and appropriate regulatory authorities direct access to source
documents to perform this verification.
13.3 Quality Assurance
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits
performed by BioCryst, and/or to inspection by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the
monitoring visits and possible audits or inspections and that sufficient time is devoted to the
process.
13.4 Study Termination and Site Closure
BioCryst reserves the right to discontinue the trial prior to inclusion of the intended number of
subjects but intends only to exercise this right for valid scientific or administrative reasons. After
such a decision, the Investigator must contact all participating subjects immediately after
notification. As directed by BioCryst, all study materials must be collected and all case report
forms completed to the greatest extent possible.
13.5 Records Retention
To enable evaluations and/or audits from regulatory authorities or BioCryst, the Investigator
agrees to keep records, including the identity of all participating subjects (sufficient information
to link records, case report forms and hospital records), all original signed informed consent
forms, copies of all case report forms and detailed records of treatment disposition. The records
should be retained by the Investigator according to local regulations or as specified in the Clinical
Trial Agreement, whichever is longer.
If the Investigator relocates, retires, or for any reason withdraws from the study, the study records
may be transferred to an acceptable designee, such as another investigator, another institution, or
to BioCryst. The Investigator must obtain BioCryst’s written permission before disposing of any
records.
13.6 Study Organization
13.6.1 Data Monitoring Committee
BioCryst will assemble an independent Data Monitoring Committee (DMC) to assess safety
parameters of the trial on a periodic, ongoing basis while the trial is in progress. The committee
will include a statistician and three physicians, two of whom will be Infectious Disease / Clinical
Virology specialists. Full details of the composition of the DMC and how the DMC is to operate
will be described in a separate DMC charter.
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13.7 Confidentiality of Information
BioCryst affirms the subject’s right to protection against invasion of privacy. Only a subject
identification number, initials and/or date of birth will identify subject data retrieved by BioCryst.
However, in compliance with federal regulations, BioCryst requires the investigator to permit
BioCryst’s representatives and, when necessary, representatives of the FDA or other regulatory
authorities to review and/or copy any medical records relevant to the study.
BioCryst will ensure that the use and disclosure of protected health information obtained during a
research study complies with the HIPAA Privacy Rule, where this rule is applicable. The Rule
provides federal protection for the privacy of protected health information by implementing
standards to protect and guard against the misuse of individually identifiable health information
of subjects participating in BioCryst-sponsored Clinical Trials. "Authorization" is required from
each research subject, i.e., specified permission granted by an individual to a covered entity for
the use or disclosure of an individual's protected health information. A valid authorization must
meet the implementation specifications under the HIPAA Privacy Rule. Authorization may be
combined in the Informed Consent document (approved by the IRB/IEC) or it may be a separate
document, (approved by the IRB/IEC) or provided by the Investigator or Sponsor (without
IRB/IEC approval). It is the responsibility of the investigator and institution to obtain such
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are
required for U.S. sites only.
13.8 Study Publication
All data generated from this study are the property of BioCryst and shall be held in strict
confidence along with all information furnished by BioCryst. Independent analysis and/or
publication of these data by the Investigator or any member of his/her staff are not permitted
without prior written consent of BioCryst. Written permission to the Investigator will be
contingent on the review by BioCryst of the statistical analysis and manuscript and will provide
for nondisclosure of BioCryst confidential or proprietary information. In all cases, the parties
agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This
will enable all parties to protect proprietary information and to provide comments based on
information that may not yet be available to other parties.
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14 REFERENCES
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282.
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality associated with
influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179–186.
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment on
influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med
2003;163(14):1667–1672.
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral neuraminidase
inhibitor oseltamivir in experimental human influenza: randomized controlled trials for
prevention and treatment. JAMA 1999;282(13):1240–1246.
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant influenza
A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759–
765.
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-influenza
virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents
Chemother 2001;45(4):1162–1167.
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to
different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147.
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir,
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase
inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45(12):3403–3408.
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine
combinations exert additive and synergistic anti-influenza virus effects in MDCK cells.
Antimicrob Agents Chemother 2004;48(12):4855–4863.
10. BioCryst Pharmaceuticals. Unpublished data.
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. Injectable
peramivir promotes survival in mice and ferrets infected with highly pathogenic avian
influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San Francisco
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA.
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival against
lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03.
14. Tamiflu® Package Insert. Roche Pharmaceuticals. Rev. December 2005.
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product
information sheets
16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the oral
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283(8): 1016-
1024.
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of oseltamivir in
treatment of influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-1850.
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18. US Department of Health and Human Services, Food and Drug Administration Center for
Drug Evaluation and Reserach (CDER). Attachment to Guidance on Antiviral Product
Development- Conducting and Submitting Virology Studies to the Agency: Guidance for
Submitting Influenza Resistance Data. http://www.fda.gov/cder/guidance/7070fnlFLU.htm
19. Gehan EA (1965): A generalized Wilcoxon test
for co mparing arbitrarily singl y censored
samples. Biometrika 52:203-223
20. Hochberg, Y. A sharper Bonferroni pr ocedure for multiple tests of significance. Biometrika.
1988;75:800-2
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15 APPENDICES
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina
NYHA Functional Classification of Heart Failure
Class I
No symptoms. Ordinary physical activity such as walking and climbing stairs
does not cause fatigue or dyspnea.
Class II
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly;
walking uphill; walking or stair climbing after meals, in cold weather, in wind,
or when under emotional stress causes undue fatigue or dyspnea.
Class III
Symptoms w ith less than ordinary phy
sical activity. Walking one to two
blocks on t he level and clim bing m ore th an one flight of stai rs in norm al
conditions causes undue fatigue or dyspnea.
Class IV
Symptoms at rest. Inability to carry on any physical activity without fatigue or
dyspnea.
NYHA Functional Classification of Angina
Class I
Angina only with unusually strenuous activity.
Class II
Angina with slightl y more prolonged o r slightly more vigorous activit y than
usual.
Class III
Angina with usual daily activity.
Class IV
Angina at rest.
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15.2 Criteria for Severe COPD and Severe Asthma
The following guidelines are provided to assist in the evaluation of subjects who have a medical
history for Chronic Obstructive Pulmonary Disease (COPD) and/or Asthma. Subjects with severe
COPD or severe persistent Asthma are to be excluded from this study. (See section 8.1.2,
exclusion criteria number 3).
Classification of Asthma from National Asthma and Education and Prevention Program
For Adults and Children (> 5 yrs) who
can use a spirometer or peak flow meter
Classification
Days with
Symptoms
Nights with
Symptoms
FEV1 or PEF
% Predicted Normal
PEF Variability
(%)
Severe persistent
Continual
Frequent
≤ 60
> 30
Moderate Persistent
Daily
> 1/ week
> 60 - < 80
> 30
Mild Persistent
> 2 / week
but < 1
times / day
> 2/ month
≥ 80
20 – 30
Mild Intermittent
≤ 2 / week
< 2 / month
≥ 80
< 20
FEV1: percentage predicted value for forced expiratory volume in 1 second.
PEF: percentage of personal best for peak expiratory flow.
Extracted from: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart,
Lung, and Blood Institute, National Asthma Education and Prevention Program. HHS/NIH 2007
Spirometric Classification of COPD Severity based upon Post-Bronchodilator FEV1
(GOLD Criteria)
Stage
Characteristics
Mild COPD
FEV1/FVC < 70%
FEV1 ≥ 80% predicted
Moderate COPD
FEV1/FVC < 70%
50 % ≤ FEV1 < 80% predicted
Severe COPD
FEV1/FVC < 70%
30 % ≤ FEV1 < 50% predicted
Very Severe COPD
FEV1/FVC < 70%
FEV1 < 30% predicted or FEV1 < 50%
predicted plus chronic respiratory failure
FEV1: percentage predicted value for forced expiratory volume in one second.
FVC: forced vital capacity
Extracted from: Rabe KF, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease (GOLD Executive Summary). Am. J. Respir. Crit. Care Med. 2007:176;532-555.
373
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CLINICAL STUDY PROTOCOL
Protocol No. BCX1812-311
IND No. 76,350
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE
INFLUENZA
THE IMPROVE I STUDY
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy)
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza
Protocol Date(s):
Version 1.0: 04 September 2007
Version 2.0: 05 October 2007
Version 3.0: 20 November 2007
Version 4.0: 18 December 2007
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35244, USA
Phone: +1 919 859 1302
Fax: +1 919 851 1416
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals,
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information
contained herein should be disclosed without prior written approval.
CONFIDENTIAL
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1
TITLE PAGE
Protocol Number:
BCX1812-311
Study Title:
A phase 3 multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of
intramuscular peramivir in subjects with uncomplicated acute
influenza.
IND Number:
76, 350
Investigational Product:
Peramivir (BCX1812)
Indication Studied:
Uncomplicated acute influenza
Sponsor:
BioCryst Pharmaceuticals, Inc.
2190 Parkway Lake Drive
Birmingham, AL 35233
Development Phase:
3
Sponsor Medical Officer:
W. James Alexander, M.D., M.P.H.
Senior Vice President, Clinical Development
Chief Medical Officer
Phone: +1 919 859 1302
Fax: +1 919 851 1416
Email Address: jalexander@biocryst.com
Compliance Statement:
This study will be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki
and clinical research guidelines established by the Code of
Federal Regulations (Title 21, CFR Parts 50, 56, and 312)
and ICH Guidelines. Essential study documents will be
archived in accordance with applicable regulations.
Final Protocol Date:
Version 1.0: 04 September 2007
Amendment(s) Date(s):
Version 2.0: 05 October 2007
Version 3.0: 20 November 2007
Version 4.0: 18 December 2007
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1.2
Clinical Study Protocol Agreement
Protocol No.
BCX1812-311
Protocol Title:
A phase 3 multicenter, random ized, double-blind, placebo-controlled
study to evaluate the effic acy and safety of intramuscular peramivir in
subjects with uncomplicated acute influenza
I have carefully read this protocol and agree that it contains all of the necessary information
required to conduct this study. I agree to c onduct this study as described and according t o
the Decl aration of Helsinki, Internationa l Conference on Har monization Guidelines for
Good Clinical Practices, and all applicable regulatory requirements.
Investigator’s Signature
Date
Name (Print)
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2
SYNOPSIS
Protocol No.
BCX1812-311
Protocol Title:
A phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of
intramuscular peramivir in subjects with uncomplicated acute
influenza.
Sponsor:
BioCryst Pharmaceuticals, Inc.
Investigators/Study Sites:
Multinational
Development Phase:
3
Objectives:
Primary:
To evaluate the efficacy of peramivir administered
intramuscularly compared to placebo on the time to alleviation
of clinical symptoms in adult subjects with uncomplicated acute
influenza.
Secondary:
1.
To evaluate the safety and tolerability of peramivir
administered intramuscularly
2.
To evaluate secondary clinical outcomes in response to
treatment
3.
To evaluate changes in influenza virus titer in
nasopharyngeal samples (viral shedding) in response to
treatment
Exploratory:
1. To assess pharmacoeconomic measures as response to
treatment
2. To assess changes in influenza viral susceptibility to
neuraminidase inhibitors following treatment
Number of Subjects:
Total enrollment: approximately 600 subjects will be
randomized. Subjects will be allocated to treatment using a 2:1
randomization schema.
An evaluable subject is one who is randomized, receives study
drug, and has confirmed acute influenza A or B by primary viral
culture or PCR. A positive Rapid Antigen Test (RAT) for
influenza A and B at screening will be required for enrollment.
Because results of clinic-based RAT tests may not precisely
indicate presence of influenza infection, it is expected that
approximately 600 subjects will be randomized to treatment to
ensure enrollment of approximately 450 subjects that are
positive for influenza A.
Study Design:
This is a multinational, randomized, double-blind study
comparing the efficacy and safety of a 300 mg dose of peramivir
administered intramuscularly versus placebo in adults with
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uncomplicated acute influenza. All subjects will be centrally
randomized to treatment with 300 mg of peramivir or placebo in
a ratio of 2:1, and will be stratified according to smoking status
and RAT test for influenza A or B.
Study drug will be administered as bilateral 2mL intramuscular
injections (total of 4mL injected in equally divided doses).
Procedures for gluteal intramuscular injection, with a
recommended needle length appropriate to the physical
characteristics of the subject, are provided in the study drug
administration manual.
Subjects eligible for screening will have an anterior nasal swab
collected for testing by rapid antigen testing (RAT) for influenza
A and B in accordance with the commercially available RAT kit
instructions. If the initial RAT is negative, the test should be
repeated within one hour. Subjects meeting the
inclusion/exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following information in a
Study Diary:
• Assessment of the presence and severity of each of seven
symptoms of influenza on a 4-point scale (0, absent; 1, mild;
2, moderate; 3, severe) twice daily (AM, PM) through Day 9
following treatment, then once daily (AM) through Day 14.
• Oral temperature measurements taken with an electronic
thermometer every 12 hours. With the exception of the
baseline measurement, all temperature measurements will be
obtained at least 4 hours after, or immediately before,
administration of oral acetaminophen (Tylenol or
paracetamol) or other anti-pyretic medications.
• Assessment of subject’s time lost from work or usual
activities and rating of productivity compared to normal
(rated as 0-10 on a visual analog scale) once daily through
Day 14.
• Doses of antipyretic, expectorant, and/or throat lozenges
taken for symptomatic relief each day through Day 14.
Anterior nose (bilateral) and posterior pharynx specimens
(swabs) will be collected at Day 1 (pre-treatment) and at Days 3,
5, and 9, for quantitative virologic assessments. Specimens from
all subjects yielding influenza virus will also be assessed for
susceptibility to neuraminidase inhibitors (Day 1 and last
specimen yielding positive result on culture) as well as other
virologic assessments (e.g. PCR, genotypic testing). All
virologic assessments will be performed by a central laboratory.
Two samples for pharmacokinetic (PK) testing for plasma levels
of peramivir will be obtained from all subjects randomized. The
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first PK sample will be obtained between 30 and 60 minutes
following study drug administration in all subjects. The second
PK sample will be obtained at the day 3 visit in all subjects. The
data from these PK samples will be utilized in a population
exposure-response analysis.
At selected sites a separate sub-study will be conducted to
collect additional PK samples between treatment and Day 3 for
the purpose of conducting a separate exposure-response
analysis. This sub-study will be conducted under a separate
protocol, BCX1812-311PK.
Study Population:
Male and female subjects, 18 years of age and older, with
symptoms consistent with a diagnosis of uncomplicated acute
influenza infection may be screened for enrollment. Subject
eligibility will require the presence of two or more symptoms of
at least moderate severity consistent with acute influenza as well
as positive results obtained from a rapid antigen test (RAT) for
influenza A and/or B at screening.
Inclusion Criteria:
1. Male and non-pregnant female subjects age ≥18 years.
2. A positive Influenza A and/or B Rapid Antigen Test (RAT)
performed with a commercially available test kit on an
adequate anterior nasal specimen, in accordance with the
manufacturer’s instructions. A negative initial RAT should
be repeated within one-hour.
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4
ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. A
subject self-report of a history of fever or feverishness
within the 24 hours prior to screening will also qualify for
enrollment in the absence of documented fever at the time of
screening.
4. Presence of at least one respiratory symptom (cough, sore
throat, or nasal symptoms) of at least moderate severity.
5. Presence of at least one constitutional symptom (myalgia
[aches and pains], headache, feverishness, or fatigue) of at
least moderate severity.
6. Onset of symptoms no more than 48 hours before
presentation for screening.
7. Written informed consent.
Exclusion Criteria:
1. Women who are pregnant or breast-feeding.
2. Presence of clinically significant signs of acute respiratory
distress.
3. History of severe chronic obstructive pulmonary disease
(COPD) or severe persistent asthma (See section 15.2).
4. History of congestive heart failure requiring daily
pharmacotherapy with symptoms consistent with New York
Heart Association Class III or IV functional status within the
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past 12 months.
5. Screening ECG which suggests acute ischemia or presence
of medically significant dysrhythmia.
6. History of chronic renal impairment requiring hemodialysis
and/or known or suspected to have moderate or severe renal
impairment (actual or estimated creatinine clearance <50
mL/min).
7. Clinical evidence of worsening of any chronic medical
condition (temporally associated with the onset of symptoms
of influenza) which, in the investigator’s opinion, indicates
that such finding(s) could represent complications of
influenza.
8. Current clinical evidence, including clinical signs and/or
symptoms consistent with otitis, bronchitis, sinusitis and/or
pneumonia, or active bacterial infection at any body site that
requires therapy with oral or systemic antibiotics.
9. Presence of immunocompromised status due to chronic
illness, previous organ transplant, or use of
immunosuppressive medical therapy which would include
oral or systemic treatment with > 10 mg prednisone or
equivalent on a daily basis within 30 days of screening.
10. Currently receiving treatment for viral hepatitis B or viral
hepatitis C.
11. Presence of known HIV infection with a CD4 count <350
cell/mm3.
12. Current therapy with oral warfarin or other systemic
anticoagulant.
13. Receipt of any doses of rimantadine, amantadine, zanamivir,
or oseltamivir in the 7 days prior to screening.
14. Immunized against influenza with live attenuated virus
vaccine (FluMist®) in the previous 21 days.
15. Immunized against influenza with inactivated virus vaccine
within the previous 14 days.
16. Receipt of any intramuscular injection within the previous
14 days.
17. History of alcohol abuse or drug addiction within 1 year
prior to admission in the study.
18. Participation in a previous study of intramuscular or
intravenous peramivir or previous participation in this study.
19. Participation in a study of any investigational drug or device
within the last 30 days.
Study Endpoints:
Primary Endpoint:
Clinical:
Time to alleviation of clinical symptoms of influenza.
Secondary Endpoint(s):
Safety:
Incidence of treatment-emergent adverse events and treatment-
emergent changes in clinical laboratory tests.
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Clinical:
Time to resolution of fever.
Incidence of influenza related complications.
Virologic:
Quantitative change in influenza virus shedding, measured by
viral titer assay (TCID50).
Exploratory Endpoint(s):
Pharmacoeconomic:
Medical resource utilization (MRU), missed days of work, and
impact of influenza illness on subject’s work performance
and/or productivity.
Virologic:
Quantitative change in influenza virus shedding, measured by
PCR.
Change in influenza virus susceptibility to neuraminidase
inhibitors.
Investigational Product, Dose, and Mode of Administration:
Peramivir (BCX-1812), 75mg/mL, 2mL (150mg) per injection, administered as bilateral
intramuscular injections.
Reference Therapy, Dose, and Mode of Administration:
Matching Placebo (buffered diluent), 2mL per injection administered as bilateral intramuscular
injections.
Duration of Treatment:
Following treatment on day 1, study duration for all subjects is
expected to be up to 14 days (including all visits). Presence of
unresolved adverse events and/or treatment-emergent laboratory
findings at the Day 14 visit, or persistent or recurrent symptoms
of influenza (of the seven symptoms assessed) of either
moderate or severe intensity at the Day 14 visit, will require
additional follow up.
Statistical Methods:
Study Hypothesis:
The null hypothesis (H0) for this study is that the time to
alleviation of influenza symptoms is the same for subjects
treated with placebo and for subjects treated with peramivir
300mg.
The alternative hypothesis (H1) is that subjects treated with
peramivir 300mg have an improvement in time to alleviation of
influenza symptoms over those treated with placebo.
Sample Size:
From preliminary results of a phase 2 study evaluating peramivir
treatment of uncomplicated influenza, it is expected that the
median time to alleviation of symptoms will be 137.0 hours
(95% CI: 115.9, 165.8) for subjects receiving placebo treatment.
Additionally, it is expected that the median time to alleviation
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for the 300 mg dose peramivir arm will be reduced by 30%
compared to placebo yielding a hazard ratio of 0.70. Data from
the phase 2 study suggested that the activity of peramivir against
influenza B was limited. Therefore, this study will be sized to
ensure that a minimum number of influenza A subjects is
enrolled to achieve study power.
Using these assumptions, a sample size of 450 evaluable
subjects with influenza A (300 in the 300 mg treatment group
and 150 evaluable subjects in the placebo group) is sufficient to
provide at least 90% power to detect a hazard ratio of 0.70 using
a log-rank statistic and α = 0.05 (SAS version 9.1.3; total
accrual time 7 months; total enrollment time 6 months).
Efficacy:
The primary efficacy analysis will be completed with the intent-
to-treat infected population (ITTI). The ITTI population will
include all subjects who are randomized, received study drug,
and have confirmed influenza A and/or B by primary viral
culture or PCR. The primary efficacy variable is the time to
alleviation of symptoms, defined as the time from injection of
study drug to the start of the time period when each of seven
symptoms of influenza are either absent or are present at no
more than mild severity level and remain at no worse than this
severity status for a 21.5 hour (24 hours – 10%) period.
Descriptive statistics for the primary efficacy variable will be
tabulated by treatment group. Alleviation of symptoms will be
determined by assessment of symptoms as reported on each
subject’s diary card. Time to alleviation of symptoms will be
summarized for each treatment group. Treatment differences
between the 300 mg peramivir dose and placebo will be assessed
using a Wilcoxon-Gehan statistic stratified by smoking status
and positive PCR or viral culture for influenza A or B at
screening. Subjects who do not experience alleviation of
symptoms will be censored at the date of their last non-missing
assessment.
Efficacy analyses will be repeated for Intent To Treat Infected
with influenza A (ITTI-A) population and Per-Protocol Infected
population (PPI). The ITTI-A population includes all subjects
who are randomized, received study drug, and have confirmed
influenza A by primary viral culture or PCR. The PPI
population will include those subjects in the ITTI population
who received an adequate intramuscular injection. Details of
this population will be described in the statistical analysis plan.
Changes in influenza virus TCID50 (viral titers from
nasopharyngeal specimens) will be compared using the van
Elteren statistic controlling for smoking status and positive PCR
or viral culture for influenza A or B at screening. Analyses of
other continuous endpoints will be analyzed in a similar manner.
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The number and percentage of subjects experiencing influenza
related complications (IRC) will be summarized by
complication preferred term and treatment group. The
difference between the treatment groups (300 mg peramivir and
placebo) will be assessed using a Cochran-Mantel-Haenszel
(CMH) test statistic controlling for smoking status, and positive
PCR or viral culture for influenza A or B at screening.
Safety:
Safety analyses will be presented for all subjects in the safety
population, defined as all randomized subjects who receive at
least one dose of study drug. Adverse events will be mapped to
a Medical Dictionary for Regulatory Activities (MedDRA)
preferred term and system organ classification.
The occurrence of treatment-emergent AEs will be summarized
using preferred terms, system organ classifications, and severity.
Separate summaries of treatment-emergent SAEs and treatment-
emergent AEs that are related to study medication will be
generated. All AEs will be listed for individual subjects
showing both verbatim and preferred terms.
Descriptive summaries of vital signs and quantitative clinical
laboratory changes will be presented by study visit. Frequency
and percentages of subjects with abnormal laboratory test results
will be summarized by toxicity grade.
Concomitant medications will be mapped to a WHO preferred
term and drug classification. The number and percent of
subjects taking concomitant medications will be summarized
using preferred terms and drug classifications. The number and
percent of subjects experiencing each abnormal physical
examination finding will be presented.
The number and percent of subjects discontinuing study as well
as the reasons for discontinuation will be summarized by
treatment group.
Date of Protocol:
Version 1.0: 04-September-2007
Amendment (Dates):
Version 2.0: 05-October-2007
Version 3.0: 20-November-2007
Version 4.0: 18-December-2007
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3
TABLE OF CONTENTS
1
TITLE PAGE...............................................................................................................................2
1.1
PROTOCOL APPROVAL SIGNATURE PAGE......................................................................................3
1.2
CLINICAL STUDY PROTOCOL AGREEMENT....................................................................................4
2
SYNOPSIS...................................................................................................................................5
3
TABLE OF CONTENTS...........................................................................................................12
3.1
LIST OF FIGURES .........................................................................................................................14
3.2
LIST OF TABLES ..........................................................................................................................14
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................................15
5
INTRODUCTION......................................................................................................................17
5.1
BACKGROUND.............................................................................................................................17
5.2
RATIONALE FOR STUDY ..............................................................................................................17
5.3
NON-CLINICAL EXPERIENCE WITH PERAMIVIR...........................................................................18
5.3.1
In vitro Assays.......................................................................................................................18
5.3.2
Animal Models......................................................................................................................18
5.4
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR...........................................19
5.5
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR.........................................19
5.6
PHASE 2 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR .........................................................21
5.7 DOSE RATIONALE................................................................................................................................23
6
STUDY OBJECTIVES..............................................................................................................24
6.1
OBJECTIVES ................................................................................................................................24
6.1.1
Primary Objective..................................................................................................................24
6.1.2
Secondary Objective(s) .........................................................................................................24
6.1.3
Exploratory Objective(s) .......................................................................................................24
6.2
STUDY ENDPOINTS......................................................................................................................24
6.2.1
Primary Endpoint...................................................................................................................24
6.2.2
Secondary Endpoint(s) ..........................................................................................................24
6.2.3
Exploratory Endpoints...........................................................................................................24
7
STUDY DESIGN.......................................................................................................................25
7.1
OVERALL STUDY DESIGN AND PLAN ..........................................................................................25
8
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................................26
8.1.1
Inclusion Criteria...................................................................................................................26
8.1.2
Exclusion Criteria..................................................................................................................26
8.1.3
Removal of Subjects from Therapy or Assessment...............................................................27
9
TREATMENTS .........................................................................................................................28
9.1
TREATMENTS ADMINISTERED.....................................................................................................28
9.2
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .............................................................................28
9.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................28
9.4
STUDY MEDICATION ACCOUNTABILITY......................................................................................29
9.5
BLINDING/UNBLINDING OF TREATMENTS...................................................................................29
9.6
PRIOR AND CONCOMITANT THERAPIES.......................................................................................29
9.7
OVERDOSE AND TOXICITY MANAGEMENT..................................................................................29
9.8
DOSE INTERRUPTION...................................................................................................................29
10
STUDY CONDUCT..................................................................................................................30
10.1
EVALUATIONS.............................................................................................................................30
10.1.1
Informed Consent .............................................................................................................30
10.1.2
Medical History ................................................................................................................30
10.1.3
Rapid Antigen Test for Influenza .....................................................................................30
10.1.4
Physical Examination and Influenza-related Complications Assessments .......................30
10.1.5
Vital Signs ........................................................................................................................30
10.1.6
Electrocardiogram Measurements ....................................................................................31
10.1.7
Clinical Laboratories ........................................................................................................31
10.1.8
Urine Pregnancy Test .......................................................................................................31
10.1.9
Serology for Influenza ......................................................................................................31
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10.1.10
Samples for Virologic Laboratory Assessments...............................................................31
10.1.11
Subject Self Assessments..................................................................................................32
10.1.12
Concomitant Medications.................................................................................................32
10.1.13
Adverse Events.................................................................................................................32
10.1.14
Pharmacokinetic Exposure Samples.................................................................................32
10.2
SCREENING PERIOD.....................................................................................................................33
10.2.1
Informed Consent .............................................................................................................33
10.2.2
Screening/Baseline Evaluation and Enrollment................................................................33
10.3
TREATMENT PERIOD—STUDY DAY 1 .........................................................................................33
10.3.1
Pre-dose Evaluations-Study Day 1 ...................................................................................34
10.3.2
Post-dose Evaluations-Study Day 1..................................................................................34
10.4
POST-TREATMENT ASSESSMENT PERIOD....................................................................................34
10.4.1
Days 2, 3, 5, 9 and 14 .......................................................................................................34
10.4.2
Adverse Events Reported at Post-treatment Visits ...........................................................35
11
ADVERSE EVENT MANAGEMENT......................................................................................38
11.1
DEFINITIONS ...............................................................................................................................38
11.1.1
Adverse Event...................................................................................................................38
11.1.2
Serious Adverse Event......................................................................................................38
11.2
METHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING ADVERSE EVENTS AND REPORTING
SERIOUS ADVERSE EVENTS ........................................................................................................39
11.2.1
Definition of Severity .......................................................................................................39
11.2.2
Definition of Relationship to Study Drug.........................................................................40
11.2.3
Reporting Serious Adverse Events ...................................................................................40
11.2.4
Emergency Procedures .....................................................................................................41
12
STATISTICAL METHODS ......................................................................................................41
12.1
DATA COLLECTION METHODS ....................................................................................................41
12.2
STATISTICAL ANALYSIS PLAN ....................................................................................................42
12.3
STUDY HYPOTHESIS....................................................................................................................42
12.4
SAMPLE SIZE ESTIMATES............................................................................................................42
12.5
ANALYSIS POPULATIONS ............................................................................................................42
12.6
INTERIM AND END OF STUDY ANALYSES....................................................................................43
12.7
EFFICACY ANALYSES..................................................................................................................43
12.7.1
Primary Efficacy Endpoint ...............................................................................................43
12.7.2
Secondary Efficacy Endpoints..........................................................................................44
12.7.3
Exploratory Endpoints......................................................................................................44
12.8
SAFETY ANALYSES .....................................................................................................................45
12.9
SUB-STUDY AND PHARMACOKINETIC ANALYSIS........................................................................45
12.10
GENERAL ISSUES FOR STATISTICAL ANALYSIS ...........................................................................46
12.10.1
Multiple Comparisons and Multiplicity............................................................................46
12.10.2
Covariates.........................................................................................................................46
12.10.3
Planned Sub-Groups .........................................................................................................46
12.10.4
Missing Data.....................................................................................................................46
13
STUDY ADMINISTRATION...................................................................................................47
13.1
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................................................47
13.1.1
Regulatory Authority Approvals.......................................................................................47
13.1.2
Ethics Committee Approvals............................................................................................47
13.1.3
Subject Informed Consent ................................................................................................47
13.1.4
Payment to Subjects..........................................................................................................48
13.1.5
Investigator Reporting Requirements ...............................................................................48
13.2
STUDY MONITORING...................................................................................................................48
13.3
QUALITY ASSURANCE.................................................................................................................48
13.4
STUDY TERMINATION AND SITE CLOSURE..................................................................................48
13.5
RECORDS RETENTION .................................................................................................................49
13.6
STUDY ORGANIZATION...............................................................................................................49
13.6.1
Data Monitoring Committee.............................................................................................49
13.7
CONFIDENTIALITY OF INFORMATION ..........................................................................................49
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13.8
STUDY PUBLICATION ..................................................................................................................49
14
REFERENCES...........................................................................................................................51
15
APPENDICES ...........................................................................................................................53
15.1
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA ......................53
15.2
CRITERIA FOR SEVERE COPD AND SEVERE ASTHMA .................................................................54
3.1
List of Figures
Figure 1
Study Measurements and Visit Schedule.................................................................36
3.2
List of Tables
Table 1
Results of study BC-01-03.......................................................................................19
Table 2
Pharmacokinetic parameters from study Him-06-111. ............................................20
Table 3
Summary of Efficacy from BCX1812-211. .............................................................22
Table 4
Summary of Safety from BCX1812-211. ................................................................23
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0–72
area under the curve from time 0 to 72 hours
AUC0–∞
area under the curve extrapolated from time 0 to infinity
BMI
Body Mass Index in kg/m2
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CIOMS
Council for International Organizations of Medical sciences
Cmax
maximum plasma concentration
CK
creatine kinase
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CRF
Case Report Form
CV
coefficient of variation
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
IC50
median inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRC
influenza related complications
ITT
intent-to-treat
ITTI
intent-to-treat infected (Includes ITTI and ITTI-A)
IUD
intrauterine device
IVRS
interactive voice response system
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
NSAID
non-steroidal anti-inflammatory drug
PCR
polymerase chain reaction
PPI
per-protocol infected
RAT
Rapid Antigen Test
RBC
red blood cell
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SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Event
t1/2
elimination half-life
t1/2 λz
terminal half-life
TCID50
tissue-culture infective dose50
TEAEs
treatment-emergent adverse events
Tmax
time to attain maximum plasma concentration
UPEP
Urine protein electrophoresis
WBC
white blood cell
WHO
World Health Organization
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5
INTRODUCTION
5.1
Background
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of the
respiratory tract. Typical influenza illness is characterized by abrupt onset of fever, headache,
myalgia, sore throat, and nonproductive cough.1 The illness is usually self-limiting, with relief of
symptoms occurring within 5 to 7 days. Nevertheless, it is an important disease for several
reasons, including ease of communicability, short incubation time, rapid rate of viral mutation,
morbidity with resultant loss of productivity, risk of complicating conditions, and increased risk
of death, particularly in the elderly. During 19 of the 23 influenza seasons between 1972/1973
and 1994/1995, estimated influenza-associated deaths in the United States ranged from
approximately 25 to more than 150 per 100,000 persons above 65 years of age, accounting for
more than 90% of the deaths attributed to pneumonia and influenza.2
Presently, only a few measures are available that can reduce the impact of influenza: active
immunoprophylaxis with an inactivated or live attenuated vaccine and chemoprophylaxis or
therapy with an influenza-specific antiviral drug. Neuraminidase inhibitors are the current
mainstay of antiviral treatment for influenza. Marketed neuraminidase inhibitors include
zanamivir (Relenza®, GlaxoSmithKline) and oseltamivir (Tamiflu®, Roche-Gilead), an oral
prodrug of the active agent, oseltamivir carboxylate. Influenza neuraminidase is a surface
glycoprotein that cleaves sialic acid residues from glycoproteins and glycolipids. The enzyme is
responsible for the release of new viral particles from infected cells and may also assist in the
spreading of virus through the mucus within the respiratory tract. The neuraminidase inhibitors
represent an important advance in the treatment of influenza with respect to activity against
influenza A and B viruses, with proven therapeutic value in reducing influenza lower respiratory
complications,3 and lower rates of antiviral drug resistance4.
The use of currently available neuraminidase inhibitors has been limited by concerns including,
the degree of effectiveness, the requirement for an inhaler device (zanamivir), and the emergence
of resistant influenza virus variants in some treated populations.5 In addition, there are risks of
bronchospasm with zanamivir; and gastrointestinal side effects, with oseltamivir.
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to the
armamentarium of drugs for the treatment of influenza infections due to its potential for
parenteral administration and lower frequency of dosing.
5.2
Rationale for Study
An oral formulation of peramivir has previously been evaluated in a full range of safety,
tolerability, pharmacokinetic, and efficacy studies. In a multinational phase 3 clinical trial
conducted in 1999-2001, oral peramivir demonstrated antiviral activity against influenza A and B
infections, and improvement in the relief of clinical symptoms. Because of the limited
bioavailability of peramivir following oral administration (<5%), it was determined that the
parenteral route of administration is more appropriate for the delivery of peramivir. Subsequent
phase 1 studies of intravenous and intramuscular formulations of peramivir have confirmed that
parenteral routes of administration result in plasma levels of drug that are as much as 100 times
those achieved via the oral route. In a phase 2 study of intramuscular peramivir in subjects with
acute uncomplicated influenza, subjects who received a single injection of 150mg or 300mg
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peramivir had clinically meaningful reductions in the time to alleviation of symptoms of
influenza, compared to subjects who received a placebo injection. Further details of these studies
are provided below and in the Investigator Brochure.
Because of the previous demonstration of clinical efficacy of intramuscular peramivir in acute
influenza in the phase 2 study, and the encouraging pharmacokinetic and preliminary safety
profile of the intramuscular formulation of peramivir demonstrated to date, this phase 3 study will
be conducted to evaluate the efficacy and safety profile of an intramuscular 300 mg peramivir
dose compared to placebo.
5.3
Non-Clinical Experience with Peramivir
5.3.1
In vitro Assays
Peramivir is a selective inhibitor of viral neuraminidase, with 50% inhibitory concentrations
(IC50) for bacterial and mammalian enzymes of >300µM.6 In an in vitro study, 42 influenza A and
23 influenza B isolates were collected from untreated subjects during the 1999–2000 influenza
season in Canada.7 These isolates were tested for their susceptibility to the neuraminidase
inhibitors zanamivir, oseltamivir carboxylate, and peramivir using a chemiluminescent
neuraminidase assay. Inhibition of Type A influenza neuraminidase by peramivir was
approximately an order of magnitude greater than inhibition of neuraminidase from Type B
viruses. IC50 values for the Type A enzymes ranged from <0.1 to 1.4nM, whereas the Type B
enzymes ranged from <0.1 to 11nM, with three out of four values in the 5- to 11nM range.
Peramivir was the most potent drug against influenza A (H3N2) viruses with a mean IC50 of
0.60nM as well as most potent against influenza B with a mean IC50 of 0.87nM.
In another in vitro comparison of peramivir, oseltamivir, and zanamivir, using a neuraminidase
inhibition assay with influenza A viruses, the median IC50 of peramivir (approximately 0.34nM)
was comparable to that of oseltamivir (0.45nM) and significantly lower than zanamivir (0.95nM).
For influenza B virus clinical isolates, the median IC50 of peramivir (1.36nM) was comparable to
that of zanamivir (2.7nM) and lower than that of oseltamivir (8.5nM).8
The potency of peramivir was evaluated against five zanamivir-resistant and six oseltamivir-
resistant influenza viruses.9 Peramivir remained a potent inhibitor against all oseltamivir-resistant
viruses including the mutations H274Y, R292K, E119V, and D198N, with IC50 values ≤40nM.
Peramivir also potently inhibited (IC50 ≤ 26nM) the neuraminidase activity of zanamivir-resistant
strains, which had the following mutations: R292K, E119G, E119A, and E119D. However, one
zanamivir-resistant influenza B virus, B/Mem/96, with a mutation R152K isolated from cell
culture, was relatively resistant to all neuraminidase inhibitors, including peramivir (IC50 =
400nM).
5.3.2
Animal Models
In a mouse model of influenza infection, a single intramuscular injection of peramivir (10mg/kg)
given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain resulted in 100%
survival in contrast to 100% mortality in a control group injected with saline.6 In the same mouse
model, treatment of mice up to 72 hours after influenza infection using peramivir (20mg/kg)
resulted in 100% survival, compared to 100% mortality in the control group injected with
vehicle.10
Peramivir has also demonstrated activity in animal models utilizing a clinical H5N1 isolate as the
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infecting virus strain. In a mouse model, a single intramuscular dose of peramivir (30mg/kg)
injected 1 hour after inoculation with the highly pathogenic (H5N1) A/Vietnam/1203/04 strain,
resulted in a 70% survival rate that was similar to that seen in mice treated with oseltamivir given
orally at 10mg/kg/day for 5 days11. In similar experiments, mice inoculated with the same strain
of H5N1 virus that were then treated for up to 8 days with intramuscular peramivir exhibited
100% survival12. This longer duration of peramivir treatment also prevented viral replication in
the lungs, brain and spleen at days 3, 6 and 9 post inoculations.
5.4
Previous Phase 3 Clinical Experience with Oral Peramivir
An oral formulation of peramivir has previously demonstrated antiviral activity and preliminary
clinical efficacy in challenge studies in human volunteers, as well as in treatment studies in
patients with uncomplicated acute influenza infections during the influenza seasons of 1999-
2001. A Phase 3 multinational study (BC-01-03) of oral peramivir was conducted. Two dose
regimens of oral peramivir, 800mg QD for 5 days, or 800mg QD on Day 1, followed by 400mg
QD for 4 days, were compared to a matched placebo treatment group. A total of 1246 subjects
were randomized to treatment at sites in the USA, Western and Eastern Europe, South America,
Australia and New Zealand. As presented in the Table 1 below, the primary end-point of time to
relief of influenza symptoms in 694 subjects with confirmed influenza was not found to be
significantly different (p=0.17) between the three treatment groups.13 A sub-group analysis of the
time to relief of symptoms by country or region demonstrated marked differences in the primary
endpoint.. In the subset of influenza-infected subjects enrolled at sites in the US, clinically
meaningful differences in time to relief of influenza symptoms between the placebo and the two
peramivir arms were observed, however statistical significance (p=0.07) was not achieved.
However, a number of secondary endpoints in this phase 3 study, such as time to overall well-
being, time to normal activity, incidence of influenza related complications and quantity of viral
shedding, achieved or approached statistically significant differences between the peramivir and
placebo treatment groups (p=0.03-0.06).
Table 1
Results of study BC-01-03
Median Time to Relief of Influenza Symptoms (Hours)
Dose and Regimen
Overall Results
(n=694)
US Sites
(n=198)
Peramivir 800mg po x 5d
89.0
70.8
Peramivir 800mg po x 1d
and 400mg po x 4d
91.7
88.8
Placebo x 5 days
104.4
106.8
p value
0.17
0.07
5.5
Previous Phase 1 Experience with Intramuscular Peramivir
Two phase 1 studies evaluating the safety and pharmacokinetics of an intramuscular formulation
of peramivir have been conducted in a total of 45 healthy volunteers receiving peramivir. An
additional phase 1 study has recently been initiated to evaluate the pharmacokinetics and
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tolerability of higher single doses (up to 600 mg) of intramuscular peramivir.
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability of
75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma levels of
i.m. peramivir generally occurred within 30 minutes following injection. Plasma
pharmacokinetic parameters for i.m. peramivir are summarized in Table 2 below for the three
intramuscular single dose regimens evaluated.
Table 2
Pharmacokinetic parameters from study Him-06-111.
Dose (mg)
Cmax (ng/mL)
AUC0-∞ (hr·ng/mL)
t½a (hr)
75 i.m.
4296 ± 812
11659 ± 1123
19.8 ± 7.9
150 i.m.
7612 ± 884
23952 ± 3804
24.3 ± 4.1
300 i.m.
15150 ± 2367
49649 ± 5619
22.8 ± 2.5
aterminal half life
In a second phase 1 study, Peramivir-Him-06-112, the same dose levels of peramivir were
administered as single i.m. injections on two consecutive days (6 subjects per group). This
double-blind study also included a placebo arm. The pharmacokinetic parameters of i.m.
peramivir following the second day of dosing were consistent with those seen following single
doses of the drug.
An additional phase 1 study, BCX1812-117, was initiated to evaluate the effect of needle length
adjustment according to gender and body mass index on the pharmacokinetics and safety of
peramivir following ventrogluteal intramuscular injection, and dorsogluteal intramuscular
injection in a subgroup of subjects. Interim data are available for the first 40 subjects who
received single peramivir doses of 600 mg, consisting of directly observed tolerability
assessments, safety laboratory studies, reported adverse events, and pharmacokinetic data.
Clinical laboratory results obtained 72 hours after dosing showed no abnormalities with regards
to hematology or urinary analytes and the only chemistry analytes outside normal ranges (CK and
AST) were related to receipt of intramuscular injection.
A majority of the first 40 subjects treated complained of acute pain immediately after injection at
the ventrogluteal site and a number of these subjects reported that the pain was also associated
with muscle cramping. Some subjects reported radiation of pain to the lower extremities. In most
instances, these reactions abated after 15-30 minutes.
This protocol also evaluated the acute tolerability of doses of 450 mg and 600 mg of peramivir
administered at the dorsogluteal site. Direct observations determined that the use of the
dorsogluteal injection site resulted in an acute tolerability profile of the 600 mg dose of peramivir
that was improved compared to that observed with ventrogluteal site injections. However, a
number of these subjects also experienced acute pain and discomfort and some reported muscle
cramping in the gluteal area which persisted for up to 30 minutes.
In summary, this study confirmed that the intramuscular injection of peramivir results in acute
pain and discomfort after gluteal injection in the majority of subjects in whom total doses of up to
600mg are administered. In some subjects, the acute pain at the injection site may also be
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associated with muscle cramping. Based on these findings, the dorsogluteal site will be utilized
in future trials.
The safety data for i.m. peramivir administered as single doses ranging from 75 mg to 600mg at
the dorsogluteal injection site in each of the 3 phase 1 studies conducted to date have been
unremarkable. No serious adverse events were reported. The most commonly observed adverse
events or laboratory abnormalities were injection site pain or discomfort, headache, and transient
increases in muscle enzymes (CK). There have been several reports of signs and symptoms of
self-limited vasovagal reactions following injections. No consistent differences in frequency of
adverse events or laboratory toxicities were observed between the active and placebo treatment
groups in the controlled phase 1 studies, with the exception that CK elevations appeared to be
dose related in the peramivir treatment groups.
5.6
Phase 2 Experience with Intramuscular Peramivir
A phase 2 study BCX1812-211 was completed in 2007. This study was a randomized, double-
blind placebo- controlled study to evaluate the efficacy and safety of two single dose regimens of
peramivir. A total of 344 subjects were enrolled into this study with 115 subjects randomized to
Placebo; 114 subjects randomized to peramivir 150 mg; and 114 subjects randomized to
peramivir 300 mg. The primary endpoint of the study was the time to alleviation of clinical
symptoms in adult subjects with uncomplicated acute influenza. Based on preliminary data, the
primary endpoint of time to alleviation of clinical symptoms in BCX1812-211 did not achieve
statistical significance in the pre-planned ITTI study population (Table 3). Based on pre-planned
and post hoc analyses, it appeared that a majority of subjects within this phase 2 study did not
receive an adequate intramuscular injection.
In phase 1 studies (Him-06-111 and Him-06-112) of i.m. peramivir, significant increases in
creatine kinase (CK) were observed at Day 3 compared with Baseline (Day 1) in all subjects who
received active study drug or placebo. CK is a well established marker of muscle damage, and it
was hypothesized that CK increase may act as a surrogate marker of an adequate i.m. injection.
Within the phase 2 study, an increase in CK between Baseline (Day 1) and Day 3 was not
observed in a majority of subjects. In the phase 1 studies study drug was administered with a 1½
inch needle. In the phase 2 study a shorter needle (1 inch) was supplied with the study drug, with
guidance that a longer needle (1½ inch) should be used for larger subjects. Based on the observed
lack of CK increases at Day 3 compared to baseline, the Sponsor hypothesized that the needle
used for injection failed to penetrate muscle and deliver intramuscular study medication in many
subjects.
A sub group of subjects was identified in which a Day 3 CK increase of at least 50U/L was
observed over baseline. Within this adequate intramuscular injection sub-group, notable
improvements in the time to alleviation of symptoms were observed for both peramivir dose
groups: 44.6 hours for peramivir 150 mg treatment and 64.8 hours for the peramivir 300 mg
treatment (Table 3). A further sub-group analysis suggested that in subjects with an influenza B
infection confirmed by PCR a single dose of peramivir had limited activity (Table 3). These
efficacy data support the further development of peramivir as a single dose, intramuscular
treatment for acute influenza.
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Table 3
Summary of Efficacy from BCX1812-211.
Placebo
Peramivir
150mg
Peramivir
300mg
Intent-to-Treat Infected Population1 (n=313)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=107
137.0
115.9-163.8
n=104
114.1
95.2-145.5
22.9
n=102
115.9
77.8-136.6
21.1
Adequate Injection Population2 (n=101)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=40
152.2
103.8-183.9
n=32
107.6
76.8-175.1
44.6
n=29
87.4
40.8-163.8
64.8
ITTI Influenza A infected population (n=247)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=83
138.4
117.0-173.4
n=85
115.7
92.2-145.5
22.7
n=79
115.9
51.1-195.9
22.5
ITTI Influenza B infected population (n=66)
Median time to alleviation of symptoms (hrs)
(95% Confidence Interval)
Improvement over Placebo (hrs)
n=24
117.1
100.3-162.3
n=19
100.8
68.2-162.0
16.3
n=23
123.3
67.5-178.7
-6.2
1: Intent-to-Treat Infected Population: PCR+ for either Influenza A and/or Influenza B at
baseline/screening visit.
2: Adequate Injection Population: ITTI subjects in who study drug reached target muscle tissue,
as evidenced by an increase in serum CK levels of ≥ 50 U/L over baseline at the Day 3 study
visit.
An independent data monitoring committee reviewed grouped blinded safety data throughout
study BCX1812-211. In the overall safety population (n=342), doses of peramivir 150 mg and
300 mg were both found to be well tolerated and no safety concerns were identified by the DMC.
The three treatment groups were similar with respect to the frequency and severity of adverse
events. Two serious adverse events were reported in the study, and neither was considered by the
investigator to be related to treatment. One SAE (pyelonephritis) occurred 5-days after study
treatment in a subject who received placebo, and one SAE (meningitis, resulting in death)
occurred 10-days after study treatment in a subject who received 300 mg of peramivir. There
were no meaningful differences among the three treatment groups with respect to the frequency
or severity of graded laboratory toxicities. A summary of the adverse events and graded toxicities,
together with a list of the most frequently reported adverse events, is presented in Table 4.
