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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
[
5
] | 21
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
Participants (n=20) will be identified at routine care visits performed at the Rochester Multiple Sclerosis Center. Eligible participants will have MS by McDonald Criteria,7 and will have a modified Ashworth spasticity rating8 of two or higher in at least one lower extremity muscle group. Participants will be seen at screening, one, and three months, and will be evaluated using the modified Ashworth scale,8 pendulum test,9 toe tapping test,10 manual muscle testing,11 timed 25 foot walk,12 and Multiple Sclerosis Functional Composite.13 The type and severity of any adverse events will be recorded using standard definitions. Participants will be instructed to call between visits to inform the investigators regarding any adverse events they experience. Follow-up will continue until all adverse events resolve or stabilize.
|
This is a randomized, placebo controlled, double-blind, parallel group trial of memantine in patients with MS and spasticity. Participants will be identified at routine care visits at the Rochester Multiple Sclerosis Center. After obtaining informed consent, patients will undergo screening, which will include a physical/neurologic exam and an assessment of the Expanded