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Table 4
Summary of Safety from BCX1812-211.
Safety Parameters
Placebo
(n=114)
Peramivir 150 mg
(n=113)
Peramivir 300 mg
(n=115)
Any Clinical Adverse Event
49 (43%)
43 (38%)
44 (38%)
Any Graded Laboratory Toxicity
99 (87%)
93 (82%)
92 (80%)
Any Serious Adverse Event
1 (<1%)
0
1 (<1%)
Most Frequent Adverse Events
Assessed as Study Drug-Related
Diarrhea
Nausea
Vasovagal Reaction
5 (4%)
7 (6%)
4 (4%)
5 (4%)
7 (6%)
2 (2%)
6 (5%)
9 (8%)
0
5.7 Dose Rationale
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 75mg
twice daily in adults14. Oseltamivir was shown to be clinically effective in a phase 3 study of oral
oseltamivir versus placebo in naturally occurring seasonal influenza, and these data were
sufficient for regulatory approval for marketing of oseltamivir. At least 75% of an oral dose of
oseltamivir reaches the systemic circulation as oseltamivir carboxylate. When oseltamivir is
administered orally at a dose of 75mg twice daily, the serum Cmax of oseltamivir carboxylate is
approximately 348ng/mL and the AUC0-48 is 10,876 h·ng/mL. The clinical data indicate that this
level of exposure to oseltamivir was sufficient to provide clinical improvement in uncomplicated
acute influenza.
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular doses of
peramivir are approximately 7600ng/mL and 24,000 h·ng/mL for the 150mg dose and are
approximately 15,000ng/mL and 49,000 h·ng/mL for the 300mg dose. Previous studies have
assessed the concentrations of the neuraminidase inhibitor zanamivir in nasal and pharyngeal
secretions after parenteral administration of this drug. . Within several hours after administration,
the concentrations in secretions were approximately 100-fold lower than in serum or plasma. In
theory, relatively high levels of a neuraminidase inhibitor in respiratory secretions are desirable in
order to rapidly inactivate influenza virus and to delay or prevent the development of resistance in
infecting virus strains. Intramuscular doses of peramivir, including doses of 300mg and 600mg
have been shown to be tolerated in previous Phase 1 studies. In the completed Phase 2 study,
both doses of peramivir (150 mg and 300 mg) were well tolerated and no safety concerns were
apparent. The evidence of a dose response between the 150mg and 300mg doses observed in
study BCX1812-211 indicates that the 300 mg dose should be studied further. The results of
study BCX1812-211 support advancing the 300 mg dose to undergo further evaluation in this
Phase 3 study.
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6
STUDY OBJECTIVES
6.1
Objectives
6.1.1
Primary Objective
To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the
time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza.
6.1.2
Secondary Objective(s)
The secondary objectives of this study are:
1. To evaluate the safety and tolerability of peramivir administered intramuscularly.
2. To evaluate secondary clinical outcomes in response to treatment.
3. To evaluate changes in influenza virus titer in nasopharyngeal samples (viral shedding) in
response to treatment.
6.1.3
Exploratory Objective(s)
The following exploratory objectives have been identified for this study.
1. To assess pharmacoeconomic measures as response to treatment.
2. To assess changes in influenza viral susceptibility to neuraminidase inhibitors following
treatment.
6.2
Study Endpoints
6.2.1
Primary Endpoint
The primary clinical endpoint is the time to alleviation of clinical symptoms of influenza.
6.2.2
Secondary Endpoint(s)
Secondary safety, clinical, and virologic endpoints will include evaluations in each subject of:
Safety:
Incidence of treatment-emergent adverse events and treatment-emergent changes
in clinical laboratory tests.
Clinical:
Time to resolution of fever; Incidence of influenza related complications.
Virologic:
Quantitative change in influenza virus shedding, measured by viral titer assay
(TCID50).
6.2.3
Exploratory Endpoints
Pharmacoeconomic and virologic evaluations in each subject for exploratory endpoints will also
be assessed and include:
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Pharmacoeconomic:
Medical resource utilization (MRU), missed days of work, and impact of
influenza illness on subject’s work performance and/or productivity.
Virologic:
Quantitative change in influenza virus shedding, measured by PCR;
Change in influenza virus susceptibility to neuraminidase inhibitors.
7
STUDY DESIGN
7.1
Overall Study Design and Plan
This is a multinational, randomized, double-blind study comparing the efficacy and safety of a
300 mg dose of peramivir administered intramuscularly versus placebo in adults with
uncomplicated acute influenza. Approximately 600 subjects will be randomized to treatment to
ensure enrollment of approximately 450 subjects that are positive for influenza A. All subjects
will be centrally randomized to 300 mg of peramivir or placebo in a ratio of 2:1 and will be
stratified according to smoking status and RAT test for influenza A or B.
Study drug will be administered as bilateral 2mL intramuscular injections (total of 4mL injected
in equally divided doses). Procedures for intramuscular injection, with a recommended needle
length appropriate to the physical characteristics of the subject, are provided in the study drug
administration manual.
Subjects eligible for screening will have an anterior nasal swab collected for testing by RAT for
influenza A and B, in accordance with the commercially available RAT kit instructions. If the
initial RAT is negative, the test should be repeated within one hour. Subjects meeting the
inclusion/ exclusion criteria may be enrolled into the study.
All enrolled subjects will record the following information in a Study Diary.
•
Assessment of the presence and severity of each of seven symptoms of influenza on a
4-point scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily (AM, PM) through
Day 9 following treatment, then once daily (AM) through Day 14.
•
Oral temperature measurements will be taken with an electronic thermometer every 12
hours. With the exception of the baseline measurement, all temperature measurements
will be obtained at least 4 hours after, or immediately before, administration of oral
acetaminophen (paracetamol) or other antipyretic medication.
•
Assessment of subject’s time lost from work or usual activities and rating of productivity
compared to normal (rated as 0-10 on a visual analog scale) once daily through Day 14
•
Doses of antipy retic, expectorant, and/or th roat lozenges taken for s ymptomatic relief
each day through Day 14
Anterior nose (bilateral) and posterior pharynx specimens (swabs) will be collected at Day 1 (pre-
treatment) and at Days 3, 5, and 9, for quantitative virologic assessments. Specimens from all
subjects yielding influenza virus will also be assessed for susceptibility to neuraminidase
inhibitors (Day 1 and last specimen yielding positive result) as well as other virologic
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assessments (e.g. PCR, genotypic testing). All virologic assessments will be performed by a
central laboratory.
Two samples for pharmacokinetic (PK) testing for plasma levels of peramivir will be obtained
from all subjects randomized. The first PK sample will be obtained between 30 and 60 minutes
following study drug administration in all subjects. The second PK sample will be obtained at the
day 3 visit in all subjects. The data from these PK samples will be utilized in a population
exposure-response analysis.
At selected sites a separate sub-study will be conducted to collect additional PK samples between
treatment and Day 3 for the purpose of conducting a separate exposure-response analysis. This
sub-study will be conducted under a separate protocol, BCX1812-311PK.
8
SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.1
Inclusion Criteria
Subjects must meet all of the following criteria for inclusion in this study:
1. Male and non-pregnant female subjects age ≥18 years.
2. A positive Influenza A and/or B Rapid Antigen Test (RAT) performed with a
commercially available test kit on an adequate anterior nasal specimen, in accordance
with the manufacturer’s instructions. A negative initial RAT should be repeated within
one hour.
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC
(≥101.2 ºF) taken rectally. A subject self-report of a history of fever or feverishness
within the 24 hours prior to screening will also qualify for enrollment in the absence of
documented fever at the time of screening.
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of
at least moderate severity.
5. Presence of at least one constitutional symptom (myalgia [aches and pains], headache,
feverishness, or fatigue) of at least moderate severity.
6. Onset of symptoms no more than 48 hours before presentation for screening.
7. Written informed consent.
8.1.2
Exclusion Criteria
Subjects to whom any of the following criteria apply will be excluded from the study:
1. Women who are pregnant or breast-feeding.
2. Presence of clinically significant signs of acute respiratory distress
3. History of severe chronic obstructive pulmonary disease (COPD) or severe persistent
asthma. (See Section 15.2).
4. History of congestive heart failure requiring daily pharmacotherapy with symptoms
consistent with New York Heart Association Class III or IV functional status within the
past 12 months. (See Section 15.1).
5. Screening ECG which suggests acute ischemia or presence of medically significant
dysrhythmia.
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6. History of chronic renal impairment requiring hemodialysis and/or known or suspected to
have moderate or severe renal impairment (actual or estimated creatinine clearance <50
mL/min).
7. Clinical evidence of worsening of any chronic medical condition (temporally associated
with the onset of symptoms of influenza) which, in the investigator’s opinion, indicates
that such finding(s) could represent complications of influenza.
8. Current clinical evidence, including clinical signs and/or symptoms consistent with otitis,
bronchitis, sinusitis and/or pneumonia, or active bacterial infection at any body site that
requires therapy with oral or systemic antibiotics.
9. Presence of immunocompromised status due to chronic illness, previous organ transplant,
or use of immunosuppressive medical therapy which would include oral or systemic
treatment with > 10 mg prednisone or equivalent on a daily basis within 30 days of
screening.
10. Currently receiving treatment for viral hepatitis B or viral hepatitis C.
11. Presence of known HIV infection with a CD4 count <350 cell/mm3.
12. Current therapy with oral warfarin or other systemic anticoagulant.
13. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the 7 days
prior to screening.
14. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the
previous 21 days.
15. Immunized against influenza with inactivated virus vaccine within the previous 14 days.
16. Receipt of any intramuscular injection within the previous 14 days.
17. History of alcohol abuse or drug addiction within 1 year prior to admission in the study.
18. Participation in a previous study of intramuscular or intravenous peramivir or previous
participation in this study.
19. Participation in a study of any investigational drug or device within the last 30 days.
8.1.3
Removal of Subjects from Therapy or Assessment
All subjects are permitted to withdraw from participation in this study at any time and for any
reason, specified or unspecified, and without prejudice. The Investigator or sponsor may
terminate the subject’s participation in the study at any time for reasons including the following:
1. Adverse event;
2. Intercurrent illness;
3. Non-compliance with study procedures;
4. Subject’s decision;
5. Administrative reasons;
6. Lack of efficacy;
7. Investigator’s opinion to protect the subject’s best interest.
Any subject who withdraws because of an adverse event will be followed until the sign(s) or
symptom(s) that constituted the adverse event has/have resolved or is determined to represent a
stable medical condition.
A subject should be withdrawn from the trial if, in the opinion of the Investigator, it is medically
necessary, or if it is the desire of the subject. If a subject does not return for a scheduled visit,
every effort should be made to contact the subject and determine the subject’s medical condition.
In any circumstance, every effort should be made to document subject outcome, if possible.
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If the subject withdraws consent, no further evaluations should be performed and no attempts
should be made to collect additional data.
9
TREATMENTS
9.1
Treatments Administered
Peramivir is an investigational drug. Peramivir for intramuscular injection is a small-volume
parenteral and will be supplied as a 75mg/mL solution in sodium citrate/ citric acid buffer. The
pH is approximately 3.0.
A matched placebo solution of sodium citrate/ citric acid buffer with 1.2% sodium chloride at a
pH of approximately 3.0 will be supplied.
The gluteal site of injection and the syringe needle length are to be recorded in the subjects CRF.
Procedures for intramuscular injection, with a recommended needle length appropriate to the
physical characteristics of the subject, are provided in the study drug administration manual.
9.2
Identity of Investigational Product(s)
Peramivir and placebo peramivir will be supplied in clear 2mL vials. An individual study drug
kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending upon the
treatment group). Syringes and needles will be provided in which to draw up the solution for
intramuscular injection. All study drug kits must be stored at 2-8oC.
Each individual study drug kit will be labeled with some or all of the following information as
required by local regulations:
•
Sponsor name and contact information, study protocol number, kit number, description of
the contents of the container, instructions for the preparation of the syringe and
administration of the study drug, conditions for storage, statement regarding the
investigational (clinical trial) use of the study drug and date for retest or expiry date.
Each vial of study drug will be labeled with some or all of the following information as required
by local regulations:
•
Sponsor name, study protocol number, description of the contents of the vial, instructions
for the preparation of the syringe, statement regarding the investigational (clinical trial)
use of the study drug and lot number.
9.3
Method of Assigning Subjects to Treatment Groups
Subjects will be centrally randomized in a ratio of 2:1 to a single dose peramivir 300mg or
placebo, in accordance with a computer-generated randomization schedule prepared by a non-
study statistician. Each subject’s assignment to treatment will be stratified according to smoking
status and RAT test for influenza A or B.
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Once a subject is eligible for randomization, he/she will be assigned a study drug kit number that
will be obtained by study staff from the study interactive voice response system (IVRS). Once a
study drug kit number has been assigned to a subject, it cannot be reassigned to any other subject.
9.4
Study Medication Accountability
The Investigator/pharmacist must maintain accurate records of the disposition of all study drugs
received from the sponsor, issued to the subject or directly administered to the subject (including
date and time), and any drug accidentally destroyed. The sponsor will supply a specific drug-
accountability form. At the end of the study, information describing study drug supplies (e.g., lot
numbers) and disposition of supplies for each subject must be provided, signed by the
Investigator or designee, and collected by the study monitor. If any errors or irregularities in any
shipment of study medication to the site are discovered at any time, the Project Manager must be
contacted immediately.
At the end of the study, all medication not dispensed or administered and packaging materials
will be collected with supervision of the monitor and returned to the sponsor or destroyed on site
as dictated by the appropriate Standard Operating Procedure at the participating institution.
9.5
Blinding/Unblinding of Treatments
This is a double-blind study. The treatment group assignment will not be known by the study
subjects, the investigator, the clinical staff, the CRO, or Sponsor staff during the conduct of the
study.
Section 11.2.4 provides information regarding the process for unblinding the treatment
assignment, if necessary, in the event of an SAE.
9.6
Prior and Concomitant Therapies
All medications, by any route of administration, used during this study must be documented on
the Case Report Form (CRF). Prescription as well as non-prescription medications should be
recorded. Medication used for the treatment of influenza-related symptoms will be captured by
the subject in the diary card provided by BioCryst.
9.7
Overdose and Toxicity Management
To date there is no experience with overdose of intramuscular or intravenous peramivir. If
overdose occurs, subjects should receive indicated supportive therapy and evaluation of
hematologic and clinical chemistry laboratory tests should be conducted. The effect of
hemodialysis on elimination of peramivir is unknown.
9.8
Dose Interruption
As this is a study of a single dose of peramivir or placebo, guidelines for treatment interruption
for drug related SAEs or toxicities are not applicable.
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10 STUDY CONDUCT
A study schedule of evaluations is presented in Figure 1. A detailed list of the evaluations and
visits is also provided in the following sections.
10.1 Evaluations
All subjects enrolled in this study will undergo the following evaluations:
10.1.1 Informed Consent
Prior to any study-related procedure subjects will be administered informed consent. For further
discussion of consent see section 10.2.1.
10.1.2 Medical History
Medical history, influenza vaccination status within the previous 12 months and demographic
data (including smoking behavior) will be recorded at Screening/Baseline.
10.1.3 Rapid Antigen Test for Influenza
At Screening/Baseline, a commercially available, rapid antigen test (RAT) for influenza A and B
will be performed on an adequate specimen collected by swabbing the anterior nose in
accordance with the RAT manufacturer’ instructions. A negative initial RAT should be repeated
within one hour. Refer to the Study Manual [or RAT test package insert(s)] for instructions
regarding the use of the RAT kits provided for this study. Sites may use the kits provided by the
Sponsor or any other commercially approved RAT available at their site to document a confirmed
influenza infection.
10.1.4 Physical Examination and Influenza-related Complications Assessments
The Investigator will perform a physical examination at Screening/Baseline. Subject’s height and
weight, and BMI will be recorded at Screening/Baseline in the subjects CRF.
Study personnel will be provided with an influenza-related complications (IRC) checklist in the
CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following
influenza-related complications: sinusitis, otitis, bronchitis and pneumonia. Note that subjects
with clinical signs and/or symptoms consistent with otitis, bronchitis, sinusitis, and/or pneumonia
at screening are not eligible for enrollment in this study (See Section 8.1.2: exclusion criteria
number 8).
If an IRC is suspected then a targeted physical examination will be conducted to record the
presence/absence of the IRC. If the investigator determines that the subject experiences (or is
presumed to experience) an IRC as noted above, he/she will record that assessment on the IRC
CRF page and any medication used to treat the condition will be recorded on the concomitant
medication page. The investigator will promptly provide appropriate treatment for any suspected
or proven IRC. Such information describing IRC signs and/or symptoms should not be reported
as adverse events. Any injection site reactions noted will be recorded in the CRFs as adverse
events.
10.1.5 Vital Signs
Vital signs evaluations will include blood pressure, pulse rate, and respiration rate. The
investigator will record oral or rectal body temperature at baseline. Thereafter the subject will
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record oral temperature twice daily in the study diary card.
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following the
study drug injection on Day 1, then once daily on Days 3, 5, 9, and 14.
10.1.6 Electrocardiogram Measurements
A 12-lead electrocardiogram (ECG) will be obtained at Screening/Baseline. The principal
investigator will be responsible for interpretation of the Screening ECG. This interpretation may
be performed by the investigator or he/she may delegate this action to another physician and the
investigator will acknowledge the interpretation. If this baseline ECG is interpreted as meeting
the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study. If the
ECG is interpreted as being abnormal but does not meet the exclusionary criteria, the subject may
be enrolled unless other exclusion criteria apply. The principal investigator is responsible to
ensure that such an enrolled subject be informed of the nature of the abnormal ECG and that any
medically indicated repeat ECG examinations and/or referral of the subject for further evaluation
is made either during subject's participation in the study or immediately after the subject's
discharge from the study.
10.1.7 Clinical Laboratories
Clinical chemistry profiles will include a Chemistry 20 panel (includes sodium, potassium,
chloride, total CO2 [bicarbonate], creatinine, glucose, urea nitrogen, albumin, total calcium, total
magnesium, phosphorus, alkaline phosphatase, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), total bilirubin, direct bilirubin, lactate dehydrogenase [LDH], total
protein, total creatine kinase, and uric acid).
Hematology will include complete blood count (CBC) with differential.
Urinalysis will include tests for protein, glucose, ketones, blood, urobilinogen, nitrite, pH, and
specific gravity and microscopic evaluation for RBCs and WBCs. For any subject with a Day 3
positive test for urine protein of 2+ or higher, who had a Baseline/ Day 1 protein of <2+, a 24
hour urine collection for assessment of protein will be completed. All urinalysis tests will be
completed by the central laboratory.
Clinical laboratory studies (clinical chemistries, hematology, and urinalysis) will be completed at
Screening/Baseline, and on Days 3, 5 and 14.
10.1.8 Urine Pregnancy Test
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and Day
14 using a urine pregnancy test.
10.1.9 Serology for Influenza
Paired blood samples for determination of antibody to influenza A and B (serology) will be
obtained with the clinical laboratory tests at Screening/Enrollment and at Day 14. These
specimens will be stored at the central laboratory and will be analyzed if needed to confirm the
diagnosis of influenza.
10.1.10 Samples for Virologic Laboratory Assessments
An adequate specimen will be collected by swabbing the anterior nose (bilateral) and posterior
pharynx for virologic laboratory assessments including culture for the isolation of influenza virus
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and/or quantitative PCR assay at Screening/Baseline, and at Days 3, 5, and 9. Refer to the
Laboratory Manual for instructions regarding the processing and shipment of these specimens.
10.1.11 Subject Self Assessments
Subject self assessments will be performed beginning pre-dose on Day 1 and recorded in the
subject’s Study Diary including the following:
•
Oral temperature measurements with an electronic thermometer (provided by the Sponsor for
the study) every 12 hours. With the exception of the baseline measurement, all temperature
measurements will be obtained at least 4 hours after, or immediately before, administration of
oral acetaminophen (paracetamol, provided) or other anti-pyretic medications. The times of
each temperature determination will be recorded in the Study Diary. The baseline
temperature will be recorded at the screening/Day 1 visit prior to dosing, regardless of
whether the subject had recently taken an anti-pyretic.
•
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia
[aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent;
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 and through Day 9,
then once daily through Day 14.
•
Assessment of the subject’s time lost from work or usual activities and productivity compared
to normal using a 0-10 visual analogue scale once daily through Day 14.
The subject’s diary card will be reviewed by study staff at each visit for completion of the record
of all required items, with particular emphasis on alleviation of symptoms as well as relapse of
symptoms. Relapse is defined as the recurrence of at least one respiratory symptom and one
constitutional symptom (both greater than mild in severity) for 24 hours and the presence of fever
(unless influenced by antipyretic use). Relapse can only occur after the subject has met the
endpoint criteria for alleviation of symptoms. Study staff will not attempt to ask subjects to
retrospectively complete missing diary card data for any scheduled assessments that have not
been completed prior to the clinic visit. Study staff should, however, remind the subject to
complete the diary card at all scheduled times.
10.1.12 Concomitant Medications
All concomitant medications used during this study, with the exception of those medications
taken for symptomatic relief of influenza symptoms, which will be recorded by the subject in
their diary card, must be documented on the Case Report Form (CRF).
10.1.13 Adverse Events
AEs will be assessed from the time of administration of study medication through the final study
visit.
10.1.14 Pharmacokinetic Exposure Samples
All subjects will have two pharmacokinetic (PK) samples drawn to assess peramivir drug levels.
The first PK sample will be drawn on day 1 between 30 and 60 minutes following study drug
administration in all subjects. The second PK sample will be drawn at the day 3 visit in all
subjects. The sample will be drawn at the same time as the blood draw is completed for clinical
laboratory investigations. The 30-60 minute sample (treatment day 1) and the day 3 PK sample
will be analyzed for plasma concentrations of peramivir (ng/mL) and evaluated in a population
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exposure response analysis.
At selected sites a separate sub-study will also be conducted to collect additional PK samples for
the purpose of conducting an exposure-response analysis. This sub-study will be conducted
under a separate protocol, BCX1812-311PK. Data from these two PK samples in all subjects will
be combined with data from the PK sub-study (BCX1812-311PK) to perform a population based
exposure-response analysis. This analysis will be described as part of the sub-study analysis plan.
All PK samples will be processed at a central bioanalytical laboratory. Refer to the instructions
provided regarding the processing and shipment of these PK samples.
10.2 Screening Period
10.2.1 Informed Consent
The nature and purpose of the study and the expectations of a participating subject will be
described to potential study subjects, their questions will be answered, and the subjects will then
be asked to sign an informed consent document. Study subjects will then undergo the screening
evaluation as noted in Section 10.2.2
10.2.2 Screening/Baseline Evaluation and Enrollment
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or in the
subject’s home, in which case all evaluations must be conducted by appropriately trained and
qualified staff.
Clinical laboratory assessments performed at Screening are for the purpose of establishing a
baseline. Subjects may be enrolled and receive treatment with study drug prior to receiving
results of the laboratory assessments (with the exception of urine pregnancy test result, which
must be known).
Eligible subjects will be enrolled and randomized to blinded study treatment. The randomization
will be stratified by smoking status and RAT test for influenza A or B. The Investigator will
prepare a request for blinded study drug assignment which includes the subject’s screening
number. The Investigator or designee at the clinical study center will contact the central
randomization Interactive Voice System (IVRS call center). The IVRS call center will advise the
study center of the investigational study drug kit number that is assigned to that subject at
enrollment.
Subjects that are determined to be ineligible will be advised accordingly, and the reason for
ineligibility will be discussed. If desired by the subject the reason for ineligibility may be
provided and/or discussed with their health-care provider by the Investigator or designee.
Ineligible subjects who have been screened for the study will also be entered on the IVRS. For
such subjects, the screening number assigned, subject’s date of birth and a reason for ineligibility
will be entered on to the IVRS. All ineligible subjects must be entered onto the IVRS within
24 hours of screening, to assist with surveillance analysis during the course of the study.
10.3 Treatment Period—Study Day 1
Day 1 represents the only day of study drug dosing. Study drug administration should occur as
soon as possible following informed consent, screening and randomization. Therefore, it is
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expected that the date of Screening/ Baseline and Day 1 will usually be the same date.
10.3.1 Pre-dose Evaluations-Study Day 1
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the subject
shall complete the record of these assessments in their Study Diary prior to dosing. The subject
will be counseled regarding the expectations for recording these assessments through Day 14.
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) and a
12 lead ECG will be obtained prior to dosing.
A nasopharyngeal swab for influenza culture/ PCR assay will be obtained prior to dosing.
10.3.2 Post-dose Evaluations-Study Day 1
The blinded study drug will be administered (hour 0) as bilateral intramuscular injections within a
period of ≤ 10 minutes. The calendar date and 24-hour clock time of the first and second
injections will be recorded. The gluteal site of injection and the syringe needle length are also to
be recorded in the subjects CRF. Sites are instructed to follow procedures for intramuscular
injection, with a recommended needle length appropriate to the physical characteristics of the
subject, provided in the study drug administration manual.
The following evaluations will be performed post-dose on Study Day 1:
•
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) 15
minutes following the second intramuscular injection of blinded study drug; record the exact
24-hour clock time of the vital sign measurements in the subjects CRF.
•
Draw a PK sample between 30 and 60 minutes following the second intramuscular injection
of blinded study drug; record the exact 24-hour clock time of the blood draw.
•
Record any concomitant medications.
•
Record any AEs.
10.4 Post-Treatment Assessment Period
10.4.1 Days 2, 3, 5, 9 and 14
Study evaluations will be performed on Days 2, 3, 5, 9 and 14 in accordance with the schedule of
evaluations (Figure 1). Subjects with persistent moderate or severe influenza symptoms at day 14
will also complete a Day 21 visit, and if required a Day 28 visit.
Visits may be conducted in the investigator’s office or clinic, or in the subject’s home, in which
case all evaluations must be conducted by appropriately trained and qualified staff.
Study staff will attempt to contact the subjects on Day 2 by telephone to confirm their compliance
with completion of the Subject Self Assessments, to note any concomitant medications and
adverse events. Any adverse events reported by the subject during this telephone contact will be
recorded on the adverse event form and verified during the visit on day 3.
For any subject with a Day 3 positive test for urine protein of 2+ or higher, who had a Baseline/
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Day 1 protein of <2+, a 24 hour urine collection for assessment of protein will be completed.
At each visit it is important that the subject’s Study Diary record be reviewed for completion of
daily Subject Self Assessments. The subjects should be counseled as necessary regarding self
assessments and Study Diary record requirements. The subject’s diary card will be reviewed by
study staff for alleviation of symptoms as well as relapse of symptoms. Relapse is defined as the
recurrence of at least one respiratory symptom and one constitutional symptom (both greater than
mild in severity) for 24 hours and the presence of fever (unless influenced by antipyretic use).
Relapse can only occur after the subject has met the endpoint criteria for alleviation of symptoms.
Day 3:
The second PK sample for all subjects will be obtained on Day 3 at the same time as the clinical
laboratory blood specimen is obtained. The exact 24-hour clock time of the blood draw will be
recorded in the subjects CRF.
Day 14:
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven
symptoms assessed) of either moderate or severe intensity at the Day 14 visit then the subject
must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required at day 28 (± 3
days) If a subject reports moderate or severe influenza symptoms then the investigator will
record the intensity of each of the influenza symptoms on a visit specific CRF page at the day 21
and day 28 visits. After day 14 the subject will not record symptoms in a diary.
Day 21 (if applicable):
The day 21 visit is to be completed only if the subject reports symptoms of influenza of moderate
or severe intensity at day 14. The investigator will make a clinical judgment as to the appropriate
medical course of action for such subjects at the Day 21 visit and such action(s) will be recorded
on the Day 21 CRF page. The investigator will recall the subject for a further study visit at day 28
(± 3 days) if moderate or severe symptom(s) of influenza persist at Day 21.
Day 28 (if applicable):
The day 28 visit is to be completed only if the subject reports symptoms of influenza of moderate
or severe intensity at day 21. The investigator will make a clinical judgment as to the appropriate
medical course of action for such subjects at this visit and such action(s) will be recorded on the
Day 28 CRF page. No further follow-up visits beyond day 28 are to be formally scheduled unless
in the clinical judgment of the investigator further follow-up is required. The investigator will use
his/her clinical judgment to manage the subject, referring the subject, if appropriate, for further
medical care.
10.4.2 Adverse Events Reported at Post-treatment Visits
In this study, symptoms of influenza will be considered separately from adverse events reported
during the post-treatment period. Accordingly, adverse events that have onset in the post-
treatment period will be assessed and followed as specified in 11.2. Specifically, the investigator
should attempt to follow all unresolved AEs and/or SAEs observed during the study until they are
resolved, or are judged medically stable, or are otherwise medically explained.
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Figure 1
Study Measurements and Visit Schedule
Treatment
Period
Assessment Day
End of Study
Early Withdrawal
Assessments
Screening 1
(Baseline)
Day 11
Day 22
Day 3
Day 5
(±1 day)
Day 9
(±3 day)
Day 14
(±3 day) 8
Informed Consent
X
Rapid Antigen test for
Influenza A and B
X
Medical History/Physical Exam
X
Influenza-related complications (IRC)
checklist3
X
X
X
X
X
Inclusion/Exclusion
X
Clinical Chemistries4
X
X
X
X
Hematology4
X
X
X
X
Exposure Pharmacokinetic Sample9
X
X4
Serology (serum) Sample
X
X
Urinalysis10
X
X
X
X
Urine Pregnancy Test
X
X
Vital Signs5
X
X
X
X
X
X
ECG6
X
Sample (nasopharyngeal swab) for
Influenza Virus Culture/ PCR assay
and for resistance studies
X
X
X
X
Study Drug Administration
X
Subject Diary Review7
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Study Measurements and Visit Schedule Figure Legend on Next Page
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Study Measurements and Visit Schedule Figure Legend
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on
subsequent study days may occur in subject’s home by the investigator (all visits) or appropriately trained study center staff (Day 3, 5, 9
visits).
2 Day 2 will be a telephone contact with the subject to ensure compliance with diary card completion, concomitant medication and adverse
event review.
3 If an IRC is suspected then a targeted physical examination will be conducted to record the presence/absence of the IRC.
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subject may be enrolled and begin
treatment with study drug prior to receiving results. A PK sample will be drawn 30-60 minutes following the second treatment
administration injection. On Day 3 an extra tube will be included with the safety blood sample to collect the second PK sample for
evaluation of peramivir concentrations.
5 Vital sign measures will include blood pressure, pulse rate and respiration rate. Vital signs will be recorded at Screening, pre-dose and at
15 min following the study drug administration on Day 1, then once on remaining days as stipulated. The investigator will record oral
temperature at baseline. Thereafter the subject will report oral temperature measurements twice daily in the Study Diary
6 If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will
not be enrolled in this study. If the ECG is interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia,
medically significant dysrhythmia) then this subject may be enrolled If the conditions highlighted in section 10.1.5 are met for the subject.
7 Subjects record symptom assessment in Study Diary, twice daily, beginning pre-dose on Day 1 through Day 9, then once daily through
Day 14. Subjects record time lost from work or usual activities and rating of productivity compared to normal once daily through Day 14.
Subjects record oral temperature twice daily throughout as well as all influenza related medications.
8 For any subject with unresolved moderate or severe intensity influenza symptoms a follow up assessment will be scheduled at Day 21 (±
3 days) and Day 28 (± 3 days) if required (See Section 10.4.1).
9 A PK sample will be drawn 30-60 minutes following the second treatment injection on Day 1, and on Day 3.
10For any subject with a Day 3 positive test for urine protein of 2+ or higher, who had a Baseline/ Day 1 protein of <2+, a 24 hour urine
collection for assessment of protein will be completed.
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11 ADVERSE EVENT MANAGEMENT
11.1 Definitions
11.1.1 Adverse Event
An AE is any untoward medical occurrence in a clinical study subject. No causal relationship
with the study drug or with the clinical study itself is implied. An AE may be an unfavorable and
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical
study. Clinically relevant abnormal results of diagnostic procedures including abnormal
laboratory findings (e.g., requiring unscheduled diagnostic procedures or treatment measures, or
resulting in withdrawal from the study) are considered to be AEs.
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2).
Surgical procedures are not AEs but may constitute therapeutic measures for conditions that
require surgery. The condition for which the surgery is required is an AE, if it occurs or is
detected during the study period. Planned surgical measures permitted by the clinical study
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was
(were) known before the start of study treatment. In the latter case the condition should be
reported as medical history.
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia [aches
and pains], headache, feverishness, and fatigue) will be documented in a subject’s study diary and
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as
AEs unless the symptom(s) worsen to the extent that the outcome fulfils the definition of an SAE,
which then must be recorded as such (see Section 11.1.2). Likewise, a RAT for influenza is
required at screening in order to determine eligibility for the study, and therefore a positive RAT
is not considered an AE.
11.1.2 Serious Adverse Event
A SAE is an adverse event that results in any of the following outcomes:
•
Death
•
Is life-threatening (subject is at immediate risk of death at the time of the event; it does not
refer to an event that hypothetically might have caused death if it were more severe)
•
Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or
prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity (i.e., there is a substantial disruption
of a person’s ability to carry out normal life functions)
•
Is a congenital anomaly/birth defect
•
Is an important medical event
Important medical events that may not result in death, are not life-threatening, or do not require
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they
may jeopardize the subject or may require medical or surgical intervention to prevent one of the
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outcomes listed in this definition. Examples of such events include allergic bronchospasm
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions
that do not result in subject hospitalization, or the development of drug dependency or drug
abuse.
In addition Suspected Unexpected Serious Adverse Reactions (SUSAR) may also be reported to
competent authorities where this type of reporting is required (e.g. European Union Directives).
See section 11.2.3.
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and Reporting
Serious Adverse Events
Reports of AEs are to be collected from the time of study drug administration through the
follow-up period ending on Day 14. The Investigator or designee must completely and promptly
record each AE on the appropriate CRF. The Investigator should attempt, if possible, to establish
a diagnosis based on the presenting signs and symptoms. In such cases, the diagnosis should be
documented as the AE and not the individual sign/symptom. If a clear diagnosis cannot be
established, each sign and symptom must be recorded individually.
The Investigator should attempt to follow all unresolved AEs and/or SAEs observed during the
study until they are resolved, or are judged medically stable, or are otherwise medically
explained.
11.2.1 Definition of Severity
All AEs will be assessed (graded) for severity and classified into one of four clearly defined
categories as follows:
•
Mild:
(Grade 1): Transient or mild symptoms; no limitation in activity; no
intervention required. The AE does not interfere with the participant’s
normal functioning level. It may be an annoyance.
•
Moderate:
(Grade 2): Symptom results in mild to moderate limitation in activity;
no or minimal intervention required. The AE produces some
impairment of functioning, but it is not hazardous to health. It is
uncomfortable or an embarrassment.
•
Severe:
(Grade 3): Symptom results in significant limitation in activity;
medical intervention may be required. The AE produces significant
impairment of functioning or incapacitation.
•
Life-threatening:
(Grade 4): Extreme limitation in activity, significant assistance
required; significant medical intervention or therapy required;
hospitalization.
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11.2.2 Definition of Relationship to Study Drug
The blinded Principal Investigator must review each AE and make the determination of
relationship to study drug using the following guidelines:
Not Related:
The event can be readily explained by other factors such as the subject’s
underlying medical condition, concomitant therapy, or accident, and no
temporal relationship exists between the study drug and the event.
Unlikely:
The event does not follow a reasonable temporal sequence from drug
administration and is readily explained by the subject’s clinical state or
by other modes of therapy administered to the subject.
Possibly Related:
There is some temporal relationship between the event and the
administration of the study drug and the event is unlikely to be explained
by the subject’s medical condition, other therapies, or accident.
Probably Related:
The event follows a reasonable temporal sequence from drug
administration, abates upon discontinuation of the drug, and cannot be
reasonably explained by the known characteristics of the subject’s
clinical state.
Definitely Related:
The event follows a reasonable temporal sequence from administration
of the medication, follows a known or suspected response pattern to the
medication, is confirmed by improvement upon stopping the medication
(dechallenge), and reappears upon repeated exposure (rechallenge, if
rechallenge is medically appropriate).
11.2.3 Reporting Serious Adverse Events
Any SAE / SUSAR (Suspected Unexpected Serious Adverse Reaction) must be reported to
BioCryst or its designee within 24 hours of the Investigator’s recognition of the SAE by first
notifying the Medical Monitor at the number listed below:
Telephone:
Europe: +44 1628 548000;
North America: 1-888-724-4908
Facsimile:
Europe: +44 1628 540028;
North America: 1-888-887-8097
or 1-609-734-9208
In addition to the telephone numbers listed above, local country-specific toll free numbers may be
provided within the study reference manual.
The site is required to fax a completed SAE / SUSAR Report Form (provided as a separate report
form) within 24 hours. All additional follow-up evaluations of the SAE / SUSAR must be
reported and sent by facsimile to BioCryst or its designee as soon as they are available.
The Principal Investigator or designee at each site is responsible for submitting the IND safety
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) to
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and for retaining a copy
in their files.
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If the Investigator becomes aware of any SAE / SUSAR occurring within 30 days after a subject
has completed or withdrawn from the study, he or she should notify BioCryst or its designee.
Any SAEs / SUSARs considered possibly related to treatment will be reported to the FDA and
other Regulatory Competent Authorities as applicable via the MedWatch / CIOMS reporting
system in accordance with FDA and other applicable regulations. However, the Investigator is not
obligated to actively seek reports of AEs in former study participants.
While pregnancy is not considered an AE, all cases of fetal drug exposure via parent as study
participant (see Section 4.4) are to be reported immediately to BioCryst or its designee.
Information related to the pregnancy must be given on a “Pregnancy Confirmation and Outcome”
form that will be provided by the Sponsor or its designee.
11.2.4 Emergency Procedures
In the event of an SAE / SUSAR, the Principal Investigator may request the unblinding of the
treatment assignment for the subject affected. If time allows (i.e., if appropriate treatment for the
SAE is not impeded), the Principal Investigator will first consult with the Medical Monitor
regarding the need to unblind the treatment assignment for the subject. At all times, the clinical
well-being of any subject outweighs the need to consult with the Medical Monitor.
The Principal Investigator may contact the IVRS central randomization center and request the
unblinding of the treatment assignment that corresponds to the affected subject. The IVRS center
will record the name of the Investigator making the request, the date and time of the request, the
subject number and date of birth. The Sponsor will be informed within 24 hours if unblinding
occurred.
12 STATISTICAL METHODS
Descriptive statistical methods will be used to summarize the data from this study, with
hypothesis testing performed for the primary and other selected efficacy endpoints. Unless stated
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median,
standard deviation (SD), minimum, and maximum for continuous data and frequencies and
percentages for categorical data. The term “treatment group” refers to randomized treatment
assignment: peramivir 300 mg or placebo. All data collected during the study will be included in
data listings. Unless otherwise noted, the data will be sorted first by treatment assignment,
subject number, and then by date within each subject number.
Unless specified otherwise, all statistical testing will be two-sided and will be performed using a
significance (alpha) level of 0.05.
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher.
12.1 Data Collection Methods
The data will be recorded on the CRF approved by BioCryst. All documentation supporting the
CRF data, such as laboratory or hospital records, must be readily available to verify entries in the
CRF.
Documents (including laboratory reports, hospital records subsequent to SAEs, etc.) transmitted
to BioCryst should not carry the subject’s name. This will help to ensure subject confidentiality.
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12.2 Statistical Analysis Plan
A statistical analysis plan (SAP) will be created and approved prior to the review of any data.
This document will provide a more technical and detailed description of the proposed data
analysis methods and procedures.
12.3 Study Hypothesis
The primary hypothesis for evaluating the primary objective may be stated as follows:
The null hypothesis (H0) is that the time to alleviation of influenza symptoms is the same for
subjects treated with placebo and for subjects treated with peramivir 300mg.
The alternative hypothesis (H1) is that subjects treated with peramivir 300mg have an
improvement in time to alleviation of influenza symptoms over those treated with placebo.
12.4 Sample Size Estimates
From preliminary results of a phase 2 study evaluating peramivir treatment of uncomplicated
influenza, it is expected that the median time to alleviation of symptoms will be 137.0 hours (95%
CI: 115.9, 165.8) for subjects receiving placebo treatment. Additionally, it is expected that the
median time to alleviation for the 300 mg dose peramivir arm will be reduced by 30% compared
to placebo yielding a hazard ratio of 0.70. Data from the phase 2 study suggested that the activity
of peramivir against influenza B was limited. Therefore, this study will be sized to ensure that a
minimum number of influenza A subjects is enrolled to achieve study power.
Using these assumptions, a sample size of 450 evaluable subjects with influenza A (300 in the
300 mg treatment group and 150 evaluable subjects in the placebo group) is sufficient to provide
at least 90% power to detect a hazard ratio of 0.70 using a log-rank statistic and α = 0.05 (SAS
version 9.1.3; total accrual time 7 months; total enrollment time 6 months).
12.5 Analysis Populations
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected (ITTI
and ITTI-A), per-protocol infected (PPI), and safety populations. Additional analysis populations
may be defined to evaluate study results. Any additional analysis populations will be defined in
the SAP.
Intent-To-Treat Population: The ITT population will include all subjects who are randomized.
Subjects will be analyzed in the treatment group to which they were randomized. The ITT
population will be used for analyses of accountability and demographics.
Intent-To-Treat Infected Population: The ITTI population will include all subjects who are
randomized, received study drug, and have confirmed influenza by culture or PCR. Subjects will
be analyzed according to the treatment randomized. If a discrepancy is noted in the final database
for any subject, such that the drug differs from the randomized treatment assignment, efficacy
analyses may be repeated with the subjects analyzed according to the treatment received. The
ITTI population will be used for primary analyses of efficacy.
Intent-To-Treat Infected Population-A: The ITTI-A population will include all subjects who
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are randomized, received study drug, and have confirmed influenza A by culture or PCR.
Subjects will be analyzed according to the treatment randomized. If a discrepancy is noted in the
final database for any subject, such that the drug differs from the randomized treatment
assignment, efficacy analyses may be repeated with the subjects analyzed according to the
treatment received. The ITTI-A population will be used for supportive analyses of efficacy.
Per-Protocol Infected: The PPI population includes all subjects in the ITTI population who
receive an adequate intramuscular injection. The definition of an adequate intramuscular injection
will be further described in the SAP. The PPI population will be used for supportive analyses of
efficacy.
Safety Population: The safety population will include all subjects who received study drug.
Subjects will be analyzed according to the treatment received. This population will be used for
all safety analyses.
12.6 Interim and End of Study Analyses
Interim Analysis
An independent DMC will review safety data on an ongoing basis. Safety analyses will be
presented in a manner consistent with the presentations intended for the final analysis.
End of Study Analysis
A final analysis is planned after the last subject completes or discontinues the study, and the
resulting clinical database has been cleaned, quality checked, and locked.
12.7 Efficacy Analyses
12.7.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the time to alleviation of symptoms of influenza in subjects
diagnosed with influenza, defined as the time from injection of study drug to the start of the time
period when a subject has Alleviation of Symptoms. A subject has Alleviation of Symptoms if
all of the seven symptoms of influenza (nasal congestion, sore throat, cough, aches and pains,
fatigue (tiredness), headache, feeling feverish) assessed on his/her subject diary are either absent
or are present at no more than mild severity level and at this status for at least 21.5 hours (24
hours - 10%).
Descriptive statistics for the primary efficacy variable will be tabulated by treatment group.
Alleviation of symptoms will be determined by assessment of symptoms as reported on each
subject’s diary card. Time to alleviation of symptoms will be summarized for each treatment
group (300 mg peramivir and placebo). Treatment comparisons between the 300 mg peramivir
group and placebo will be assessed using a Wilcoxon-Gehan19 statistic stratified by smoking
status and positive PCR or viral culture for influenza A or B at screening for the ITTI and PPI
populations. Subjects who do not experience alleviation of symptoms will be censored at the date
of their last non-missing post-baseline assessment.
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12.7.2 Secondary Efficacy Endpoints
All secondary endpoints will be summarized using descriptive statistics by treatment group, and
study day/time, if appropriate. Statistical comparisons for each endpoint will be constructed
without adjustment for multiple endpoints.
The reduction in viral shedding will be assessed as the change in viral titers defined as the time-
weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and will be
summarized for each treatment group. The time-weighted average change from baseline will be
calculated on a by-subject basis through Day 9 using the trapezoidal rule with all available data
(data after initiation of study treatment) minus the baseline value. Specifically, the time-weighted
area under the curve for time a (ta) to time b (tb) is given by the formula
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
,
where
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
and ti represents the date of the ith viral titer
assessment and yi represents the log10 value of the ith viral titer assessment. If there is a baseline
value and only one follow-up value, yi then the time-weighted change from baseline is defined as
the difference between yi and baseline. If there is a baseline value and no follow-up value, the
subject is excluded from analysis. The differences between the 300 mg peramivir treatment
group and placebo will be evaluated using a van Elteren Test adjusting for smoking status and
positive PCR or viral culture for influenza A or B at screening.
Subject’s oral temperature will be summarized by study visit and treatment group. Differences
between the 300 mg peramivir treatment group and placebo will be assessed using the van Elteren
test controlling for smoking status and positive PCR or viral culture for influenza A or B at
screening. A subject has Resolution of Fever if he/she has a temperature < 37.2°C (99.0°F) and
no antipyretic medications have been taken for at least 12 hours. The time to resolution of fever
will be estimated using the method of Kaplan-Meier using temperature and symptom relief
medication information obtained from the subject diary data. Differences between the treatment
groups will be assessed using the Wilcoxon-Gehan statistic controlling for smoking status and
positive PCR or viral culture for influenza A or B at screening. Subjects who do not have
resolution of fever will be censored at the time of their last non-missing post-baseline temperature
assessment.
The number and percentage of subjects experiencing influenza related complications will be
summarized by complication preferred term and treatment group. The difference between the
treatment groups (300 mg peramivir and placebo) will be assessed using a Cochran-Mantel-
Haenszel (CMH) test statistic controlling for smoking status, and positive PCR or viral culture for
influenza A or B at screening, if applicable.
12.7.3 Exploratory Endpoints
The MRU, MRU-related direct costs, and indirect costs attributable to days missed of work and
work productivity and/or performance losses will be summarized by treatment group, smoking
status, and positive PCR or viral culture for influenza A or B at screening, if applicable. Methods
for describing differences between treatment groups will be presented in the SAP.
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Genotypic (including Hemagglutinin and Neuraminidase), phenotypic, viral culture and PCR data
will be listed for each subject. These listings will be constructed in a manner consistent with the
FDA June 2006 Guidance Document: “Guidance for Submitting Influenza Resistance Data”.18
Additionally, the number and percentage of genotypic changes from wild-type amino acid will be
summarized separately for treatment group, protein type, and study visit.
12.8 Safety Analyses
AEs will be mapped to a MedDRA-preferred term and system organ classification. The
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred terms,
system organ classifications, and severity. If a subject experiences multiple events that map to a
single preferred term, the greatest severity and strongest Investigator assessment of relation to
study drug will be assigned to the preferred term for the appropriate summaries. All AEs will be
listed for individual subjects showing both verbatim and preferred terms. Separate summaries of
treatment-emergent SAEs and AEs related to study drug will be generated.
Descriptive summaries of vital signs and clinical laboratory results will be presented by study
visit. Laboratory abnormalities will be graded according to the DAIDS Table for Grading
Adverse Events for Adults and Pediatrics (Publish Date: December 2004). The number and
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by
treatment group. Laboratory toxicity shifts from baseline to Day 3, Day 5, and Day 14 will be
summarized by treatment group.
Abnormal physical examination findings will be presented by treatment group. The number and
percent of subjects experiencing each abnormal physical examination finding will be included.
Concomitant medications will be coded using the WHO dictionary. These data will be
summarized by treatment group.
Subject disposition will be presented for all subjects. The number of subjects who completed the
study and discontinued from the study will be provided. The reasons for early discontinuation
also will be presented.
12.9 Sub-Study and Pharmacokinetic Analysis
A sub-study to collect pharmacokinetic samples in up to 60 peramivir treated subjects to examine
exposure response will be conducted at selected sites. The data from the sub-study will be
combined with the two PK samples (collected on all subjects at 30-60 minutes following
administration of study drug and on study day 3) to perform a population exposure-response
analysis. All analyses related to exposure-response will be completed as part of the sub-study. All
statistical methods will be outlined as part of the sub-study protocol and exposure-response
analysis plan. All sub-study analyses, and exposure-response analyses from PK samples obtained
in this study and a companion study BCX1812-312, will be reported in a separate sub-study
report.
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12.10
General Issues for Statistical Analysis
12.10.1
Multiple Comparisons and Multiplicity
No adjustments for multiple comparisons are currently planned.
12.10.2
Covariates
Primary and secondary efficacy analyses will be adjusted for smoking status and positive PCR or
viral culture for influenza A or B at screening, where appropriate.
12.10.3
Planned Sub-Groups
The primary efficacy endpoint will be summarized separately by smoking status and positive
PCR or viral culture for influenza A or B at screening using descriptive statistics by treatment
group and study day, where appropriate. No formal statistical testing will be utilized.
Additional analyses may be performed by country, if necessary, for submission to local
regulatory authorities.
12.10.4
Missing Data
Every effort will be made to obtain required data at each scheduled evaluation from all subjects
who have been randomized. No attempt will be made retrospectively to obtain missing subject
reported data (including influenza symptom severity assessments, temperature, ability to perform
usual activities, missed days of work and impact of influenza on subject’s work performance
and/or productivity) that has not been completed by the subject at the time of return of the subject
diary to the investigative site. In situations where it is not possible to obtain all data, it may be
necessary to impute missing data.
In assessing the primary efficacy endpoint, for subjects who withdraw or who do not experience
alleviation of symptoms, missing data will be censored using the date of subject’s last non-
missing assessment of influenza symptoms. Missing assessments of influenza symptoms
conservatively will be imputed as having severity above absent or mild (as failures). For the
subject diary data, the following data conventions will be utilized. Missing diary completion will
be imputed as 11:59 for diary entries designated as morning and 23:59 for evening and daily
reported values. Select exploratory sensitivity analyses may be conducted to ascertain the effect,
if any, of these methods. These sensitivity analyses are further described in the SAP. Secondary
efficacy endpoints with time to event data will be censored using the date of subject’s last non-
missing assessment of the given endpoint.
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13 STUDY ADMINISTRATION
13.1 Regulatory and Ethical Considerations
13.1.1 Regulatory Authority Approvals
This study will be conducted in compliance with the protocol; GCPs, including International
Conference on Harmonization (ICH) of Technical Requirements for Registration of
Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements and in accordance
with the ethical principles of the Declaration of Helsinki. In addition, all applicable local laws
and regulatory requirements relevant to the use of new therapeutic agents in the countries
involved will be adhered to.
The Investigator should submit written reports of clinical study status to their Institutional
Review Board (IRB)/ Independent Ethics Committee (IEC) annually or more frequently if
requested by the IRB/ IEC. A final study notification will also be forwarded to the IRB/IEC after
the study is completed or in the event of premature termination of the study in accordance with
the applicable regulations. Copies of all contact with the IRB/ IEC should be maintained in the
study documents file. Copies of clinical study status reports (including termination) should be
provided to BioCryst.
13.1.2 Ethics Committee Approvals
Before initiation of the study at each investigational site, the protocol, the informed consent form,
the subject information sheet, and any other relevant study documentation will be submitted to
the appropriate IRB/IEC. Written approval of the study must be obtained before the study center
can be initiated or the investigational medicinal product is released to the Investigator. Any
necessary extensions or renewals of IRB/IEC approval must be obtained, in particular, for
changes to the study such as modification of the protocol, the informed consent form, the written
information provided to subjects and/or other procedures.
The Investigator will report promptly to the IRB/IEC any new information that may adversely
affect the safety of the subjects or the conduct of the study. On completion of the study, the
Investigator will provide the IRB/IEC with a report of the outcome of the study.
13.1.3 Subject Informed Consent
Signed informed consent must be obtained from each subject prior to performing any study-
related procedures. Each subject should be given both verbal and written information describing
the nature and duration of the clinical study. The informed consent process should take place
under conditions where the subject has adequate time to consider the risks and benefits associated
with his/her participation in the study. Subjects will not be screened or treated until the subject
has signed an approved ICF written in a language in which the subject is fluent.
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC. The
informed consent should be in accordance with the current revision of the Declaration of
Helsinki, current ICH and GCP guidelines, and BioCryst policy.
The Investigator must explain to potential subjects or their legal representatives the aims,
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methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it
may entail. Subjects will be informed that they are free not to participate in the trial and that they
may withdraw consent to participate at any time. They will be told that refusal to participate in
the study will not prejudice future treatment. They will also be told that their records may be
examined by competent authorities and authorized persons but that personal information will be
treated as strictly confidential and will not be publicly available. Subjects must be given the
opportunity to ask questions. After this explanation and before entry into the trial, consent should
be appropriately recorded by means of the subject’s dated signature. The subject should receive a
signed and dated copy of the ICF. The original signed informed consent should be retained in the
study files. The Investigator shall maintain a log of all subjects who sign the ICF and indicate if
the subject was enrolled into the study or reason for non-enrollment.
13.1.4 Payment to Subjects
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC
responsible for the study at the Investigator’s site.
13.1.5 Investigator Reporting Requirements
The Investigator will provide timely reports regarding safety to his/her IRB/IEC as required.
13.2 Study Monitoring
During trial conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure
that the protocol and GCPs are being followed. The monitors may review source documents to
confirm that the data recorded on CRFs is accurate. The investigator and institution will allow
BioCryst monitors or its designees and appropriate regulatory authorities direct access to source
documents to perform this verification.
13.3 Quality Assurance
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits
performed by BioCryst, and/or to inspection by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the
monitoring visits and possible audits or inspections and that sufficient time is devoted to the
process.
13.4 Study Termination and Site Closure
BioCryst reserves the right to discontinue the trial prior to inclusion of the intended number of
subjects but intends only to exercise this right for valid scientific or administrative reasons. After
such a decision, the Investigator must contact all participating subjects immediately after
notification. As directed by BioCryst, all study materials must be collected and all case report
forms completed to the greatest extent possible.
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13.5 Records Retention
To enable evaluations and/or audits from regulatory authorities or BioCryst, the Investigator
agrees to keep records, including the identity of all participating subjects (sufficient information
to link records, case report forms and hospital records), all original signed informed consent
forms, copies of all case report forms and detailed records of treatment disposition. The records
should be retained by the Investigator according to local regulations or as specified in the Clinical
Trial Agreement, whichever is longer.
If the Investigator relocates, retires, or for any reason withdraws from the study, the study records
may be transferred to an acceptable designee, such as another investigator, another institution, or
to BioCryst. The Investigator must obtain BioCryst’s written permission before disposing of any
records.
13.6 Study Organization
13.6.1 Data Monitoring Committee
BioCryst will assemble an independent Data Monitoring Committee (DMC) to assess safety
parameters of the trial on a periodic, ongoing basis while the trial is in progress. The committee
will include a statistician and three physicians, two of whom will be Infectious Disease / Clinical
Virology specialists. Full details of the composition of the DMC and how the DMC is to operate
will be described in a separate DMC charter.
13.7 Confidentiality of Information
BioCryst affirms the subject’s right to protection against invasion of privacy. Only a subject
identification number, initials and/or date of birth will identify subject data retrieved by BioCryst.
However, in compliance with federal regulations, BioCryst requires the investigator to permit
BioCryst’s representatives and, when necessary, representatives of the FDA or other regulatory
authorities to review and/or copy any medical records relevant to the study.
BioCryst will ensure that the use and disclosure of protected health information obtained during a
research study complies with the HIPAA Privacy Rule, where this rule is applicable. The Rule
provides federal protection for the privacy of protected health information by implementing
standards to protect and guard against the misuse of individually identifiable health information
of subjects participating in BioCryst-sponsored Clinical Trials. "Authorization" is required from
each research subject, i.e., specified permission granted by an individual to a covered entity for
the use or disclosure of an individual's protected health information. A valid authorization must
meet the implementation specifications under the HIPAA Privacy Rule. Authorization may be
combined in the Informed Consent document (approved by the IRB/IEC) or it may be a separate
document, (approved by the IRB/IEC) or provided by the Investigator or Sponsor (without
IRB/IEC approval). It is the responsibility of the investigator and institution to obtain such
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are
required for U.S. sites only.
13.8 Study Publication
All data generated from this study are the property of BioCryst and shall be held in strict
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confidence along with all information furnished by BioCryst. Independent analysis and/or
publication of these data by the Investigator or any member of his/her staff are not permitted
without prior written consent of BioCryst. Written permission to the Investigator will be
contingent on the review by BioCryst of the statistical analysis and manuscript and will provide
for nondisclosure of BioCryst confidential or proprietary information. In all cases, the parties
agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This
will enable all parties to protect proprietary information and to provide comments based on
information that may not yet be available to other parties.
423
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14 REFERENCES
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282.
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality associated with
influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179–186.
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment on
influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med
2003;163(14):1667–1672.
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral neuraminidase
inhibitor oseltamivir in experimental human influenza: randomized controlled trials for
prevention and treatment. JAMA 1999;282(13):1240–1246.
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant influenza
A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759–
765.
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-influenza
virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents
Chemother 2001;45(4):1162–1167.
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to
different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147.
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir,
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase
inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45(12):3403–3408.
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine
combinations exert additive and synergistic anti-influenza virus effects in MDCK cells.
Antimicrob Agents Chemother 2004;48(12):4855–4863.
10. BioCryst Pharmaceuticals. Unpublished data.
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. Injectable
peramivir promotes survival in mice and ferrets infected with highly pathogenic avian
influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San Francisco
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA.
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival against
lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03.
14. Tamiflu® Package Insert. Roche Pharmaceuticals. Rev. December 2005.
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product
information sheets
16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the oral
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283(8): 1016-
1024.
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of oseltamivir in
treatment of influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-1850.
424
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18. US Department of Health and Human Services, Food and Drug Administration Center for
Drug Evaluation and Reserach (CDER). Attachment to Guidance on Antiviral Product
Development- Conducting and Submitting Virology Studies to the Agency: Guidance for
Submitting Influenza Resistance Data. http://www.fda.gov/cder/guidance/7070fnlFLU.htm
19. Gehan EA (1965): A generalized Wilcoxon test
for co mparing arbitrarily singl y censored
samples. Biometrika 52:203-223
425
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CONFIDENTIAL
15 APPENDICES
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina
NYHA Functional Classification of Heart Failure
Class I
No symptoms. Ordinary physical activity such as walking and climbing stairs
does not cause fatigue or dyspnea.
Class II
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly;
walking uphill; walking or stair climbing after meals, in cold weather, in wind,
or when under emotional stress causes undue fatigue or dyspnea.
Class III
Symptoms w ith less than ordinary phy
sical activity. Walking one to two
blocks on t he level and clim bing m ore th an one flight of stai rs in norm al
conditions causes undue fatigue or dyspnea.
Class IV
Symptoms at rest. Inability to carry on any physical activity without fatigue or
dyspnea.
NYHA Functional Classification of Angina
Class I
Angina only with unusually strenuous activity.
Class II
Angina with slightl y more prolonged o r slightly more vigorous activit y than
usual.
Class III
Angina with usual daily activity.
Class IV
Angina at rest.
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CONFIDENTIAL
15.2 Criteria for Severe COPD and Severe Asthma
The following guidelines are provided to assist in the evaluation of subjects who have a medical
history for Chronic Obstructive Pulmonary Disease (COPD) and/or Asthma. Subjects with severe
COPD or severe persistent Asthma are to be excluded from this study. (See section 8.1.2,
exclusion criteria number 3).
Classification of Asthma from National Asthma and Education and Prevention Program
For Adults and Children (> 5 yrs) who
can use a spirometer or peak flow meter
Classification
Days with
Symptoms
Nights with
Symptoms
FEV1 or PEF
% Predicted Normal
PEF Variability
(%)
Severe persistent
Continual
Frequent
≤ 60
> 30
Moderate Persistent
Daily
> 1/ week
> 60 - < 80
> 30
Mild Persistent
> 2 / week
but < 1
times / day
> 2/ month
≥ 80
20 – 30
Mild Intermittent
≤ 2 / week
< 2 / month
≥ 80
< 20
FEV1: percentage predicted value for forced expiratory volume in 1 second.
PEF: percentage of personal best for peak expiratory flow.
Extracted from: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart,
Lung, and Blood Institute, National Asthma Education and Prevention Program. HHS/NIH 2007
Spirometric Classification of COPD Severity based upon Post-Bronchodilator FEV1
(GOLD Criteria)
Stage
Characteristics
Mild COPD
FEV1/FVC < 70%
FEV1 ≥ 80% predicted
Moderate COPD
FEV1/FVC < 70%
50 % ≤ FEV1 < 80% predicted
Severe COPD
FEV1/FVC < 70%
30 % ≤ FEV1 < 50% predicted
Very Severe COPD
FEV1/FVC < 70%
FEV1 < 30% predicted or FEV1 < 50%
predicted plus chronic respiratory failure
FEV1: percentage predicted value for forced expiratory volume in one second.
FVC: forced vital capacity
Extracted from: Rabe KF, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease (GOLD Executive Summary). Am. J. Respir. Crit. Care Med. 2007:176;532-555.
427
427
| 2
|
arm 1: Placebo intramuscular injection arm 2: Single intramuscular injection of 300mg peramivir
|
[
2,
0
] | 2
|
[
0,
0
] |
intervention 1: To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza. intervention 2: Single intramuscular injection
|
intervention 1: Peramivir intervention 2: Placebo
| 96
|
Millbrook | Alabama | United States | -86.36192 | 32.47986
Tuscaloosa | Alabama | United States | -87.56917 | 33.20984
Phoenix | Arizona | United States | -112.07404 | 33.44838
Jonesboro | Arkansas | United States | -90.70428 | 35.8423
Jonesboro | Arkansas | United States | -90.70428 | 35.8423
Mountain Home | Arkansas | United States | -92.38516 | 36.33534
Anaheim | California | United States | -117.9145 | 33.83529
Beverly Hills | California | United States | -118.40036 | 34.07362
Buena Park | California | United States | -117.99812 | 33.86751
Fair Oaks | California | United States | -121.27217 | 38.64463
Fresno | California | United States | -119.77237 | 36.74773
Fresno | California | United States | -119.77237 | 36.74773
Garden Grove | California | United States | -117.94145 | 33.77391
Long Beach | California | United States | -118.18923 | 33.76696
Los Angeles | California | United States | -118.24368 | 34.05223
Paramount | California | United States | -118.15979 | 33.88946
San Diego | California | United States | -117.16472 | 32.71571
San Luis Obispo | California | United States | -120.65962 | 35.28275
Boulder | Colorado | United States | -105.27055 | 40.01499
Colorado Springs | Colorado | United States | -104.82136 | 38.83388
Longmont | Colorado | United States | -105.10193 | 40.16721
Gainesville | Florida | United States | -82.32483 | 29.65163
Hialeah | Florida | United States | -80.27811 | 25.8576
Hialeah | Florida | United States | -80.27811 | 25.8576
Holly Hill | Florida | United States | -81.03756 | 29.24359
Jacksonville | Florida | United States | -81.65565 | 30.33218
Jacksonville | Florida | United States | -81.65565 | 30.33218
Jacksonville | Florida | United States | -81.65565 | 30.33218
Lake Worth | Florida | United States | -80.07231 | 26.61708
Largo | Florida | United States | -82.78842 | 27.90979
Miami | Florida | United States | -80.19366 | 25.77427
Orlando | Florida | United States | -81.37924 | 28.53834
Pembroke Pines | Florida | United States | -80.22394 | 26.00315
Saint Cloud | Florida | United States | -81.28118 | 28.2489
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Sandersville | Georgia | United States | -82.81014 | 32.98154
Quincy | Illinois | United States | -91.40987 | 39.9356
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Newburgh | Indiana | United States | -87.40529 | 37.94449
Dubuque | Iowa | United States | -90.66457 | 42.50056
Shawnee Mission | Kansas | United States | -94.66583 | 39.02
Topeka | Kansas | United States | -95.67804 | 39.04833
Wichita | Kansas | United States | -97.33754 | 37.69224
Hazard | Kentucky | United States | -83.19323 | 37.24954
Whitley City | Kentucky | United States | -84.47049 | 36.72341
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
Lafayette | Louisiana | United States | -92.01984 | 30.22409
Shreveport | Louisiana | United States | -93.75018 | 32.52515
Benzonia | Michigan | United States | -86.09926 | 44.62139
Cadillac | Michigan | United States | -85.40116 | 44.25195
Interlochen | Michigan | United States | -85.7673 | 44.64472
Saint Clair Shores | Michigan | United States | -82.88881 | 42.49698
Olive Branch | Mississippi | United States | -89.82953 | 34.96176
Springfield | Missouri | United States | -93.29824 | 37.21533
Bozeman | Montana | United States | -111.03856 | 45.67965
Butte | Montana | United States | -112.53474 | 46.00382
Fremont | Nebraska | United States | -96.49808 | 41.43333
Hamilton | New Jersey | United States | -74.08125 | 40.20706
Elmira | New York | United States | -76.80773 | 42.0898
Ithaca | New York | United States | -76.49661 | 42.44063
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Canfield | Ohio | United States | -80.76091 | 41.02506
Columbus | Ohio | United States | -82.99879 | 39.96118
Lyndhurst | Ohio | United States | -81.48873 | 41.52005
Edmond | Oklahoma | United States | -97.4781 | 35.65283
Owasso | Oklahoma | United States | -95.85471 | 36.26954
Ashland | Oregon | United States | -122.70948 | 42.19458
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Warminster | Pennsylvania | United States | -75.09962 | 40.20678
Cranston | Rhode Island | United States | -71.43728 | 41.77982
Johnston | Rhode Island | United States | -71.50675 | 41.82186
Greenville | South Carolina | United States | -82.39401 | 34.85262
Greenville | South Carolina | United States | -82.39401 | 34.85262
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Bristol | Tennessee | United States | -82.18874 | 36.59511
Kingsport | Tennessee | United States | -82.56182 | 36.54843
Beaumont | Texas | United States | -94.10185 | 30.08605
Bryan | Texas | United States | -96.36996 | 30.67436
Corpus Christi | Texas | United States | -97.39638 | 27.80058
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Saratoga Springs | Utah | United States | -111.90466 | 40.34912
West Jordan | Utah | United States | -111.9391 | 40.60967
Richmond | Virginia | United States | -77.46026 | 37.55376
Weber City | Virginia | United States | -78.28389 | 37.75514
Bellevue | Washington | United States | -122.20068 | 47.61038
| 0
|
NCT00610935
|
[
3
] | 126
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 1FEMALE
| null |
The purpose of the study is to assess the efficacy, safety and tolerability of Ospemifene 5 mg, 15 mg, and 30 mg in the treatment of VVA in postmenopausal women to find the minimum effective dose below the lowest dose of 30 mg tested earlier in Phase II.
| null |
Atrophy Vaginal Diseases
|
Menopausal symptoms Urogenital atrophy Vulvar and vaginal atrophy in postmenopausal women Vaginal atrophy
| null | 4
|
arm 1: Subjects will self-administer 1 placebo tablet daily (in the morning with food) for 12 weeks arm 2: Subjects will self-administer 1 ospemifene 5 mg tablet daily (in the morning with food) for 12 weeks arm 3: Subjects will self-administer 1 ospemifene 15 mg tablet daily (in the morning with food) for 12 weeks arm 4: Subjects will self-administer 1 ospemifene 30 mg tablet daily (in the morning with food) for 12 weeks
|
[
2,
0,
0,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: 1 tablet per day, orally, in the morning, with food for 12 weeks - from Visit 2 (Randomization, Day 1) to Visit 4 (End of therapy, Week 12). intervention 2: 1 tablet of ospemifene 5 mg (QD), orally, in the morning, with food for 12 weeks - from Visit 2 (Randomization, Day 1) to Visit 4 (End of therapy, Week 12). intervention 3: 1 tablet of ospemifene 15 mg (QD), orally, in the morning, with food for 12 weeks - from Visit 2 (Randomization, Day 1) to Visit 4 (End of therapy, Week 12). intervention 4: 1 tablet of ospemifene 30 mg (QD), orally, in the morning, with food for 12 weeks - from Visit 2 (Randomization, Day 1) to Visit 4 (End of therapy, Week 12).
|
intervention 1: Placebo intervention 2: Ospemifene 5 mg intervention 3: Ospemifene 15 mg intervention 4: Ospemifene 30 mg
| 0
| null | 0
|
NCT00630539
|
[
0
] | 20
|
RANDOMIZED
|
FACTORIAL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| true
|
A total of 20 subjects will participate in this four week, between groups, double-blind, placebo controlled study. Subjects will participate in two experimental sessions separated by approximately one week. Subjects will be randomized to receive either 50 mg cycloserine or placebo combined with cue exposure. Several physiological and subjective outcome measures (e.g., heart rate, blood pressure, galvanic skin response) will be obtained during the sessions. Experimental sessions will last approximately 4.5 hours with follow-up sessions lasting approximately thirty minutes. Our aims are:
1. To examine the effect of cycloserine vs. placebo on extinction of smoking cue reactivity in overnight abstinent smokers. Reactivity to smoking cues will be captured with self-report smoking urges and physiological measures (heart rate, blood pressure, and skin conductance).
We hypothesize that cycloserine, relative to placebo, will facilitate extinction of smoking cue reactivity.
2. To examine the effect of cycloserine vs. placebo when combined with two 4.5 hour laboratory cue exposure training sessions, on smoking behavior in smokers. Smoking behavior will be measured with self-report smoking and saliva cotinine levels.
3. To examine the effect of cycloserine vs. placebo on memory performance in nicotine dependent smokers. Memory performance will be measured with verbal learning, recognition and recall tasks.
4\) To examine the safety and tolerability of cycloserine treatment in smokers. We hypothesize that cycloserine will be well tolerated by smokers.
| null |
Smoking
| null | 2
|
arm 1: 50 mg cycloserine arm 2: Matched placebo
|
[
0,
3
] | 2
|
[
0,
0
] |
intervention 1: 50 mg Cycloserine given in two separate experimental sessions separated by approximately one week. intervention 2: Matched placebo for subjects randomized to placebo arm. Given in two experimental sessions separated by approximately one week.
|
intervention 1: Cycloserine intervention 2: Placebo
| 1
|
West Haven | Connecticut | United States | -72.94705 | 41.27065
| 0
|
NCT00633256
|
|
[
0
] | 57
|
RANDOMIZED
|
CROSSOVER
| 1PREVENTION
| 2DOUBLE
| true
| 0ALL
| false
|
Question #1: Will glycine ameliorate cognitive deficits? Hypothesis #1: Based on positive findings conducted with glycine and milacemide, a glycine prodrug, in schizophrenia and dementia, we expect that glycine will ameliorate cognitive deficits.
Question #2: Will alcoholic patients show enhanced endocrinal effects to glycine? Hypothesis #2: Based on the dose-related effects of glycine in healthy subjects, we expect that glycine will increase the endocrinal response to glycine in alcoholic patients with, supposedly, dysregulated NMDA receptor function.
Question #3: Will D-cycloserine have ethanol-like effects? Hypothesis #3: If inhibition of NMDA receptor function is fundamental to the subjective effects of ethanol, then the NMDA antagonist properties of D-cycloserine should be recognized as ethanol-like (relative to placebo) in recently detoxified alcoholics and healthy subjects.
Question #4: Will D-cycloserine reverse cognitive benefits of glycine? Hypothesis 4: Based on the dose related NMDA antagonist activity of D-cycloserine, we expect that D-cycloserine will compete with the agonist activity of glycine and therefore it will reverse the cognitive benefits of glycine.
Question #5: Will D-cycloserine inhibit endocrinal effects of glycine? Hypothesis #5: If the agonist activity of glycine is necessary to determine endocrine response, then the dose-related NMDA antagonist properties of D-cycloserine should block these effects.
|
The purpose of this study is to investigate the interaction between glycine and D-cycloserine in alcoholic patients and healthy subjects. Preclinical studies have shown that compounds acting at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, such as glycine, may reverse the effects of ethanol on the NMDA receptor function (Rabe et al., 1990). The amino acid glycine is a co-agonist of the NMDA receptor complex (Kemp et al., 1993). It binds to the strychnine-insensitive site and positively modulates the NMDA receptor (Mc Donald et al., 1990). Physiologically, the glycine site is not saturated, and administration of glycine can potentiate NMDA receptor mediated responses. In contrast, D-cycloserine (Hood et al., 1989) is a partial-agonist at the glycine site of the NMDA receptor, with dose-dependent NMDA antagonist properties. The NMDA antagonist activity of D-cycloserine should produce ethanol like-effects that can be reversed by the agonist glycine. This study is intended to evaluate possible contributions of the glycine site to the reduction of cognitive deficits of alcoholism and complements the current work at VA Connecticut Healthcare System on the NMDA antagonists in alcoholic and healthy subjects.
|
Alcohol Dependence
|
Alcohol Dependence, Alcoholism, Glycine, D-Cycloserine
| null | 2
|
arm 1: Alcohol dependent patients will receive 4 interventions arm 2: Healthy subjects will receive 4 interventions
|
[
1,
1
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine. intervention 2: Placebo intervention 3: None intervention 4: None
|
intervention 1: D-Cycloserine PO and Glycine IV intervention 2: Placebo D-Cycloserine PO and placebo Glycine IV intervention 3: Placebo D-Cycloserine PO and Glycine IV intervention 4: D-Cycloserine PO and placebo Glycine IV
| 1
|
West Haven | Connecticut | United States | -72.94705 | 41.27065
| 0
|
NCT00635102
|
[
2
] | 38
|
RANDOMIZED
|
SINGLE_GROUP
| null | 4QUADRUPLE
| true
| 0ALL
| false
|
The product is being tested to see if exposure to light causes toxic reactions on the skin.
| null |
Healthy
|
wound healing phototoxicity Healthy Subjects
| null | 3
|
arm 1: Drug arm 2: Placebo comparator arm 3: Subjects serve as own controls.
|
[
0,
2,
4
] | 2
|
[
0,
0
] |
intervention 1: 20mg under Finn chambers intervention 2: 20mg under Finn chambers
|
intervention 1: Xenaderm intervention 2: Placebo
| 0
| null | 0
|
NCT00644917
|
[
5
] | 23
|
RANDOMIZED
|
CROSSOVER
| 7BASIC_SCIENCE
| 2DOUBLE
| true
| 0ALL
| false
|
A single center, double blind, randomized, placebo controlled, two-treatments, two-period crossover study conducted in adult smokers.
|
The main objective of this study is to use blood oxygen level-dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) in abstinent smokers to directly evaluate the effect of the 4 milligrams (mg) nicotine lozenge on brain activation associated with visual attention. The experimental task featured 3 conditions: 1. a highly demanding cognitive/attention task, 2. a simple cognitive/attention task, and 3. simply look at a '+' symbol. During the experiment these conditions are each presented a number of times in an alternating manner while acquiring images.
|
Smoking
|
nicotine therapy fMRI/EEG replacement
| null | 2
|
arm 1: Nicotine lozenge containing 4 mg of nicotine to be placed in mouth and suck to dissolution. arm 2: Placebo lozenge to be placed in mouth and suck to dissolution.
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Nicotine lozenge containing 4 mg of nicotine intervention 2: Placebo lozenge
|
intervention 1: Nicotine intervention 2: Placebo
| 0
| null | 0
|
NCT00657020
|
[
3
] | 40
|
RANDOMIZED
|
SINGLE_GROUP
| 1PREVENTION
| 2DOUBLE
| true
| 0ALL
| false
|
To characterize features of metabolic syndrome in volunteers. To undertake a randomised trial to determine whether treatment with a statin improves muscle microvascular blood flow.
|
To characterise features of the metabolic syndrome, including body fat, insulin sensitivity, and liver fat together with muscle micorvascular blood flow.
To undertake a randomised controlled trial of atorvastatin 40 mg. o.d for 6 months to determine whether any of the above measures change with treatment.
|
Metabolic Syndrome
|
metabolic syndrome Volunteers recruited from the community
| null | 2
|
arm 1: Active arm atorvastatin 40 mg. o.d. arm 2: Placebo arm dummy pill
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: 40 m.g. o.d. tablets for 6 months intervention 2: Placebo
|
intervention 1: atorvastatin intervention 2: placebo
| 0
| null | 0
|
NCT00666029
|
[
5
] | 114
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| true
| 0ALL
| true
|
The purpose of this study is to evaluate the amount of anxiety and pain felt by children during procedures that require a needle stick after using a topical anesthetic or placebo cream.
|
Pediatric patients frequently receive eutectic mixture of local anesthetics (EMLA) or other anesthetic medications prior to venipuncture. However, the time for the anesthetic to take affect is approximately 60 minutes. Another anesthetic medication besides EMLA is lidocaine 4% topical anesthetic cream (LMX4), which has a shorter acting time (30 minutes) compared to the EMLA, making it a more desirable medication when urgent labs are required. This medication is being evaluated to assess the anxiety and pain associated with venipuncture in 15 minutes versus the approved 30 minutes of pediatric patients treated as an inpatient or outpatient in the local Emergency Department, compared to standard care (no prior treatment).
|
Pain Anxiety
|
pediatric patients pain anxiety topical anesthetic randomized control trial
| null | 2
|
arm 1: This group received topical 4% lidocaine anesthetic cream under occlusive dressing for 15 minutes prior to needle stick. arm 2: This group received matching placebo cream under occlusive dressing for 15 minutes prior to needle stick.
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: A dollop of 4% lidocaine cream was applied under occlusive dressing for 15 mins prior to venipuncture intervention 2: A dollop of matching placebo cream was applied under occlusive dressing for 15 mins prior to venipuncture
|
intervention 1: 4% lidocaine topical anesthetic cream intervention 2: Placebo cream
| 1
|
Allentown | Pennsylvania | United States | -75.49018 | 40.60843
| 0
|
NCT00676364
|
[
5
] | 20
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| false
|
The purpose of this research study is to evaluate the use of Biafine Cream on wounds created by removal of actinic keratosis using cryotherapy in a clinical setting.
|
Subjects were randomized to apply Biafine® to wounds on one forearm and polysporin (standard of care) to wounds on the other. Medications were applied three times a day for 4 weeks to the areas that have been treated with cryotherapy at the baseline visit.
|
Actinic Keratosis
| null | 2
|
arm 1: Subjects were randomized to apply Biafine® to wounds on the left forearm and polysporin (standard of care) to wounds on the right forearm. Medications were applied three times a day for 4 weeks to the areas that have been treated with liquid nitrogen at the baseline visit. arm 2: Subjects were randomized to apply Biafine to wounds on the right forearm and Polysporin to wounds on the left forearm. Medications were applied three times a day for 4 weeks to the areas that have been treated with liquid nitrogen at the baseline visit.
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Apply to wounds 3 times daily for 4 weeks: ingredients: purified water, liquid paraffin, glycol monostearate, stearic acid, propylene glycol, paraffin wax, squalene, avocado oil, trolamine sodium alginate, cetyl palmitate, methylparaben, sorbic acid, propyl paraben and fragrance. intervention 2: over the counter Polysporin ointment 3 times daily for 4 weeks to wounds
|
intervention 1: Biafine intervention 2: Polysporin
| 1
|
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
| 0
|
NCT00695578
|
|
[
2
] | 26
|
RANDOMIZED
|
CROSSOVER
| 6HEALTH_SERVICES_RESEARCH
| 2DOUBLE
| true
| 2MALE
| false
|
The purpose of the study is to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of Humalog (insulin lispro) or Humulin-R (recombinant human insulin) when administered as a single subcutaneous (SC) injection of 20 units (U) with or without coadministration of recombinant human hyaluronidase PH20 (rHuPH20).
The study hypothesizes that the time required to reach maximum insulin concentration (tmax) when insulin is administered with rHuPH20 will be comparable or shorter than the time required without rHuPH20.
| null |
Diabetes Mellitus
|
rHuPH20 Hyaluronidase Insulin
| null | 4
|
arm 1: Humalog first, then Humalog + recombinant human hyaluronidase PH20 (rHuPH20)
A single subcutaneous (SC) injection of 20 units (U) Humalog on Day 1 of the study, followed by a single SC injection of 20 U Humalog + 300 U rHuPH20 after a washout period of at least 6 days arm 2: Humalog + recombinant human hyaluronidase PH20 (rHuPH20) first, then Humalog
A single subcutaneous (SC) injection of 20 units (U) Humalog + 300 U rHuPH20 on Day 1 of the study, followed by a single SC injection of 20 U Humalog after a washout period of at least 6 days arm 3: Humulin-R (recombinant human insulin) first, then Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20)
A single subcutaneous (SC) injection of 20 units (U) Humulin-R on Day 1 of the study, followed by a single SC injection of 20 U Humulin-R + 240 U rHuPH20 after a washout period of at least 6 days arm 4: Humulin-R (recombinant human insulin) + recombinant human hyaluronidase PH20 (rHuPH20) first, then Humulin-R
A single subcutaneous (SC) injection of 20 units (U) Humulin-R + 240 U rHuPH20 on Day 1 of the study, followed by a single SC injection of 20 U Humulin-R after a washout period of at least 6 days
|
[
1,
1,
1,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: None intervention 2: None intervention 3: None
|
intervention 1: Humalog intervention 2: Humulin-R intervention 3: Recombinant human hyaluronidase PH20 (rHuPH20)
| 1
|
San Antonio | Texas | United States | -98.49363 | 29.42412
| 0
|
NCT00705536
|
[
5
] | 25
|
RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 1SINGLE
| true
| 1FEMALE
| false
|
A study to compare the skin irritation potential of two marketed gels for acne treatment, each applied to half of the face of healthy volunteers.
|
At the Baseline Visit, following satisfaction of entry criteria and screening procedures, all subjects will be applying two products on their faces, each on half face. The side of face receiving each product is randomly assigned. One group will use tretinoin facial gel on the left side and adapalene facial gel on the right side of the face daily for two consecutive weeks after washing with study-supplied facial wash. The other group will use the same products, but on opposite sides of the face for two consecutive weeks after washing with the same study-supplied facial wash.
Subjects will return to the study center every weekday morning for evaluation and for the morning application of both study products. Study personnel will monitor application on the weekdays. There will be a daily clinical evaluation of skin irritation by a blinded dermatologist and by subjects. At baseline and at the end of each week subjects will be photographed and have chromometer readings.
|
Acne Vulgaris
|
acne irritation objective sensory methods
| null | 1
|
arm 1: Adapalene facial gel and tretinoin facial gel applied daily for two weeks on opposite sides of the face (in a split-face model)
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: adapalene gel 0.3% topically applied daily in a split-face model for two weeks intervention 2: Tretinoin 0.1% topically applied daily in a split face model for two weeks
|
intervention 1: Adapalene Gel intervention 2: Tretinoin Gel
| 1
|
Broomall | Pennsylvania | United States | -75.35658 | 39.9815
| 0
|
NCT00714714
|
[
3
] | 45
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to assess the efficacy of bortezomib in combination with melphalan and prednisone to achieve complete responses for patients with previously untreated multiple myeloma compared to an historical control group. This trial will also evaluate the safety and toxicity of this regimen as well as evaluate the duration of response of this regimen.
|
Based on the need to improve front-line therapy for patients less likely to undergo transplant, the promising recent in vitro and clinical work on melphalan and bortezomib, we propose a prospective trial with bortezomib added to standard melphalan and prednisone therapy for previously untreated patients with multiple myeloma. Bortezomib 1.3 mg/m2 will be given twice weekly for two weeks and will be added to standard melphalan and prednisone on a 4-week cycle. This three-drug combination will be compared to historical data. We have treated 2 patients with relapsed disease following \>2 prior regimens including high-dose therapy with autologous stem cell support. Each patient received melphalan, prednisone, and bortezomib as described below and both had marked declines in M-protein within 2 cycles. These responses have been sustained for at least 3 months and treatment was well tolerated.
Eligible patients will have histologically confirmed Multiple Myeloma (MM) having not received prior systemic therapy given with the intent to induce remission, be adults, have life expectancy greater than 3 months, adequate performance status, organ and marrow function as described in the protocol, not be pregnant, HIV positive, or taking any investigational agents. Patients must not have history of allergic reactions to study drugs or similar compounds or have uncontrolled intercurrent illness or social situation that would limit compliance with study requirements. Patients must also have the ability to give informed consent.
Study drugs will be administered on an inpatient or outpatient basis. Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle. Supportive care measures such as antiemetics and growth factors may be given.
|
Multiple Myeloma
|
Multiple myeloma
| null | 1
|
arm 1: Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle.
|
[
0
] | 3
|
[
0,
0,
0
] |
intervention 1: None intervention 2: None intervention 3: None
|
intervention 1: Bortezomib intervention 2: Melphalan intervention 3: Prednisone
| 1
|
Durham | North Carolina | United States | -78.89862 | 35.99403
| 0
|
NCT00734149
|
[
5
] | 4
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 1FEMALE
| null |
Women with Systemic Lupus Erythematosus (SLE) are prone to cardiovascular disease. Early detection of improvement of endothelial function with simvastatin could be a clue for future intervention trials.
| null |
Systemic Lupus Erythematosus
| null | 2
|
arm 1: Arm 1: Drug arm 2: Arm 2: Placebo
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: simvastatin 20mg daily at nights for 12 weeks. Tablets intervention 2: placebo daily at nights for 12 weeks. Tablets
|
intervention 1: simvastatin intervention 2: Comparator: Placebo
| 0
| null | 0
|
NCT00739050
|
|
[
3
] | 27
|
RANDOMIZED
|
CROSSOVER
| 7BASIC_SCIENCE
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of the study is to compare frequency and content of reflux episodes in patients with gastroesophageal reflux disease.
| null |
Reflux Episodes
|
GERD transient lower esophageal sphincter relaxations (TLESRs) reflux
| null | 2
|
arm 1: AZD3355 arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 65 mg capsules, oral, 3 single doses intervention 2: capsules, oral, 3 single doses
|
intervention 1: AZD3355 intervention 2: Placebo
| 0
| null | 0
|
NCT00743444
|
[
5
] | 30
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 1SINGLE
| true
| 0ALL
| false
|
Keloids are thought to result from derailments in the typical wound healing process following cutaneous injury. Current treatment options for keloids include intralesional corticosteroids, silicone gel sheeting, compression, surgery and adjuvants to surgery, including radiation and cryotherapy.
0.5% hydrocortisone, silicone, vitamin E lotion (HSE) and onion extract gel (OE) are widely used over-the-counter medications for the treatment of keloids and hypertrophic scars. However, their efficacy and safety have not been compared in a blinded, placebo-controlled, prospective fashion. This study is being undertaken to determine the efficacy and safety of HSE versus OE versus placebo (Cetearyl alcohol; CEA) in subjects with hypertrophic scars and keloids.
This is an investigator-blinded study, which means that the doctor evaluating you will not know if you are receiving the study medication or not. Another doctor will be supplying you with the medication and discussing any problems that you may have with the medication.
You will be assigned to one of the three treatment groups: HSE, OE, or CEA. The group will be assigned by chance and you will have two in three chances of receiving treatment with a study medication, HSE or OE. The no treatment group will receive CEA, a bland lotion, containing no active ingredients such as steroids, silicone, vitamin E, or onion extract.
|
This study will last up to 16 weeks, with a total of 5 visits to the clinic (Baseline visit, Week 4, 8, 12, and 16 ), excluding the Screening Visit.
Screening Visit/Baseline Visit:
Patients will read and be explained the informed consent. Patients who agree to participate will sign the informed consent and a copy will be given to them. Medical history and exclusion/inclusion criteria will be reviewed; if a patient qualifies he/she will be assigned a randomization number for the treatment.
At the baseline visit, medical history and exclusion/inclusion criteria since the screening visit will be reviewed. Patients randomized to the HSE group will receive one tube and apply the first application to the keloid/hypertrophic scar during the baseline visit. Patients randomized to the OE group will be given a tube of OE gel and will apply the first application to the keloid/hypertrophic scar. Patients in the placebo group will be given a bottle of CEA lotion, the placebo medication, and will apply the first application to the keloid/hypertrophic scar. The medications will be given by the unblinded investigator and the blinded investigator will be evaluating the patients. Photographs of the patient's keloid/hypertrophic scar will be taken, and the keloid/hypertrophic scar will be measured/assessed according to Methods of Study Lesion Assessment (below). A urine pregnancy test will be obtained for all women of child-bearing potential.
Week 4, 8, 12, and 16 Visit:
Patients will be asked about side effects since last visit. Photographs of the patient's keloid/hypertrophic scar will be taken and the keloid/hypertrophic scar will be measured/assessed according to Methods of Study Lesion Assessment (below). A urine pregnancy test will be obtained at for all women of child-bearing potential.
Methods of Study Lesion Assessment
A. Volume B. Linear dimensions
Investigator's Assessments w/ Visual Analog Scale (VAS):
C. Cosmetic assessment D. Induration (hardness) \[compared to standardized hard discs with numerical ranking of increased induration\] E. Erythema (redness) F. Pigmentary alteration
Patient's Assessments w/ VAS:
G. Cosmetic assessment H. Pain I. Tenderness J. Pruritus (itching) K. Patient satisfaction
L. Digital photographs
|
Keloid Hypertrophic Scar Cicatrix, Hypertrophic
|
Keloid Hypertrophic scar Hydrocortisone, silicone, vitamin E lotion HSE Onion extract gel OE Cetearyl alcohol lotion CEA
| null | 3
|
arm 1: 0.5% hydrocortisone, silicone, vitamin E lotion arm 2: Onion extract gel arm 3: Cetearyl alcohol lotion
|
[
0,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: 0.5% hydrocortisone, silicone, vitamin E lotion will be applied topically to cover the selected scar twice daily for 16 weeks. The lesion will be cleansed with soap and water and dried thoroughly. The medication will be applied with a brush and allow it to dry for one minute before contact with clothing. intervention 2: Onion extract gel is applied and massaged into the selected scar 3 to 4 times daily according to product instructions for 16 weeks. intervention 3: Placebo is cetearyl alcohol lotion with no steroids, silicone, vitamin E, or onion extract and will be applied 2 times a day to the lesion.
|
intervention 1: 0.5% hydrocortisone, silicone, vitamin E lotion intervention 2: Onion extract gel intervention 3: Cetearyl alcohol lotion
| 1
|
Miami | Florida | United States | -80.19366 | 25.77427
| 0
|
NCT00754247
|
[
3
] | 10
|
RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The purpose of this study is to provide decitabine to patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) who have completed participation per protocol in the DACO-018 study.
|
The objectives of this trial are:
* To generate additional information about the overall safety profile,
* To generate safety information of hepatically or renally impaired patients, as appropriate, and
* To generate safety information when patients are also taking concomitant medications and/or therapies without trial restrictions when decitabine is administered at a dose of 20 mg/m² over a 1-hour intravenous infusion for 5 consecutive days every 4 weeks in patients with MDS or AML (≥ 30% blasts).
The purpose of this open-label, expanded-access trial is to provide decitabine to patients with AML or MDS who have completed participation per protocol in the DACO-018 study and for whom continuation of treatment with decitabine is indicated, per the opinion of the investigator. In order to continue treatment with decitabine, at a minimum, there must be no disease progression while the patient was participating in the DACO-018 trial and during the period after the patient discontinued from the DACO-018 study and before entering this trial. Patients must enroll in this trial within 8 weeks of discontinuing from the DACO-018 study and not have received any other chemotherapy for their disease during this interim period.
Decitabine will be administered at a dose of 20 mg/m² over a 1-hour intravenous infusion for 5 consecutive days every 4 weeks.
|
Acute Myelogenous Leukemia Myelodysplastic Syndrome
|
Acute Myelogenous Leukemia Myelodysplastic Syndrome Dacogen Decitabine
| null | 1
|
arm 1: Decitabine will be administered at a dose of 20 mg/m² over a 1-hour intravenous infusion for 5 consecutive days every 4 weeks.
|
[
0
] | 1
|
[
0
] |
intervention 1: Decitabine is administered at a dose of 20 mg/m² over a 1-hour intravenous infusion for 5 consecutive days every 4 weeks in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; ≥ 30% blasts).
|
intervention 1: Decitabine
| 1
|
St Louis | Missouri | United States | -90.19789 | 38.62727
| 0
|
NCT00760084
|
[
3,
4
] | 17
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| true
|
This study is designed to compare the efficacy and safety of higher doses of Rituxan with a regimen combining standard doses of Rituxan + CVP in patients with chronic ITP who did not respond to or relapsed after standard doses of Rituxan. Patients eligible for this protocol will be stratified into two subgroups according to their initial response to Rituxan.
|
The rationale for using chemotherapy in combination with Rituximab:
Since Rituximab is an anti-B cell therapy, in order to improve the rate of durable responses beyond the 32% (18 of 57) seen with Rituximab alone, it seems appropriate to combine it with a therapy that would also target T cells and/or macrophages. Our plan is therefore to combine Rituximab with a standard chemotherapy (CHOP)-like regimen as previously successfully tested in patients with follicular or diffuse large-B-cell lymphomas 13-15. The "CHOP" chemotherapy regimen is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (or prednisolone) that has been considered the "gold standard" for treating lymphomas for more than 20 years.
This combination of medications was used in a Hodgkin's patient with refractory ITP and became the template for developing the use of cyclophosphamide, vincristine, and prednisone for ITP as initially reported in 1993. Since reports on doxorubicin efficacy by itself in ITP are only anecdotal 16 and this drug has a potential cardiac toxicity, a CVP regimen (namely a combination of cyclophosphamide + vincristine and prednisone) should be similar in efficacy to CHOP in patients with ITP and have less toxicity. Indeed, the efficacy of such a chemotherapy12 as well as pulses cyclophosphamide therapy alone11 have already been reported in patients with refractory ITP.
Since attempts to increase the efficacy of CHOP by increasing the doses or adding other cytotoxic drugs have failed, a new therapeutic strategy combining CHOP with Rituxan has been successfully developed in the last few years in various types of B-cell lymphomas 13-15. In elderly patients with diffuse large-B-cell lymphoma, the addition of Rituxan to standard CHOP chemotherapy significantly reduced the risk of treatment failure and deaths without increasing toxicity 13. Moreover, in autoimmune disorders, there are few preliminary data suggesting that Rituxan and cyclophopshamide given in combination could be effective and relatively safe in patients with active rheumatoid arthritis 17.
Therefore, the rationale for combining Rituxan with a CHOP-like regimen in ITP is threefold:
Both Rituxan and CHOP or IV cyclophosphamide have efficacy in ITP The treatments have different mechanisms of action. They have minimally-overlapping toxicities.
The rationale for using higher doses of Rituxan in patients who had no response, or relapsed, to the drug at the standard dose:
The standard dose of Rituxan is arbitrary in that one dose of Rituxan has been used in the great majority of the clinical trials and virtually all patients since the FDA approval of Rituxan in 1997: 375 mg/m2 weekly x 4 weeks. To date, because Rituxan is a monoclonal antibody rather than a chemotherapeutic agent, it was recognized that a true maximum tolerated dose (MTD) might not be achieved. Among other factors that could influence the tolerance of higher doses of Rituxan are the rate of CD20 surface expression and the serum level of the antibody11. Limited trials of higher doses have been pursued in CLL18 (up to 2,250 mg/m2 per dose), but not in other types of lymphoma or in autoimmune diseases. In CLL, mild to severe toxicity was exclusively observed with the first dose (375 mg/m2) while toxicity on subsequent higher doses was minimal. In ITP, some of the few patients that have been retreated responded better to the second dose of rituximab than to the initial treatment (although the opposite is also true). Full depletion of the marrow and especially the lymph nodes is not achieved by the current dose regimen and B cells return in substantial number to the peripheral blood within 3-6 months in patients with ITP treated at the conventional dose. We therefore anticipate that in ITP patients who relapsed or did not respond after a previous course of rituximab, doubling the dose could lead to a deeper and more prolonged B cell depletion and to a better increase in the platelet count without enhancing toxicity.
|
Immune Thrombocytopenic Purpura
|
Pts w/ Chronic ITP who have fail/relap after Rituxan rx
| null | 2
|
arm 1: 'Standard Dose of Rituximab administered with C, V, P (CVP)'
Interventions: Rituximab will be administered as an IV infusion at the standard dose of 375 mg/m2 for 4 doses at standard rates and use of premedication. The schedule will be to give the first rituximab infusion 5 days (± 3 days) prior to first administration of CVP, and the following 3 infusions will be given on the same day as the 3 cycles of C, V, P. On those days, the IV Cyclophosphamide and Vincristine will be given first so that the administration of fluids with the rituximab can be used as post-cyclophosphamide hydration, Cyclophosphamide dosing will be 750mg/m2 (maximum 2000mg), vincristine 1.4 mg/m2 (up to 1.6 mg), prednisone 100mg po daily for 5 days. arm 2: In this arm, Rituximab will be administered at a dose of 750 mg/m2 once a week x 4 consecutive weeks (4 infusions in total). We will perform EKG monitor tracings before, during and after Rituxan infusions. This will be a single-lead tracing that will allow us to look at the Q-T interval.
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: 'Rituximab, Cyclophosphamide, Vincristine, Prednisone interventions are as follows: Rituximab will be administered as an IV infusion at the standard dose of 375 mg/m2 for 4 doses. However, the schedule of the infusions will be different than the usual one: Rather than administrating the 4 doses once weekly, the first infusion will be given 5 days (± 3 days) prior to the first infusions of C and V and oral P, and the following 3 rituximab infusions will be given on the same day as the 3 cycles of C, V, and P. intervention 2: rituximab 750mg/m2 (twice the standard dose of 375mg/m2) will be given weekly for 4 weeks. Premedication and infusion rate escalation will be exactly the same as for standard dose rituximab. The additional dose will thus run at 400ml/hr.
|
intervention 1: Rituxan, Cyclophosphamide, Vincristine, Prednisone intervention 2: Higher Dose of Rituximab
| 1
|
New York | New York | United States | -74.00597 | 40.71427
| 0
|
NCT00774202
|
[
0
] | 89
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| true
| 1FEMALE
| true
|
The aim of this study is to estimate the efficacy of intracervical versus paracervical block on pain experienced during first trimester suction curettage without the use of preoperative cervical ripening. Because of the theoretical improved reliability of stromal block, the investigators hypothesize that intracervical block would produce lower pain scores than paracervical block at the time of cervical dilation.
| null |
Abortion, Induced Pain
|
Local anesthesia Paracervical Intracervical Abortion Pain Local anesthesia for elective first trimester abortion
| null | 2
|
arm 1: None arm 2: None
|
[
1,
0
] | 3
|
[
3,
3,
0
] |
intervention 1: The paracervical block was administered using 20 ml of buffered lidocaine and a 5/8 inch, 25-gauge needle. A small amount was injected at the tenaculum site, and the remainder equally distributed around the cervicovaginal junction at 3, 5, 7, and 9 o'clock. The depth was standardized at 5/8 inch by inserting the needle to the hub. intervention 2: The intracervical block was administered using 20 ml of buffered lidocaine and a 1-1/2 inch, 20 gauge needle in order to overcome the increased resistance to injection caused by the cervical stroma. A small amount was injected at the tenaculum site, and the remainder into the cervical stroma at 12, 3, 6, and 9 o'clock, at a depth of 1-1/2 inch by inserting the needle to the hub. intervention 3: The buffered lidocaine preparation for both block techniques consisted of 50 mL of 1% lidocaine, 5 units of vasopressin, and 5 mL 8% sodium bicarbonate.
|
intervention 1: Paracervical block intervention 2: Intracervical intervention 3: Buffered Lidocaine, vasopressin, sodium bicarbonate
| 1
|
San Diego | California | United States | -117.16472 | 32.71571
| 0
|
NCT00816751
|
[
0
] | 40
|
RANDOMIZED
|
PARALLEL
| 4SUPPORTIVE_CARE
| 0NONE
| true
| 1FEMALE
| false
|
The purpose of this study to assess the safety of the etonogestrel-releasing subdermal implant (Implanon) inserted during the immediate puerperium of healthy women.
|
Many contraceptive methods are currently available. However, about 50% of all pregnancies in the world are not planned, most of them occurring in developing countries. Long-lasting reversible contraceptives such as the etonogestrel implant represent an option for the reduction of unwanted pregnancies, especially among patients at risk for a short intergestational period. In addition to preventing an undesired pregnancy, these methods have an impact on the reduction of the maternal-fetal morbidity-mortality known to be associated with these short intervals, also minimizing the malnutrition and the cycle of poverty caused by multiparity.
On the basis of inclusion and exclusion criteria, we will selected 40 puerperae aged 18 to 35 years at the Low Risk Prenatal Care Program of the University Hospital of Ribeirão Preto, University of São Paulo (HC-FMRP). The subjects will be randomized to two types of treatment (etonogestrel-releasing implant to be inserted 24 to 48 hours after delivery or 150 mg medroxyprogesterone administered every three months starting 6 weeks after delivery). Blood samples (40 mL) will be collected in a single procedure from these patients and stored for later determination of multiple hemostatic and metabolic variables at 24-48 hours and at 6 and 12 weeks after delivery. Data on maternal and neonatal clinical parameter will be also collected.
|
Breastfeeding Contraception
|
Adverse Effects Etonogestrel Postpartum period Contraception Hemostasis Metabolism
| null | 2
|
arm 1: Etonogestrel releasing contraceptive implant (Implanon®, NV Organon, Oss, The Netherlands) inserted 24-48 h after delivery. It is compounded by 68mg of etonogestrel, 3years of duration. arm 2: At the 6th week postpartum, this group received intramuscular 150 mg of depot medroxyprogesterone acetate (Contracept®, EMS Sigma Pharma, Hortolandia, Brazil).
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Etonogestrel-releasing subdermal implant (Implanon) inserted during the immediate postpartum period (from 24 to 48 hours postpartum) intervention 2: 150 mg medroxyprogesterone administered I.M. every three months starting 6 weeks after delivery
|
intervention 1: etonogestrel implant intervention 2: depot medroxyprogesterone acetate
| 1
|
Ribeirão Preto | São Paulo | Brazil | -47.81028 | -21.1775
| 0
|
NCT00828542
|
[
0
] | 34
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The investigators' primary specific aims are to demonstrate that:
1. Pediatric patients with normal airways, undergoing elective surgical procedures, can be successfully intubated when deeply sedated, without the use of muscle relaxants using the Shikani Optical Stylet.
2. Shikani intubation of pediatric patients is equally effective in children that are deeply sedated or paralyzed as evidenced by a non-significant difference in:
* Time to intubation (defined as no more than a 30 second time difference between the two groups);
* Incidence of adverse events.
| null |
Intubation,Endotracheal
|
Pediatric
| null | 2
|
arm 1: Normal saline volume calculated to be equal to the volume of cisatracurium 0.2mg/kg arm 2: Subjects in this arm will be given Cisatracurium 0.2mg/kg IV dose one time prior to intubation.
|
[
2,
1
] | 2
|
[
0,
0
] |
intervention 1: One intravenous dose: 0.2mg/kg/dose intervention 2: One Intravenous dose
|
intervention 1: Cisatracurium intervention 2: Normal saline
| 1
|
San Diego | California | United States | -117.16472 | 32.71571
| 0
|
NCT00912990
|
[
2
] | 54
|
RANDOMIZED
|
CROSSOVER
| 7BASIC_SCIENCE
| 0NONE
| true
| 0ALL
| false
|
This study will evaluate the pharmacokinetic linearity of a single 35 mg fenofibric acid dose and demonstrate the bioequivalence of three 35 mg fenofibric acid tablets (105 mg total single dose) to a single 105 mg fenofibric acid tablet in healthy adult volunteers when each dose is administered under fasted conditions. Safety and tolerability of these regimens will also be evaluated.
|
This study will evaluate the pharmacokinetic linearity of a single 35 mg fenofibric acid dose and demonstrate the bioequivalence of three 35 mg fenofibric acid tablets (105 mg total single dose) to a single 105 mg fenofibric acid tablet in healthy adult volunteers when each dose is administered under fasted conditions. Fifty-four healthy, non-smoking, non-obese, 18-45 year old, male and female volunteers will be randomly assigned in a crossover fashion to receive each of three fenofibric acid dosing regimens in sequence with a 7 day washout period between dosing periods. On the morning of the first day of each dosing period, after an overnight fast of at least 10 hours, subjects will receive single doses of fenofibric acid (1 x 35 mg tablet), fenofibric acid (3 x 35 mg tablets - 105 mg total dose), or fenofibric acid (1 x 105 mg tablet). Fasting will continue for 4 hours after dose administration. Blood samples will be drawn from all participants prior to dosing and for 72 hours post-dose, at times sufficient to adequately define fenofibric acid pharmacokinetics. Subjects will be monitored throughout their participation for adverse reactions to the study drug and/or procedures. Seated blood pressure and pulse will be measured prior to each dose and approximately 2 hours after each dose to coincide with peak plasma concentrations. All adverse experiences, whether elicited by query, spontaneously reported, or observed by clinic staff, will be documented in the subject's case report form.
|
Healthy
|
healthy pharmacokinetics therapeutic equivalency fenofibric acid
| null | 3
|
arm 1: 1 x 35 mg tablet administered after an overnight fast of at least 10 hours arm 2: 3 x 35 mg tablets administered after an overnight fast of at least 10 hours arm 3: 1 x 105 mg tablet administered after an overnight fast of at least 10 hours
|
[
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: 1 x 35 mg tablet administered after an overnight fast of at least 10 hours intervention 2: 3 x 35 mg tablets administered after an overnight fast of at least 10 hours intervention 3: 105 mg tablet administered after an overnight fast of at least 10 hours
|
intervention 1: Fenofibric Acid 35 mg Tablet intervention 2: Fenofibric Acid 35 mg Tablet intervention 3: Fenofibric Acid 105 mg Tablet
| 0
| null | 0
|
NCT00961259
|
[
5
] | 30
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
The purpose of this study is:
* To identify the common factor for L5 prevalence in patients with Metabolic Syndrome.
* To determine whether Ezetimibe, Simvastatin, and Vytorin can correct the L5- promoting factor and reduce L5 in Metabolic Syndrome patients.
|
Epidemiological evidence indicates that metabolic syndrome (MS) is a strong predisposing condition for atherosclerosis. Elevation of plasma low-density lipoprotein (LDL) cholesterol(LDL-C) concentration is the most important risk factor for atherosclerosis; however, LDL-C elevation is not a criterion for metabolic syndrome, raising the question of LDL's role in the syndrome's association with atherosclerosis. L5, a highly electronegative and mildly oxidized LDL subfraction that we recently isolated from hypercholesterolemic human plasma, may provide a key to answering this question. In cultured vascular endothelial cells (EC), L5 inhibits proliferation and induces apoptosis and monocyte-EC adhesion. In our preliminary studies, L5 could also be detected in patients with MS without elevated LDL-C. Because other LDL subfractions were harmless to EC, the presence of MS-L5 prompted us to hypothesize that the atherogenic role of LDL is not solely determined by plasma LDL-C concentration, but more importantly, by its composition. The proposed study is designed to test this hypothesis. The first question we will address is what lipid factor determines the prevalence of L5 in MS.
Subsequently, we will examine whether treatment with selected medicines can effectively reduce L5 in MS patients by correcting the factor favorable for L5 formation.
We are in the process of identifying the active components of L5 to fully characterize the atherogenic role of L5 in MS,. In the current proposal, we focus our interest on the efficacy of Ezetimibe, Simvastatin, and Vytorin in reducing L5 from the plasma of MS patients.
|
Metabolic Syndrome
|
Metabolic Syndrome LDL subfraction L5 The reduction of LDL in patients with Metabolic Syndrome The prevalence of L5 in patients with Metabolic Syndrome The reduction of L5 in patients with Metabolic Syndrome
| null | 4
|
arm 1: Randomly chosen participants will receive ezetimibe 10mg daily for 3 months. arm 2: Randomly chosen participants will receive Simvastatin 20mg daily for 3 months. arm 3: Randomly chosen participants will receive Vytorin 20/10mg daily for 3 months. arm 4: Randomly chosen participants will receive Placebo tab 1 daily for 3 months.
|
[
1,
1,
1,
2
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Simvastatin 20mg daily for 3 months. intervention 2: Vytorin 20/10mg daily for 3 months. intervention 3: Placebo one tablet daily times 3 months. intervention 4: Ezetimibe 10mg daily for 3 months.
|
intervention 1: Simvastatin intervention 2: Vytorin intervention 3: Placebo intervention 4: Ezetimibe
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00988364
|
[
5
] | 162
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
The objectives of the study are to evaluate the analgesic and hypnotic efficacy of naproxen sodium and diphenhydramine combination when compared to naproxen sodium, diphenhydramine, and an ibuprofen and diphenhydramine combination
| null |
Sleep
|
Naproxen sodium Diphenhydramine Drugs, Investigational
| null | 6
|
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
|
[
0,
1,
0,
1,
1,
1
] | 6
|
[
0,
0,
0,
0,
0,
0
] |
intervention 1: Participants received 2 tablets of Naproxen Sodium 220 mg and 2 tablets of Diphenhydramine hydrochloride (DPH) 25 mg, single dose, orally. intervention 2: Participants received 2 tablets of Naproxen Sodium 220mg and 2 tablets of placebo, single dose, orally. intervention 3: One dose of naproxen sodium 220 mg plus diphenhydramine 50 mg intervention 4: Participants received 1 tablet of Naproxen Sodium 220 mg and 3 tablets of placebo, single dose, orally. intervention 5: Participants received 2 tablets of Diphenhydramine hydrochloride (DPH) 25 mg and 2 tablets of placebo, single dose, orally. intervention 6: Participants received 2 tablets of Advil PM (ibuprofen 200 mg and diphenhydramine citrate 38 mg) and 2 tablets of Placebo, single dose, orally.
|
intervention 1: Naproxen Sodium 440 mg (BAYH6689) / DPH 50mg intervention 2: Naproxen Sodium 440 mg (BAYH6689) intervention 3: Naproxen Sodium 220 mg (BAYH6689) / DPH 50mg intervention 4: Naproxen Sodium 220 mg (BAYH6689) intervention 5: DPH 50mg intervention 6: Ibuprofen 400 mg / Diphenhydramine citrate 76 mg
| 1
|
Salt Lake City | Utah | United States | -111.89105 | 40.76078
| 0
|
NCT01118273
|
[
4
] | 301
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 1SINGLE
| false
| 0ALL
| null |
The purpose of this study is to determine whether hydration with sodium bicarbonate is superior to hydration with saline to prevent contrast-induced nephropathy.
| null |
Renal Failure
|
contras-induced nephropathy
| null | 2
|
arm 1: hydration with sodium bicarbonate arm 2: hydration with saline 1ml/Kg/h for 6 hours
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: hydration with sodium bicarbonate 1ml/Kg/h for 6 hours intervention 2: hydration with saline 1ml/Kg/h for 6 hours
|
intervention 1: sodium bicarbonate intervention 2: saline
| 1
|
Porto Alegre | Rio Grande do Sul | Brazil | -51.23019 | -30.03283
| 0
|
NCT01172353
|
[
4
] | 332
| null | null | null | null | null | 0ALL
| null |
To investigate that the efficacy of 3% DE-089 ophthalmic solution (one drop at a time, 6 times daily, 4 weeks topical administration), in comparison to 0.1% sodium hyaluronate ophthalmic solution (0.1% HA) (one drop at a time, 6 times daily, 4 weeks topical administration), is at least non-inferior in the change in fluorescein staining score, and is superior in the change in Rose bengal score, in a multicenter, double-masked, parallel-group comparison study. Safety profile will likewise be compared.
| null |
Dry Eye
| null | 2
|
arm 1: None arm 2: None
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: 3% DE-089 ophthalmic solution intervention 2: 0.1% sodium hyaluronate ophthalmic solution
| 1
|
Osaka | Osaka | Japan | 135.50107 | 34.69379
| 0
|
NCT01240382
|
|
[
3
] | 123
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| true
| 1FEMALE
| false
|
Evaluate the adequacy of ovulation suppression, cycle control, and safety of three transdermal contraceptive delivery systems (TCDSs).
|
The primary objective was to evaluate the adequacy of ovulation suppression, cycle control, and safety of three transdermal contraceptive delivery systems (TCDSs) containing 2 different doses of levonorgestrel (LNG) and 3 different doses of ethinyl estradiol (EE) during 3 consecutive cycles of administration of each treatment.
|
Ovulation Suppression
|
contraception pregnancy prevention
| null | 3
|
arm 1: Drug intervention with levonorgestrel and ethinyl estradiol : AG200-15 a transdermal contraceptive system containing 2.60 mg of levonorgestrel and 2.30 mg of ethinyl estradiol. arm 2: Drug intervention with levonorgestrel and ethinyl estradiol: AG200 a transdermal contraceptive system containing 2.17 mg of levonorgestrel and 1.92 of ethinyl estradiol. arm 3: Drug intervention with levonorgestrel and ethinyl estradiol: AG200LE a transdermal contraceptive system containing 2.17 mg of levonorgestrel and 1.28 mg of ethinyl estradiol.
|
[
0,
0,
0
] | 1
|
[
0
] |
intervention 1: pregnancy prevention
|
intervention 1: levonorgestrel and ethinyl estradiol
| 11
|
Tucson | Arizona | United States | -110.92648 | 32.22174
San Diego | California | United States | -117.16472 | 32.71571
Denver | Colorado | United States | -104.9847 | 39.73915
Pembroke Pines | Florida | United States | -80.22394 | 26.00315
Tampa | Florida | United States | -82.45843 | 27.94752
Sandy Springs | Georgia | United States | -84.37854 | 33.92427
Cary | North Carolina | United States | -78.78112 | 35.79154
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Jenkintown | Pennsylvania | United States | -75.12517 | 40.09594
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Bristol | Tennessee | United States | -82.18874 | 36.59511
| 0
|
NCT01250210
|
[
2
] | 18
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| true
|
This Phase I/IIa, multi-center, randomized, placebo-controlled, single-blinded dose-escalation study evaluated TNX-832 (also referred to as ALT-836 and Sunol cH36) in subjects with suspected or proven bacteria-induced ALI/ARDS. Up to five cohorts of at least six subjects each were originally planned. Subjects were to be randomized in a 5:1 ratio to receive TNX-832 or placebo,respectively, administered as a single bolus infusion over 15 minutes. Three cohorts of subjects were enrolled to the study and safety and pharmacokinetics of the study treatment were evaluated.
|
Tissue factor (TF) is a transmembrane glycoprotein that acts as the principal initiator of the extrinsic coagulation pathway. TF is a key mediator between the immune system and coagulation and is the principal activator of coagulation. The TF-FVIIa complex activates FX and FIX, resulting in the cleavage of prothrombin to thrombin. Normally, localized activation of the coagulation cascade associated with inflammatory responses plays a role in controlling the spread of infectious agents; however, aberrant TF expression often leads to serious thrombotic disorders. TF-dependent thrombosis has been associated with many diseases including septic shock, coronary artery disease (CAD), cancer, and many inflammatory and autoimmune disorders such as lupus, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are forms of acute respiratory failure characterized by diffuse pulmonary infiltrates, pulmonary hypertension, refractory hypoxemia, loss of pulmonary compliance and normal hydrostatic pressures. ALI and ARDS commonly occur in patients with acute catastrophic events such as sepsis, trauma and severe pulmonary infections. The incidence of ALI and ARDS is extremely high in patients with sepsis. By blocking the initiating events of extrinsic coagulation activation, their effects on pro-inflammatory events in the lungs and disordered fibrin deposition may be corrected and the evolution of severe structural and functional injury may be averted during ALI/ARDS. TNX-832 (formerly known as Sunol-cH36), directed against human TF, which can block the pathological complications of TF-dependent thrombus formation. The blockage by TNX-832 of initiating events in the extrinsic coagulation pathway may attenuate the effects on pro-inflammatory events in ALI/ARDS patients, thereby averting or decreasing disordered fibrin deposition and averting the evolution of severe structural and functional injury.
|
Sepsis Acute Lung Injury Acute Respiratory Distress Syndrome
|
Sepsis Acute Lung Injury Acute Respiratory Distress Syndrome ALI/ARDS Lung Disease
|
Prot_SAP_000.pdf:
CONFIDENTIAL
The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-
832 (Sunol-cH36) in Subjects with Acute Lung Injury/Acute
Respiratory Distress Syndrome
TNX-832
Active Ingredient: TNX-832 (Sunol c-H36)
Indication: Acute Lung Injury/Acute Respiratory Distress Syndrome
Study TNX-832.201
Phase I/IIa
Study Initiation Date: December 16, 2004
Date of Early Termination: July 26, 2006
Abbreviated Clinical Study Report
Prepared for Genentech, Inc.
by XTrials Research Services
265 Davidson Ave, Suite 202
Somerset, NJ 08873
Report Issue Date: 11 February, 2008
Sponsor Signatory:
Alex Bajamonde
Director, DATA Group, Genentech, Inc.
Medical Director:
Sean Bohen, M.D., Genentech, Inc.
This study was performed in compliance with good clinical practice (GCP), including the
archiving of essential documents.
Page 1 of 3638
Page 2 of 3638
Page 3 of 3638
Page 4 of 3638
CONFIDENTIAL
February 11, 2008
5
2. Synopsis
Sponsor Name:
Study Drug:
Active Ingredient:
Genentech
TNX-832
TNX-832 (Sunol-cH36)
Title: The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome
Investigators/Study Centers: This study was conducted at 12 sites in the United States
and 5 sites in Canada.
Publications: None
Study Period: 16 Dec 2004 to 30 July 2006
Phase of development: I/IIa
Objectives: The objectives of this study were:
x To evaluate the safety and pharmacokinetics of six dose levels of TNX-832
(0.06 mg/kg, 0.08 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg) in
subjects with suspected or proven bacteria-induced ALI/ARDS.
x To evaluate the pharmacodynamic effects of six dose levels of TNX-832
(0.06 mg/kg, 0.08 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg) in
subjects with suspected or proven bacteria-induced ALI/ARDS.
Methodology: This multi-center, randomized, placebo-controlled, single-blinded
dose-escalation study was to evaluate TNX-832 in subjects with suspected or proven
bacteria-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).
Five cohorts of at least six subjects each were originally planned. Subjects were to be
randomized in a 5:1 ratio to receive TNX-832 or placebo, respectively, administered as
a single bolus infusion over 15 minutes. In November, 2005, a Data Safety Monitoring
Board (DSMB) review of adverse events in the 0.1 mg/kg in led to an observation of
probably-related hematuria in all subjects who received TNX-832 at 0.1 mg/kg. This
review required the studying of TNX-832 at a lower dose cohort than previously
planned. One additional cohort (0.08 mg/kg) of at least 6 subjects was planned.
Additionally, the DSMB recommended administering study drug through a slow IV
infusion (over 2 hours; 50 cc/hr). In September, 2006, upon a subsequent DSMB review
of adverse events in the 0.08 mg/kg dose group, a decision was made to prematurely
discontinue the study.
Subject Population: Eligible subjects were 18 years of age or older with a suspected or
proven bacterial infection. Subjects were also required to: 1). Have a diagnosis of acute
lung injury/acute respiratory distress syndrome ALI/ARDS; 2). be receiving positive
pressure ventilation through an endotracheal tube; and 3). provide signed informed
consent, authorization in accordance with the Health Inisurance Portability
Accountability Act of 1996 (HIPAA) and agree to comply with all protocol-specified
procedures and evaluations.
Page 5 of 3638
CONFIDENTIAL
February 11, 2008
6
Sponsor Name:
Study Drug:
Active Ingredient:
Genentech
TNX-832
TNX-832 (Sunol-cH36)
Title: The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome
Study Medication: Subjects were to be randomized in a 5:1 ratio to receive TNX-832 or
placebo, respectively, administered as a single bolus infusion over 15 minutes. The
TNX-832 dose for each cohort dosed was:
x Cohort 1:
0.06 mg/kg TNX-832
x Cohort 2:
0.1 mg/kg TNX-832
x Cohort 3:
0.08 mg/kg TNX-832
The original planned dose in Cohort 3 was .2 mg/kg. This was lowered to 0.08 mg/kg
following a recommendation by the DSMB upon a review of adverse events in Cohort 2.
Criteria for Evaluation:
Pharmacokinetics: The following PK parameters were to be determined: Cmax
(maximum serum concentration), Tmax (time to maximum serum concentration), AUClast
(area under the serum concentration-time curve from the time of dosing to the time of
the last observed concentration), AUCf (area under the serum concentration-time curve
from the time of dosing extrapolated to infinity), CL (serum clearance), Vd (apparent
volume of distribution at elimination phase), Vss (apparent volume of distribution at
steady state), t1/2 (terminal elimination phase half life).
Pharmacodynamics: Sample for the following inflammatory markers were collected but
not analyzed: C-reactive protein [CRP], IL-6, IL-8, IL-1ȕ, and TNF-Į.
Safety: Safety assessments performed during this study included adverse events, clinical
laboratory parameters (hematology, chemistry, coagulation, urinalysis, hematoccult),
vital signs measurements (body temperature, heart rate, respiratory rate, blood pressure),
physical examinations and electrocardiograms. Additional assessments included arterial
blood gases, ventilation assessments, chest radiograph, hospital indices, and
immunogenicity.
Statistical Methods: Serum concentration and pharmacokinetic parameters were to be
summarized by and compared among dosing cohorts using descriptive statistics.
Parametric and/or non-parametric statistical comparisons were to be done if suggested
by the data, but were not performed. Continuous data variables were summarized by
sample size, mean and its standard error, median, standard deviation , minimum, and
maximum values. PD samples were not analyzed as the data were not anticipated to
provide any meaningful information about the action of the study drug. Safety
evaluations were based on the incidence, intensity and type of AEs and clinically
significant changes in the subject’s physical examination findings, vital signs, and
Page 6 of 3638
CONFIDENTIAL
February 11, 2008
7
Sponsor Name:
Study Drug:
Active Ingredient:
Genentech
TNX-832
TNX-832 (Sunol-cH36)
Title: The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome
clinical laboratory results. Safety variables were tabulated and presented for all subjects
who received TNX-832 or placebo. Subjects who received TNX-832 were grouped by
cohort. Subjects who received placebo were treated as one group.
Summary:
Number of Subjects: Eighteen subjects were assigned to study treatment. Two subjects
were withdrawn from the study following administration of study drug. Subject 10-005
died during the study. The death occurred after removal of respiratory support for acute
hypoxia; the death was determined by both the Investigator and the Sponsor to be not
related to study drug administration. Subject 08-002 withdrew consent 48 days after
administration of 0.06 mg/kg TNX-832.
Demographics: Demographics and baseline characteristics are summarized in the table
below.
Placebo
N=3
0.06 mg/kg
TNX-832
N=5
0.1 mg/kg
TNX-832
N=5
0.08 mg/kg
TNX-832
N=5
Age, [Mean (SD)]
49.67 (24.3)
40.40 (18.2)
54.60 (13.7)
54.00 (16.9)
Gender, [N (%)]
-Male
1 (33.3)
1 (20.0)
0 (0.0)
2 (40.0)
-Female
2 (66.7)
4 (80.0)
5 (100.0)
3 (60.0)
Race, [N (%)]
-Caucasian
1 (33.3)
4 (80.0)
3 (60.0)
2 (40.0)
-Black
1 (33.3)
0 (0)
2 (40.0)
2 (40.0)
-Hispanic
1 (33.3)
1 (20.0)
0 (0.0)
1 (20.0)
Pharmacokinetic: Pharmacokinetic results are provided as an appendix to this report.
Pharmacodynamic: Pharmacodynamic samples were not analyzed.
Safety Results: There was one death during the study. Subject 10005 died after
removal of respiratory support for acute hypoxia. The subject died 10 days after
administration of 0.08 mg/kg TNX-832. The death was considered unrelated to study
medication by the Investigator. Four subjects experienced non-fatal SAEs during the
study, including bilateral pulmonary embolism, hypoxic respiratory failure secondary to
hospital-acquired pneumonia, worsening acute renal failure, and worsening anemia and
empyema. Of these SAEs, the hypoxic respiratory failure secondary to hospital-
acquired pneumonia in one subject was considered possibly related to study medication.
The worsening anemia and empyema in one subject were considered possibly related to
study medication, with empyema considered unrelated at the time of resolution. Of the
Page 7 of 3638
CONFIDENTIAL
February 11, 2008
8
Sponsor Name:
Study Drug:
Active Ingredient:
Genentech
TNX-832
TNX-832 (Sunol-cH36)
Title: The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome
18 subjects enrolled in this study, 16 subjects reported a total of 87 AEs during the
study. Of the 87 treatment-emergent AEs in this study, 48 (55%) AEs were moderate in
intensity, 35 (40%) AEs were mild in intensity, and 4 (5%) AEs were severe in intensity.
Of the 87 treatment-emergent AEs, 16 AEs were considered by the Investigator to be
related to study medication. Two AEs were considered related to placebo
administration; 3 AEs were considered related to 0.06 mg/kg TNX-832 administration; 5
AEs were considered related to 0.1 mg/kg TNX-832 administration; 6 AEs were
considered related to 0.08 mg/kg TNX-832 administration. A summary of treatment-
emergent AEs is presented in the table below.
Placebo
0.06 mg/kg
TNX-832
0.1 mg/kg
TNX-832
0.08 mg/kg
TNX-832
Total
Dosed
3
5
5
5
18
Number of AEs
20
18
20
29
87
Subjects with AEs
3
4
5
4
16
Subjects with SAEs
0
1
2
2
5
Subjects with severe
AEs
2
0
1
0
3
Subjects who
discontinued due to
AEs
0
0
0
1
1
Seven subjects had 16 laboratory values that were reported as AEs. None of these
laboratory values reported as Aes were assessed as related to study medication by the
Investigator, with the exception of decreased hemoglobin which resolved one day after
onset with red blood cell transfusion. There were no clinically significant trends in vital
signs during the study. Three subjects had changes in vital signs that were reported as
AEs during the study. None of these changes in vital signs reported as Aes were
assessed as related to study medication by the Investigator. Four subjects had ECG
findings reported as Aes, none of which were assessed as related to study medication by
the Investigator. There were no clinically significant trends in any ventilation evaluation
during the study. Two subjects had clinically significant findings on chest x-ray
following administration of study medication. One subject experienced pulmonary
oedema, which resolved 22 days after onset. One subject experienced empyema and
right pleural effusion, which resolved 8 days and 2 days after onset, respectively.
Conclusions:
This study was prematurely discontinued due to the high incidence of hematuria (nine
occurrences) during the study. All instances of hematuria were experienced by patients
who received study drug. In this study, the most frequent AEs were hematuria (n=9) and
anemia (n=6). At the highest dose level of TNX-832 administered during this study (0.1
mg/kg), all five subjects dosed had AEs of hematuria. Hematuria was considered
Page 8 of 3638
CONFIDENTIAL
February 11, 2008
9
Sponsor Name:
Study Drug:
Active Ingredient:
Genentech
TNX-832
TNX-832 (Sunol-cH36)
Title: The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832
(Sunol-cH36) in Subjects with Acute Lung Injury/Acute Respiratory Distress Syndrome
related to study medication by the Investigator in four of the five subjects. After the
dose level was reduced to 0.08 mg/kg in Cohort 3, 2 subjects experienced hematuria (1
related to study medication). Based upon the bleeding related AEs of hematuria, the
DSMB decided to discontinue the study. In conclusion, the study was prematurely
discontinued due to the high incidence of treatment-related hematuria reported during
the study, and the continued observation of hematuria in spite of the lowered dose in the
third cohort .
x
Although there was one death during the study, the death was considered unrelated
to study medication and was not the cause for discontinuation of the study.
Date of Report: 11 February 2008
Page 9 of 3638
| 2
|
arm 1: Anti-tissue factor antibody arm 2: Placebo control
|
[
0,
2
] | 2
|
[
2,
0
] |
intervention 1: Single intravenous dose of TNX-832 at 0.06, 0.08 or 0.10 mg/kg intervention 2: Single intravenous dose of saline control
|
intervention 1: TNX-832 intervention 2: Placebo
| 7
|
Miami | Florida | United States | -80.19366 | 25.77427
Boston | Massachusetts | United States | -71.05977 | 42.35843
St Louis | Missouri | United States | -90.19789 | 38.62727
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Akron | Ohio | United States | -81.51901 | 41.08144
Houston | Texas | United States | -95.36327 | 29.76328
Halifax | Nova Scotia | Canada | -63.57688 | 44.64269
| 0
|
NCT01438853
|
[
3
] | 38
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will evaluate the efficacy and safety of MabThera/Rituxan in patients with relapsed low-grade centroblastic centrocytic non-Hodgkin's lymphoma. Patients will receive once-weekly intravenous MabThera/Rituxan for 4 weeks; responding patients will be treated a second time in case of relapse (defined as progression after complete or partial response). The anticipated time on study treatment is \<3 months.
| null |
Non-Hodgkin's Lymphoma
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: 375 mg/m2 iv weekly for 4 weeks; for responders to first course of therapy a second course is possible after relapse
|
intervention 1: rituximab [MabThera/Rituxan]
| 11
|
Cologne | N/A | Germany | 6.95 | 50.93333
Erlangen | N/A | Germany | 11.00783 | 49.59099
Göttingen | N/A | Germany | 9.93228 | 51.53443
Grenzach-Wyhlen | N/A | Germany | 7.68333 | 47.55
Hanover | N/A | Germany | 9.73322 | 52.37052
Homburg/saar | N/A | Germany | N/A | N/A
München | N/A | Germany | 13.31243 | 51.60698
München | N/A | Germany | 13.31243 | 51.60698
Münster | N/A | Germany | 7.62571 | 51.96236
Stuttgart | N/A | Germany | 9.17702 | 48.78232
Tübingen | N/A | Germany | 9.05222 | 48.52266
| 0
|
NCT01998893
|
|
[
3
] | 6
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will evaluate the efficacy and safety of Herceptin in patients with metastatic or advanced gastric cancer with disease progression during platinum-based or 5-fluoropyrimidine-based chemotherapy. The anticipated time on study treatment is until disease progression.
| null |
Gastric Cancer
| null | 1
|
arm 1: Initial dose of 4 milligrams (mg) per (/) kilogram (kg) by body weight (BW), followed by 2 mg/kg BW at each subsequent visit
|
[
0
] | 1
|
[
0
] |
intervention 1: 4 mg/kg initial dose, followed by 2 mg/kg
|
intervention 1: Trastuzumab
| 12
|
Vienna | N/A | Austria | 16.37208 | 48.20849
Dresden | N/A | Germany | 13.73832 | 51.05089
Erlangen | N/A | Germany | 11.00783 | 49.59099
Essen | N/A | Germany | 7.01228 | 51.45657
Grenzach-Wyhlen | N/A | Germany | 7.68333 | 47.55
Halle | N/A | Germany | 11.97947 | 51.48158
Kassel | N/A | Germany | 9.5 | 51.31667
Kiel | N/A | Germany | 10.13489 | 54.32133
Mannheim | N/A | Germany | 8.46694 | 49.4891
München | N/A | Germany | 13.31243 | 51.60698
München | N/A | Germany | 13.31243 | 51.60698
Oldenburg | N/A | Germany | 8.21467 | 53.14118
| 0
|
NCT02005484
|
|
[
3
] | 24
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
The objectives of this study are:
* To assess the effect of ophthalmic phentolamine mesylate in mesopic conditions on the four endpoints:
1. Contrast sensitivity
2. Low contrast visual acuity
3. Wavefront aberrometry
4. Subjective questionnaire
* To assess the safety of ophthalmic phentolamine mesylate
|
Double-masked, placebo-controlled, single-dose Phase 2 study in 24 patients experiencing severe night vision difficulties to evaluate ocular and systemic safety and efficacy following administration of one drop of phentolamine mesylate 1.0% QD in each eye for 1 day.
|
Decrease in Night Vision Disturbance; Vision, Loss
|
Night Vision Disturbances NVD Glare Halos Starbursts Nyxol
| null | 2
|
arm 1: 1 drop in each eye (QD) for one day. arm 2: 1 drop in each eye (QD) for one day.
|
[
0,
2
] | 2
|
[
0,
10
] |
intervention 1: Topical Sterile Ophthalmic Solution intervention 2: Topical Sterile Ophthalmic Solution
|
intervention 1: Phentolamine Mesylate Ophthalmic Solution 1% intervention 2: Phentolamine Mesylate Ophthalmic Solution Vehicle (Placebo)
| 1
|
Lynbrook | New York | United States | -73.6718 | 40.65483
| 0
|
NCT04004507
|
[
4
] | 374
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| null |
This study will evaluate the safety and efficacy of two different dose regimens (12 milligrams \[mg\] and 24 mg) of IV MOA-728 versus placebo in shortening the time to return of bowel function in participants receiving opioid analgesia administered via patient-controlled anesthesia (PCA), and who had undergone repair of large (greater than or equal to \[≥\]10 centimeters) ventral hernias with or without a mesh prosthesis via laparotomy or laparoscopy.
| null |
Ileus
|
POI Hernia Ventral Wall Hernia Repair Post Operative Ileus
| null | 3
|
arm 1: Participants will receive methylnaltrexone (MOA-728) 12 mg as an IV infusion over approximately 20 minutes for approximately every 6 hours for a total of 4 doses in 24-hour period. The first dose of study drug will be administered within approximately 90 minutes after completion of the surgical procedure (defined as the time when the last skin suture or staple is placed in the participant). Dose administration will be continued for a maximum of 10 days. arm 2: Participants will receive MOA-728 24 mg as an IV infusion over approximately 20 minutes for approximately every 6 hours for a total of 4 doses in 24-hour period. The first dose of study drug will be administered within approximately 90 minutes after completion of the surgical procedure (defined as the time when the last skin suture or staple is placed in the participant). Dose administration will be continued for a maximum of 10 days. arm 3: Participants will receive placebo matching to MOA-728 as an IV infusion over approximately 20 minutes for approximately every 6 hours for a total of 4 doses in 24-hour period. The first dose of study drug will be administered within approximately 90 minutes after completion of the surgical procedure (defined as the time when the last skin suture or staple is placed in the participant). Dose administration will be continued for a maximum of 10 days.
|
[
0,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: MOA-728 will be administered per the dose and schedule specified in the arm. intervention 2: Placebo matching to MOA-728 will be administered per the schedule specified in the arm.
|
intervention 1: MOA-728 intervention 2: Placebo
| 106
|
Benton | Arkansas | United States | -92.58683 | 34.56454
Colton | California | United States | -117.31365 | 34.0739
Laguna Hills | California | United States | -117.71283 | 33.61252
Loma Linda | California | United States | -117.26115 | 34.04835
Long Beach | California | United States | -118.18923 | 33.76696
Los Angeles | California | United States | -118.24368 | 34.05223
Orange | California | United States | -117.85311 | 33.78779
San Jose | California | United States | -121.89496 | 37.33939
Santa Barbara | California | United States | -119.69819 | 34.42083
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Inverness | Florida | United States | -82.33037 | 28.83582
Jacksonville | Florida | United States | -81.65565 | 30.33218
Jacksonville | Florida | United States | -81.65565 | 30.33218
Melbourne | Florida | United States | -80.60811 | 28.08363
Miami | Florida | United States | -80.19366 | 25.77427
Miami | Florida | United States | -80.19366 | 25.77427
Naples | Florida | United States | -81.79596 | 26.14234
Orlando | Florida | United States | -81.37924 | 28.53834
Pensacola | Florida | United States | -87.21691 | 30.42131
Tampa | Florida | United States | -82.45843 | 27.94752
Peoria | Illinois | United States | -89.58899 | 40.69365
Des Moines | Iowa | United States | -93.60911 | 41.60054
Kansas City | Kansas | United States | -94.62746 | 39.11417
Lexington | Kentucky | United States | -84.47772 | 37.98869
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
Boston | Massachusetts | United States | -71.05977 | 42.35843
Springfield | Massachusetts | United States | -72.58981 | 42.10148
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Detroit | Michigan | United States | -83.04575 | 42.33143
Flint | Michigan | United States | -83.68746 | 43.01253
Jackson | Mississippi | United States | -90.18481 | 32.29876
Columbia | Missouri | United States | -92.33407 | 38.95171
Omaha | Nebraska | United States | -95.94043 | 41.25626
Omaha | Nebraska | United States | -95.94043 | 41.25626
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Albany | New York | United States | -73.75623 | 42.65258
New York | New York | United States | -74.00597 | 40.71427
Stony Brook | New York | United States | -73.14094 | 40.92565
Syracuse | New York | United States | -76.14742 | 43.04812
The Bronx | New York | United States | -73.86641 | 40.84985
Chapel Hill | North Carolina | United States | -79.05584 | 35.9132
Durham | North Carolina | United States | -78.89862 | 35.99403
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cleveland | Ohio | United States | -81.69541 | 41.4995
Columbus | Ohio | United States | -82.99879 | 39.96118
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Bend | Oregon | United States | -121.31531 | 44.05817
Portland | Oregon | United States | -122.67621 | 45.52345
Hershey | Pennsylvania | United States | -76.65025 | 40.28592
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Sellersville | Pennsylvania | United States | -75.3049 | 40.35399
Providence | Rhode Island | United States | -71.41283 | 41.82399
Sioux Falls | South Dakota | United States | -96.70033 | 43.54997
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Memphis | Tennessee | United States | -90.04898 | 35.14953
Nashville | Tennessee | United States | -86.78444 | 36.16589
Fort Worth | Texas | United States | -97.32085 | 32.72541
San Antonio | Texas | United States | -98.49363 | 29.42412
Temple | Texas | United States | -97.34278 | 31.09823
Norfolk | Virginia | United States | -76.28522 | 36.84681
Winchester | Virginia | United States | -78.16333 | 39.18566
Bellevue | Washington | United States | -122.20068 | 47.61038
Tacoma | Washington | United States | -122.44429 | 47.25288
Morgantown | West Virginia | United States | -79.9559 | 39.62953
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Adelaide SA | N/A | Australia | N/A | N/A
Elizabeth Vale SA | N/A | Australia | N/A | N/A
Wilrijkstraat 10 | Edegem | Belgium | N/A | N/A
De Pintelaan 185 | Gent Belgium | Belgium | N/A | N/A
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Montreal | Quebec | Canada | -73.58781 | 45.50884
Nussbaumstrasse 20 | Muenchen | Germany | N/A | N/A
Augustenburger Platz 1 | State of Berlin | Germany | N/A | N/A
Heidelberg | N/A | Germany | 8.69079 | 49.40768
Nyíregyháza | N/A | Hungary | 21.71671 | 47.95539
Pécs | N/A | Hungary | 18.23083 | 46.0725
Székesfehérvár | N/A | Hungary | 18.41034 | 47.18995
Veszprém | N/A | Hungary | 17.91149 | 47.09327
Corso Giovecca 203 | Ferrara | Italy | N/A | N/A
Gemelli | Rome | Italy | N/A | N/A
Padua | Via Giustiniani 2 | Italy | 11.88586 | 45.40797
Bergamo | N/A | Italy | 9.66721 | 45.69601
Jan Toorpstraat 164 | Amsterdam | Netherlands | N/A | N/A
Roosendaal | N/A | Netherlands | 4.46528 | 51.53083
Powstancow Wielkopolskich 72 | Szczecin | Poland | N/A | N/A
Bydgoszcz | N/A | Poland | 18.00762 | 53.1235
Polnocna 42 | Łódź Voivodeship | Poland | N/A | N/A
Durban Kwa-Zulu | KwaZulu-Natal | South Africa | N/A | N/A
Somerset West | Western Cape | South Africa | 18.82113 | -34.08401
Worcester | Western Cape | South Africa | 19.44852 | -33.64651
Moreletapark Pretoria | N/A | South Africa | N/A | N/A
Pretoria | N/A | South Africa | 28.18783 | -25.74486
Pretoria Gauteng | N/A | South Africa | N/A | N/A
Pretoria Gauteng | N/A | South Africa | N/A | N/A
Seoul | N/A | South Korea | 126.9784 | 37.566
| 0
|
NCT00528970
|
[
3
] | 6
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| null |
RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving vaccine therapy and chemotherapy after surgery may kill any tumor cells that remain after surgery.
PURPOSE: This phase II trial is studying how well giving vaccine therapy together with paclitaxel and carboplatin works in treating patients who are undergoing surgery for stage III or stage IV ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
|
OBJECTIVES:
* Determine the immunogenicity of vaccine therapy comprising synthetic ovarian cancer-associated peptides administered with a synthetic tetanus toxoid helper peptide emulsified in Montanide ISA-51 before or after paclitaxel and carboplatin in patients with stage III-IV ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer undergoing optimal cytoreductive surgery.
OUTLINE: This is an open-label study. Patients are assigned to 1 of 2 treatment groups.
* Group 1:
* Neoadjuvant chemotherapy:Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to surgical debulking.
* Surgical debulking: Patients undergo primary optimal cytoreductive surgery.
* Vaccine therapy: Within 14 days after surgery, patients receive vaccine therapy comprising synthetic ovarian cancer-associated peptides, MAGE-A1:161-169, FBP:1901-199, Her-2/neu:369-377, MAGE-A1:96-104, and Her-2/neu:754-762, and tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, and 15. Treatment repeats every 14 weeks for 2 courses.
* Adjuvant chemotherapy: Patients receive 4 courses of paclitaxel and carboplatin as in neoadjuvant chemotherapy after completion of course 1 of vaccine therapy.
* Group 2:
* Surgical debulking: Patients undergo up-front optimal cytoreductive surgery. Patients with non-optimal primary debulking may undergo interval debulking surgery within 6 weeks after completing course 4 of adjuvant chemotherapy. If interval debulking surgery is performed, tumor and/or lymph node tissue is collected.
* Vaccine therapy: Patients receive 2 courses of vaccine therapy as in group 1.
* Adjuvant chemotherapy: Patients receive paclitaxel and carboplatin as in group 1, neoadjuvant chemotherapy. Treatment repeats every 21 days for up to 8 courses.
Patients undergo periodic blood and tumor tissue collection during study for correlative immunological analysis.
After completion of study treatment, patients with progressive disease are followed at 30 days and then every six months thereafter. All other patients are followed every 3 months for 36 months until disease progression or until another therapy is initiated, and then every six months thereafter.
PROJECTED ACCRUAL: A total of 28 patients will be accrued for this study.
|
Fallopian Tube Cancer Ovarian Cancer Primary Peritoneal Cavity Cancer
|
fallopian tube cancer stage III ovarian epithelial cancer stage IV ovarian epithelial cancer primary peritoneal cavity cancer
| null | 2
|
arm 1: Patients in group one will receive a 3-hour infusion of paclitaxel and an infusion of carboplatin in week 1. Treatment may repeat every 3 weeks for up to four courses. They will then undergo surgery to remove as much of the tumor as possible. Within 2 weeks after surgery, patients will receive an injection of the vaccine once a week for 3 weeks. Treatment may repeat every 14 weeks for two courses. After finishing the first course of vaccine therapy, patients will receive a 3-hour infusion of paclitaxel and an infusion of carboplatin every 3 weeks for up to four courses. arm 2: Patients in group two will undergo surgery to remove as much of the tumor as possible. Within 2 weeks after surgery, patients will receive an injection of the vaccine once a week for 3 weeks. Treatment may repeat every 14 weeks for two courses. After finishing the first course of vaccine therapy, patients will receive a 3-hour infusion of paclitaxel and an infusion of carboplatin every 3 weeks for up to eight courses. Some patients may undergo a second surgery within 6 weeks after completing the fourth course of chemotherapy and undergo tumor and/or lymph node tissue collection.
|
[
0,
0
] | 5
|
[
2,
2,
0,
0,
3
] |
intervention 1: Given intradermally or subcutaneously intervention 2: Given intradermally or subcutaneously intervention 3: Given IV intervention 4: Given IV intervention 5: Patients undergo primary optimal cytoreductive surgery
|
intervention 1: MAGE-A1, Her-2/neu, FBP peptides ovarian cancer vaccine intervention 2: tetanus toxoid helper peptide intervention 3: carboplatin intervention 4: paclitaxel intervention 5: conventional surgery
| 1
|
Charlottesville | Virginia | United States | -78.47668 | 38.02931
| 0
|
NCT00373217
|
[
2
] | 60
|
RANDOMIZED
|
CROSSOVER
| 9OTHER
| 4QUADRUPLE
| true
| 0ALL
| false
|
ICH E14 recommends that a thorough QT/QTc (TQT) study should be performed to determine whether intensive monitoring of QT interval in target patient populations is required during later stages of development. The current study is designed to ascertain whether CP-690,550 is associated with QTc prolongation.
|
The current study is designed to ascertain whether CP-690,550 is associated with QTc prolongation
|
Healthy
|
TQT study CP-690 550
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
2,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Single dose 100 mg (5 x 20 mg tablets) intervention 2: Single dose placebo tablets (5 tablets) intervention 3: Single dose Avelox 400 mg tablet
|
intervention 1: CP-690,550 intervention 2: Placebo intervention 3: Moxifloxacin
| 2
|
Brussels | N/A | Belgium | 4.34878 | 50.85045
Singapore | N/A | Singapore | 103.85007 | 1.28967
| 0
|
NCT01743677
|
[
3
] | 287
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
Study RN624-CL007 is planned to be an open-label protocol to enroll subjects who have previously participated in Study No. RN624-CL006. In this study, subjects will receive RN624 on an open-label basis.
| null |
Osteoarthritis OA Knee Pain Arthritis
|
Monoclonal antibody
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: 50 mcg/kg
|
intervention 1: RN624 (PF-04383119)
| 36
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
Phoenix | Arizona | United States | -112.07404 | 33.44838
Anaheim | California | United States | -117.9145 | 33.83529
Anaheim | California | United States | -117.9145 | 33.83529
National City | California | United States | -117.0992 | 32.67811
Stamford | Connecticut | United States | -73.53873 | 41.05343
Stamford | Connecticut | United States | -73.53873 | 41.05343
Daytona Beach | Florida | United States | -81.02283 | 29.21081
Ocala | Florida | United States | -82.14009 | 29.1872
Tampa | Florida | United States | -82.45843 | 27.94752
Tampa | Florida | United States | -82.45843 | 27.94752
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Boise | Idaho | United States | -116.20345 | 43.6135
Merrillville | Indiana | United States | -87.33281 | 41.48281
Louisville | Kentucky | United States | -85.75941 | 38.25424
Wheaton | Maryland | United States | -77.05526 | 39.03983
Worcester | Massachusetts | United States | -71.80229 | 42.26259
Kansas City | Missouri | United States | -94.57857 | 39.09973
Omaha | Nebraska | United States | -95.94043 | 41.25626
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Rochester | New York | United States | -77.61556 | 43.15478
Greensboro | North Carolina | United States | -79.79198 | 36.07264
Greensboro | North Carolina | United States | -79.79198 | 36.07264
Zanesville | Ohio | United States | -82.01319 | 39.94035
Duncansville | Pennsylvania | United States | -78.4339 | 40.42341
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Austin | Texas | United States | -97.74306 | 30.26715
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Midvale | Utah | United States | -111.89994 | 40.61106
Charlottesville | Virginia | United States | -78.47668 | 38.02931
Yakima | Washington | United States | -120.5059 | 46.60207
| 0
|
NCT00399490
|
[
4
] | 419
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this trial is to investigate the efficacy, safety and tolerability of esmirtazapine (Org 50081) compared to placebo in patients with chronic primary insomnia.
|
Insomnia is a common complaint or disorder throughout the world. About one third of the population in the industrial countries reports difficulty initiating or maintaining sleep, resulting in a non-refreshing or non-restorative sleep. The majority of the insomniacs suffer chronically from their complaints. It has been reported that in patients with chronic insomnia lasting longer than six months, 50% had a past or current mental disorder. This raises the possibility that treatment of insomnia may reduce the risk for psychological conditions. This double-blind, placebo-controlled, parallel, randomized clinical trial is designed to assess the efficacy and safety of esmirtazapine in patients suffering from chronic primary insomnia.
|
Insomnia
|
Sleep Initiation and Maintenance Disorders, Sleep Disorders, Intrinsic Dyssomnias, Sleep Disorders, Nervous System Diseases, Mental Disorders
| null | 3
|
arm 1: Participants took placebo tablets on Days -7 and -6, esmirtazapine 3.0 mg tablets on Days 1-42, and placebo tablets on Days 43-50. Tablets were taken by mouth once daily in the evening. arm 2: Participants took placebo tablets on Days -7 and -6, esmirtazapine 4.5 mg tablets on Days 1-42, and placebo tablets on Days 43-50. Tablets were taken by mouth once daily in the evening. arm 3: Participants took placebo tablets on Days -7 and -6, placebo tablets on Days 1-42, and placebo tablets on Days 43-50. Tablets were taken by mouth once daily in the evening.
|
[
0,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Esmirtazapine maleate was provided as tablets for oral use containing 3.0 mg, or 4.5 mg of active compound. In addition, tablets contain the following excipients: hydroxypropyl cellulose, maize starch (United States Pharmacopeia \[USP\] name corn starch), magnesium stearate, and lactose monohydrate. intervention 2: The placebo tablets contained the following excipients: hydroxypropyl cellulose, maize starch (USP name corn starch), magnesium stearate, and lactose monohydrate.
|
intervention 1: Esmirtazapine intervention 2: Placebo
| 0
| null | 0
|
NCT00506389
|
[
3
] | 334
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
This is a dose-ranging study that will evaluate the efficacy, safety and tolerability of a range of doses of investigational product and pioglitazone, compared to placebo, administered as monotherapy over 12 weeks in treatment naive patients with T2DM
| null |
Diabetes Mellitus, Type 2
|
Pioglitazone HbA1c Diabetes mellitus
| null | 3
|
arm 1: GSK189075 arm 2: Placebo arm 3: pioglitazone (active control)
|
[
0,
2,
5
] | 3
|
[
0,
0,
10
] |
intervention 1: Experimental Drug intervention 2: Active Control intervention 3: Placebo Comparator
|
intervention 1: GSK189075 intervention 2: pioglitazone intervention 3: Placebo
| 136
|
Mesa | Arizona | United States | -111.82264 | 33.42227
Hollywood | Florida | United States | -80.14949 | 26.0112
Miami | Florida | United States | -80.19366 | 25.77427
Saint Cloud | Florida | United States | -81.28118 | 28.2489
Sunset | Louisiana | United States | -92.06845 | 30.41131
Oxon Hill | Maryland | United States | -76.9897 | 38.80345
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Canal Fulton | Ohio | United States | -81.59762 | 40.88978
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
San Antonio | Texas | United States | -98.49363 | 29.42412
Burke | Virginia | United States | -77.27165 | 38.79345
Buenos Aries | Buenos Aires | Argentina | N/A | N/A
Ciudad Autonoma de Buenos Aires | Buenos Aires | Argentina | N/A | N/A
Ciudad Autónoma de Buenos Aires | Buenos Aires | Argentina | N/A | N/A
Córdoba | Córdoba Province | Argentina | -64.18853 | -31.40648
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Córdoba | N/A | Argentina | -64.18853 | -31.40648
Mendoza | N/A | Argentina | -68.84582 | -32.88946
Quilmes | N/A | Argentina | -58.25454 | -34.72065
San Miguel de Tucumán | N/A | Argentina | -65.21051 | -26.81601
Pleven | N/A | Bulgaria | 24.61667 | 43.41667
Plovdiv | N/A | Bulgaria | 24.75 | 42.15
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Varna | N/A | Bulgaria | 27.91667 | 43.21667
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
San José | N/A | Costa Rica | -84.08489 | 9.93388
Brno | N/A | Czechia | 16.60796 | 49.19522
Brno | N/A | Czechia | 16.60796 | 49.19522
Brno | N/A | Czechia | 16.60796 | 49.19522
Cheb | N/A | Czechia | 12.37392 | 50.07963
České Budějovice | N/A | Czechia | 14.47434 | 48.97447
Havirov - Soumbrak | N/A | Czechia | N/A | N/A
Olomouc | N/A | Czechia | 17.25175 | 49.59552
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Semily | N/A | Czechia | 15.33552 | 50.60191
Šumperk | N/A | Czechia | 16.97061 | 49.96528
Ústí nad Labem | N/A | Czechia | 14.03227 | 50.6607
Znojmo | N/A | Czechia | 16.0488 | 48.8555
Bammental | Baden-Wurttemberg | Germany | 8.77944 | 49.35611
Kippenheim | Baden-Wurttemberg | Germany | 7.8251 | 48.29564
Mannheim | Baden-Wurttemberg | Germany | 8.46694 | 49.4891
Weinheim | Baden-Wurttemberg | Germany | 8.66697 | 49.54887
Haag | Bavaria | Germany | 12.07614 | 50.30379
Höhenkirchen-Siegertsbrunn | Bavaria | Germany | 11.71906 | 48.01932
Lampertheim | Hesse | Germany | 8.4725 | 49.59786
Damme | Lower Saxony | Germany | 8.19793 | 52.52157
Hanover | Lower Saxony | Germany | 9.73322 | 52.37052
Hildesheim | Lower Saxony | Germany | 9.95112 | 52.15077
Bergkamen | North Rhine-Westphalia | Germany | 7.64451 | 51.61633
Mainz | Rhineland-Palatinate | Germany | 8.2791 | 49.98419
Rhaunen | Rhineland-Palatinate | Germany | 7.34198 | 49.8638
Speyer | Rhineland-Palatinate | Germany | 8.43111 | 49.32083
Berlin | N/A | Germany | 13.41053 | 52.52437
Budapest | N/A | Hungary | 19.04045 | 47.49835
Budapest | N/A | Hungary | 19.04045 | 47.49835
Budapest | N/A | Hungary | 19.04045 | 47.49835
Budapest | N/A | Hungary | 19.04045 | 47.49835
Debrecen | N/A | Hungary | 21.62444 | 47.53167
Érd | N/A | Hungary | 18.91361 | 47.39489
Győr | N/A | Hungary | 17.63512 | 47.68333
Miskolc | N/A | Hungary | 20.77806 | 48.10306
Miskolc | N/A | Hungary | 20.77806 | 48.10306
Mosonmagyaróvár | N/A | Hungary | 17.26994 | 47.86789
Nyirtegyhaza | N/A | Hungary | N/A | N/A
Pécs | N/A | Hungary | 18.23083 | 46.0725
Szentes | N/A | Hungary | 20.2608 | 46.65834
Szigetvár | N/A | Hungary | 17.80554 | 46.04865
Szombathely | N/A | Hungary | 16.62155 | 47.23088
Veszprém | N/A | Hungary | 17.91149 | 47.09327
Zalaegerszeg | N/A | Hungary | 16.84389 | 46.84
Bangalore | N/A | India | 77.59369 | 12.97194
Bangalore | N/A | India | 77.59369 | 12.97194
Bangalore | N/A | India | 77.59369 | 12.97194
Kochi | N/A | India | 76.26022 | 9.93988
Mumbai | N/A | India | 72.88261 | 19.07283
New Delhi | N/A | India | 77.2148 | 28.62137
Pune | N/A | India | 73.85535 | 18.51957
Jelgava | N/A | Latvia | 23.71278 | 56.65
Limbaži | N/A | Latvia | 24.71941 | 57.51287
Riga | N/A | Latvia | 24.10589 | 56.946
Riga | N/A | Latvia | 24.10589 | 56.946
Riga | N/A | Latvia | 24.10589 | 56.946
Riga | N/A | Latvia | 24.10589 | 56.946
Riga | N/A | Latvia | 24.10589 | 56.946
Talsi | N/A | Latvia | 22.58137 | 57.24562
Tukums | N/A | Latvia | 23.15554 | 56.96764
Kaunas | N/A | Lithuania | 23.90961 | 54.90272
Kaunas | N/A | Lithuania | 23.90961 | 54.90272
Kaunas | N/A | Lithuania | 23.90961 | 54.90272
Vilnius | N/A | Lithuania | 25.2798 | 54.68916
Vilnius | N/A | Lithuania | 25.2798 | 54.68916
Tijuana | Baja California Norte | Mexico | -117.00371 | 32.5027
Monterrey | Nuevo León | Mexico | -100.31721 | 25.68435
México | State of Mexico | Mexico | -99.12355 | 19.69237
Durango | N/A | Mexico | -104.65756 | 24.02032
Mexico | N/A | Mexico | -98.43784 | 18.88011
Mexico | N/A | Mexico | -98.43784 | 18.88011
Auckland | N/A | New Zealand | 174.76349 | -36.84853
Auckland | N/A | New Zealand | 174.76349 | -36.84853
Hamilton | N/A | New Zealand | 175.28333 | -37.78333
Rotorua | N/A | New Zealand | 176.24516 | -38.13874
Lima | N/A | Peru | -77.02824 | -12.04318
Lima | N/A | Peru | -77.02824 | -12.04318
Bydgoszcz | N/A | Poland | 18.00762 | 53.1235
Grudziądz | N/A | Poland | 18.75366 | 53.48411
Lodz | N/A | Poland | 19.47395 | 51.77058
Porąbka | N/A | Poland | 19.21835 | 49.81716
Siemianowice Śląskie | N/A | Poland | 19.02901 | 50.32738
Wroclaw | N/A | Poland | 17.03333 | 51.1
Ponce | N/A | Puerto Rico | -66.62398 | 18.01031
Brasov | N/A | Romania | 25.60613 | 45.64861
Bucharest | N/A | Romania | 26.10626 | 44.43225
Deva | N/A | Romania | 22.9 | 45.88333
Iași | N/A | Romania | 27.6 | 47.16667
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Tomsk | N/A | Russia | 84.98204 | 56.50032
Tyumen | N/A | Russia | 65.52722 | 57.15222
Ufa | N/A | Russia | 55.96779 | 54.74306
Bellville | N/A | South Africa | 18.62847 | -33.90022
Gauteng | N/A | South Africa | N/A | N/A
Orangegrove, Linksfield West | N/A | South Africa | N/A | N/A
Parow | N/A | South Africa | 18.59992 | -33.89723
Roodepoort | N/A | South Africa | 27.8725 | -26.1625
| 0
|
NCT00500331
|
[
4
] | 354
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
To assess the impact on glucose control by inhaled insulin in patients with type 2 diabetes who are not well controlled on 2 or more oral anti-diabetic agents
| null |
Diabetes Mellitus Type 2
|
Type 2 diabetes melllitus
| null | 2
|
arm 1: Inhaled insulin plus oral therapy arm 2: Standard of Care: All licensed diabetes drugs can be prescribed per discretion of investigators
|
[
0,
5
] | 2
|
[
0,
10
] |
intervention 1: Addition of inhaled insulin to pre-existing oral diabetes therapy. intervention 2: Standard of Care: All licensed diabetes drugs can be prescribed per discretion of investigators
|
intervention 1: Inhaled Insulin (Exubera) intervention 2: Standard of Care
| 64
|
Coquitlam | British Columbia | Canada | -122.78217 | 49.2846
Winnipeg | Manitoba | Canada | -97.14704 | 49.8844
Bathurst | New Brunswick | Canada | -65.65112 | 47.61814
London | Ontario | Canada | -81.23304 | 42.98339
Orillia | Ontario | Canada | -79.42068 | 44.60868
Charlottetown | Prince Edward Island | Canada | -63.1256 | 46.23459
Bonaventure | Quebec | Canada | -65.49259 | 48.04573
Chicoutimi | Quebec | Canada | -71.06369 | 48.41963
Drummondville | Quebec | Canada | -72.48241 | 45.88336
Gatineau | Quebec | Canada | -75.70164 | 45.47723
Greenfield Park | Quebec | Canada | -73.46223 | 45.48649
Saint-Foy | Quebec | Canada | N/A | N/A
Saint-Marc-des-Carrieres | Quebec | Canada | -72.0491 | 46.68335
Trois-Rivières | Quebec | Canada | -72.5477 | 46.34515
Nantes | Cedex 01 | France | -1.55336 | 47.21725
Amiens | N/A | France | 2.3 | 49.9
Armentières | N/A | France | 2.88214 | 50.68568
Bondy | N/A | France | 2.48931 | 48.9018
Brest | N/A | France | -4.48628 | 48.39029
Cean Cedex | N/A | France | N/A | N/A
Chartres | N/A | France | 1.48925 | 48.44685
Lille | N/A | France | 3.05858 | 50.63297
Lorient | N/A | France | -3.37177 | 47.74817
Montpellier | N/A | France | 3.87635 | 43.61093
Paris | N/A | France | 2.3488 | 48.85341
Paris | N/A | France | 2.3488 | 48.85341
Reims | N/A | France | 4.02853 | 49.26526
Rennes | N/A | France | -1.67429 | 48.11198
Roubaix | N/A | France | 3.17456 | 50.69421
Toul | N/A | France | 5.89115 | 48.68075
Athens | N/A | Greece | 23.72784 | 37.98376
Athens | N/A | Greece | 23.72784 | 37.98376
Haidari | N/A | Greece | N/A | N/A
Pireaus | N/A | Greece | N/A | N/A
Thessaloniki | N/A | Greece | 22.93086 | 40.64361
Aveiro | N/A | Portugal | -8.64554 | 40.64427
Coimbra | N/A | Portugal | -8.41955 | 40.20564
Lisbon | N/A | Portugal | -9.1498 | 38.72509
Lisbon | N/A | Portugal | -9.1498 | 38.72509
Porto | N/A | Portugal | -8.61099 | 41.14961
Torres Vedras | N/A | Portugal | -9.2586 | 39.09109
Santiago de Compostela | A Coruña | Spain | -8.54569 | 42.88052
Santiago de Compostela | A Coruña | Spain | -8.54569 | 42.88052
L'Hospitalet de Llobregat | Barcelona | Spain | 2.10028 | 41.35967
Terrassa | Barcelona | Spain | 2.01667 | 41.56667
Pamplona | Navarre | Spain | -1.64323 | 42.81687
Oviedo | Principality of Asturias | Spain | -5.84476 | 43.36029
Alicante | N/A | Spain | -0.48149 | 38.34517
Barcelona | N/A | Spain | 2.15899 | 41.38879
Barcelona | N/A | Spain | 2.15899 | 41.38879
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Málaga | N/A | Spain | -4.42034 | 36.72016
Pontevedra | N/A | Spain | -8.64435 | 42.431
Valencia | N/A | Spain | -0.37966 | 39.47391
Valencia | N/A | Spain | -0.37966 | 39.47391
Zaragoza | N/A | Spain | -0.87734 | 41.65606
Ängelholm | N/A | Sweden | 12.86219 | 56.2428
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Ankara | N/A | Turkey (Türkiye) | 32.85427 | 39.91987
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Izmir | N/A | Turkey (Türkiye) | 27.13838 | 38.41273
| 0
|
NCT00282971
|
[
3
] | 30
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This study was conducted to test the safety and tolerability of afegostat tartrate in participants with type 1 Gaucher disease already receiving enzyme replacement therapy.
|
This was a Phase 2, open-label study in participants with Gaucher disease, a lysosomal storage disorder. Afegostat tartrate (also known as AT2101 or isofagomine tartrate) is designed to act as a pharmacological chaperone by selectively binding to misfolded β-glucocerebrosidase (GCase) and helping it fold correctly, intended to restore GCase activity. The study consisted of a 14-day screening period, a 28-day treatment period, and a 7-day wash-out period. Participants received 1 of 4 dosing regimens for afegostat tartrate.
|
Gaucher Disease, Type 1 Type 1 Gaucher Disease Gaucher Disease
|
afegostat tartrate isofagomine tartrate AT2101 Amicus Therapeutics
| null | 4
|
arm 1: Afegostat tartrate was administered orally during the 4-week treatment period. arm 2: Afegostat tartrate was administered orally once per day during the 4-week treatment period. arm 3: Afegostat tartrate was administered orally once every 4 days during the 4-week treatment period. arm 4: Afegostat tartrate was administered orally once every 7 days during the 4-week treatment period.
|
[
0,
0,
0,
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: Afegostat tartrate
| 10
|
San Francisco | California | United States | -122.41942 | 37.77493
Coral Springs | Florida | United States | -80.2706 | 26.27119
Decatur | Georgia | United States | -84.29631 | 33.77483
Iowa City | Iowa | United States | -91.53017 | 41.66113
New York | New York | United States | -74.00597 | 40.71427
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Portland | Oregon | United States | -122.67621 | 45.52345
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00433147
|
[
2,
3
] | 66
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
A major factor in the respiratory health of cystic fibrosis (CF) subjects is acquisition of chronic Pseudomonas aeruginosa infections. The infection rate with P. aeruginosa increases with age and by age 18 years, 80% of CF subjects in the U.S. are infected. Liposomal Amikacin for Inhalation (Arikace™) is a sterile aqueous liposomal suspension consisting of amikacin sulfate encapsulated in liposomes. This formulation of amikacin maximizes the achievable dose and delivery to the lungs of subjects infected via a nebulizer. Because liposome particles are small enough to penetrate and diffuse through sputum into the bacterial biofilm, they deposit drug in close proximity to the bacterial colonies, thus improving the bioavailability of amikacin at the infection site. The clinically achievable doses of amikacin in the LAI formulation can effectively increase the half-life of the drug in the lungs, and decrease the potential for systemic toxicity. LAI offers several advantages over current therapies in treating CF subjects with chronic infection caused by P. aeruginosa.
|
Cystic fibrosis is a genetic disease resulting from mutations in a 230 kb gene on chromosome 7 known as the cystic fibrosis transmembrane conductance regulator (CFTR). Study subjects with CF manifest pathological changes in a variety of organs that express CFTR. The lungs are frequently affected, the sequelae being chronic infections and airway inflammation. The principal goal of treatment of subjects with CF is to slow the chronic deterioration of lung function.
This is a Phase 2a study of safety, and tolerability of 28 days of daily dosing of two dose (280 mg, and 560 mg) cohorts of Arikace™ versus placebo. Study subjects will be randomized to receive either study drug or placebo (1.5% NaCl) by inhalation via a PARI eFlow® nebulizer. Cohort 1 (280mg) will complete 28 days of daily dosing with Arikace™ and 14 day post dosing safety evaluation by the Safety Committee (DSMB) before initiation of enrollment in Cohort 2 (560mg). Cohort 2 will complete 28 days of daily dosing, and a 14 day post dosing safety assessment by the DSMB to evaluate safety data. All study patients will be followed for safety, pharmacokinetics, clinical, and microbiologic activity for 28 days post completion of study treatment.
The total study period will be up to 56 days, with screening visit occurring within the preceding 14 days prior to randomization. Patients will be clinically evaluated during the first 48 hours post-randomization, and weekly for the 28 days treatment period, and during the follow up visits at study days 35, 42, 49, and 56 days to determine safety, tolerability, pharmacokinetics (PK), and clinical, and microbiologic activity.
Clinical laboratory parameters, audiology testing, clinical adverse events, and pulmonary function will be evaluated for all study subjects in order to determine the qualitative and quantitative safety and tolerability of Arikace™ compared to Placebo. Serum, urine, and sputum specimens will be collected at periodic intervals to assess PK. Additionally; sputum samples will be collected to determine changes in bacterial density. Pulmonary function testing and CFQ-R measurements will be assessed at selected time points throughout the study.
DSMB has recommended the amendment of the main study to evaluate safety and efficacy of additional cycles of treatment with Arikace™. All patients who were randomized in the main study, were compliant with the study protocol, and continue meeting study eligibility criteria can be consented to participate in the open-label extension to evaluate the safety, tolerability and efficacy of 560 mg once daily dose of Arikace™ administered for six cycles over eighteen months. Each cycle will comprise of 28 days of treatment followed by 56 days off treatment. The total extension period will be up to 518 days (74 weeks, about 18 months).
Clinical laboratory parameters, audiology testing, clinical adverse events, and pulmonary function will be evaluated for all study subjects in order to determine the longer term safety, tolerability, and efficacy of Arikace™. Serum specimens will be collected at periodic intervals to assess PK for safety. Additionally, sputum samples will be collected to determine changes in bacterial density. Pulmonary function testing and CFQ-R measurements will be assessed at selected time points throughout the study. Arikace™, Arikayce™, Liposomal Amikacin for Inhalation (LAI) and Amikacin Liposome Inhalation Suspension (ALIS) are all the same may be used interchangeably throughout the study and other studies evaluating amikacin liposome inhalation suspension.
|
Cystic Fibrosis
|
Cystic Fibrosis Respiratory Infections Pulmonary Cystic Fibrosis CFTR
| null | 4
|
arm 1: Subjects in this cohort will receive 280 mg of ARIKACE™ arm 2: Subjects in this arm of cohort 1 will receive matching placebo arm 3: Subjects in this cohort will receive 560 mg of ARIKACE™ arm 4: Subjects in this arm of cohort 2 will receive matching placebo
|
[
0,
2,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Study start date is before Jan 18, 2017. intervention 2: Study start date is before Jan 18, 2017.
|
intervention 1: ARIKACE™ intervention 2: Placebo
| 11
|
Leuven | N/A | Belgium | 4.70093 | 50.87959
Budapest | N/A | Hungary | 19.04045 | 47.49835
Kaposvár | N/A | Hungary | 17.8 | 46.36667
Skopje | N/A | North Macedonia | 21.43141 | 41.99646
Rabka-Zdrój | N/A | Poland | 19.96654 | 49.60889
Warsaw | N/A | Poland | 21.01178 | 52.22977
Belgrade | N/A | Serbia | 20.46513 | 44.80401
Bratislava | N/A | Slovakia | 17.10674 | 48.14816
Košice | N/A | Slovakia | 21.25808 | 48.71395
Kharkiv | N/A | Ukraine | 36.25475 | 49.98177
Kiev | N/A | Ukraine | 30.5238 | 50.45466
| 0
|
NCT00777296
|
[
3
] | 28
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
A double-blind, placebo-controlled study to evaluate changes in pain, urgency and urinary frequency following administration of URG101 compared to placebo.
| null |
Painful Bladder Syndrome Interstitial Cystitis Bladder Pain Syndrome
|
bladder pain urgency frequency
| null | 2
|
arm 1: Placebo Treatment on Visit 1 followed by URG101 Treatment on Visit 2 arm 2: URG101 Treatment on Visit 1 followed by Placebo Treatment on Visit 2
|
[
5,
5
] | 2
|
[
0,
0
] |
intervention 1: Bladder instillation of URG101 or Placebo in random order on treatment 1 and treatment 2 followed by an open-label URG101 on treatment 3 within the same week. intervention 2: Liquid formulation without active URG101 drug components
|
intervention 1: URG101 intervention 2: Placebo
| 6
|
Glendora | California | United States | -117.86534 | 34.13612
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
Cartersville | Georgia | United States | -84.80231 | 34.16533
San Antonio | Texas | United States | -98.49363 | 29.42412
| 0
|
NCT00517868
|
[
4
] | 524
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| null |
To evaluate the safety and efficacy of MNTX in participants who have undergone segmental colectomy and to assess if the time between the end of surgery and the first bowel movement is significantly shorter in the MNTX regimen than the equivalent assessment using a placebo regimen.
| null |
Post-Operative Ileus (POI)
| null | 3
|
arm 1: Participants will receive methylnaltrexone (MNTX) 12 milligrams (mg) as an intravenous (IV) infusion over approximately 20 minutes for every 6 hours until one of the following occurs: 1) 24 hours elapsed after the first bowel movement and the participant was tolerating clear liquids, 2) the participant was discharged from the hospital, or 3) a maximum of 10 days elapsed. The first dose of study drug will be administered within the first 90 minutes after the end of surgery (defined as the time when the last skin suture or staple is placed in the participant). arm 2: Participants will receive MNTX 24 mg as an IV infusion over approximately 20 minutes for every 6 hours until one of the following occurs: 1) 24 hours elapsed after the first bowel movement and the participant was tolerating clear liquids, 2) the participant was discharged from the hospital, or 3) a maximum of 10 days elapsed. The first dose of study drug will be administered within the first 90 minutes after the end of surgery (defined as the time when the last skin suture or staple is placed in the participant). arm 3: Participants will receive placebo matching to MNTX as an IV infusion over approximately 20 minutes for every 6 hours until one of the following occurs: 1) 24 hours elapsed after the first bowel movement and the participant was tolerating clear liquids, 2) the participant was discharged from the hospital, or 3) a maximum of 10 days elapsed. The first dose of study drug will be administered within the first 90 minutes after the end of surgery (defined as the time when the last skin suture or staple is placed in the participant).
|
[
0,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Methylnaltrexone will be administered as per the dose and schedule specified in the respective arms. intervention 2: Placebo matching to methylnaltrexone will be administered as per the schedule specified in the respective arm.
|
intervention 1: Methylnaltrexone intervention 2: Placebo
| 1
|
Tarrytown | New York | United States | -73.85875 | 41.07621
| 0
|
NCT00401375
|
|
[
3
] | 30
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
In some participants with cystic fibrosis (CF), the disease is caused by a nonsense mutation (premature stop codon) in the gene that makes the cystic fibrosis transmembrane regulator (CFTR) protein. Ataluren has been shown to partially restore CFTR production in animals with CF due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely increase functional CFTR protein in the cells of participants with CF due to a nonsense mutation.
|
In this study, participants with CF due to a nonsense mutation will be treated with a new investigational drug called ataluren. Evaluation procedures (history, physical examination, blood and urine tests to assess organ function, electrocardiogram \[ECG\], chest x-ray, and CF-specific tests) to determine if a participant qualifies for the study will be performed within 21 days prior to the start of treatment. Eligible participants with nonsense-mutation-mediated CF will receive 2 repeated 28-day cycles, each comprising of 14 days on therapy and 14 days off therapy. In a crossover design, participants will be randomized to receive ataluren treatment in Cycle 1 by either of the following regimens:
* Ataluren, given 3 times per day (TID) with a regimen of 4 milligrams/kilograms (mg/kg) at breakfast, 4 mg/kg at lunch, and 8 mg/kg at dinner, or
* Ataluren, given 3 TID with a regimen of 10 mg/kg at breakfast, 10 mg/kg at lunch and 20 mg/kg at dinner.
In Cycle 2, participants will then receive the drug according to the regimen opposite from that given in Cycle 1.
There will be a 2-night stay at the clinical research center at the beginning and at the end of each 14 days of ataluren treatment, which means that there will be four 2-night stays at the clinical research center during the study. During the study, ataluren efficacy, safety, and pharmacokinetics (PK) will be evaluated periodically with measurements of transepithelial potential difference (TEPD), nasal mucosal brushing to assess for cellular CFTR messenger ribonucleic acid (mRNA) and protein, medical history, physical examinations, blood tests, sputum test, urinalysis, ECGs, chest x-ray, and pulmonary function tests.
The measurement of TEPD, also known as nasal potential difference, provides a sensitive evaluation of sodium and chloride transport directly in secretory epithelial cells. TEPD assessments are made on the nasal epithelium cells lining the inferior turbinate because these cells are easier to access than the respiratory epithelial cells lining the lower airways and have been shown to have the same ion transport characteristics. As an endpoint, TEPD has the advantage that it can detect chloride transport changes that are a quantitative integration of the presence, functional activity, and apical location of the CFTR in airway cells. Furthermore, it is a direct measure of CFTR activity that is not likely to be affected by supportive or palliative treatments for CF (with the possible exception of systemically administered aminoglycoside antibiotics).
|
Cystic Fibrosis
|
Cystic fibrosis Nonsense mutation Premature stop codon
| null | 2
|
arm 1: During Cycle 1, participants will receive ataluren at 4 mg/kg in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants will crossover to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2. arm 2: During Cycle 1, participants will receive ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants will crossover to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2.
|
[
0,
0
] | 1
|
[
0
] |
intervention 1: Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, or apple juice. Participants are to receive a total of 42 doses of ataluren during each cycle, for a total of 84 doses of ataluren in both cycles.
|
intervention 1: Ataluren
| 3
|
Brussels | N/A | Belgium | 4.34878 | 50.85045
Leuven | N/A | Belgium | 4.70093 | 50.87959
Paris | N/A | France | 2.3488 | 48.85341
| 0
|
NCT00458341
|
[
4
] | 752
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| true
|
The purpose of this clinical research study is to learn if BMS-247550 added to the approved therapy of capecitabine is better than capecitabine alone in shrinking or slowing the growth of the cancer in women with metastatic breast cancer who are resistant to taxane and received anthracycline chemotherapy. The safety of this treatment will also be studied.
| null |
Breast Cancer Metastases
|
Metastatic Breast Cancer
| null | 2
|
arm 1: None arm 2: None
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Ixabepilone - Intravenous Solution, IV 40mg/m², Day 1 every 21 days, Until progression/unacceptable toxicity
Capecitabine (Active Comparator) - Tablet, Oral, 2000 mg/m², Bid Days 1-14 every 21 days, Until progression/unacceptable toxicity intervention 2: Tablet, Oral, 2500 mg/m², Bid Days 1-14 every 21 days, Until progression/unacceptable toxicity
|
intervention 1: Ixabepilone + Capecitabine intervention 2: Capecitabine
| 127
|
Little Rock | Arkansas | United States | -92.28959 | 34.74648
San Francisco | California | United States | -122.41942 | 37.77493
Vallejo | California | United States | -122.25664 | 38.10409
Denver | Colorado | United States | -104.9847 | 39.73915
Hartford | Connecticut | United States | -72.68509 | 41.76371
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Orlando | Florida | United States | -81.37924 | 28.53834
Baltimore | Maryland | United States | -76.61219 | 39.29038
Burlington | Massachusetts | United States | -71.19561 | 42.50482
Jackson | Mississippi | United States | -90.18481 | 32.29876
Columbia | Missouri | United States | -92.33407 | 38.95171
Kansas City | Missouri | United States | -94.57857 | 39.09973
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Livingston | New Jersey | United States | -74.31487 | 40.79593
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
New York | New York | United States | -74.00597 | 40.71427
Columbus | Ohio | United States | -82.99879 | 39.96118
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Columbia | South Carolina | United States | -81.03481 | 34.00071
Greenville | South Carolina | United States | -82.39401 | 34.85262
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Nashville | Tennessee | United States | -86.78444 | 36.16589
Austin | Texas | United States | -97.74306 | 30.26715
Houston | Texas | United States | -95.36327 | 29.76328
Ogden | Utah | United States | -111.97383 | 41.223
Burlington | Vermont | United States | -73.21207 | 44.47588
Tacoma | Washington | United States | -122.44429 | 47.25288
Morgantown | West Virginia | United States | -79.9559 | 39.62953
Capital Federal | Buenos Aires | Argentina | N/A | N/A
Haedo | Buenos Aires | Argentina | -58.59212 | -34.64239
La Plata | Buenos Aires | Argentina | -57.95442 | -34.92126
Mar del Plata | Buenos Aires | Argentina | -57.5562 | -38.00042
Pilar | Buenos Aires | Argentina | -58.91398 | -34.45867
Quilmes | Buenos Aires | Argentina | -58.25454 | -34.72065
Lanús | BuenosAires | Argentina | -58.39132 | -34.70757
Rosario | Santa Fe Province | Argentina | -60.63932 | -32.94682
Córdoba | N/A | Argentina | -64.18853 | -31.40648
Neuquén | N/A | Argentina | -68.0592 | -38.95078
Santa Fe | N/A | Argentina | -60.70868 | -31.64881
Edegem | N/A | Belgium | 4.44504 | 51.15662
Ghent | N/A | Belgium | 3.71667 | 51.05
Leuven | N/A | Belgium | 4.70093 | 50.87959
Liège | N/A | Belgium | 5.56749 | 50.63373
Fortaleza | Ceará | Brazil | -38.54306 | -3.71722
Belo Horizonte | Mina Gerais | Brazil | -43.93778 | -19.92083
Curitiba | Paraná | Brazil | -49.27306 | -25.42778
Porto Alegre | Rio Grande do Sul | Brazil | -51.23019 | -30.03283
Jaú | São Paulo | Brazil | -48.55778 | -22.29639
Santo André | São Paulo | Brazil | -46.53833 | -23.66389
Sao Paulo - Sp | São Paulo | Brazil | N/A | N/A
São Paulo | N/A | Brazil | -46.63611 | -23.5475
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Oshawa | Ontario | Canada | -78.84957 | 43.90012
Toronto | Ontario | Canada | -79.39864 | 43.70643
Montreal | Quebec | Canada | -73.58781 | 45.50884
Beijing | Beijing Municipality | China | 116.39723 | 39.9075
Guangzhou | Guangdong | China | 113.25 | 23.11667
Nanjing | Jiangsu | China | 118.77778 | 32.06167
Jinan | Shandong | China | 116.99722 | 36.66833
Beijing | Shanghai Municipality | China | N/A | N/A
Xi’an | Shanxi | China | 113.52486 | 35.99785
Beijing | N/A | China | 116.39723 | 39.9075
Shanghai | N/A | China | 121.45806 | 31.22222
Angers | N/A | France | -0.55202 | 47.47156
Avignon | N/A | France | 4.80892 | 43.94834
Bayonne | N/A | France | -1.473 | 43.49316
Besançon | N/A | France | 6.01815 | 47.24878
Bobigny | N/A | France | 2.45012 | 48.90982
Bordeaux | N/A | France | -0.5805 | 44.84044
Clermont-Ferrand | N/A | France | 3.08682 | 45.77969
Lyon | N/A | France | 4.84671 | 45.74846
Nantes | N/A | France | -1.55336 | 47.21725
Nice | N/A | France | 7.26608 | 43.70313
Saint-Brieuc | N/A | France | -2.76838 | 48.51513
Saint-Cloud | N/A | France | 2.20289 | 48.84598
Saint-Herblain | N/A | France | -1.651 | 47.21154
Strasbourg | N/A | France | 7.74553 | 48.58392
Toulouse | N/A | France | 1.44367 | 43.60426
Berlin | N/A | Germany | 13.41053 | 52.52437
Duisburg | N/A | Germany | 6.76516 | 51.43247
Erlangen | N/A | Germany | 11.00783 | 49.59099
Athens | N/A | Greece | 23.72784 | 37.98376
Thessaloniki | N/A | Greece | 22.93086 | 40.64361
Budapest | N/A | Hungary | 19.04045 | 47.49835
Debrecen | N/A | Hungary | 21.62444 | 47.53167
Győr | N/A | Hungary | 17.63512 | 47.68333
Pécs | N/A | Hungary | 18.23083 | 46.0725
Brescia | N/A | Italy | 10.21472 | 45.53558
Candiolo (To) | N/A | Italy | 7.59812 | 44.95858
Forlì | N/A | Italy | 12.04144 | 44.22177
San Giovanni Rotondo | N/A | Italy | 15.7277 | 41.70643
Kampung Baharu Nilai | Negeri Sembilan | Malaysia | 101.7972 | 2.8033
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Acapulco de Juárez | Guerrero | Mexico | -99.90891 | 16.84942
Mérida | Yucatán | Mexico | -89.62318 | 20.967
Chihuahua City | N/A | Mexico | -106.08889 | 28.63528
Distrito Federal | N/A | Mexico | -93.02694 | 16.59
San Luis Potosí City | N/A | Mexico | -100.97135 | 22.15234
Lima | N/A | Peru | -77.02824 | -12.04318
Manila | N/A | Philippines | 120.9822 | 14.6042
Quezon | N/A | Philippines | 125.09889 | 7.73028
Quezon City | N/A | Philippines | 121.0509 | 14.6488
Gdansk | N/A | Poland | 18.64912 | 54.35227
Opole | N/A | Poland | 17.92533 | 50.67211
Incheon | N/A | South Korea | 126.70515 | 37.45646
Seoul | N/A | South Korea | 126.9784 | 37.566
Barcelona | N/A | Spain | 2.15899 | 41.38879
Girona | N/A | Spain | 2.82493 | 41.98311
Madrid | N/A | Spain | -3.70256 | 40.4165
Valencia | N/A | Spain | -0.37966 | 39.47391
Zaragoza | N/A | Spain | -0.87734 | 41.65606
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Tainan City | N/A | Taiwan | 120.21333 | 22.99083
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Bristol | Avon | United Kingdom | -2.59665 | 51.45523
Chelmsford | Essex | United Kingdom | 0.46958 | 51.73575
London | Greater London | United Kingdom | -0.12574 | 51.50853
Manchester | Greater Manchester | United Kingdom | -2.23743 | 53.48095
Sheffield | South Yorkshire | United Kingdom | -1.4659 | 53.38297
Guildford | Surrey | United Kingdom | -0.57427 | 51.23536
Newcastle upon Tyne | Tyne and Wear | United Kingdom | -1.61396 | 54.97328
| 1
|
NCT00080301
|
[
4
] | 1,221
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| true
|
The purpose of this clinical research study is to learn if BMS-247550 added to the approved therapy of capecitabine (Xeloda) provides measurable clinical benefits over capecitabine alone in women with metastatic breast cancer. Patients should have previously received an anthracycline and a taxane. The safety of this treatment will also be studied.
| null |
Cancer Breast Cancer
| null | 2
|
arm 1: None arm 2: None
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Ixabepilone lypholized powder/Diluent for solution for injection/Tablets, IV/Oral, 40 mg/m2 + Capecitabine 2000 mg/m2, Ixabepilone on Day 1 and Capecitabine twice daily Days 1-14 of 21 day cycle intervention 2: Tablet, Oral, 2500 mg/m2, Capecitabine twice daily Days 1-14 of 21 day cycle
|
intervention 1: Ixabepilone + Capecitabine intervention 2: Capecitabine
| 186
|
Tucson | Arizona | United States | -110.92648 | 32.22174
Beverly Hills | California | United States | -118.40036 | 34.07362
Corona | California | United States | -117.56644 | 33.87529
Hartford | Connecticut | United States | -72.68509 | 41.76371
Plantation | Florida | United States | -80.23184 | 26.13421
Boise | Idaho | United States | -116.20345 | 43.6135
Evanston | Illinois | United States | -87.69006 | 42.04114
Iowa City | Iowa | United States | -91.53017 | 41.66113
Louisville | Kentucky | United States | -85.75941 | 38.25424
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
Bethesda | Maryland | United States | -77.10026 | 38.98067
Boston | Massachusetts | United States | -71.05977 | 42.35843
Jackson | Mississippi | United States | -90.18481 | 32.29876
Columbia | Missouri | United States | -92.33407 | 38.95171
Voorhees Township | New Jersey | United States | -74.49062 | 40.4795
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Latham | New York | United States | -73.75901 | 42.74702
Mineola | New York | United States | -73.64068 | 40.74927
New York | New York | United States | -74.00597 | 40.71427
The Bronx | New York | United States | -73.86641 | 40.84985
Durham | North Carolina | United States | -78.89862 | 35.99403
Goldsboro | North Carolina | United States | -77.99277 | 35.38488
Hickory | North Carolina | United States | -81.3412 | 35.73319
Kinston | North Carolina | United States | -77.58164 | 35.26266
Canton | Ohio | United States | -81.37845 | 40.79895
Columbus | Ohio | United States | -82.99879 | 39.96118
Langhorne | Pennsylvania | United States | -74.92267 | 40.17455
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Memphis | Tennessee | United States | -90.04898 | 35.14953
Dallas | Texas | United States | -96.80667 | 32.78306
Charlottesville | Virginia | United States | -78.47668 | 38.02931
Norfolk | Virginia | United States | -76.28522 | 36.84681
Richmond | Virginia | United States | -77.46026 | 37.55376
Marshfield | Wisconsin | United States | -90.1718 | 44.66885
Avellaneda | Buenos Aires | Argentina | -58.36744 | -34.66018
Bahía Blanca | Buenos Aires | Argentina | -62.26545 | -38.7176
Belén de Escobar | Buenos Aires | Argentina | -58.79442 | -34.34602
Ciudad Autonoma de Buenos Aires | Buenos Aires | Argentina | N/A | N/A
Resistencia | Chaco Province | Argentina | -58.98665 | -27.46363
Barrio Alto Verde | Córdoba Province | Argentina | N/A | N/A
San Miguel de Tucumán | Tucumán Province | Argentina | -65.21051 | -26.81601
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Mendoza | N/A | Argentina | -68.84582 | -32.88946
Salta | N/A | Argentina | -65.41999 | -24.80645
Santa Fe | N/A | Argentina | -60.70868 | -31.64881
Sydney | New South Wales | Australia | 151.20732 | -33.86785
Westmead | New South Wales | Australia | 150.98768 | -33.80383
Brisbane | Queensland | Australia | 153.02809 | -27.46794
Herston | Queensland | Australia | 153.01852 | -27.44453
South Brisbane | Queensland | Australia | 153.02049 | -27.48034
Toowoomba | Queensland | Australia | 151.95386 | -27.56056
Adelaide | South Australia | Australia | 138.59863 | -34.92866
Woodville | South Australia | Australia | 138.54291 | -34.877
East Melbourne | Victoria | Australia | 144.9879 | -37.81667
Parkville | Victoria | Australia | 144.95 | -37.78333
Perth | Western Australia | Australia | 115.8614 | -31.95224
Graz | N/A | Austria | 15.45 | 47.06667
Vienna | N/A | Austria | 16.37208 | 48.20849
Vöcklabruck | N/A | Austria | 13.65652 | 48.00279
Brussels | N/A | Belgium | 4.34878 | 50.85045
Charleroi | N/A | Belgium | 4.44448 | 50.41136
Ghent | N/A | Belgium | 3.71667 | 51.05
Hasselt | N/A | Belgium | 5.33781 | 50.93106
Kortrijk | N/A | Belgium | 3.26487 | 50.82803
Wilrijk | N/A | Belgium | 4.39513 | 51.16734
Centro-Porto Alegre | Rio Grande do Sul | Brazil | N/A | N/A
Bela Vista | São Paulo | Brazil | -46.64758 | -23.56086
Higienopolis | São Paulo | Brazil | N/A | N/A
São Paulo | São Paulo | Brazil | -46.63611 | -23.5475
Rio de Janeiro | N/A | Brazil | -43.18223 | -22.90642
Thunder Bay | Ontario | Canada | -89.25018 | 48.38202
Montreal | Quebec | Canada | -73.58781 | 45.50884
Santiago | Santiago Metropolitan | Chile | -70.64827 | -33.45694
Beijing | Beijing Municipality | China | 116.39723 | 39.9075
Guangzhou | Guangdong | China | 113.25 | 23.11667
Nanjing | Jiangsu | China | 118.77778 | 32.06167
Dalian | Liaoning | China | 121.60222 | 38.91222
Dilian | Liaoning | China | N/A | N/A
Jinan | Shandong | China | 116.99722 | 36.66833
Shanghai | Shanghai Municipality | China | 121.45806 | 31.22222
Xi’an | Shanxi | China | 113.52486 | 35.99785
Hangzhou | Zhejiang | China | 120.16142 | 30.29365
Split | N/A | Croatia | 16.43915 | 43.50891
Zagreb | N/A | Croatia | 15.97798 | 45.81444
Brno | N/A | Czechia | 16.60796 | 49.19522
Hradec Králové | N/A | Czechia | 15.83277 | 50.20923
Prague | N/A | Czechia | 14.42076 | 50.08804
Aalborg | N/A | Denmark | 9.9187 | 57.048
Herlev | N/A | Denmark | 12.43998 | 55.72366
København Ø | N/A | Denmark | 12.56862 | 55.70968
Angers | N/A | France | -0.55202 | 47.47156
Bordeaux | N/A | France | -0.5805 | 44.84044
Caen | N/A | France | -0.35912 | 49.18585
Clermont-Ferrand | N/A | France | 3.08682 | 45.77969
Colmar | N/A | France | 7.35584 | 48.08078
Le Mans | N/A | France | 0.20251 | 48.0021
Metz | N/A | France | 6.17269 | 49.11911
Paris | N/A | France | 2.3488 | 48.85341
Pierre-Bénite | N/A | France | 4.82424 | 45.70359
Reims | N/A | France | 4.02853 | 49.26526
Saint-Brieuc | N/A | France | -2.76838 | 48.51513
Saint-Grégoire | N/A | France | -1.68579 | 48.15101
Saint-Herblain | N/A | France | -1.651 | 47.21154
Tours | N/A | France | 0.70398 | 47.39484
Villejuif | N/A | France | 2.35992 | 48.7939
Berlin | N/A | Germany | 13.41053 | 52.52437
Erlangen | N/A | Germany | 11.00783 | 49.59099
Essen | N/A | Germany | 7.01228 | 51.45657
Hanover | N/A | Germany | 9.73322 | 52.37052
Karlsruhe | N/A | Germany | 8.40444 | 49.00937
Kiel | N/A | Germany | 10.13489 | 54.32133
Marburg | N/A | Germany | 8.77069 | 50.80904
München | N/A | Germany | 13.31243 | 51.60698
Rehling | N/A | Germany | 10.93333 | 48.48333
Saarbrücken | N/A | Germany | 7.00982 | 49.23262
Tübingen | N/A | Germany | 9.05222 | 48.52266
Ulm | N/A | Germany | 9.99155 | 48.39841
Wiesbaden | N/A | Germany | 8.24932 | 50.08258
Athens | N/A | Greece | 23.72784 | 37.98376
Crete | N/A | Greece | N/A | N/A
Pátrai | N/A | Greece | 21.73444 | 38.24444
Thessaloniki | N/A | Greece | 22.93086 | 40.64361
Wilton | Cork | Ireland | N/A | N/A
Cork | N/A | Ireland | -8.47061 | 51.89797
Dublin | N/A | Ireland | -6.24889 | 53.33306
Galway | N/A | Ireland | -9.05095 | 53.27245
Haifa | N/A | Israel | 34.99928 | 32.81303
Jerusalem | N/A | Israel | 35.21633 | 31.76904
Ramat Gan | N/A | Israel | 34.81065 | 32.08227
Tel Aviv | N/A | Israel | 34.78057 | 32.08088
Rozzano | Milan | Italy | 9.1559 | 45.38193
Bari | N/A | Italy | 16.86982 | 41.12066
Florence | N/A | Italy | 11.24626 | 43.77925
Genova | N/A | Italy | 11.87211 | 45.21604
Milan | N/A | Italy | 12.59836 | 42.78235
Modena | N/A | Italy | 10.92539 | 44.64783
Perugia | N/A | Italy | 12.38878 | 43.1122
Potenza | N/A | Italy | 15.80794 | 40.64175
Roma | N/A | Italy | 11.10642 | 44.99364
San Giovanni Rotondo | N/A | Italy | 15.7277 | 41.70643
Sora | N/A | Italy | 13.61356 | 41.71829
Torino | N/A | Italy | 11.99138 | 44.88856
Arnhem | N/A | Netherlands | 5.91111 | 51.98
Enschede | N/A | Netherlands | 6.89583 | 52.21833
The Hague | N/A | Netherlands | 4.29861 | 52.07667
Zwolle | N/A | Netherlands | 6.09444 | 52.5125
Coimbra | N/A | Portugal | -8.41955 | 40.20564
Lisbon | N/A | Portugal | -9.1498 | 38.72509
Kazan' | N/A | Russia | 49.12214 | 55.78874
Moscow | N/A | Russia | 37.61556 | 55.75222
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Singapore | N/A | Singapore | 103.85007 | 1.28967
Port Elizabeth | Eastern Cape | South Africa | 25.61494 | -33.96109
Johannesburg | Gauteng | South Africa | 28.04363 | -26.20227
Pretoria | Gauteng | South Africa | 28.18783 | -25.74486
Panorama | Western Cape | South Africa | N/A | N/A
Gyeonggi-do | N/A | South Korea | 126.76917 | 37.58944
Incheon | N/A | South Korea | 126.70515 | 37.45646
Seoul | N/A | South Korea | 126.9784 | 37.566
Terassa | Barcelona | Spain | N/A | N/A
Barcelona | N/A | Spain | 2.15899 | 41.38879
Cadiz | N/A | Spain | -6.2891 | 36.52672
Córdoba | N/A | Spain | -4.77275 | 37.89155
Elche (Alicante) | N/A | Spain | -0.70107 | 38.26218
Jaén | N/A | Spain | -3.79028 | 37.76922
L'Hospitalet de Llobregat | N/A | Spain | 2.10028 | 41.35967
Madrid | N/A | Spain | -3.70256 | 40.4165
Pontevedra | N/A | Spain | -8.64435 | 42.431
Reus | N/A | Spain | 1.10687 | 41.15612
Salamanca | N/A | Spain | -3.67975 | 40.42972
Santa Cruz de Tenerife | N/A | Spain | -16.25462 | 28.46824
Seville | N/A | Spain | -5.97317 | 37.38283
Valencia | N/A | Spain | -0.37966 | 39.47391
Zaragoza | N/A | Spain | -0.87734 | 41.65606
Bern | N/A | Switzerland | 7.44744 | 46.94809
Thun | N/A | Switzerland | 7.62166 | 46.75118
Zurich | N/A | Switzerland | 8.55 | 47.36667
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Ankara | N/A | Turkey (Türkiye) | 32.85427 | 39.91987
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Izmir | N/A | Turkey (Türkiye) | 27.13838 | 38.41273
Belfast | Armagh | United Kingdom | -5.92541 | 54.59682
Glasgow | Central | United Kingdom | -4.25763 | 55.86515
London | Greater London | United Kingdom | -0.12574 | 51.50853
Shrewsbury | Shropshire | United Kingdom | -2.75208 | 52.71009
Birmingham | West Midlands | United Kingdom | -1.89983 | 52.48142
| 1
|
NCT00082433
|
|
[
4
] | 200
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
The purpose of this study is to compare the safety and efficacy of XERECEPT® to dexamethasone (Decadron) a common treatment for symptoms of brain swelling (edema). This study is specifically aimed at patients who require chronic high doses of dexamethasone to manage symptoms.
|
XERECEPT® is not a potential treatment for cancer, but may reduce the edema associated with tumors and as a result, decrease neurological symptoms.
|
Brain Edema Brain Tumor
|
peritumoral brain edema edema malignant brain tumor astrocytoma brain tumor dexamethasone Decadron
| null | 2
|
arm 1: Patients will take hCRF (XERECEPT) 2mg/day and open label-dexamethasone they are currently taking. arm 2: Patient will receive placebo hCRF and any open-label dexamethasone that they are currently taking
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: hCRF ; open-label dexamethasone that the patient is currently taking intervention 2: placebo hCRF 2mg/day and open-label dexamethasone that they are taking
|
intervention 1: hCRF intervention 2: placebo hCRF
| 34
|
Phoenix | Arizona | United States | -112.07404 | 33.44838
Fresno | California | United States | -119.77237 | 36.74773
Newport Beach | California | United States | -117.92895 | 33.61891
Palo Alto | California | United States | -122.14302 | 37.44188
Sacramento | California | United States | -121.4944 | 38.58157
San Diego | California | United States | -117.16472 | 32.71571
Aurora | Colorado | United States | -104.83192 | 39.72943
Englewood | Colorado | United States | -104.98776 | 39.64777
Jacksonville | Florida | United States | -81.65565 | 30.33218
Orlando | Florida | United States | -81.37924 | 28.53834
Tampa | Florida | United States | -82.45843 | 27.94752
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Evanston | Illinois | United States | -87.69006 | 42.04114
Boston | Massachusetts | United States | -71.05977 | 42.35843
Detroit | Michigan | United States | -83.04575 | 42.33143
Ridgewood | New Jersey | United States | -74.11653 | 40.97926
Amherst | New York | United States | -78.79976 | 42.97839
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Columbus | Ohio | United States | -82.99879 | 39.96118
Portland | Oregon | United States | -122.67621 | 45.52345
Seattle | Washington | United States | -122.33207 | 47.60621
Madison | Wisconsin | United States | -89.40123 | 43.07305
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Winnipeg | Manitoba | Canada | -97.14704 | 49.8844
Moncton | New Brunswick | Canada | -64.7965 | 46.09454
Halifax | Nova Scotia | Canada | -63.57688 | 44.64269
Kingston | Ontario | Canada | -76.48098 | 44.22976
Ottawa | Ontario | Canada | -75.69812 | 45.41117
Toronto | Ontario | Canada | -79.39864 | 43.70643
| 1
|
NCT00088166
|
[
3
] | 61
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to test whether sunitinib (SU011248) has activity and is safe in patients with renal cell carcinoma (RCC) who have failed prior therapy with bevacizumab (Avastin) -based treatment.
| null |
Carcinoma, Renal Cell
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: 50 mg orally daily for 4 weeks followed by 2 weeks off treatment for approximately 1 year or until disease progression/unacceptable toxicity; after completion of 1 year, pts with clinical benefit can continue the study treatment in a separate continuation protocol
|
intervention 1: Sunitinib
| 11
|
Duarte | California | United States | -117.97729 | 34.13945
Pasadena | California | United States | -118.14452 | 34.14778
San Francisco | California | United States | -122.41942 | 37.77493
Chicago | Illinois | United States | -87.65005 | 41.85003
Boston | Massachusetts | United States | -71.05977 | 42.35843
Boston | Massachusetts | United States | -71.05977 | 42.35843
Boston | Massachusetts | United States | -71.05977 | 42.35843
Durham | North Carolina | United States | -78.89862 | 35.99403
Cleveland | Ohio | United States | -81.69541 | 41.4995
Nashville | Tennessee | United States | -86.78444 | 36.16589
Dallas | Texas | United States | -96.80667 | 32.78306
| 1
|
NCT00089648
|
|
[
4
] | 4,628
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 2DOUBLE
| false
| 0ALL
| true
|
To assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in a population of high-risk patients with atrial fibrillation/atrial flutter (AF/AFL).
To assess that dronedarone is well tolerated in this population.
|
This is a prospective, multinational, double-blind, randomized, multi-center, placebo-controlled, parallel-group trial evaluating the effects of dronedarone versus placebo (ratio 1:1) over a minimum treatment duration of 12 months and a mean follow-up duration of 1.75 years (in AF/AFL patients). Patients can be included in the study while in atrial fibrillation/flutter or in sinus rhythm if conversion has occurred either spontaneously or following a procedure such as electrical cardioversion (or overdrive pacing) or administration of an antiarrhythmic drug.After randomization all patients will be followed until the common study end date; the last patient included in the study will be followed for 1 year. Visits will be at baseline, after 7 days, after 14 days, after one month, after three months and then every three months until end of the study. At each visit patients will be asked for the occurrence of hospitalizations or other events since the last visit. The study will be monitored by an independent Data Monitoring Committee (DMC) for safety, tolerability and efficacy.
|
Atrial Fibrillation Atrial Flutter
|
Mortality, Hospitalization
| null | 2
|
arm 1: Dronedarone 400mg tablets twice daily (bid) arm 2: matching placebo tablets
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: oral administration (tablets) intervention 2: oral administration (tablets)
|
intervention 1: dronedarone (SR33589) intervention 2: placebo
| 37
|
Bridgewater | New Jersey | United States | -74.64815 | 40.60079
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
New South Wales | N/A | Australia | N/A | N/A
Vienna | N/A | Austria | 16.37208 | 48.20849
Diegem | N/A | Belgium | 4.43354 | 50.89727
Laval | N/A | Canada | -73.692 | 45.56995
Santiago | N/A | Chile | -70.64827 | -33.45694
Shangaï | N/A | China | N/A | N/A
Prague | N/A | Czechia | 14.42076 | 50.08804
Helsinki | N/A | Finland | 24.93545 | 60.16952
Berlin | N/A | Germany | 13.41053 | 52.52437
Athens | N/A | Greece | 23.72784 | 37.98376
Causeway Bay | N/A | Hong Kong | 114.18515 | 22.28189
Budapest | N/A | Hungary | 19.04045 | 47.49835
Mumbai | N/A | India | 72.88261 | 19.07283
Netanya | N/A | Israel | 34.85992 | 32.33291
Milan | N/A | Italy | 12.59836 | 42.78235
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Mexico | N/A | Mexico | -98.43784 | 18.88011
Casablanca | N/A | Morocco | -7.61138 | 33.58831
Gouda | N/A | Netherlands | 4.70833 | 52.01667
Macquarie Park | N/A | New Zealand | N/A | N/A
Lysaker | N/A | Norway | 10.63545 | 59.90994
Makati City | N/A | Philippines | 121.03269 | 14.55027
Warsaw | N/A | Poland | 21.01178 | 52.22977
Porto Salvo | N/A | Portugal | -9.30473 | 38.72293
Moscow | N/A | Russia | 37.61556 | 55.75222
Singapore | N/A | Singapore | 103.85007 | 1.28967
Midrand | N/A | South Africa | 28.118 | -25.976
Seoul | N/A | South Korea | 126.9784 | 37.566
Barcelona | N/A | Spain | 2.15899 | 41.38879
Bromma | N/A | Sweden | 17.94 | 59.34
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Mégrine | N/A | Tunisia | 10.23639 | 36.76917
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Guildford Surrey | N/A | United Kingdom | N/A | N/A
| 1
|
NCT00174785
|
[
3
] | 69
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of the study is to determine if treatment of older patients indicated with untreated Acute Myeloid Leukemia (AML) who are not considered to be suitable for intensive chemotherapy, can effectively be treated with Clofarabine.
|
Note: This clinical trial was conducted by Bioenvision Ltd. Bioenvision Ltd. was acquired by Genzyme Corporation Oct 2007.
|
Acute Myeloid Leukemia
|
acute myelogenous leukemia acute myeloid leukemia clolar evoltra clofarabine untreated acute leukemia adult acute leukemia
| null | 1
|
arm 1: Clofarabine 30 mg/m\^2/day intravenously over 1 hour for 5 days every 28 to 42 days (one cycle), then 20mg/m\^2/day intravenously over 1 hour for 5 days every 29 to 43 days for the second and subsequent cycles, up to a maximum of 3 cycles.
|
[
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: clofarabine
| 15
|
Dublin | N/A | Ireland | -6.24889 | 53.33306
Bologna | N/A | Italy | 11.33875 | 44.49381
Rome | N/A | Italy | 12.51133 | 41.89193
Belfast | Northern Ireland | United Kingdom | -5.92541 | 54.59682
Aberdeen | N/A | United Kingdom | -2.09814 | 57.14369
Birmingham | N/A | United Kingdom | -1.89983 | 52.48142
Cardiff | N/A | United Kingdom | -3.18 | 51.48
Edinburgh | N/A | United Kingdom | -3.19648 | 55.95206
Leicester | N/A | United Kingdom | -1.13169 | 52.6386
Liverpool | N/A | United Kingdom | -2.97794 | 53.41058
London | N/A | United Kingdom | -0.12574 | 51.50853
Manchester | N/A | United Kingdom | -2.23743 | 53.48095
Nottingham | N/A | United Kingdom | -1.15047 | 52.9536
Somerset | N/A | United Kingdom | N/A | N/A
Taunton | N/A | United Kingdom | -3.10293 | 51.01494
| 1
|
NCT00924443
|
[
3
] | 42
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
This study will determine the safety and effectiveness of a combination of the immune-suppressing drugs antithymocyte globulin (ATG) and cyclosporine for treating myelodysplasia, a disorder of low blood cell counts. It will: evaluate whether this drug combination can increase blood counts in patients and reduce their need for transfusions; compare survival of patients who respond to ATG and cyclosporine treatment with those who do not respond; and determine the side effects of the treatment.
Myelodysplasia is thought to result from an immune system abnormality in which cells called lymphocytes attack the marrow's blood-forming cells. The resulting deficiencies of platelets and red and white blood cells cause anemia, susceptibility to infections, and easy bruising and bleeding. Various therapies, such as blood transfusions for anemia and bleeding, antibiotics for infection, chemotherapy and bone marrow transplantation are used to treat myelodysplasia, but all have disadvantages and some carry serious risks.
Patients 18 years of age and older with myelodysplasia may be eligible for this study. Candidates will be screened with a physical examination and medical history, blood tests, chest X-ray, electrocardiogram and bone marrow biopsy (removal of a marrow sample from the hipbone for microscopic examination).
|
Participants will be admitted to the NIH Clinical Center for the first 10 to 14 days of treatment and will then continue therapy on an outpatient basis. They will undergo the following tests and procedures:
* Placement of central line-An intravenous (IV) catheter (flexible tube inserted into a vein) is placed in a large vein of the neck, chest or arm. Medicines are delivered through this line and blood samples are drawn from it.
* ATG skin testing- ATG is injected under the skin to check for sensitization to horse serum, from which the drug is derived.
* ATG treatment-Four doses of ATG are given through the IV line on each of 4 consecutive days. Prednisone is taken by mouth beginning the first day of ATG therapy and continuing for a total of 17 days. This drug is given to reduce the side effects of ATG, such as fever, skin rash and chills.
* Cyclosporine treatment- Cyclosporine capsules are taken by mouth twice a day for at least 6 months.
During hospitalization, blood will be drawn daily for blood counts and other tests. Upon the patient's discharge after 10 days, the referring physician will do blood tests weekly during the first month of treatment and then every 2 weeks for the rest of the time the patient is taking cyclosporine. Dosages of this drug may be adjusted depending on the test results. Patients will be evaluated at the NIH Clinical Center at 3-month intervals for the first year, then every 6 months for the next 3 years and then at yearly intervals. A blood sample will be drawn at each visit. Bone marrow biopsies will be done at 6-month intervals for the first 3 years after treatment.
A growing body of laboratory and clinical evidence suggests that the cytopenia of MDS is at least partly a result of cytotoxic T cell activity. Treatments to abrogate T cell activity such as anti-thymocyte globulin alone and cyclosporine alone have demonstrated varying degrees of success in alleviating the cytopenia of MDS. A response to such therapy in MDS is associated with improved survival. Experience with aplastic anemia suggests that the combination of these two agents should be more effective in suppressing cytotoxic T cell activity and alleviating cytopenia. This protocol proposes using the combination of antithymocyte globulin (ATG) and cyclosporine (CSA) to treat the cytopenia of MDS, in an effort to improve the response rate to immunosuppressive therapy in this disease.
|
Myelodysplastic Syndrome
|
MDS Immunosuppression ATG Cyclosporine Myelodysplastic Syndrome
| null | 1
|
arm 1: Myelodysplastic syndromes (MDS) subjects will be treated with Anti-thymocyte Globulin (ATG) and cyclosporine (CsA). The subjects will receive ATG at a dose of 40mg/kg orally on days 1-4 in combination with oral prednisone at a dose of 1mg/kg/day on day one. The prednisone will be tapered on day 10. The taper schedule will be every two days over a total of eight days (days 10-17). Drug the ATG administration the subjects will receive at least 4 units of platelets daily for platelet counts less than 20,000/ microliters. Cyclosporine (CsA) will be started on day 14 at a dose of 5mg/kg twice daily with dose adjustments based on drug levels (target 200-400 ng/ml). Cyclosporine therapy will be continued for six months.
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: Antithymocyte globulin (ATG) intravenous infusion: 40mg/kg/day. Infusion over 6 hours on day 1-4. intervention 2: Cyclosporine (CsA) intravenous infusion: 5mg/kg. Infusion on day 14 administered twice a day.
|
intervention 1: Antithymocyte globulin intervention 2: Cyclosporine
| 1
|
Bethesda | Maryland | United States | -77.10026 | 38.98067
| 0
|
NCT00005937
|
[
4
] | 488
|
RANDOMIZED
|
FACTORIAL
| 0TREATMENT
| 4QUADRUPLE
| true
| 0ALL
| null |
This randomized, controlled trial compared the efficacy of the medication sertraline (Zoloft®), cognitive-behavioral therapy, the combination of these treatments, and placebo for youth with anxiety disorders.
|
Anxiety disorders are among the most common conditions affecting children and adolescents. These disorders impair school, social, and family functioning. When left untreated, they also put children at risk for major depression and substance abuse in late adolescence and adulthood. Previous studies demonstrated the efficacy of cognitive behavioral therapy and selective serotonin-reuptake inhibitors for the treatment of child anxiety disorders. This study is testing the relative and combined efficacy of cognitive behavioral therapy and selective serotonin reuptake inhibitors as compared to each other and pill placebo.
During Phase I of this two-phase study, 488 participants were randomly assigned to receive sertraline (Zoloft), cognitive behavioral therapy, a combination of these treatments, or a placebo for 12 weeks. Phase II involved a 6-month maintenance period for participants.
|
Anxiety Disorders Social Phobia Generalized Anxiety Disorder
|
Phobic Disorders Anxiety, Separation
| null | 4
|
arm 1: Participants received sertraline for 12 weeks. arm 2: Participants received cognitive behavioral therapy for 12 weeks arm 3: Participants received both sertraline and CBT for 12 weeks. arm 4: Participants received a placebo pill for 12 weeks.
|
[
1,
1,
1,
2
] | 3
|
[
0,
5,
0
] |
intervention 1: Participants were treated with sertraline. intervention 2: Participants received CBT. intervention 3: Participants were treated with a placebo pill.
|
intervention 1: Sertraline (SRT) intervention 2: Cognitive Behavioral Therapy (CBT) intervention 3: Placebo
| 6
|
Los Angeles | California | United States | -118.24368 | 34.05223
Baltimore | Maryland | United States | -76.61219 | 39.29038
New York | New York | United States | -74.00597 | 40.71427
Durham | North Carolina | United States | -78.89862 | 35.99403
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
| 0
|
NCT00052078
|
[
2,
3
] | 31
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| null |
This phase I/II trial studies the best dose of suramin when given together with paclitaxel in treating women with stage IIIB-IV breast cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Suramin may increase the effectiveness of paclitaxel by making tumor cells more sensitive to the drug.
|
PRIMARY OBJECTIVES:
I. Determine the dose of suramin in combination with paclitaxel (TXT) that results in suramin plasma concentrations approaching 10-50 uM over the duration, when TXT in the plasma is at therapeutically significant levels, in women with stage IIIB or IV breast cancer. (Phase I) II. Determine the objective response rate in patients treated with this regimen. (Phase II)
SECONDARY OBJECTIVES:
I. Determine the pharmacokinetics of low-dose suramin in these patients. (Phase I) II. Determine the time to tumor progression in patients treated with this regimen. (Phase II) III. Determine the 1-year survival of patients treated with this regimen. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of suramin followed by a phase II multicenter study.
PHASE I: Patients receive low-dose suramin intravenously (IV) over 30 minutes and paclitaxel IV over 1 hour once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive adjusted doses of suramin until a target dose is determined. The suramin target dose is defined as the dose at which at least 5 of 6 patients achieve the target plasma concentration of 10-50 uM over the duration when paclitaxel levels are therapeutic.
PHASE II: Patients receive paclitaxel in combination with the target dose of suramin as above.
PROJECTED ACCRUAL: A total of 6-18 patients will be accrued for the phase I study within 9 months. A total of 28 patients will be accrued for the phase II study within 18-24 months.
|
Recurrent Breast Cancer Stage IIIB Breast Cancer Stage IV Breast Cancer
| null | 1
|
arm 1: PHASE I: Patients receive low-dose suramin IV over 30 minutes and paclitaxel IV over 1 hour once weekly. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive adjusted doses of suramin until a target dose is determined. The suramin target dose is defined as the dose at which at least 5 of 6 patients achieve the target plasma concentration of 10-50 uM over the duration when paclitaxel levels are therapeutic.
PHASE II: Patients receive paclitaxel in combination with the target dose of suramin as above.
|
[
0
] | 3
|
[
0,
0,
10
] |
intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies
|
intervention 1: suramin intervention 2: paclitaxel intervention 3: pharmacological study
| 1
|
Columbus | Ohio | United States | -82.99879 | 39.96118
| 0
|
NCT00054028
|
|
[
3
] | 28
| null | null | 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
Nonalcoholic Steatohepatitis (NASH) is associated with progressive liver disease, fibrosis, and cirrhosis. Although the cause of NASH is unknown, it is often associated with obesity, type 2 diabetes, and insulin resistance. At present, there are no approved treatments for NASH patients, but an experimental approach has focused on improving their insulin sensitivity. Metformin is one of the most commonly used medications for the treatment of diabetes.
The purpose of this study is to determine whether the medical problems of NASH patients, specifically liver damage, improves when their insulin sensitivity is enhanced with metformin.
The study will last 3 to 5 years and will enroll up to 30 patients. Participants will undergo a complete medical examination, a series of lab tests, and a liver biopsy. They will then start taking a single 500-mg tablet of metformin once a day for 2 weeks, then the same dosage twice a day for 2 more weeks, if they tolerate the first dosage. The dosage will increase to 1,000 mg twice a day for the remaining 44 weeks of the study. After 1 year, participants will undergo a repeat medical examination and liver biopsy.
|
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple fatty liver (steatosis) to steatosis with inflammation and necrosis to cirrhosis, that occurs in persons who drink little or no alcohol. Nonalcoholic steatohepatitis (NASH) represents the more severe end of this spectrum and is associated with progressive liver disease, fibrosis and cirrhosis. The etiology of NASH is unclear, but it is often associated with obesity, type 2 diabetes, hyperlipidemia and insulin resistance. We have recently conducted a study of a 48-week course of pioglitazone in 21 non-diabetic patients with NASH. Serum aminotransferase levels and liver histology improved in most patients and the improvements correlated with changes in insulin sensitivity. These results are promising, but pioglitazone is associated with significant weight gain, is quite expensive, and its long-term safety is yet to be proven. In contrast, metformin is inexpensive, extremely well tolerated, and of proven long-term safety in patients with diabetes and pre-diabetes.
In this study, we propose to treat 20 non-diabetic patients with NASH with metformin for 48-weeks. After an initial evaluation for insulin sensitivity, fat distribution and liver biopsy, patients will receive gradually increasing doses of metformin orally to a maximum of 2000 mg daily. Patients will be monitored at regular intervals for symptoms of liver disease, side effects of metformin and serum biochemical and metabolic indices. At the end of 48-weeks, patients will have a repeat medical evaluation and liver biopsy. Pre and post treatment liver histology, fat distribution and insulin sensitivity will be compared. The primary end point of successful therapy will be improvement in hepatic histology as determined by reduction of at least three points in NASH activity score. Secondary end points will be improvement in insulin sensitivity, body fat distribution, and liver biochemistry.
|
Hepatitis
|
Insulin Obesity Fatty Liver Diabetes Cirrhosis Metformin Insulin Resistance Nonalcoholic Steatohepatitis Hepatitis NASH
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: After complete medical evaluation and liver biopsy, patients who qualified for therapy were started on metformin in an initial dose of 500 mg once daily. After 2 weeks, the dose was increased to 500 mg twice daily and after 4 weeks to the full dose of 1000 mg twice daily. Subsequent dose reductions were carried out based on tolerance, with particular attention to gastrointestinal upset and abdominal bloating. Patients were seen in the out-patient clinic, had a brief medical history and examination and routine blood tests at 2 and 4 weeks after enrolment and every 4 weeks thereafter. The oral and intravenous glucose tolerance tests were repeated after 40 and 44 weeks respectively and liver biopsy and imaging tests at 48 weeks. Metformin was discontinued after 48 weeks in patients without diabetes on the pre-treatment evaluation.
|
intervention 1: Metformin
| 1
|
Bethesda | Maryland | United States | -77.10026 | 38.98067
| 0
|
NCT00063232
|
[
3
] | 7
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy before surgery may shrink the tumor so that it can be removed. Giving combination chemotherapy after surgery may kill any remaining tumor cells.
PURPOSE: This phase II trial is studying how well surgery and/or combination chemotherapy work in treating children with fibrosarcoma.
|
OBJECTIVES:
Primary
* Determine the event-free and relapse-free survival of children with initially unresectable congenital, infantile, or childhood fibrosarcoma treated with neoadjuvant chemotherapy comprising vincristine, dactinomycin, and cyclophosphamide (VAC) before definitive local control.
Secondary
* Determine the event-free and relapse-free survival of patients initially treated with this regimen followed by observation after local control with positive microscopic margins.
* Determine the event-free and relapse-free survival of patients initially treated with this regimen followed by additional chemotherapy comprising etoposide and ifosfamide after local control with gross positive margins.
* Determine the event-free and relapse-free survival of patients treated with surgery alone.
OUTLINE: This is a pilot, multicenter study. Patients begin treatment according to lesion resectability.
Patients with resectable lesions proceed to surgery.
* Surgery: Patients undergo resection of disease lesions. Patients with clear or microscopically positive margins undergo observation only. Patients with grossly positive margins undergo re-resection if feasible. Patients with grossly positive margins after re-resection or for whom re-resection is not feasible receive chemotherapy comprising vincristine, dactinomycin, and cyclophosphamide (VAC).
Patients with unresectable lesions receive VAC chemotherapy.
* VAC chemotherapy: Patients receive vincristine intravenously (IV) on days 1, 8, and 15 and dactinomycin IV and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Patients with disease progression after 2-4 courses of VAC chemotherapy proceed to chemotherapy comprising etoposide and ifosfamide (IE).
Patients with stable disease after 4 courses of VAC chemotherapy proceed to IE chemotherapy.
Patients with a partial response (PR) and unresectable lesions after 4 courses of VAC chemotherapy receive 2 additional courses of VAC and are then re-evaluated. Patients proceed to surgery if they continue to have a PR or achieve a complete response (CR) and lesions are now resectable.
Patients with a CR or PR and resectable lesions after 4 courses of VAC chemotherapy proceed to surgery.
Patients with stable disease, progressive disease, or a PR and unresectable lesions after 6 courses of VAC proceed to IE chemotherapy.
* IE chemotherapy: Patients receive etoposide IV over 1 hour and ifosfamide IV over 1 hour on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Patients with a CR or PR and resectable lesions after 2-4 courses of IE chemotherapy proceed to surgery.
All patients are followed every 3 months for 6 months, every 6 months for 1 year, and then as clinically indicated.
PROJECTED ACCRUAL: A total of 60-70 patients will be accrued for this study within 8 years.
|
Sarcoma
|
childhood fibrosarcoma nonmetastatic childhood soft tissue sarcoma
| null | 2
|
arm 1: Comprised of patients with disease lesions that are initially unresectable, or resected but with resulting grossly positive margins. All patients receive vincristine sulfate, dactinomycin, and cyclophosphamide (VAC), and mercaptoethane sulfonate (MESNA). Depending on response, patients may receive ifosfamide and etoposide (IE). Filgrastim may also be given, as needed. In addition to Chemotherapy, patients may receive Conventional Surgery.
(See Interventions section for drug dosage and administration details.) arm 2: Comprised of patients with initially resectable disease lesions. All patients undergo Conventional Surgery. Those with a result of clear or microscopically positive margins remain on study in this arm, for observation with no further intervention.
|
[
0,
0
] | 8
|
[
2,
0,
0,
0,
0,
3,
2,
2
] |
intervention 1: Given Slow intravenous (IV) push over 1-5 minutes, dose \< 1yr 0.025 mg/kg \> or = 1 yr 0.045 mg/kg (max dose 2.5 mg) on days 1,22,43 and 64 intervention 2: Given IV over 60 minutes, dose 25 mg/kg on days 1,22,43 and 64. intervention 3: Given IV over 1 hour, dose 3.3 mg/kg in normal saline (NS) 10 cc/kg (or to equal 0.4 mg/mL concentration) on days 1-5 of IE cycle. intervention 4: Given IV over 1 hour, dose 60mg/kg in D5 1/4 NS 10 cc/kg IV on days 1-5 of IE Cycle intervention 5: Given IV Push over 1 minute, dose 0.05 mg/kg (max dose 2 mg) on days 1,8,15,22,29,36,43,50,57 and 64 intervention 6: Applied only when lesion is resectable. Surgery is the primary means of local control in this study and reasonable attempts at achieving clear margins with an "envelope" of normal tissue should be undertaken at the initial and/or subsequent resections. intervention 7: Given orally. Oral daily MESNA dose is equal to at least 60% of the daily cyclophosphamide dose. intervention 8: Given IV - Only use filgrastim if chemotherapy has been delayed or modified for hematologic toxicity, or if patient experiences a significant life-threatening toxicity due to bone marrow suppression
|
intervention 1: dactinomycin intervention 2: cyclophosphamide intervention 3: etoposide intervention 4: ifosfamide intervention 5: vincristine sulfate intervention 6: Conventional Surgery intervention 7: MESNA (mercaptoethane sulfonate) intervention 8: Filgrastim
| 74
|
Phoenix | Arizona | United States | -112.07404 | 33.44838
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Downey | California | United States | -118.13257 | 33.94001
Loma Linda | California | United States | -117.26115 | 34.04835
Long Beach | California | United States | -118.18923 | 33.76696
Sacramento | California | United States | -121.4944 | 38.58157
San Francisco | California | United States | -122.41942 | 37.77493
Stanford | California | United States | -122.16608 | 37.42411
Farmington | Connecticut | United States | -72.83204 | 41.71982
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Fort Myers | Florida | United States | -81.84059 | 26.62168
Miami | Florida | United States | -80.19366 | 25.77427
Pensacola | Florida | United States | -87.21691 | 30.42131
St. Petersburg | Florida | United States | -82.67927 | 27.77086
Tampa | Florida | United States | -82.45843 | 27.94752
Atlanta | Georgia | United States | -84.38798 | 33.749
Augusta | Georgia | United States | -81.97484 | 33.47097
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Louisville | Kentucky | United States | -85.75941 | 38.25424
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Bangor | Maine | United States | -68.77265 | 44.79884
Boston | Massachusetts | United States | -71.05977 | 42.35843
Flint | Michigan | United States | -83.68746 | 43.01253
Grand Rapids | Michigan | United States | -85.66809 | 42.96336
Grosse Pointe Woods | Michigan | United States | -82.90686 | 42.44365
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Jackson | Mississippi | United States | -90.18481 | 32.29876
Kansas City | Missouri | United States | -94.57857 | 39.09973
Hackensack | New Jersey | United States | -74.04347 | 40.88593
Morristown | New Jersey | United States | -74.48154 | 40.79677
New York | New York | United States | -74.00597 | 40.71427
Syracuse | New York | United States | -76.14742 | 43.04812
Chapel Hill | North Carolina | United States | -79.05584 | 35.9132
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Durham | North Carolina | United States | -78.89862 | 35.99403
Akron | Ohio | United States | -81.51901 | 41.08144
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cleveland | Ohio | United States | -81.69541 | 41.4995
Columbus | Ohio | United States | -82.99879 | 39.96118
Dayton | Ohio | United States | -84.19161 | 39.75895
Youngstown | Ohio | United States | -80.64952 | 41.09978
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Danville | Pennsylvania | United States | -76.61273 | 40.96342
Hershey | Pennsylvania | United States | -76.65025 | 40.28592
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Providence | Rhode Island | United States | -71.41283 | 41.82399
Charleston | South Carolina | United States | -79.93275 | 32.77632
Greenville | South Carolina | United States | -82.39401 | 34.85262
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Memphis | Tennessee | United States | -90.04898 | 35.14953
Nashville | Tennessee | United States | -86.78444 | 36.16589
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
Lubbock | Texas | United States | -101.85517 | 33.57786
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Spokane | Washington | United States | -117.42908 | 47.65966
Green Bay | Wisconsin | United States | -88.01983 | 44.51916
Marshfield | Wisconsin | United States | -90.1718 | 44.66885
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Westmead | New South Wales | Australia | 150.98768 | -33.80383
North Adelaide | South Australia | Australia | 138.59141 | -34.90733
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Halifax | Nova Scotia | Canada | -63.57688 | 44.64269
Toronto | Ontario | Canada | -79.39864 | 43.70643
Montreal | Quebec | Canada | -73.58781 | 45.50884
Montreal | Quebec | Canada | -73.58781 | 45.50884
Saskatoon | Saskatchewan | Canada | -106.66892 | 52.13238
Auckland | N/A | New Zealand | 174.76349 | -36.84853
| 0
|
NCT00072280
|
[
3
] | 5
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| true
|
RATIONALE: Giving chemotherapy, such as fludarabine and melphalan, before a donor peripheral blood stem cell transplant helps stop the growth of tumor cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining tumor cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin, cyclosporine, and methotrexate before or after the transplant may stop this from happening.
PURPOSE: This phase II trial is studying how well antithymocyte globulin, high-dose melphalan, fludarabine, and allogeneic peripheral stem cell transplant work in treating patients with metastatic adenocarcinoma of the breast.
|
OBJECTIVES:
Primary
* Determine the toxicity and tolerability of allogeneic peripheral blood stem cell transplantation after a nonmyeloablative preparative regimen comprising anti-thymocyte globulin, high-dose melphalan, and fludarabine in women with chemotherapy-refractory or poor-prognosis metastatic adenocarcinoma of the breast.
* Determine the ability of this preparative regimen to facilitate long-term engraftment of allogeneic stem cells and lymphocytes in these patients.
* Determine the response in measurable/evaluable disease and its temporal relationship to the preparative chemotherapy used and to the onset of clinical graft-versus-host disease (GVHD) in patients treated with this regimen.
Secondary
* Determine the progression-free and overall survival of patients treated with this regimen.
* Determine the tumor response and its temporal relationship to administration of high-dose chemotherapy and to the onset of GVHD in patients treated with this regimen.
* Determine the frequency and durability of the induction of full donor chimerism of lymphocytes in patients treated with this regimen.
OUTLINE: This is a nonrandomized, pilot study.
* Nonmyeloablative preparative regimen: Patients receive fludarabine IV over 30 minutes on days -8 to -4, anti-thymocyte globulin IV over 4 hours on days -7 to -4, and high-dose melphalan IV over 30 minutes on days -3 and -2.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV (and then orally when tolerated) every 12 hours beginning on day -4 and tapered after day 42 (if no GVHD occurs) or after day 90 (if grade I acute GVHD occurs). Patients also receive methotrexate IV on days 1, 3, and 6.
* Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 0 and continuing until blood counts recover.
* Donor lymphocyte infusion (DLI): Patients who show disease progression or fail to achieve full donor type T-cell chimerism (at least 90% donor derived T-cells) by the 90-day assessment posttransplantation, and have no evidence of active GVHD may receive DLI. Patients who have unresponsive disease with no active GVHD receive subsequent DLIs every 6-8 weeks.
Patients are followed at 1, 3, 6, 12, 18, 24, 30, and 36 months.
PROJECTED ACCRUAL: A total of 10 patients will be accrued for this study.
|
Breast Cancer
|
recurrent breast cancer stage IV breast cancer
| null | 1
|
arm 1: None
|
[
0
] | 9
|
[
2,
2,
2,
2,
0,
0,
0,
0,
3
] |
intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None
|
intervention 1: anti-thymocyte globulin intervention 2: filgrastim intervention 3: graft-versus-tumor induction therapy intervention 4: therapeutic allogeneic lymphocytes intervention 5: cyclosporine intervention 6: fludarabine phosphate intervention 7: melphalan intervention 8: methotrexate intervention 9: peripheral blood stem cell transplantation
| 1
|
La Jolla | California | United States | -117.2742 | 32.84727
| 0
|
NCT00074269
|
[
4
] | 628
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| null |
A substance called immunoglobulin E (IgE), which is naturally produced by our body, has a key role in generating asthma attacks. In patients with allergies, there is an exaggerated production of IgE in response to specific substances such as pollens. Omalizumab is a new drug that inactivates IgE. This study tested the safety and efficacy of omalizumab against asthma attacks in children with allergic asthma.
|
This study was designed to provide one year efficacy and safety data for subcutaneous (SC) omalizumab, compared to placebo in children (6 to \< 12 years) with moderate to severe persistent asthma who have inadequate asthma control despite treatment according to National Heart, Lung and Blood Institute (NHLBI) step 3 or 4 (at least medium dose inhaled corticosteroids with or without other controller asthma medications).
|
Asthma
|
allergic asthma atopic omalizumab immunoglobulin E IgE anti-IgE
| null | 2
|
arm 1: Participants received omalizumab administered by subcutaneous injection every 2 or 4 weeks for a duration of 52 weeks. The omalizumab dose was based on the patient's body weight and total serum IgE level at Screening. The first 24 weeks of the treatment period was a fixed steroid phase where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition. Following the 52-week treatment period, patients were followed up for an additional 16 weeks. arm 2: Placebo was administered by subcutaneous injection every 2 or 4 weeks depending on the dosing schedule in the protocol for a total of 52 weeks. The first 24 weeks of the treatment period was a fixed steroid phase where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition. Following the 52-week treatment period, patients were followed up for an additional 16 weeks.
|
[
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: The omalizumab dose administered, based on the patient's body weight and total serum IgE level at Screening, and the number of injections and injection volume was determined from the dosing tables in the protocol. Omalizumab 75 to 375 mg was administered subcutaneous (SC) every 2 or 4 weeks depending on the dose. intervention 2: Placebo was administered subcutaneous (SC) every 2 or 4 weeks depending on the dosing schedule in the protocol. intervention 3: Patients entered the study using their current formulation of any inhaled steroid (proprietary drug and device) ≥ 200 μg/day equivalent of fluticasone administered with a dry-powder inhaler.
|
intervention 1: Omalizumab intervention 2: Placebo intervention 3: Fluticasone
| 56
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Huntington Beach | California | United States | -117.99923 | 33.6603
Huntington Beach | California | United States | -117.99923 | 33.6603
Long Beach | California | United States | -118.18923 | 33.76696
Mission Viejo | California | United States | -117.672 | 33.60002
Orange | California | United States | -117.85311 | 33.78779
Palmdale | California | United States | -118.11646 | 34.57943
Palo Alto | California | United States | -122.14302 | 37.44188
Riverside | California | United States | -117.39616 | 33.95335
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Jose | California | United States | -121.89496 | 37.33939
Santa Monica | California | United States | -118.49138 | 34.01949
Stockton | California | United States | -121.29078 | 37.9577
Walnut Creek | California | United States | -122.06496 | 37.90631
Denver | Colorado | United States | -104.9847 | 39.73915
Miami | Florida | United States | -80.19366 | 25.77427
Albany | Georgia | United States | -84.15574 | 31.57851
Atlanta | Georgia | United States | -84.38798 | 33.749
Savannah | Georgia | United States | -81.09983 | 32.08354
Chicago | Illinois | United States | -87.65005 | 41.85003
Elliott | Maryland | United States | -75.99632 | 38.31012
North Dartmouth | Massachusetts | United States | -70.97032 | 41.63899
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Brick | New Jersey | United States | -74.13708 | 40.05928
Newark | New Jersey | United States | -74.17237 | 40.73566
Buffalo | New York | United States | -78.87837 | 42.88645
Ithaca | New York | United States | -76.49661 | 42.44063
Liverpool | New York | United States | -76.2177 | 43.10646
Rockville Centre | New York | United States | -73.64124 | 40.65871
Durham | North Carolina | United States | -78.89862 | 35.99403
High Point | North Carolina | United States | -80.00532 | 35.95569
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Medford | Oregon | United States | -122.87559 | 42.32652
Altoona | Pennsylvania | United States | -78.39474 | 40.51868
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Upland | Pennsylvania | United States | -75.38269 | 39.85261
Lincoln | Rhode Island | United States | -71.435 | 41.92111
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Nashville | Tennessee | United States | -86.78444 | 36.16589
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Fort Worth | Texas | United States | -97.32085 | 32.72541
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
South Jordan | Utah | United States | -111.92966 | 40.56217
Norfolk | Virginia | United States | -76.28522 | 36.84681
Richmond | Virginia | United States | -77.46026 | 37.55376
Seattle | Washington | United States | -122.33207 | 47.60621
Spokane | Washington | United States | -117.42908 | 47.65966
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
| 0
|
NCT00079937
|
[
3
] | 138
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| false
|
This phase II study will evaluate and compare the efficacy and tolerability of two dose schedules (1500 mg QD and 500 mg BID) of oral Lapatinib as treatment for patients with advanced or metastatic breast cancer.
| null |
Neoplasms, Breast
|
lapatinib advanced metastatic breast cancer GW572016 ErbB2
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: None
|
intervention 1: Lapatinib
| 31
|
Hollywood | Florida | United States | -80.14949 | 26.0112
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
Pokfulam | N/A | Hong Kong | N/A | N/A
Delhi | N/A | India | 77.23149 | 28.65195
Hyderabad, Andhra Pradesh | N/A | India | 78.45636 | 17.38405
Pune | N/A | India | 73.85535 | 18.51957
Bandar Tun Razak, Cheras | N/A | Malaysia | N/A | N/A
Kubang Kerian | N/A | Malaysia | 102.27938 | 6.09123
Tanjong Bungah | N/A | Malaysia | 100.29161 | 5.45828
Tanjong Bungah | N/A | Malaysia | 100.29161 | 5.45828
Ixtaltepec / Espinal | Oaxaca | Mexico | N/A | N/A
Mérida | Yucatán | Mexico | -89.62318 | 20.967
Mexico | N/A | Mexico | -98.43784 | 18.88011
Karachi | N/A | Pakistan | 67.0104 | 24.8608
Karachi | N/A | Pakistan | 67.0104 | 24.8608
Karachi | N/A | Pakistan | 67.0104 | 24.8608
Lahore | N/A | Pakistan | 74.35071 | 31.558
Rawalpindi | N/A | Pakistan | 73.0479 | 33.59733
Lima | Lima Province | Peru | -77.02824 | -12.04318
Lima | Lima Province | Peru | -77.02824 | -12.04318
Lima | Lima Province | Peru | -77.02824 | -12.04318
Callao | N/A | Peru | -77.13452 | -12.05162
Bydogoszcz | N/A | Poland | N/A | N/A
Krakow | N/A | Poland | 19.93658 | 50.06143
Olsztyn | N/A | Poland | 20.49416 | 53.77995
Singapore | N/A | Singapore | 103.85007 | 1.28967
Singapore | N/A | Singapore | 103.85007 | 1.28967
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Taipei | N/A | Taiwan | 121.52639 | 25.05306
| 0
|
NCT00089999
|
[
3
] | 197
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this clinical research study is to learn if BMS-354825 will have activity, defined by hematologic response, in subjects who have accelerated phase chronic myeloid leukemia (CML) who are resistant to or intolerant to imatinib mesylate. The safety of this treatment will also be studied.
| null |
Chronic Myelogenous Leukemia
|
Chronic myelogenous leukemia (CML): Accelerated phase
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Tablets, Oral, 70 mg, twice daily, until disease progression or intolerable toxicity, switch to the roll-over study or study closure
|
intervention 1: Dasatinib
| 70
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Anaheim | California | United States | -117.9145 | 33.83529
Los Angeles | California | United States | -118.24368 | 34.05223
Stanford | California | United States | -122.16608 | 37.42411
Vallejo | California | United States | -122.25664 | 38.10409
Jacksonville | Florida | United States | -81.65565 | 30.33218
Tampa | Florida | United States | -82.45843 | 27.94752
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Kansas City | Kansas | United States | -94.62746 | 39.11417
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
Detroit | Michigan | United States | -83.04575 | 42.33143
St Louis | Missouri | United States | -90.19789 | 38.62727
Hackensack | New Jersey | United States | -74.04347 | 40.88593
New York | New York | United States | -74.00597 | 40.71427
Portland | Oregon | United States | -122.67621 | 45.52345
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Nashville | Tennessee | United States | -86.78444 | 36.16589
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
Buenos Aires | Buenos Aires | Argentina | N/A | N/A
Córdoba | Córdoba Province | Argentina | -64.18853 | -31.40648
St Leonards | New South Wales | Australia | 151.19836 | -33.82344
South Brisbane | Queensland | Australia | 153.02049 | -27.48034
East Melbourne | Victoria | Australia | 144.9879 | -37.81667
Parkville | Victoria | Australia | 144.95 | -37.78333
Wien | N/A | Australia | N/A | N/A
B-Leuven | N/A | Belgium | N/A | N/A
Edegem | N/A | Belgium | 4.44504 | 51.15662
Rio de Janeiro | Rio de Janeiro | Brazil | -43.18223 | -22.90642
São Paulo | São Paulo | Brazil | -46.63611 | -23.5475
Campinas | N/A | Brazil | -47.06083 | -22.90556
Toronto | Ontario | Canada | -79.39864 | 43.70643
Aarhus | N/A | Denmark | 10.21076 | 56.15674
Helsinki | N/A | Finland | 24.93545 | 60.16952
Lille | N/A | France | 3.05858 | 50.63297
Lyon | N/A | France | 4.84671 | 45.74846
Nantes | N/A | France | -1.55336 | 47.21725
Paris | N/A | France | 2.3488 | 48.85341
Pessac | N/A | France | -0.6324 | 44.80565
Poitiers | N/A | France | 0.34348 | 46.58261
Strasbourg | N/A | France | 7.74553 | 48.58392
Hamburg | N/A | Germany | 9.99302 | 53.55073
Mainz | N/A | Germany | 8.2791 | 49.98419
Mannheim | N/A | Germany | 8.46694 | 49.4891
Ramat Gan | N/A | Israel | 34.81065 | 32.08227
Bologna | N/A | Italy | 11.33875 | 44.49381
Napoli | N/A | Italy | 14.5195 | 40.87618
Orbassano | N/A | Italy | 7.53813 | 45.00547
Roma | N/A | Italy | 11.10642 | 44.99364
Nijmegen | N/A | Netherlands | 5.85278 | 51.8425
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Trondheim | N/A | Norway | 10.39506 | 63.43049
Lima | Lima Province | Peru | -77.02824 | -12.04318
Quezon City | N/A | Philippines | 121.0509 | 14.6488
Singapore | N/A | Singapore | 103.85007 | 1.28967
Jeollanam-Do | N/A | South Korea | N/A | N/A
Kyunggi-Do | N/A | South Korea | N/A | N/A
Seoul | N/A | South Korea | 126.9784 | 37.566
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Lund | N/A | Sweden | 13.19321 | 55.70584
Umeå | N/A | Sweden | 20.25972 | 63.82842
Uppsala | N/A | Sweden | 17.63889 | 59.85882
Basel | N/A | Switzerland | 7.57327 | 47.55839
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Taoyuan District | N/A | Taiwan | 121.3187 | 24.9896
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Glasgow | Central | United Kingdom | -4.25763 | 55.86515
London | Greater London | United Kingdom | -0.12574 | 51.50853
| 0
|
NCT00101647
|
[
3
] | 124
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to see what effect an investigational drug (BMS-354825) has on subjects who are currently in the myeloid blast phase of chronic myeloid leukemia (CML) and who are either resistant to or intolerant of imatinib mesylate. Another purpose of the study is to see what side effects this drug may have on subjects.
| null |
Chronic Myeloid Leukemia Blast Crisis
|
Myeloid blast phase Chronic Myeloid Leukemia (CML)
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Tablets, Oral, 70 mg, twice daily, Until disease progression or intolerable toxicity, switch to the roll-over study or study closure.
|
intervention 1: Dasatinib
| 62
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Anaheim | California | United States | -117.9145 | 33.83529
Los Angeles | California | United States | -118.24368 | 34.05223
Stanford | California | United States | -122.16608 | 37.42411
Vallejo | California | United States | -122.25664 | 38.10409
Denver | Colorado | United States | -104.9847 | 39.73915
Jacksonville | Florida | United States | -81.65565 | 30.33218
Tampa | Florida | United States | -82.45843 | 27.94752
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Kansas City | Kansas | United States | -94.62746 | 39.11417
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
Detroit | Michigan | United States | -83.04575 | 42.33143
St Louis | Missouri | United States | -90.19789 | 38.62727
Hackensack | New Jersey | United States | -74.04347 | 40.88593
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
New York | New York | United States | -74.00597 | 40.71427
Portland | Oregon | United States | -122.67621 | 45.52345
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Nashville | Tennessee | United States | -86.78444 | 36.16589
Houston | Texas | United States | -95.36327 | 29.76328
Seattle | Washington | United States | -122.33207 | 47.60621
Adelaide | South Australia | Australia | 138.59863 | -34.92866
Vienna | N/A | Austria | 16.37208 | 48.20849
B-Leuven | N/A | Belgium | N/A | N/A
Edegem | N/A | Belgium | 4.44504 | 51.15662
Montreal | Quebec | Canada | -73.58781 | 45.50884
Aarhus | N/A | Denmark | 10.21076 | 56.15674
Helsinki | N/A | Finland | 24.93545 | 60.16952
Lille | N/A | France | 3.05858 | 50.63297
Lyon | N/A | France | 4.84671 | 45.74846
Nantes | N/A | France | -1.55336 | 47.21725
Paris | N/A | France | 2.3488 | 48.85341
Pessac | N/A | France | -0.6324 | 44.80565
Poitiers | N/A | France | 0.34348 | 46.58261
Strasbourg | N/A | France | 7.74553 | 48.58392
Hamburg | N/A | Germany | 9.99302 | 53.55073
Mainz | N/A | Germany | 8.2791 | 49.98419
Mannheim | N/A | Germany | 8.46694 | 49.4891
Ramat Gan | N/A | Israel | 34.81065 | 32.08227
Bologna | N/A | Italy | 11.33875 | 44.49381
Napoli | N/A | Italy | 14.5195 | 40.87618
Orbassano | N/A | Italy | 7.53813 | 45.00547
Roma | N/A | Italy | 11.10642 | 44.99364
Nijmegen | N/A | Netherlands | 5.85278 | 51.8425
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Trondheim | N/A | Norway | 10.39506 | 63.43049
Quezon City | N/A | Philippines | 121.0509 | 14.6488
Singapore | N/A | Singapore | 103.85007 | 1.28967
Jeollanam-Do | N/A | South Korea | N/A | N/A
Kyunggi-Do | N/A | South Korea | N/A | N/A
Seoul | N/A | South Korea | 126.9784 | 37.566
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Lund | N/A | Sweden | 13.19321 | 55.70584
Umeå | N/A | Sweden | 20.25972 | 63.82842
Uppsala | N/A | Sweden | 17.63889 | 59.85882
Basel | N/A | Switzerland | 7.57327 | 47.55839
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Taoyuan District | N/A | Taiwan | 121.3187 | 24.9896
Glasgow | Central | United Kingdom | -4.25763 | 55.86515
London | Greater London | United Kingdom | -0.12574 | 51.50853
| 0
|
NCT00101816
|
[
3
] | 150
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The primary purpose of this study is to estimate the major cytogenetic response rates of BMS-354825 and imatinib (800 mg/d) in subjects with chronic phase, Philadelphia chromosome positive, chronic myeloid leukemia (PH+ CML) with disease resistant to imatinib at a dose of 400-600 mg/d.
| null |
Chronic Myeloid Leukemia Philadelphia-Positive Myeloid Leukemia
|
Chronic Phase Philadelphia chromosome Positive (Ph+) chronic myeloid leukemia
| null | 2
|
arm 1: Active Comparator arm 2: Active Comparator
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Tablets, oral, 20 mg and 50mg, twice daily, up to 96 weeks intervention 2: Tablets, Oral, 400mg and 100mg, twice daily, up to 96 weeks
|
intervention 1: Dasatinib intervention 2: Imatinib
| 131
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Anaheim | California | United States | -117.9145 | 33.83529
Bakersfield | California | United States | -119.01871 | 35.37329
Fullerton | California | United States | -117.92534 | 33.87029
Loma Linda | California | United States | -117.26115 | 34.04835
Los Angeles | California | United States | -118.24368 | 34.05223
Monterey Park | California | United States | -118.12285 | 34.06251
San Diego | California | United States | -117.16472 | 32.71571
Santa Barbara | California | United States | -119.69819 | 34.42083
Santa Maria | California | United States | -120.43572 | 34.95303
Stanford | California | United States | -122.16608 | 37.42411
Vallejo | California | United States | -122.25664 | 38.10409
Aurora | Colorado | United States | -104.83192 | 39.72943
Hartford | Connecticut | United States | -72.68509 | 41.76371
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Jacksonville | Florida | United States | -81.65565 | 30.33218
Tampa | Florida | United States | -82.45843 | 27.94752
Athens | Georgia | United States | -83.37794 | 33.96095
Atlanta | Georgia | United States | -84.38798 | 33.749
Lawrenceville | Georgia | United States | -83.98796 | 33.95621
Tucker | Georgia | United States | -84.21714 | 33.85455
Chicago | Illinois | United States | -87.65005 | 41.85003
Peoria | Illinois | United States | -89.58899 | 40.69365
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Kansas City | Kansas | United States | -94.62746 | 39.11417
Lexington | Kentucky | United States | -84.47772 | 37.98869
Boston | Massachusetts | United States | -71.05977 | 42.35843
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Rochester | Minnesota | United States | -92.4699 | 44.02163
Columbia | Missouri | United States | -92.33407 | 38.95171
Kansas City | Missouri | United States | -94.57857 | 39.09973
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Hackensack | New Jersey | United States | -74.04347 | 40.88593
Morristown | New Jersey | United States | -74.48154 | 40.79677
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Cary | North Carolina | United States | -78.78112 | 35.79154
Chapel Hill | North Carolina | United States | -79.05584 | 35.9132
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Portland | Oregon | United States | -122.67621 | 45.52345
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Greenville | South Carolina | United States | -82.39401 | 34.85262
Nashville | Tennessee | United States | -86.78444 | 36.16589
Dallas | Texas | United States | -96.80667 | 32.78306
Fort Worth | Texas | United States | -97.32085 | 32.72541
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
Tyler | Texas | United States | -95.30106 | 32.35126
Norfolk | Virginia | United States | -76.28522 | 36.84681
Seattle | Washington | United States | -122.33207 | 47.60621
Spokane | Washington | United States | -117.42908 | 47.65966
Vancouver | Washington | United States | -122.66149 | 45.63873
Buenos Aires | Buenos Aires | Argentina | N/A | N/A
Córdoba | Córdoba Province | Argentina | -64.18853 | -31.40648
Camperdown | New South Wales | Australia | 151.17642 | -33.88965
St Leonards | New South Wales | Australia | 151.19836 | -33.82344
South Brisbane | Queensland | Australia | 153.02049 | -27.48034
Adelaide | South Australia | Australia | 138.59863 | -34.92866
Perth | Western Australia | Australia | 115.8614 | -31.95224
Wein | N/A | Austria | N/A | N/A
B-Leuven | N/A | Belgium | N/A | N/A
Bruges | N/A | Belgium | 3.22424 | 51.20892
Brussels | N/A | Belgium | 4.34878 | 50.85045
Charleroi | N/A | Belgium | 4.44448 | 50.41136
Edegem | N/A | Belgium | 4.44504 | 51.15662
Yvoir | N/A | Belgium | 4.88059 | 50.3279
Curitiba | Paraná | Brazil | -49.27306 | -25.42778
Rio de Janeiro | Rio de Janeiro | Brazil | -43.18223 | -22.90642
São Paulo | São Paulo | Brazil | -46.63611 | -23.5475
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Toronto | Ontario | Canada | -79.39864 | 43.70643
Montreal | Quebec | Canada | -73.58781 | 45.50884
Beijing | N/A | China | 116.39723 | 39.9075
Shanghai | N/A | China | 121.45806 | 31.22222
Aarhus | N/A | Denmark | 10.21076 | 56.15674
Tallinn | N/A | Estonia | 24.75353 | 59.43696
Helsinki | N/A | Finland | 24.93545 | 60.16952
Lille | N/A | France | 3.05858 | 50.63297
Lyon | N/A | France | 4.84671 | 45.74846
Nantes | N/A | France | -1.55336 | 47.21725
Paris | N/A | France | 2.3488 | 48.85341
Pessac | N/A | France | -0.6324 | 44.80565
Poitiers | N/A | France | 0.34348 | 46.58261
Strasbourg | N/A | France | 7.74553 | 48.58392
Dresden | N/A | Germany | 13.73832 | 51.05089
Groenkloof | N/A | Germany | N/A | N/A
Hamburg | N/A | Germany | 9.99302 | 53.55073
Leipzig | N/A | Germany | 12.37129 | 51.33962
Mainz | N/A | Germany | 8.2791 | 49.98419
Mannheim | N/A | Germany | 8.46694 | 49.4891
Budapest | N/A | Hungary | 19.04045 | 47.49835
Dublin | N/A | Ireland | -6.24889 | 53.33306
Ramat Gan | N/A | Israel | 34.81065 | 32.08227
Bari | N/A | Italy | 16.86982 | 41.12066
Bologna | N/A | Italy | 11.33875 | 44.49381
Milan | N/A | Italy | 12.59836 | 42.78235
Napoli | N/A | Italy | 14.5195 | 40.87618
Orbassano | N/A | Italy | 7.53813 | 45.00547
Roma | N/A | Italy | 11.10642 | 44.99364
Trondheim | N/A | Norway | 10.39506 | 63.43049
Lima | Lima Province | Peru | -77.02824 | -12.04318
Quezon City | N/A | Philippines | 121.0509 | 14.6488
Katowice | N/A | Poland | 19.02754 | 50.25841
Krakow | N/A | Poland | 19.93658 | 50.06143
Lublin | N/A | Poland | 22.56667 | 51.25
Warsaw | N/A | Poland | 21.01178 | 52.22977
San Juan | N/A | Puerto Rico | -66.10572 | 18.46633
Moscow | N/A | Russia | 37.61556 | 55.75222
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Singapore | N/A | Singapore | 103.85007 | 1.28967
Bloemfontein | Free State | South Africa | 26.214 | -29.12107
Parktown | Gauteng | South Africa | 28.02671 | -26.18205
Soweto | Gauteng | South Africa | 27.85849 | -26.26781
Kyunggi-Do | N/A | South Korea | N/A | N/A
Barcelona | N/A | Spain | 2.15899 | 41.38879
Madrid | N/A | Spain | -3.70256 | 40.4165
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Lund | N/A | Sweden | 13.19321 | 55.70584
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Umeå | N/A | Sweden | 20.25972 | 63.82842
Uppsala | N/A | Sweden | 17.63889 | 59.85882
Basel | N/A | Switzerland | 7.57327 | 47.55839
Bellinzona | N/A | Switzerland | 9.01703 | 46.19278
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Taoyuan District | N/A | Taiwan | 121.3187 | 24.9896
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Glasglow | Central | United Kingdom | N/A | N/A
London | Greater London | United Kingdom | -0.12574 | 51.50853
Newcastle | Tyne and Wear | United Kingdom | -5.88979 | 54.21804
| 0
|
NCT00103844
|
[
4
] | 349
|
RANDOMIZED
|
PARALLEL
| 2DIAGNOSTIC
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this 14 week, randomized, double-blind, placebo controlled study is to assess the safety and efficacy of aripiprazole to placebo as adjunctive treatment to an assigned open-label marketed antidepressant therapy (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective eight week trial of the same assigned open-label marketed antidepressant therapy.
| null |
Major Depressive Disorder
|
Single or recurrent non-psychotic episode of Major Depressive Disorder
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Tablets, Oral, 2 - 20 mg variable dose once daily, 14 weeks intervention 2: Tablets, Oral, 2 - 20 mg variable dose once daily, 14 weeks
|
intervention 1: Aripiprazole+ ADT intervention 2: Placebo+ ADT
| 34
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
San Diego | California | United States | -117.16472 | 32.71571
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Coral Springs | Florida | United States | -80.2706 | 26.27119
Augusta | Georgia | United States | -81.97484 | 33.47097
Smyrna | Georgia | United States | -84.51438 | 33.88399
Chicago | Illinois | United States | -87.65005 | 41.85003
Edwardsville | Illinois | United States | -89.95316 | 38.81144
Hoffman Estates | Illinois | United States | -88.0798 | 42.04281
Springfield | Illinois | United States | -89.64371 | 39.80172
Witchita | Kansas | United States | N/A | N/A
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Baltimore | Maryland | United States | -76.61219 | 39.29038
Farmington Hills | Michigan | United States | -83.37716 | 42.48531
Flint | Michigan | United States | -83.68746 | 43.01253
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Saint Paul | Minnesota | United States | -93.09327 | 44.94441
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Dayton | Ohio | United States | -84.19161 | 39.75895
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Portland | Oregon | United States | -122.67621 | 45.52345
Media | Pennsylvania | United States | -75.38769 | 39.91678
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Charleston | South Carolina | United States | -79.93275 | 32.77632
Columbia | South Carolina | United States | -81.03481 | 34.00071
Austin | Texas | United States | -97.74306 | 30.26715
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Charlottesville | Virginia | United States | -78.47668 | 38.02931
Bellevue | Washington | United States | -122.20068 | 47.61038
Brown Deer | Wisconsin | United States | -87.96453 | 43.16334
Middleton | Wisconsin | United States | -89.50429 | 43.09722
| 0
|
NCT00105196
|
[
2
] | 48
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 2DIAGNOSTIC
| 0NONE
| false
| 0ALL
| false
|
The purpose of this clinical research study is to establish the maximum tolerated dose and recommended Phase II dose of Erbitux™ in combination with Irinotecan in pediatric and adolescent patients with refractory solid tumors.
| null |
Cancer Refractory Solid Tumor
| null | 2
|
arm 1: 1-12 years old arm 2: 13-18 years old
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: Intravenous (IV) cetuximab 75 - 250 mg/m2 depending on dose escalation for MTD, weekly; irinotecan was administered at a dose of 16 or 20 mg/m2 or per dose escalation, administered x5 days x2 weeks, separated by 2 days off, every 21 days. intervention 2: Intravenous (IV) cetuximab 75 - 250 mg/m2 depending on dose escalation for MTD, weekly; irinotecan was administered at a dose of 20 mg/m2 or per dose escalation, administered x5 days x2 weeks, separated by 2 days off, every 21 days.
|
intervention 1: Cetuximab + Irinotecan intervention 2: Cetuximab + Irinotecan
| 9
|
Phoenix | Arizona | United States | -112.07404 | 33.44838
Tucson | Arizona | United States | -110.92648 | 32.22174
Denver | Colorado | United States | -104.9847 | 39.73915
Gainesville | Florida | United States | -82.32483 | 29.65163
Atlanta | Georgia | United States | -84.38798 | 33.749
Baltimore | Maryland | United States | -76.61219 | 39.29038
New York | New York | United States | -74.00597 | 40.71427
Nashville | Tennessee | United States | -86.78444 | 36.16589
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00110357
|
|
[
3
] | 101
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
This is a randomized, double blind, placebo controlled, multicenter, phase II study to compare the anti-tumor activity as measured by progression-free survival (PFS) and the tolerability of Sorafenib in combination with Dacarbazine (DTIC) versus DTIC in combination with placebo in subjects with unresectable Stage III or Stage IV melanoma who have not received prior cytotoxic chemotherapy. A total of approximately 98 subjects will be randomized to receive DTIC + Sorafenib or DTIC + Placebo.
| null |
Cancer Melanoma
| null | 2
|
arm 1: Sorafenib, 2 tablets (200 mg each) orally twice daily (bid) on study days 1-21 + Dacarbazine, 1000 mg/m\^2 intravenous on study day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period. arm 2: Placebo, 2 tablets orally twice daily on study days 1-21 + Dacarbazine, 1000 mg/m\^2 intravenous on study day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
|
[
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Sorafenib, 400 mg, 2 tablets (200 mg each) po (per os) bid (twice daily) Study days 1-21 intervention 2: Placebo, 2 tablets, po (per os) bid (twice daily) Study days 1-21 intervention 3: Dacarbazine, 1000 mg/m\^2 intravenous on Study Day 1
|
intervention 1: Sorafenib (Nexavar, BAY43-9006) intervention 2: Placebo intervention 3: Dacarbazine
| 14
|
Tucson | Arizona | United States | -110.92648 | 32.22174
Aurora | Colorado | United States | -104.83192 | 39.72943
Lakeland | Florida | United States | -81.9498 | 28.03947
Park Ridge | Illinois | United States | -87.84062 | 42.01114
Boston | Massachusetts | United States | -71.05977 | 42.35843
Boston | Massachusetts | United States | -71.05977 | 42.35843
Boston | Massachusetts | United States | -71.05977 | 42.35843
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Hilton Head Island | South Carolina | United States | -80.73816 | 32.19382
Nashville | Tennessee | United States | -86.78444 | 36.16589
San Antonio | Texas | United States | -98.49363 | 29.42412
| 0
|
NCT00110994
|
|
[
3
] | 27
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This phase II trial is studying how well sorafenib works in treating patients with progressive regional or metastatic cancer of the urothelium. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
|
PRIMARY OBJECTIVES:
I. To evaluate the 4-month progression-free survival rate, response rate and toxicity of BAY 43-9006 in patients with progressing regional or metastatic transitional cell carcinoma (or mixed histologies containing a component of TCC) of the urothelium who have progressed on one and only one prior systemic chemotherapy regimen for metastatic disease.
SECONDARY OBJECTIVES:
I. To determine the time to disease progression and overall survival with BAY 43-9006.
II. To evaluate the frequency of polymorphisms in drug metabolizing enzymes and to correlate these polymorphisms with variations in BAY 43-9006 pharmacokinetics.
III. To evaluate the frequency of raf kinase mutations in tumor specimens and correlate these with response rate.
IV. To evaluate serum VEGF levels as potential markers of angiogenesis inhibition by BAY 43-9006.
V. To evaluate markers of apoptosis and kinase inhibition in peripheral blood mononuclear cells as potential biomarkers of BAY 43-9006 activity.
VI. To determine if there are proteins differentially translated from the genome in patients who respond to treatment with BAY 43-9006 versus patients who do not respond to BAY 43-9006.
OUTLINE: This is a multicenter study.
Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months until 2 years from study entry and then every 6 months until 3 years from study entry.
|
Adenocarcinoma of the Bladder Distal Urethral Cancer Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter Proximal Urethral Cancer Recurrent Bladder Cancer Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter Recurrent Urethral Cancer Regional Transitional Cell Cancer of the Renal Pelvis and Ureter Squamous Cell Carcinoma of the Bladder Stage III Bladder Cancer Stage IV Bladder Cancer Transitional Cell Carcinoma of the Bladder Urethral Cancer Associated With Invasive Bladder Cancer
| null | 1
|
arm 1: Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.
|
[
0
] | 2
|
[
0,
10
] |
intervention 1: Given PO intervention 2: Optional correlative studies
|
intervention 1: sorafenib tosylate intervention 2: laboratory biomarker analysis
| 1
|
Boston | Massachusetts | United States | -71.05977 | 42.35843
| 0
|
NCT00112905
|
|
[
2,
3
] | 6
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The goals of this clinical research study are to see how individuals with advanced head and neck cancer respond to treatment with the new drug thrombospondin (ABT-510) and to learn how effective it is in destroying cancer cells. The safety of ABT-510 and the effect ABT-510 has on cells in the body will also be studied.
|
This is a phase Ib/II, single-center, open-label study designed to assess the safety, tolerability, pharmacokinetics, and biologic efficacy of ABT-510 (thrombospondin). Participants will be patients with incurable head and neck cancer.
Patients will begin at a fixed dose level of thrombospondin subcutaneously twice daily. Cycles of treatment are 28 days (4 weeks). Patients will be treated with thrombospondin until progression of tumor or toxicity.
|
Head and Neck Cancer
|
Head and Neck Cancer Thrombospondin Analogue ABT-510 Antiangiogenic agent Lung Skin Thyroid
| null | 1
|
arm 1: Fixed dose level of thrombospondin 100 mg subcutaneously twice daily.
|
[
0
] | 1
|
[
0
] |
intervention 1: 100 mg subcutaneously twice daily
|
intervention 1: ABT-510
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00113334
|
[
4
] | 18
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
Study Question: In premature infants with apnea and/or bradycardia attributed to gastroesophageal reflux disease (GERD), does treatment with medications (acid blockers and motility agents), compared to placebo, reduce the frequency of apnea and bradycardia?
Background: Many clinicians believe that apnea and bradycardia in preterm infants may be caused by gastroesophageal reflux (GER), however, studies have failed to demonstrate even a temporal association between episodes of GER and apnea. There have been no prospective randomized trials of treatment for GERD in preterm infants with apnea or other symptoms attributed to GER.
Methods: A randomized, cross-over study will be performed. This cross-over design will provide the patient's clinician with unbiased information about the patient's response to treatment. The clinician can use this information in deciding whether or not to continue treatment after the two-week study period.
|
Study Question: In premature infants with apnea and/or bradycardia attributed to GERD, does treatment with H2 blockers and prokinetic agents, compared to placebo, reduce the frequency of apnea and bradycardia?
Background: The incidence of gastroesophageal reflux (GER) has been reported in as many as 50% of healthy term infants and 63% of preterm infants. Anecdotal observations of apnea and bradycardia clustered around feedings or with an episode of vomiting have suggested to clinicians that apnea and bradycardia in preterm infants may be caused by reflux, however, studies have failed to demonstrate even a temporal association between episodes of GER and apnea. One retrospective study concluded that anti-reflux medications did not reduce the frequency of apnea in premature infants. There have been no prospective randomized trials of treatment for GERD in preterm infants with apnea or other symptoms attributed to GER. Despite the lack of evidence supporting a causal relationship between GER and respiratory problems in preterm infants and the lack of data regarding the efficacy or safety of the treatments for GERD, many clinicians continue to believe that GER causes respiratory symptoms in preterm infants and these infants are commonly treated with medications for GERD.
Specific aims: To determine whether medications for GER are effective in reducing respiratory symptoms attributed to GER.
Methods: A randomized, controlled masked cross-over study will be performed. The cross-over design will prevent evaluation of long-term outcomes but will increase the power to evaluate short-term outcomes by using the patient as his/her own control. This cross-over design will also provide the patient's clinician with unbiased information about the patient's response to treatment. The clinician can use this information in deciding whether or not to continue treatment after the two-week study period. This approach for making therapeutic decisions in individual patients has been described as an "N of 1" trial.
|
Gastroesophageal Reflux
| null | 2
|
arm 1: 3-day course of anti-reflux medications, followed by 7-day course placebo, followed by 4-day course anti-reflux medications.
All study medication administered via nipple or orogastric (OG) tube. Metaclopramide (anti-reflux) given in 0.1mg/kg/dose q6hrs, 30min. prior to feedings. Ranitidine, 3mg/kg/dose, q12hrs. Saline placebo at same respective volumes. arm 2: 3-day course placebo, followed by 7-day course anti-reflux medication, followed by 4-day course placebo.
All study medication administered via nipple or OG tube. Metaclopramide (anti-reflux) given in 0.1mg/kg/dose q6hrs, 30min. prior to feedings. Ranitidine, 3mg/kg/dose, q12hrs. Saline placebo at same respective volumes.
|
[
5,
5
] | 3
|
[
0,
0,
0
] |
intervention 1: None intervention 2: None intervention 3: None
|
intervention 1: Metaclopramide intervention 2: Ranitidine intervention 3: placebo
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00131248
|
|
[
4
] | 336
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The purpose of this study is to evaluate long-term safety,tolerability and blood pressure effects of metoprolol versus nebivolol in patients with hypertension. These drugs may be given alone or in combination with other drugs that are commonly used in the treatment of hypertension
|
Approximately 50 million Americans have hypertension defined as a systolic blood pressure (SBP) greater then or equal to 140 mmHg and/or a diastolic blood pressure (DBP) greater then or equal to 90 mmHg. To control blood pressure, more than 2 agents are required in many patients. The current study is a randomized, titration-to-effect, open-label, multi center study. Patients will be randomized to either nebivolol or metoprolol. The dose of the randomized treatment can be titrated as needed to achieve blood pressure control. If necessary, additional antihypertensive agents (calcium antagonist, diuretic, etc.) can be added to achieve control. Patients will be seen every 1-3 months for approximately 18 months to assess long-term safety, tolerability and effectiveness of nebivolol versus metoprolol.
|
Hypertension
|
safety and tolerability study hypertension beta-blockers
| null | 2
|
arm 1: Nebivolol arm 2: Metoprolol
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Patients randomized to nebivolol will initiate therapy with nebivolol 5 mg once daily for 4 weeks. intervention 2: Patients randomized to metoprolol will initiate therapy with 100 mg once daily for 4 weeks.
|
intervention 1: Nebivolol (NEB) intervention 2: Metoprolol (MET)
| 1
|
Morgantown | West Virginia | United States | -79.9559 | 39.62953
| 0
|
NCT00142584
|
[
3
] | 114
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| true
| 1FEMALE
| false
|
The purpose of this study is to determine if the combination therapy of lifestyle intervention and use of Metformin together will improve ovulation induction and hyperandrogenemia in women with polycystic ovary syndrome, by gathering data from adult and adolescent females.
|
PCOS is characterized by excess circulating androgen levels and chronic anovulation. PCOS is also characterized by insulin resistance and hyperinsulinemia. Several recent studies in a variety of non-hospital based populations have provided evidence that the incidence of hyperandrogenic chronic anovulation is in the range of 4-6% of the female population. Improvements in insulin sensitivity in women with PCOS, either through lifestyle changes or through pharmaceutical intervention, have consistently resulted in a marked improvement in the reproductive and metabolic abnormalities in PCOS. The primary objective in the adult female population is to determine that combination therapy will improve ovulatory frequency. Secondary objective is to improve circulating hyperandrogenemia and insulin sensitivity then single agent therapy. The primary objective of the adolescent population is to determine that the combination therapy will improve hyperandrogenemia. Secondary objective is to improve ovulatory frequency and insulin sensitivity than just the use of a single agent therapy.
|
Polycystic Ovary Syndrome
|
Polycystic Ovary Syndrome (PCOS) Anovulation Elevated Testosterone
| null | 2
|
arm 1: Metformin arm 2: Placebo
|
[
0,
2
] | 3
|
[
0,
0,
5
] |
intervention 1: Medication was initiated in a step-up fashion every five days, from one tablet per day to four (500 mg per tablet). intervention 2: Placebo intervention 3: A combined intervention of diet and exercise was employed with the goal of achieving an average weight loss of at least 7% of initial body weight over six months with a prescription of 150 min/week of exercise combined with a low-calorie diet.
|
intervention 1: Metformin intervention 2: Placebo intervention 3: Lifestyle Intervention
| 1
|
Hershey | Pennsylvania | United States | -76.65025 | 40.28592
| 0
|
NCT00151411
|
[
2
] | 21
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of the study was to assess the steady-state pharmacokinetics (PK) of efavirenz (EFV) in human immunodeficiency virus type 1 (HIV-1) infected subjects on stable antiretroviral regimens containing EFV, and having selected degrees of hepatic impairment or normal hepatic function.
| null |
HIV Infections Hepatic Impairment
| null | 4
|
arm 1: None arm 2: None arm 3: None arm 4: None
|
[
0,
0,
0,
1
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Capsule or Tablet, Oral, once daily for 2 days intervention 2: Capsule or Tablet, Oral, once daily for 2 days intervention 3: Capsule or Tablet, Oral, once daily for 2 days intervention 4: Capsule or Tablet, Oral, once daily for 2 days
|
intervention 1: efavirenz containing antiretroviral regimen intervention 2: efavirenz containing antiretroviral regimen intervention 3: efavirenz containing antiretroviral regimen intervention 4: efavirenz containing antiretroviral regimen
| 4
|
Baltimore | Maryland | United States | -76.61219 | 39.29038
San Antonio | Texas | United States | -98.49363 | 29.42412
Richmond | Virginia | United States | -77.46026 | 37.55376
Milan | N/A | Italy | 12.59836 | 42.78235
| 0
|
NCT00162097
|
|
[
3
] | 28
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
Enzastaurin given daily to participants with colorectal cancer who have Stage 4 disease and have not received prior chemotherapy for advanced colorectal cancer
| null |
Colonic Neoplasms
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: 1200 milligrams (mg) loading dose orally, then 500 mg, orally, daily, up to six 28-day cycles.
|
intervention 1: Enzastaurin HCl
| 3
|
Odense | N/A | Denmark | 10.38831 | 55.39594
Vejle | N/A | Denmark | 9.5357 | 55.70927
Uppsala | N/A | Sweden | 17.63889 | 59.85882
| 0
|
NCT00192114
|
|
[
2,
3
] | 3
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
Netherton syndrome is a genetic condition that can result in abnormal skin functioning. People with this condition often have red and scaling skin; sparse or short hair; and problems with absorption of medicines or chemicals that are applied to the skin. If these chemicals are absorbed at a high level, they may cause health problems. Elidel (pimecrolimus) is a new medicine that is available as a cream. It has been shown to help improve the appearance of the skin in patients with another skin condition known as atopic dermatitis, and is approved by the United States (US) Food and Drug Administration for use in children with mild to moderate atopic dermatitis. The purpose of this study is to determine if Elidel is safe, to see whether the medication is absorbed through the skin, and to see if side effects are associated with its use in children with Netherton syndrome.
|
Patients with Netherton syndrome, a rare genodermatosis, manifest a chronic, eczematous dermatitis with erythema and scaling that is often recalcitrant to conventional therapy with emollients and topical corticosteroids. These patients display an altered epidermal barrier with increased permeability to topical agents and are therefore susceptible to evaporative transepidermal water loss and infection. Topical therapy with the calcineurin inhibitors tacrolimus and pimecrolimus has been demonstrated to improve the skin integrity and the quality of life of patients with several chronic dermatoses, including atopic dermatitis. As a result of the underlying skin barrier dysfunction, however, the possibility of significant systemic absorption and resultant side effects is a concern when these agents are used in patients with Netherton syndrome. Experience with topical tacrolimus 0.1% ointment for patients with Netherton syndrome has demonstrated both marked efficacy as well as significant systemic absorption of the drug in this patient population. Use of topical pimecrolimus in patients with Netherton syndrome has not been reported to date. Investigation of the extent of systemic absorption and side effects will help to define the safety and efficacy profile of topical pimecrolimus in patients with Netherton syndrome.
|
Netherton Syndrome
| null | 1
|
arm 1: Treatment with drug/Elidel. Single arm-open-label treatment arm. A Pilot Study of the Efficacy and Safety of Pimecrolimus Cream 1% for the Treatment of Netherton Syndrome:
|
[
0
] | 1
|
[
0
] |
intervention 1: Open label single arm
|
intervention 1: Pimecrolimus 1% Cream
| 1
|
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
| 0
|
NCT00208026
|
|
[
4
] | 63
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 2DOUBLE
| false
| 2MALE
| true
|
Risedronate is an orally administered pyridinyl bisphosphonate that is 36 times more potent than pamidronate and 72 times more potent than clodronate. Four randomized, double-blind trials have been carried out in patients with postmenopausal osteoporosis. In 2 of these studies, vertebral fracture incidence was reduced by a daily dose of 5 mg risedronate by up to 65% and 49% relative to placebo after 1 and 3 years, respectively. In these trials, risedronate improved lumbar spine, femoral neck, and femoral trochanter bone mineral density (BMD) at 6 months. In addition, preclinical studies have shown that risedronate is more potent than pamidronate and clodronate in inhibiting adhesion of prostate cancer cells to bone and preventing tumor cell invasion. The incidence of osteoporosis in prostate cancer patients has been well established; therefore, it is advantageous to assess the efficacy of oral bisphosphonate therapy.
|
OUTLINE: This is a randomized, placebo-controlled, double-blind, multicenter, 2 arm study.
The study population will consist of prostate cancer patients with metastatic bone disease for whom androgen-deprivation therapy is planned. After stratification based on the patient's age, performance status, and severity of metastatic disease, the patients will be randomized at a 1:1 ratio to the following treatment arms:
* Daily oral risedronate combined with androgen deprivation
* Daily oral placebo combined with androgen deprivation
Initial clinical evaluation will be performed during the 2-week screening period. While patients receive per-protocol treatment, study assessments will be performed every 4 weeks during the first 3 months, and every 12 weeks thereafter.
Performance Status: Eastern Cooperative Oncology Group (ECOG) 0 to 2
Life Expectancy: At least 12 weeks
Hematopoietic:
* Absolute neutrophil count (ANC) \> 1,000/mm3
* Platelet count \> 100,000/mm3
* international normalized ratio (INR) \< 1.5 x upper limit of normal unless on therapeutic anticoagulation
* Partial thromboplastin time (PTT) \< 1.5 x upper limit of normal unless on therapeutic anticoagulation
Hepatic:
* Bilirubin \< 1.5 mg/dL
* Alanine transaminase (ALT) \< 2.5 x upper limit of normal
Renal:
* Creatinine clearance of \> 30 mL/min (by Cockcroft-Gault)
Cardiovascular:
* No significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension, unstable angina, and congestive heart failure).
Pulmonary:
* Not specified
Calcium:
* Corrected serum calcium = (4.0 g/dL - actual albumin g/dL)x 0.8 + serum calcium
|
Metastatic Prostate Cancer
| null | 2
|
arm 1: Daily oral risedronate combined with androgen deprivation arm 2: daily oral placebo combined with androgen deprivation
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Daily oral risedronate combined with androgen deprivation intervention 2: Daily oral placebo combined with androgen deprivation
|
intervention 1: Risedronate intervention 2: Placebo
| 45
|
La Mesa | California | United States | -117.02308 | 32.76783
San Bernardino | California | United States | -117.28977 | 34.10834
New Britain | Connecticut | United States | -72.77954 | 41.66121
Tampa | Florida | United States | -82.45843 | 27.94752
Galesburg | Illinois | United States | -90.37124 | 40.94782
Peoria | Illinois | United States | -89.58899 | 40.69365
Evansville | Indiana | United States | -87.55585 | 37.97476
Goshen | Indiana | United States | -85.83444 | 41.58227
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Muncie | Indiana | United States | -85.38636 | 40.19338
South Bend | Indiana | United States | -86.25001 | 41.68338
Baltimore | Maryland | United States | -76.61219 | 39.29038
Greenbelt | Maryland | United States | -76.87553 | 39.00455
Rochester | Minnesota | United States | -92.4699 | 44.02163
Kansas City | Missouri | United States | -94.57857 | 39.09973
St Louis | Missouri | United States | -90.19789 | 38.62727
Reno | Nevada | United States | -119.8138 | 39.52963
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Trenton | New Jersey | United States | -74.74294 | 40.21705
Garden City | New York | United States | -73.6343 | 40.72677
Staten Island | New York | United States | -74.13986 | 40.56233
Cleveland | Ohio | United States | -81.69541 | 41.4995
Springfield | Oregon | United States | -123.02203 | 44.04624
Lancaster | Pennsylvania | United States | -76.30551 | 40.03788
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Seattle | Washington | United States | -122.33207 | 47.60621
Tacoma | Washington | United States | -122.44429 | 47.25288
La Crosse | Wisconsin | United States | -91.23958 | 43.80136
Kelowna | British Columbia | Canada | -119.48568 | 49.88307
Surrey | British Columbia | Canada | -122.82509 | 49.10635
Victoria | British Columbia | Canada | -123.35155 | 48.4359
Fredericton | New Brunswick | Canada | -66.66558 | 45.94541
Barrie | Ontario | Canada | -79.66634 | 44.40011
Burlington | Ontario | Canada | -79.83713 | 43.38621
Burlington | Ontario | Canada | -79.83713 | 43.38621
Hamilton | Ontario | Canada | -79.84963 | 43.25011
Kingston | Ontario | Canada | -76.48098 | 44.22976
London | Ontario | Canada | -81.23304 | 42.98339
Newmarket | Ontario | Canada | -79.46631 | 44.05011
Oakville | Ontario | Canada | -79.68292 | 43.45011
Scarborough Village | Ontario | Canada | -79.22124 | 43.73899
Toronto | Ontario | Canada | -79.39864 | 43.70643
| 0
|
NCT00216060
|
|
[
4
] | 243
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| true
|
In a previous phase II study, patients with pathological stage IIIb (without pleural effusion) NSCLC were treated with concurrent cisplatin and etoposide plus thoracic radiotherapy followed by 3 cycles of consolidation therapy with docetaxel. Docetaxel was selected based upon a survival benefit in patients with recurrent NSCLC.
This trial will evaluate the role of consolidation therapy with docetaxel in patients with unresectable stage III disease. The purpose of the trial is to evaluate survival and toxicities of the regimens employed.
|
OUTLINE: This is a multi-center study.
* Cisplatin 50 mg/m2 d1, 8, 29, 36
* Etoposide 50 mg/m2/day d1-5, 29-33
* Radiation 5940 cGy (180 cGy/day)
Patients with CR, PR, SD Randomized to either:Docetaxel75 mg/m2 q3wk X 3 cycles
or Observation Only
Performance Status: ECOG 0 or 1
Life Expectancy: Not specified
Hematopoietic:
* ANC \> 1,500/mm3
* Platelet count \> 100,000/mm3
* Hemoglobin \> 8 g/dl. PRBC transfusions will be allowed to increase hemoglobin to \>8 g/dl
Hepatic:
* Serum bilirubin \< institutional upper limit of normal (ULN)
* AST \< 2.5 X the upper limits of normal if alkaline phosphatase is \< ULN, or alkaline phosphatase may be up to 4 X ULN if AST are \< ULN
Renal:
* Serum creatinine of \< 2 mg/dl or calculated creatinine clearance \> 50 cc/min
Cardiovascular:
* No clinically significant history of cardiac disease, (i.e. uncontrolled hypertension, unstable angina, congestive heart failure, myocardial infarction within the past year, or cardiac ventricular arrhythmias requiring medication).
Pulmonary:
* Pre-registration FEV1 \> 1 liters by spirometry within 42 days prior to study treatment.
|
Non-Small Cell Lung Cancer
|
Non-Small Cell Lung Cancer
| null | 3
|
arm 1: Prior to randomization patients received Cisplatin 50 mg/m\^2 days 1,8,29,36 + Etoposide 50 mg/m\^2 days 1-5, 29-33 + Radiation 5940 cGy (180 cGy/day). Patients with CR, PR or SD with manageable toxicity were randomized to either Docetaxel arm or Observation only arm. arm 2: Docetaxel 75 mg/m\^2 q3wk X 3 cycles. arm 3: Patients were followed for Observation.
|
[
5,
1,
4
] | 4
|
[
0,
0,
4,
0
] |
intervention 1: Cisplatin 50 mg/m2 day 1, 8, 29, 36 intervention 2: Etoposide 50 mg/m2, days 1-5, 29-33 intervention 3: Radiation 5940 cGy (180 cGy/day) intervention 4: docetaxel 75mg/m2 q3wk x 3 cycles
|
intervention 1: Cisplatin intervention 2: Etoposide intervention 3: Radiation intervention 4: Docetaxel
| 15
|
Galesburg | Illinois | United States | -90.37124 | 40.94782
Elkhart | Indiana | United States | -85.97667 | 41.68199
Evansville | Indiana | United States | -87.55585 | 37.97476
Fort Wayne | Indiana | United States | -85.12886 | 41.1306
Goshen | Indiana | United States | -85.83444 | 41.58227
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Muncie | Indiana | United States | -85.38636 | 40.19338
New Albany | Indiana | United States | -85.82413 | 38.28562
South Bend | Indiana | United States | -86.25001 | 41.68338
Terre Haute | Indiana | United States | -87.41391 | 39.4667
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00216125
|
[
5
] | 134
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This open, multi-center randomized controlled study is designed to investigate the quality of life in patients with mycophenolate mofetil (MMF)-induced gastrointestinal (GI) adverse events after converting to enteric-coated mycophenolate sodium (EC-MPS).
| null |
Renal Transplant
|
QoL GI Side Effects MPA
| null | 2
|
arm 1: 250 mg capsules or 500 mg tablets of mycophenolate mofetil. Daily dose decided by physician, was taken morning and evening. arm 2: Oral film-coated gastroresistant tablets containing 360mg or 180mg of mycophenolate sodium. Daily dose decided by the physician, was taken morning and evening.
|
[
1,
0
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Enteric-Coated Mycophenolate Sodium (EC-MPS) intervention 2: Mycophenolate Mofetil (MMF)
| 1
|
Nottingham | N/A | United Kingdom | -1.15047 | 52.9536
| 0
|
NCT00239005
|
[
3
] | 185
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
The purpose of this study is to determine the efficacy and preferred dose of CoQ10 in individuals with ALS for a possible future phase III study.
|
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder. Available treatment for ALS remains scarce. Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of ALS. Oxidative stress refers to the effects of cell-damaging reactive oxygen species, also known as free radicals. Oxidative stress is thought to contribute to nerve cell loss in ALS. Mitochondria are organelles within each cell that are sometimes called "powerhouses of the cell" because cellular energy metabolism is located within the mitochondria.
Coenzyme Q10 (CoQ10), a mitochondrial cofactor known for its antioxidant properties, has prolonged survival in the mouse model of ALS and has slowed functional decline in another neurodegenerative disorder, Parkinson's disease. The goals of this double-blind, placebo-controlled, two-dose comparison phase II study are to obtain preliminary efficacy data and to select the preferred dose for a larger phase III study.
Participants were randomly assigned to CoQ10 (at two different dose levels) or placebo in the first stage, then the 2,700 mg dose was selected in the second stage. Duration of the trial was 9 months with a total of 7 visits.
|
Amyotrophic Lateral Sclerosis Lou Gehrig's Disease
|
amyotrophic lateral sclerosis ALS Lou Gehrig's disease CoQ10 coenzyme Q10 antioxidants free radicals mitochondrial dysfunction
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
2,
0
] | 2
|
[
0,
0
] |
intervention 1: antioxidant and mitochondrial cofactor, given in capsules three times daily intervention 2: Placebo capsules, indistinguishable from CoQ10 capsules, given three times daily
|
intervention 1: coenzyme Q10 intervention 2: Placebo
| 19
|
Little Rock | Arkansas | United States | -92.28959 | 34.74648
San Francisco | California | United States | -122.41942 | 37.77493
San Francisco | California | United States | -122.41942 | 37.77493
Denver | Colorado | United States | -104.9847 | 39.73915
New Haven | Connecticut | United States | -72.92816 | 41.30815
Chicago | Illinois | United States | -87.65005 | 41.85003
Chicago | Illinois | United States | -87.65005 | 41.85003
Kansas City | Kansas | United States | -94.62746 | 39.11417
Lexington | Kentucky | United States | -84.47772 | 37.98869
Boston | Massachusetts | United States | -71.05977 | 42.35843
Springfield | Massachusetts | United States | -72.58981 | 42.10148
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
St Louis | Missouri | United States | -90.19789 | 38.62727
New York | New York | United States | -74.00597 | 40.71427
Syracuse | New York | United States | -76.14742 | 43.04812
Cleveland | Ohio | United States | -81.69541 | 41.4995
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
San Antonio | Texas | United States | -98.49363 | 29.42412
Burlington | Vermont | United States | -73.21207 | 44.47588
| 0
|
NCT00243932
|
[
4
] | 255
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
The objective of this study is to evaluate whether Osmotic-Release Methylphenidate (OROS MPH), relative to placebo, increases the effectiveness of standard smoking treatment (i.e., nicotine patch and individual smoking cessation counseling) in obtaining prolonged abstinence for smokers with Attention Deficit Hyperactivity Disorder (ADHD).
|
The primary objective of this study is to evaluate whether OROS MPH (Concerta), relative to placebo, increases the effectiveness of standard smoking treatment (i.e., nicotine patch and individual smoking cessation counseling) in obtaining prolonged abstinence for smokers with ADHD. The study will involve an estimated 252 participants, recruited from approximately 6 sites.
|
ADHD Smoking
| null | 2
|
arm 1: None arm 2: None
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: OROS-MPH dosing strategy will start with 18 mg/day for 3 days, increasing to 36mg/day for the next three days; increasing to 54 mg/day in week two, and to 72 mg/day in week three through the remainder of the study (as tolerated). And, nicotine patch dosing schedule will be 21 mg/day during weeks 4-11; 14 mg/day during weeks 12-13; and 7 mg/day in week 14. intervention 2: OROS-MPH (placebo) dosing strategy will start with 18 mg/day for 3 days, increasing to 36mg/day for the next three days; increasing to 54 mg/day in week two, and to 72 mg/day in week three through the remainder of the study (as tolerated). And, nicotine patch dosing schedule will be 21 mg/day during weeks 4-11; 14 mg/day during weeks 12-13; and 7 mg/day in week 14.
|
intervention 1: Osmotic-Release Methylphenidate intervention 2: Placebo
| 6
|
Cambridge | Massachusetts | United States | -71.10561 | 42.3751
Rochester | Minnesota | United States | -92.4699 | 44.02163
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
Columbus | Ohio | United States | -82.99879 | 39.96118
Portland | Oregon | United States | -122.67621 | 45.52345
| 0
|
NCT00253747
|
|
[
3,
4
] | 60
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
This is a placebo controlled trial (some people receive active and some people receive inactive medication) to evaluate the effectiveness of a new protocol to treat alcohol dependence. Two main medications (plus ancillary non-placebo controlled medications) and their placebos (inactive drugs) will be utilized to treat both alcohol withdrawal, promote abstinence, and reduce drinking over approximately a six-week treatment period. All participants will meet criteria for Alcohol Dependence and be drinking heavily up until 72 hours prior to receiving the first study drug. They will be injected one drug (flumazenil or placebo) over a two day period and receive the second one (gabapentin or placebo) by mouth for 39 days. The main hypothesis is that this protocol will reduce early alcohol withdrawal symptoms and will reduce relapse to drinking and promote abstinence compared to the placebo (inactive) drug group. Secondary outcomes that will be evaluated include reduction in craving, improvement in sleep, brain activity and mood.
|
Approximately 60 alcohol dependent individuals who are drinking heavily up until 72 hours, or less, prior to study participation will be randomized to receive either flumazenil (intravenously)on two successive days and gabapentin (orally)for 39 days or their matching placebos. They also will receive hydroxyzine and vitamins. Individuals will be evaluated for alcohol withdrawal, their response to acoustic startle, cognitive ability, craving, mood, sleep and drinking during the first week. They will then be seen weekly for about 6 weeks during which they take gabapentin or placebo and are provided with Combined Behavioral Intervention Therapy (counseling) once a week, or more, as required. Over this period they will be evaluated weekly for alcohol consumption, craving, sleep, mood, and biological markers of alcohol consumption ( percent carbohydrate deficient transferrin and gamma-glutamyl transferase). Blood will be obtained on week 3 and 6 for general health (liver, blood count etc.) screening. After the end of treatment, subjects will be followed-up at 4 weeks and again at 8 weeks after treatment to evaluate alcohol consumption, craving, sleep, mood.
Subjects will undergo a functional magnetic resonance imaging (MRI) procedure sometime during the second or third week of study medication to assess cue induced regional brain activation to investigate the effect of medication on brain response to alcohol visual cues.
|
Alcohol Dependence
|
Alcoholism Alcohol Dependence Alcohol Withdrawal Treatment Pharmacotherapy
| null | 2
|
arm 1: 2 mg flumazenil given over 20 minutes on Day 1 and Day 2. Gabapentin 300 mg Day 1; gabapentin 600 mg Day 2; gabapentin 900 mg Day 3; gabapentin 1200 mg Day 4 to 30; gabapentin 900 mg day 31-33; gabapentin 600 mg day 34-36; gabapentin 300 mg day 37-39. arm 2: 20 mg Saline infused slowly over 20 minutes. Placebo 1 capsule Day 1, 2 capsules Day 2, 3 capsules Day 3, 4 capsules days 4 to 30; 3 capsules Day 31 to 33; 2 capsules day 34 to 36 and 1 capsule 37 to 39.
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 2 mg flumazenil for infusion given slowly over 20 minutes given day 1 and day 2 gabapentin 300 mg increasing to 1200 mg over 4 days and continuing to day 30. Gabapentin 900 mg Day 31 to Day 33 gabapentin 600 mg Day 34 to 36 and gabapentin 300 mg Day 37 to 39. intervention 2: 20 mg Saline infused slowly over 20 minutes. Placebo 1 capsule Day 1, 2 capsules Day 2, 3 capsules Day 3, 4 capsules days 4 to 30; 3 capsules Day 31 to 33; 2 capsules day 34 to 36 and 1 capsule 37 to 39.
|
intervention 1: Flumazenil and Gabapentin intervention 2: Placebo
| 1
|
Charleston | South Carolina | United States | -79.93275 | 32.77632
| 0
|
NCT00262639
|
[
3
] | 35
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 2MALE
| false
|
RATIONALE: Drugs used in chemotherapy, such as gemcitabine and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.
PURPOSE: This phase II trial is studying how well giving gemcitabine together with docetaxel works in treating patients with metastatic prostate cancer.
|
OBJECTIVES:
* Determine the objective response rate and toxicity in patients with androgen-independent metastatic prostate cancer treated with gemcitabine hydrochloride and docetaxel.
OUTLINE: This is an open-label study.
Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 followed by docetaxel IV over 60 minutes on day 8. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed periodically for at least 5 years.
PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.
|
Prostate Cancer
|
adenocarcinoma of the prostate stage IV prostate cancer
| null | 1
|
arm 1: None
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: docetaxel IV over 60 minutes on day 8. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. intervention 2: IV over 30 minutes on days 1 and 8 followed by docetaxel IV over 60 minutes on day 8. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
|
intervention 1: docetaxel intervention 2: gemcitabine hydrochloride
| 1
|
Cleveland | Ohio | United States | -81.69541 | 41.4995
| 0
|
NCT00276549
|
[
3
] | 200
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
RATIONALE: A peripheral stem cell transplant or an umbilical cord blood transplant from a donor may be able to replace blood-forming cells that were destroyed by chemotherapy or radiation therapy. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) after the transplant may help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells can make an immune response against the body's normal cells. Methotrexate, cyclosporine, tacrolimus, or methylprednisolone may stop this from happening.
PURPOSE: This clinical trial is studying how well a donor stem cell transplant or donor white blood cell infusions work in treating patients with hematologic cancer.
|
OBJECTIVES:
Primary
* Determine the effectiveness of unrelated donor allogeneic hematopoietic stem cells for transplantation after conditioning for the treatment of patients with high-risk hematologic malignancies.
* Compare survival, disease-free survival (DFS), response rate, and toxicity rates in these patients with historical controls.
* Compare the rate and severity of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation in patients with hematopoietic malignancies with historical controls transplanted with stem cells from related sibling donors
* Assess engraftment, long-term hematopoietic recovery, relapse rate, and disease-free survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients with high-risk hematological malignancies.
* Assess engraftment, long-term hematopoietic recovery, and overall survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients who have graft failure or graft rejection.
* Compare engraftment, long-term hematopoietic recovery, rate of GVHD, rate of relapse, toxicity rates, overall disease-free survival and overall survival when donor leukocyte infusions (DLI) are given for patients who have disease recurrence, progression, or low donor chimerisms after unrelated stem cell transplantation or before DLI with historical controls of other donor leukocyte infusions.
Secondary
* Determine the quality of life of patients undergoing hematopoietic stem cell transplantation or donor leukocyte infusions from unrelated HLA genotypically-identical donors.
OUTLINE: Patients are assigned to 1 of 8 treatment groups.
* Group 1\*: Patients undergo total body irradiation (TBI) twice a day on days -7 to -4. Patients then receive cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo stem cell transplantation (SCT). Beginning on day 7, patients receive filgrastim (G-CSF) IV once daily until blood counts recover.
* Group 2 (patients who have previously experienced dose-limiting radiotherapy): Patients receive oral busulfan 4 times daily on days -7 to -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
* Group 3 (pediatric patients only): Patients receive busulfan IV 4 times daily on days -9 to -6 and cyclophosphamide IV over 1 hour and fludarabine IV over 30 minutes on days -5 to -2. On day 0 patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
* Group 4 (second SCT for patients who have experienced graft rejection or failure)\*: Patients receive low-dose fludarabine IV over 30 minutes on days -4 to -2. Patients then undergo low-dose TBI once followed by SCT on day 0. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
* Group 5 (patients who developed grade 3 cystitis after prior cyclophosphamide-containing therapy): Patients receive carmustine IV over 2 hours on day -6, etoposide IV over 2 hours and cytarabine IV over 30 minutes on days -5 to -2, and melphalan IV over 30 minutes on day -1 (BEAM). On day 0, patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
* Group 6 (cord blood transplantation): Patients receive anti-thymocyte globulin IV once daily and methylprednisolone IV twice daily on days -3 to -1. On day 0, patients undergo an umbilical cord blood SCT.
* Group 7 (patients with relapsing or progressive disease after prior transplants or low donor chimerisms)\*: Patients must not have existing graft-versus-host disease (GVHD). Patients receive donor lymphocyte infusions with conditioning chemotherapy and/or radiotherapy at the discretion of the investigator.
* Group 8 (pediatric patients only)\*: Patients undergo TBI twice a day on days -7 to -5. Patients also receive etoposide IV over 24 hours on day -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0, patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
NOTE: \*Patients who have received \> 3000 cGy to the central nervous system or \> 2000 cGy to the lung or liver may not receive any regimen containing total body irradiation (TBI)
All patients receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11; cyclosporine and/or tacrolimus on days -2 to 100; and/or methylprednisolone IV on days 7 to 100.
Patients with an unrelated donor who experience a relapse prior to transplantation, may proceed directly to transplantation. However, if immediate transplantation from the unrelated donor is not possible, the patient must be re-induced into a complete hematological remission. Patients who experience graft failure or graft rejection after allogeneic transplantation are eligible for a second stem cell infusion from the original donor.
Quality of life is assessed at baseline and at 7 days, 3 months, and 1 year after transplantation.
After completion of study treatment, patients are followed periodically for survival.
PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.
|
Chronic Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms Unusual Cancers of Childhood
|
adult acute lymphoblastic leukemia in remission L1 adult acute lymphoblastic leukemia L2 adult acute lymphoblastic leukemia L3 adult acute lymphoblastic leukemia recurrent adult acute lymphoblastic leukemia accelerated phase chronic myelogenous leukemia blastic phase chronic myelogenous leukemia chronic phase chronic myelogenous leukemia relapsing chronic myelogenous leukemia childhood acute lymphoblastic leukemia in remission L1 childhood acute lymphoblastic leukemia L2 childhood acute lymphoblastic leukemia L3 childhood acute lymphoblastic leukemia recurrent childhood acute lymphoblastic leukemia recurrent adult Hodgkin lymphoma recurrent/refractory childhood Hodgkin lymphoma stage IV adult Hodgkin lymphoma stage IV childhood Hodgkin lymphoma adult acute myeloid leukemia in remission adult acute myeloid leukemia with 11q23 (MLL) abnormalities adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with t(16;16)(p13;q22) childhood acute myeloid leukemia in remission recurrent adult acute myeloid leukemia recurrent childhood acute myeloid leukemia myelodysplastic/myeloproliferative neoplasm, unclassifiable previously treated myelodysplastic syndromes secondary myelodysplastic syndromes secondary acute myeloid leukemia refractory anemia with excess blasts in transformation refractory anemia with excess blasts refractory anemia chronic myelomonocytic leukemia childhood chronic myelogenous leukemia chronic eosinophilic leukemia primary myelofibrosis chronic neutrophilic leukemia de novo myelodysplastic syndromes atypical chronic myeloid leukemia, BCR-ABL negative extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue juvenile myelomonocytic leukemia nodal marginal zone B-cell lymphoma noncontiguous stage II adult Burkitt lymphoma noncontiguous stage II adult diffuse large cell lymphoma noncontiguous stage II adult diffuse mixed cell lymphoma noncontiguous stage II adult diffuse small cleaved cell lymphoma noncontiguous stage II adult immunoblastic large cell lymphoma noncontiguous stage II adult lymphoblastic lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma noncontiguous stage II mantle cell lymphoma noncontiguous stage II marginal zone lymphoma noncontiguous stage II small lymphocytic lymphoma recurrent adult Burkitt lymphoma recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma recurrent childhood large cell lymphoma recurrent childhood lymphoblastic lymphoma recurrent childhood small noncleaved cell lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent mantle cell lymphoma recurrent marginal zone lymphoma recurrent small lymphocytic lymphoma refractory chronic lymphocytic leukemia refractory hairy cell leukemia refractory multiple myeloma splenic marginal zone lymphoma stage I multiple myeloma stage II multiple myeloma stage III adult Burkitt lymphoma stage III adult Hodgkin lymphoma stage III adult diffuse large cell lymphoma stage III adult diffuse mixed cell lymphoma stage III adult diffuse small cleaved cell lymphoma stage III adult immunoblastic large cell lymphoma stage III adult lymphoblastic lymphoma stage III chronic lymphocytic leukemia stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage III mantle cell lymphoma stage III marginal zone lymphoma stage III multiple myeloma stage III small lymphocytic lymphoma stage IV adult Burkitt lymphoma stage IV adult diffuse large cell lymphoma stage IV adult diffuse mixed cell lymphoma stage IV adult diffuse small cleaved cell lymphoma stage IV adult immunoblastic large cell lymphoma stage IV adult lymphoblastic lymphoma stage IV chronic lymphocytic leukemia stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma stage IV mantle cell lymphoma stage IV marginal zone lymphoma stage IV small lymphocytic lymphoma stage III childhood Hodgkin lymphoma stage III childhood large cell lymphoma stage III childhood lymphoblastic lymphoma stage III childhood small noncleaved cell lymphoma stage IV childhood large cell lymphoma stage IV childhood lymphoblastic lymphoma stage IV childhood small noncleaved cell lymphoma unusual cancers of childhood childhood myelodysplastic syndromes
| null | 8
|
arm 1: None arm 2: None arm 3: On the day of your admission, you will start to take a drug called allopurinol which helps to protect your kidneys as your body works to discharge cells killed off by your chemotherapy and TBI. Chemotherapy will begin on Day -6 with carmustine (BCNU), followed by etoposide (VP-16), cytosine arabinoside (ARA-C), and melphalan. This conditioning regimen is known as the BEAM regimen. The dose of this therapy is high enough to kill cancer cells but will also kill all of your normal blood forming cells. Subjects undergoing the BEAM regimen will not have total body irradiation (TBI). arm 4: A conditioning regimen of low-dose fludarabine and TBI is used in the event that a second donation of hematopoietic stem cells is necessary. Chemotherapy with Fludarabine will begin 4 days prior to your transplant. This drug will be given through the catheter in your chest daily for 3 days. TBI (radiation) will be given to you on the day of your transplant. After your TBI, your donor's stem cells / bone marrow will be given to you through your catheter. The drugs cyclosporine and mycophenolate mofetil (MMF) will be given orally to help you accept your donor's cells. arm 5: On the day of your admission you will start to take a drug called Dilantin which is used to help prevent seizures while you receive your chemotherapy drugs. You will also start to take a drug called allopurinol which helps to protect your kidneys as your body works to discharge cells killed off by your chemotherapy and TBI. On the next day, you will then begin your conditioning therapy with a drug called busulfan. This medicine will be given to you by an infusion into your bloodstream through a small tube in the vein of your arm four times per day for four days. After the busulfan treatment, you will receive 4 doses each of two drugs, cyclophosphamide (also known as Cytoxan) and fludarabine, over 2 hours into your vein. arm 6: If you are undergoing a pre-transplant conditioning regimen prior to undergoing a cord blood transplant, you will receive a drug called ATG to improve your chances of engraftment and decrease your risk of graft versus host disease. You may receive ATG 3 times during your transplant regimen on days -3 through days -1 in addition to your pre-transplant conditioning therapy. Methylprednisolone will also be given during each dose of ATG to help reduce any reactions during infusion. arm 7: Donor Leukocyte Infusions: You will receive DLI from your original transplant donor. This will be given through a vein , usually in your arm. It will be similar to getting a platelet or blood transfusion. You may require more than one DLI. The decision to give you another infusion will be determined by your condition, relapse status, GVHD and how much DLI you were given before. You may need chemotherapy and/or radiation to improve your disease status prior to additional DLI's. arm 8: On the day after your admission, you will start receiving radiation therapy (TBI). Radiation will be given to you 2 times a day for 3 days. On the next day, you will then begin your chemotherapy with a drug called etoposide. This medicine will be given to you by an infusion into your bloodstream through a small tube in the vein of your arm for one day. After the etoposide treatment, on the next day you will receive cyclophosphamide (also known as Cytoxan) for 2 days. When you are given cyclophosphamide, you will also be given a medication called MESNA to help protect your bladder from damage. After you have completed the cyclophosphamide you will rest one day without any anti-cancer therapy. This allows your body time to remove and inactivate the chemotherapy. After a day of rest, you will be given your donor's cells.
|
[
1,
1,
1,
1,
1,
1,
1,
1
] | 17
|
[
2,
2,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
3,
4
] |
intervention 1: Intravenous, 1.5 mg/kg of body weight daily for 7 to 14 days The first dose should be administered over a minimum of 6 hours and over at least 4 hours on subsequent doses through a high-flow vein. intervention 2: Will be given IV at 5 µg/kg/day. The first injection will be administered on day +7, i.e. 7 days after the hematopoietic stem cells are infused.
Will be administered until the ANC is 1500 / µl for 2 days. Dose and schedule of G-CSF administration is left to each center's discretion. intervention 3: Patients who take the drug PO, busulfan will be administered at 1 mg/kg/ dose given by mouth every 6 hours for 16 consecutive doses. Pediatric patients who receive busulfan IV continuous infusion will receive a dose of 3.0 mg/kg/IBW if under the age of 2.Pediatric patients over the age of 2 will receive busulfan at a dose of 0.8 mg/kg/dose. intervention 4: 300mg/m2 IV dissolved in 500 cc NS infused over 2 hours into right atrial catheter on day -6. intervention 5: For transplantation, the drug is diluted in 250 to 500 cc of NS or D5W and administered IV over 2 hours. intervention 6: Initial doses will be administered IV at a starting dose of 1.5 mg/kg BID. The infusion will vary from 2-24hr depending on the incidence of side-effects. intervention 7: 400 mg/m2 dissolved in 200cc D5W and infused over 30 minutes into right atrial catheter on days -5, -4, -3, -2. intervention 8: Etoposide administration 200 mg /m2 dissolved in 1 liter NS and infused over 2 hours into right atrial catheter. Infusion to begin after cytarabine administration on days -5, -4, -3, -2.
Etoposide administration 50 mg/kg IV over 24 hours, divided into 3 doses. Dilute in normal saline at a concentration of 0.4 mg/ml (Observe for precipitation). Administered IV with continuous infusion over 24 hours. Diuretics may be given for fluid overload. intervention 9: Fludarabine administered at 30 mg/m2 IVPB infused over 30 minutes into right atrial catheter on days -4, -3, -2.
Fludarabine administered at 40 mg/m2 IVPB infused over 30 into the right atrial catheter on days -5, -4, -3, and -2. intervention 10: 140 mg /m2 in concentration of 0.45 mg/ml of NS infused over 30 minutes into right atrial catheter on day -1. intervention 11: Administered on days +1, +3, and +7. intervention 12: Methyl-prednisolone is administered IV as a rapid infusion. intervention 13: Mycophenolate may be used as a substitute for Methotrexate intervention 14: A drug used to decrease the risk of graft versus host disease (GvHD). intervention 15: The stem cells will be given to you by intravenous injection (through your vein) using a catheter that was placed prior to beginning chemotherapy. The stem cell infusion takes 1-6 hours. intervention 16: The patient will receive ATG to improve the changes of engraftment and decrease their risk of graft versus host disease. The patient may receive ATG 3 times during their transplant regimen on days -3 through days -1 intervention 17: Radiation will be given to you 2 times a day for 3 or 4 days.
|
intervention 1: anti-thymocyte globulin intervention 2: filgrastim intervention 3: busulfan intervention 4: carmustine intervention 5: cyclophosphamide intervention 6: cyclosporine intervention 7: cytarabine intervention 8: etoposide intervention 9: fludarabine phosphate intervention 10: melphalan intervention 11: methotrexate intervention 12: methylprednisolone intervention 13: mycophenolate mofetil intervention 14: tacrolimus intervention 15: peripheral blood stem cell transplantation intervention 16: umbilical cord blood transplantation intervention 17: radiation therapy
| 1
|
Portland | Oregon | United States | -122.67621 | 45.52345
| 0
|
NCT00281879
|
[
3
] | 66
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
This study will determine whether the experimental drug LY686017 can reduce a person's desire for alcohol. A brain chemical called Substance P acts at places in the brain called NK1 receptors. Substance P is released in response to stress and gives rise to behaviors that are thought to represent anxiety. LY686017 blocks Substance P from acting at the NK1 receptors.
People between 21 and 65 years of age who have been drinking on a regular basis for at least one month before entering the study, who meet the criteria for alcohol dependence and who have an elevated score on a general test of anxiety may be eligible for this study.
Participants are admitted to the NIH Clinical Center for 35 days. They participate in an alcohol treatment program in addition to the research study. After having been withdrawn from alcohol for at least 2 days, participants receive either 50 mg of LY686017 or placebo (an inactive substance that looks like the study drug) every morning for 28 days. In addition to drug treatment, they undergo the following procedures:
* Functional magnetic resonance imaging (fMRI): In the last week of the study, subjects undergo MRI to study the amount of blood going to brain structures thought to be involved in anxiety and craving. During the procedure, they look at pictures of faces exhibiting various emotions and pictures related to alcohol.
* Cue reactivity: At the beginning and towards the end of the study, subjects are asked to rate their alcohol craving and their anxiety level while they sniff and handle their favorite alcoholic beverage or water.
* Metyrapone test: During weeks 1 and 4 of the study, subjects are given metyrapone - a drug that interferes with the body's ability to make the stress hormone cortisol - to determine how LY686017 affects the body's hormonal response. The drop in cortisol from metyrapone administration causes the brain to release ACTH, a hormone that causes the adrenal gland to make cortisol.
* Trier test: In the last week of the study, subjects give a 5-minute speech to three people and are then asked to subtract numbers in their head. Then they are asked to rate their feelings and desire for alcohol on two rating scales. Blood is drawn from a saline lock at the beginning and end of the test to measure hormone levels.
* Rating scales: Subjects complete an Obsessive Drinking Scale weekly and an Alcohol Urge Questionnaire and Comprehensive Psychiatric Rating Scale twice a week.
* Blood tests: Blood samples are collected periodically to check blood chemistries, clotting time, and the amount of LY686017 in the blood.
|
Background:
Alcoholism is a chronic relapsing disorder characterized by cycles of intoxication interspersed with phases of withdrawal and abstinence. Co-morbidity with depression and anxiety disorders is high. Even in absence of independent psychiatric co-morbidity, anxiety symptoms are almost invariably present during early as well as protracted abstinence, sensitized over repeated cycles of intoxication and withdrawal, and are correlated with craving for alcohol upon exposure to alcohol associated cues. This psychopathology is likely to maintain the dependent state since it has been shown that stress and negative affective states are major relapse triggering factors. Substance P, released in the amygdala in response to stress, acts at NK1 receptors as an important mediator of behavioral stress effects in experimental animals. Blockade of this receptor subtype represents a novel principle for anxiolytic like actions, which is well documented in animal models and has some supportive data in humans. Furthermore, decreased opiate reward following NK1 receptor inaction is indicated by the reports that deletion of the NK1 receptor decreases both conditioned place preference and self-administration of opiates, while a similar reduction of alcohol reward is suggested by preliminary data showing decreased voluntary intake of alcohol in NK1 null-mutants.
Aims:
The present study is aimed at providing an initial, exploratory evaluation of whether the NK1 receptor is a candidate target for treatment of alcohol dependence that would merit further clinical development in conventional, full-scale clinical trial designs. To evaluate this, the aim of the present study is to determine whether NK1 antagonism can beneficially affect, in anxious alcohol dependent subjects during early abstinence, surrogate variables correlated with clinical outcomes, i.e.
* reduce craving for alcohol, measured as baseline self-reported urges, or in response to presentation of alcohol associated cues
* reduce negative affect
* influence corresponding objective measures (brain fMRI responses to alcohol-associated cues and to fear stimuli, respectively; and endocrine stress responses).
This study will address this aim using a novel, orally bioavailable and brain penetrant NK1 antagonist. Positive data in this exploratory study would be the first of their kind, and provide a rationale for evaluating the NK1 antagonist for anti-craving / anti-dipsotropic and anti-anxiety actions in alcohol dependent subjects in a longer term, suggesting that it might aid relapse prevention.
Methods:
The study will be carried out in 50 subjects aged 21-65 years, with alcohol dependence as their primary complaint, and without other serious medical or psychiatric conditions. An additional inclusion criterion will be the presence or history of significant anxiety symptoms on self report. Subjects will be admitted to the NIAAA research inpatient unit at the NIH Clinical Center through a platform training and natural history protocol which provides basic assessments and standard withdrawal treatment if needed. Patients will enter into the present protocol once such treatment, if needed, is completed. The present protocol will be started with a 1 week single blind placebo lead-in. During this phase, a baseline alcohol cue-reactivity session will be carried out according to established procedures, and urges to drink will be assessed. Cue-responsive subjects only, appr. 70% of alcohol dependent inpatients, will be randomized to active treatment or placebo, and enter the active treatment phase. The active treatment arm will receive 50 mg once daily of LY686017by oral intake, while the placebo group will continue to receive placebo in a double-blind fashion. The duration of active treatment will be 3 weeks.
Patients will remain hospitalized throughout this protocol. During this period, no psychotropic medication will be allowed, and abstinence from alcohol and other drugs will be monitored. Measures of craving will be obtained using: 1) ratings completed twice a week on the established Alcohol Urge Questionnaire (AUQ); 2) assessments of urge to drink (at baseline and under medication) during an established cue reactivity paradigm during which each patient undergoes an invivo exposure to his or her preferred alcoholic beverage. The medicated cue reactivity session will follow immediately after the Trier Test, a social stress task that independently induces urges for alcohol (stress induced craving); and augments subsequent cue-induced urges (stress-potentiated cue induced craving); 3) weekly assessment of alcohol related cognitions using the Obsessive Drinking Scale (ODS), a pharmacologically validated subscale of the established Obsessive Compulsive Drinking Scale (OCDS). In addition, measures of anxiety and depression symptoms will be obtained twice-weekly using the Comprehensive Psychiatric Rating Scale (CPRS). During the last treatment week, subjects will undergo an fMRI scan using established paradigms to evoke emotional responses, and to evoke alcohol-cue associated responses, respectively. Psychophysiological measures will be obtained in conjunction with the scan. Blood draws will be carried out on the day of the scan to allow for analysis of plasma concentrations of the experimental drug. The neuroendocrine stress response will be probed, using the standard metyrapone challenge test, in unmedicated state following the baseline CR session, and then again under active treatment or placebo following the fMRI scan.
|
Alcohol Dependence Alcoholism
|
Anxiety Alcohol Dependence Alcoholism
| null | 2
|
arm 1: Subjects received 50 mg of the NK1 antagonist LY686017 orally on a daily basis. arm 2: Subjects received placebo orally on a daily basis
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 50 mg administered orally on a daily basis intervention 2: Administered on a daily basis
|
intervention 1: LY686017 intervention 2: Placebo
| 1
|
Bethesda | Maryland | United States | -77.10026 | 38.98067
| 0
|
NCT00310427
|
[
5
] | 90
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 1FEMALE
| false
|
Preemptive analgesia is an intervention which provides an anesthetic prior to initiating a painful stimulus. This trial is examining the effects of a local anesthetic given at the point of innervation prior to performing a vaginal hysterectomy with suspension sutures.
| null |
Pain, Postoperative
|
preemptive analgesia paracervical block vaginal hysterectomy
| null | 2
|
arm 1: Active preemptive local analgesia. arm 2: Placebo for preemptive local analgesia.
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 20 ml of 0.5% bupivacaine with 1:200,000 epinephrine paracervical injection. intervention 2: 20 ml normal saline injection.
|
intervention 1: bupivacaine and epinephrine intervention 2: Placebo
| 1
|
Scottsdale | Arizona | United States | -111.89903 | 33.50921
| 0
|
NCT00318292
|
[
5
] | 92
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This study looked at lipid changes in human immunodeficiency virus type 1 (HIV-1) infected patients when the nucleoside reverse transcriptase inhibitors (NRTIs) in their existing highly active antiretroviral therapy (HAART) regimen were switched to Truvada® (a fixed dose combination tablet of emtricitabine/tenofovir disoproxil fumarate 200 mg/300 mg \[FTC/TDF\]). Subjects continued their nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) at the same dose.
|
This was a Phase IV, multicenter (in France), open label study. The study was conducted in two phases: a comparative randomized phase, which served the primary objective of the study, and a follow-up phase.
Study Phase 1, Day -14 to Week 12: patients were randomized on a 1:1 basis to one of two groups:
* A. Truvada (substitution of their current NRTIs by Truvada \[FTC/TDF\] with continuation of their current NNRTI or PI at the same dose)
* B. Maintain Baseline Regimen (continuation of previous HAART regimen, i.e., maintained baseline regimen).
This phase of the study served the primary objective of the study.
Study Phase 2, roll-over follow-up, Week 12 to Week 48: Patients in the Truvada group continued with Truvada + an NNRTI or PI. Patients in the control group could switch their NRTIs to Truvada in this phase of the study (Delayed Truvada group).
Patients were assessed for efficacy and safety during both phases of the study.
|
HIV Infections
|
HIV 1 Infection
| null | 4
|
arm 1: Truvada once daily with continuation of the current NNRTI or PI at randomization arm 2: Maintain baseline regimen arm 3: Truvada once daily with NNRTI or PI (participants from the comparator group who switched to Truvada during Study Phase 2) arm 4: Truvada once daily with NNRTI or PI (all participants who received Truvada during the study, i.e., participants in the Truvada and Delayed Truvada groups)
|
[
0,
1,
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Truvada + NNRTI or PI. intervention 2: Maintain baseline regimen
|
intervention 1: Truvada intervention 2: Current HAART regimen
| 1
|
Paris | N/A | France | 2.3488 | 48.85341
| 0
|
NCT00323492
|
[
4
] | 1,554
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the safety and efficacy of alogliptin, once daily (QD), taken in combination with pioglitazone in adults with type 2 diabetes mellitus.
|
Over the past 30 years, the prevalence of diabetes has increased dramatically throughout the world due to population growth, aging, urbanization, increasing obesity, and physical inactivity. The total number of people with type 2 diabetes mellitus is projected to rise from 171 million in 2000 to 366 million in 2030. The incidence of type 2 diabetes mellitus in the United States alone is expected to increase from approximately 17 to 30.3 million by the year 2030. Type 2 diabetes mellitus is associated with a number of long-term microvascular and macrovascular complications associated with a reduced quality of life and increased morbidity and mortality. It is anticipated that the increasing incidence of type 2 diabetes mellitus will place an ever-increasing burden on families, increase national expenditures for health care services, and decrease worker productivity.
Current pharmacologic interventions for type 2 diabetes mellitus include a diverse range of antidiabetic medications with different mechanisms of action including insulin and insulin analogues, sulfonylureas, metformin, meglitinides, thiazolidinediones, inhibitors of alpha-glucosidase, analogs of glucagon-like peptide-1 and synthetic analogues of human amylin. Despite the variety of medications, many have clinically important or potentially life-threatening side effects, restricted use in many subpopulations, concerns with long-term tolerability, and challenges related to compliance due to side effects and route of administration. All of these reasons contribute to the difficulties patients have achieving the target glycosylated hemoglobin level less than 7%.
SYR-322 (alogliptin) is a selective, orally available inhibitor of the dipeptidyl peptidase-4 enzyme. Dipeptidyl peptidase-4 enzyme is thought to be primarily responsible for the in vivo degradation of 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Both peptides exert important effects on islet beta cells to stimulate glucose-dependent insulin secretion as well as regulating beta cell proliferation and cytoprotection. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits gastric emptying, glucagon secretion, and food intake. Glucose-dependent insulinotropic peptide has been shown to enhance insulin secretion by direct interaction with a glucose-dependent insulinotropic peptide -specific receptor on islet beta cells. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes mellitus.
Pioglitazone (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan) that is approved for the treatment of type 2 diabetes mellitus. Pioglitazone is a selective peroxisome proliferator-activated receptor-gamma agonist that decreases insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.
Given the complementary mechanisms of action of alogliptin (stimulation of insulin secretion) and pioglitazone (enhancement of insulin sensitivity), the goal of this study is to evaluate the efficacy of the combination of alogliptin with pioglitazone in patients who are inadequately controlled on metformin. Study participation is anticipated to be approximately 7 months.
|
Type 2 Diabetes Mellitus
|
Diabetes Mellitus, Type 2 Drug Therapy Diabetes Mellitus, Non Insulin Dependent Glucose Intolerance Hyperglycemia
| null | 12
|
arm 1: Alogliptin placebo-matching tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks. arm 2: Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks. arm 3: Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks. arm 4: Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks. arm 5: Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks. arm 6: Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks. arm 7: Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks. arm 8: Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks. arm 9: Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks. arm 10: Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks. arm 11: Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks. arm 12: Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.
|
[
2,
0,
0,
1,
0,
0,
1,
0,
0,
1,
0,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Alogliptin tablets. intervention 2: Alogliptin placebo-matching tablets. intervention 3: Pioglitazone tablets. intervention 4: Pioglitazone placebo-matching tablets.
|
intervention 1: Alogliptin intervention 2: Alogliptin placebo intervention 3: Pioglitazone intervention 4: Pioglitazone placebo
| 90
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Columbiana | Alabama | United States | -86.60721 | 33.17817
Huntsville | Alabama | United States | -86.58594 | 34.7304
Phoenix | Arizona | United States | -112.07404 | 33.44838
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Searcy | Arkansas | United States | -91.73625 | 35.25064
Sherwood | Arkansas | United States | -92.22432 | 34.81509
Burbank | California | United States | -118.30897 | 34.18084
Foothill Ranch | California | United States | -117.66088 | 33.68641
Irvine | California | United States | -117.82311 | 33.66946
Sacramento | California | United States | -121.4944 | 38.58157
San Diego | California | United States | -117.16472 | 32.71571
Temecula | California | United States | -117.14836 | 33.49364
Tustin | California | United States | -117.82617 | 33.74585
Colorado Springs | Colorado | United States | -104.82136 | 38.83388
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Hollywood | Florida | United States | -80.14949 | 26.0112
Kissimmee | Florida | United States | -81.41667 | 28.30468
Miami | Florida | United States | -80.19366 | 25.77427
New Port Richey | Florida | United States | -82.71927 | 28.24418
Pembroke Pines | Florida | United States | -80.22394 | 26.00315
Pinellas Park | Florida | United States | -82.69954 | 27.8428
Sarasota | Florida | United States | -82.53065 | 27.33643
Vero Beach | Florida | United States | -80.39727 | 27.63864
Atlanta | Georgia | United States | -84.38798 | 33.749
Roswell | Georgia | United States | -84.36159 | 34.02316
Savannah | Georgia | United States | -81.09983 | 32.08354
Warner Robins | Georgia | United States | -83.62664 | 32.61574
Chicago | Illinois | United States | -87.65005 | 41.85003
Peoria | Illinois | United States | -89.58899 | 40.69365
Lafayette | Indiana | United States | -86.87529 | 40.4167
South Bend | Indiana | United States | -86.25001 | 41.68338
Waterloo | Iowa | United States | -92.34296 | 42.49276
Munfordville | Kentucky | United States | -85.89108 | 37.27228
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
Marrero | Louisiana | United States | -90.10035 | 29.89937
Elkridge | Maryland | United States | -76.71358 | 39.21261
Prince Frederick | Maryland | United States | -76.5844 | 38.5404
Towson | Maryland | United States | -76.60191 | 39.4015
Marlborough | Massachusetts | United States | -71.55229 | 42.34593
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Cadillac | Michigan | United States | -85.40116 | 44.25195
Detroit | Michigan | United States | -83.04575 | 42.33143
Livonia | Michigan | United States | -83.35271 | 42.36837
Kansas City | Missouri | United States | -94.57857 | 39.09973
North Las Vegas | Nevada | United States | -115.1175 | 36.19886
Blackwood | New Jersey | United States | -75.06406 | 39.80234
Trenton | New Jersey | United States | -74.74294 | 40.21705
New York | New York | United States | -74.00597 | 40.71427
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Statesville | North Carolina | United States | -80.8873 | 35.78264
Gallipolis | Ohio | United States | -82.20237 | 38.8098
Marion | Ohio | United States | -83.12852 | 40.58867
Clinton | Oklahoma | United States | -98.96731 | 35.51561
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Allentown | Pennsylvania | United States | -75.49018 | 40.60843
Altoona | Pennsylvania | United States | -78.39474 | 40.51868
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Alcoa | Tennessee | United States | -83.97379 | 35.78953
Milan | Tennessee | United States | -88.75895 | 35.91979
Morristown | Tennessee | United States | -83.29489 | 36.21398
Arlington | Texas | United States | -97.10807 | 32.73569
Carrollton | Texas | United States | -96.89028 | 32.95373
Dallas | Texas | United States | -96.80667 | 32.78306
Fort Worth | Texas | United States | -97.32085 | 32.72541
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
Temple | Texas | United States | -97.34278 | 31.09823
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Burlington | Vermont | United States | -73.21207 | 44.47588
Multiple Cities | N/A | Australia | N/A | N/A
Multiple Cities | N/A | Brazil | N/A | N/A
Multiple Cities | N/A | Bulgaria | N/A | N/A
Multiple Cities | N/A | Chile | N/A | N/A
Multiple Cities | N/A | Croatia | N/A | N/A
Multiple Cities | N/A | Estonia | N/A | N/A
Multiple Cities | N/A | Guatemala | N/A | N/A
Multiple Cities | N/A | India | N/A | N/A
Multiple Cities | N/A | Israel | N/A | N/A
Multiple Cities | N/A | Latvia | N/A | N/A
Multiple Cities | N/A | Mexico | N/A | N/A
Multiple Cities | N/A | New Zealand | N/A | N/A
Multiple Cities | N/A | Peru | N/A | N/A
Multiple Cities | N/A | Romania | N/A | N/A
Multiple Cities | N/A | Russia | N/A | N/A
Multiple Cities | N/A | Serbia | N/A | N/A
Multiple Cities | N/A | South Africa | N/A | N/A
Multiple Cities | N/A | Ukraine | N/A | N/A
| 0
|
NCT00328627
|
[
4
] | 547
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
to demonstrate the efficacy of inhaled Technosphere/Insulin in combination with metformin versus combination metformin and a secretagogue
| null |
Diabetes Mellitus, Type 2
| null | 3
|
arm 1: Technosphere Insulin arm 2: Metformin \& Secretagogues arm 3: Technosphere \& Metformin
|
[
0,
1,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: Inhalation, 15U/30U, prandial intervention 2: Metformin tablets,Secretagogues supplied as any of the currently marketed brands and formulations. intervention 3: Technosphere Insulin Inhalation Powder 15U/30U, Metformin tablets
|
intervention 1: Technosphere Insulin intervention 2: Metformin & Secretagogues intervention 3: Technosphere Insulin & Metformin
| 120
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Chula Vista | California | United States | -117.0842 | 32.64005
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Waterbury | Connecticut | United States | -73.0515 | 41.55815
Hollywood | Florida | United States | -80.14949 | 26.0112
Miami | Florida | United States | -80.19366 | 25.77427
Chicago | Illinois | United States | -87.65005 | 41.85003
Chicago | Illinois | United States | -87.65005 | 41.85003
Skokie | Illinois | United States | -87.73339 | 42.03336
Towson | Maryland | United States | -76.60191 | 39.4015
Haverhill | Massachusetts | United States | -71.07728 | 42.7762
Detroit | Michigan | United States | -83.04575 | 42.33143
Livonia | Michigan | United States | -83.35271 | 42.36837
St Louis | Missouri | United States | -90.19789 | 38.62727
St Louis | Missouri | United States | -90.19789 | 38.62727
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Mineola | New York | United States | -73.64068 | 40.74927
New Hyde Park | New York | United States | -73.68791 | 40.7351
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Durham | North Carolina | United States | -78.89862 | 35.99403
Dayton | Ohio | United States | -84.19161 | 39.75895
Dayton | Ohio | United States | -84.19161 | 39.75895
Portland | Oregon | United States | -122.67621 | 45.52345
Greenville | South Carolina | United States | -82.39401 | 34.85262
Collierville | Tennessee | United States | -89.66453 | 35.04204
Memphis | Tennessee | United States | -90.04898 | 35.14953
Memphis | Tennessee | United States | -90.04898 | 35.14953
Dallas | Texas | United States | -96.80667 | 32.78306
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Tacoma | Washington | United States | -122.44429 | 47.25288
Avellaneda | Buenos Aires | Argentina | -58.36744 | -34.66018
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Porto Alegre | Rio Grande do Sul | Brazil | -51.23019 | -30.03283
Porto Alegre | Rio Grande do Sul | Brazil | -51.23019 | -30.03283
Rio de Janeiro | N/A | Brazil | -43.18223 | -22.90642
Santos | N/A | Brazil | -46.33361 | -23.96083
São Paulo | N/A | Brazil | -46.63611 | -23.5475
São Paulo | N/A | Brazil | -46.63611 | -23.5475
São Paulo | N/A | Brazil | -46.63611 | -23.5475
São Paulo | N/A | Brazil | -46.63611 | -23.5475
Markham | Ontario | Canada | -79.2663 | 43.86682
Oakville | Ontario | Canada | -79.68292 | 43.45011
Thornhill | Ontario | Canada | -79.4163 | 43.80011
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Richmond Hill | N/A | Canada | -79.43725 | 43.87111
Santiago | Santiago Metropolitan | Chile | -70.64827 | -33.45694
Santiago | N/A | Chile | -70.64827 | -33.45694
Santiago | N/A | Chile | -70.64827 | -33.45694
Santiago | N/A | Chile | -70.64827 | -33.45694
Ostrava-Kunčice | CZE | Czechia | 18.2919 | 49.7903
Prague | CZE | Czechia | 14.42076 | 50.08804
Prague | CZE | Czechia | 14.42076 | 50.08804
Ostrava | Ostrava | Czechia | 18.28204 | 49.83465
Ostrava | N/A | Czechia | 18.28204 | 49.83465
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Mexico City | Durango | Mexico | N/A | N/A
Monterrey | Nuevo León | Mexico | -100.31721 | 25.68435
Garza García | N/A | Mexico | -99.81754 | 25.18305
Mexico City | N/A | Mexico | -99.12766 | 19.42847
Mexico City | N/A | Mexico | -99.12766 | 19.42847
Monterrey | N/A | Mexico | -100.31721 | 25.68435
Bialystock | POL | Poland | N/A | N/A
Bialystok | POL | Poland | 23.16433 | 53.13333
Krakow | POL | Poland | 19.93658 | 50.06143
Lodz | POL | Poland | 19.47395 | 51.77058
Pruszków | POL | Poland | 20.81214 | 52.17072
Lodz | N/A | Poland | 19.47395 | 51.77058
Warsaw | N/A | Poland | 21.01178 | 52.22977
Warsaw | N/A | Poland | 21.01178 | 52.22977
Kemerovo | RUS | Russia | 86.08333 | 55.33333
Moscow | RUS | Russia | 37.61556 | 55.75222
Moscow | RUS | Russia | 37.61556 | 55.75222
Moscow | RUS | Russia | 37.61556 | 55.75222
Moscow | RUS | Russia | 37.61556 | 55.75222
Saint Petersburg | RUS | Russia | 30.31413 | 59.93863
Saint Petersburg | RUS | Russia | 30.31413 | 59.93863
Saint Petersburg | RUS | Russia | 30.31413 | 59.93863
Saint Petersburg | RUS | Russia | 30.31413 | 59.93863
Smolensk | RUS | Russia | 32.04371 | 54.77944
Yaroslavl | RUS | Russia | 39.87368 | 57.62987
Yaroslavl | RUS | Russia | 39.87368 | 57.62987
Moscow | N/A | Russia | 37.61556 | 55.75222
Seville | Andalusia | Spain | -5.97317 | 37.38283
Barcelona | N/A | Spain | 2.15899 | 41.38879
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Sabadell | N/A | Spain | 2.10942 | 41.54329
Chernivtsy | UKR | Ukraine | N/A | N/A
Dniepropetrovsk | UKR | Ukraine | N/A | N/A
Donetsk | UKR | Ukraine | 37.80224 | 48.023
Donetsk | UKR | Ukraine | 37.80224 | 48.023
Donetsk | UKR | Ukraine | 37.80224 | 48.023
Kiev | UKR | Ukraine | 30.5238 | 50.45466
Kiev | UKR | Ukraine | 30.5238 | 50.45466
Kiev | UKR | Ukraine | 30.5238 | 50.45466
Odesa | UKR | Ukraine | 30.74383 | 46.48572
Odesa | UKR | Ukraine | 30.74383 | 46.48572
Odesa | UKR | Ukraine | 30.74383 | 46.48572
Vinnitsa | UKR | Ukraine | 37.71861 | 49.84639
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Odesa | N/A | Ukraine | 30.74383 | 46.48572
| 0
|
NCT00332488
|
|
[
3
] | 43
|
RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| true
| 0ALL
| true
|
The purpose of this study is to compare the amount of acetylcholine release after a single injection of clonidine in normal volunteers and individuals with neuropathic pain.
|
This study is part of a pain center grant that focuses on how pain, especially chronic neuropathic pain, alters the response to traditional and non-traditional analgesics (pain medications).
The way that nerve fibers carry pain information to the brain is thought to change after surgery and in cases of chronic pain. For this reason, some medicines work better to relieve pain in healthy people who have a sudden painful injury when compared to people after surgery or to people with chronic pain. Currently available pain medications may not relieve all types of pain or may relieve pain only at doses that produce side effects and potential complications.
The aim of this study is to understand the mechanisms by which intrathecal clonidine (or clonidine injected into cerebrospinal fluid) increases in potency and efficacy by examining the cerebrospinal fluid of healthy individuals, before and after clonidine administration, as well as looking at the spinal fluid of people with chronic neuropathic nerve pain. More specifically, in this study, researchers will compare acetylcholine release (a protein-like substance found in cerebrospinal fluid) in normal volunteers and patients with neuropathic pain after a single injection of clonidine.
After baseline measurements, including blood pressure and heart rate, participants will be trained to accurately estimate pain by way of thermal heat testing. Next a small amount of spinal fluid will be withdrawn from each participant to measure the amounts of naturally-made chemicals in the participants' cerebrospinal fluid. Participants then will receive an injection of clonidine. After the injection, additional samples of spinal fluid will be taken to measure chemical changes in the fluid.
Duration of the study for participants is 1 day, and includes 1 visit to the research center, lasting approximately 3 hours.
|
Pain
|
pain, chronic pain acetylcholine clonidine a2-adrenergic agonists alpha2-adrenergic agonists
| null | 2
|
arm 1: Chronic Pain Participants will be trained to accurately estimate pain by way of thermal heat testing. Next a small amount of spinal fluid will be withdrawn from each participant to measure the amounts of naturally-made chemicals in the participants' cerebrospinal fluid. Participants then will receive an injection of clonidine. After the injection, additional samples of spinal fluid will be taken to measure chemical changes in the fluid. arm 2: Healthy Participants will be trained to accurately estimate pain by way of thermal heat testing. Next a small amount of spinal fluid will be withdrawn from each participant to measure the amounts of naturally-made chemicals in the participants' cerebrospinal fluid. Participants then will receive an injection of clonidine. After the injection, additional samples of spinal fluid will be taken to measure chemical changes in the fluid.
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: Patients will receive intrathecal clonidine (or clonidine injected into cerebrospinal fluid) intervention 2: Patients will receive intrathecal clonidine (or clonidine injected into cerebrospinal fluid)
|
intervention 1: clonidine intervention 2: clonidine
| 2
|
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
| 0
|
NCT00350532
|
[
3,
4
] | 163
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this clinical research study is to learn if BMS-512148, added to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone), can help reduce the blood sugar levels compared to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone) alone, in subjects with type 2 diabetes. The safety of this treatment will also be studied.
| null |
Type 2 Diabetes
| null | 4
|
arm 1: 20 mg arm 2: 10 mg arm 3: 20 mg arm 4: None
|
[
0,
0,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Tablets, Oral, once daily, up to 12 weeks intervention 2: Tablets, Oral, 0 mg, once daily, up to 12 weeks
|
intervention 1: Dapagliflozin intervention 2: Placebo
| 23
|
Jonesboro | Arkansas | United States | -90.70428 | 35.8423
Fresno | California | United States | -119.77237 | 36.74773
Greenbrae | California | United States | -122.5247 | 37.94854
Jacksonville | Florida | United States | -81.65565 | 30.33218
Roswell | Georgia | United States | -84.36159 | 34.02316
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Baltimore | Maryland | United States | -76.61219 | 39.29038
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
St Louis | Missouri | United States | -90.19789 | 38.62727
Syracuse | New York | United States | -76.14742 | 43.04812
Asheville | North Carolina | United States | -82.55402 | 35.60095
Mentor | Ohio | United States | -81.33955 | 41.66616
Dallas | Texas | United States | -96.80667 | 32.78306
San Antonio | Texas | United States | -98.49363 | 29.42412
Renton | Washington | United States | -122.21707 | 47.48288
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Winnipeg | Manitoba | Canada | -97.14704 | 49.8844
Bathurst | New Brunswick | Canada | -65.65112 | 47.61814
Gatineau | Quebec | Canada | -75.70164 | 45.47723
Laval | Quebec | Canada | -73.692 | 45.56995
Longueuil | Quebec | Canada | -73.46818 | 45.5152
Pointe-Claire | Quebec | Canada | -73.81669 | 45.44868
Sherbrooke | Quebec | Canada | -71.89908 | 45.40008
| 0
|
NCT00357370
|
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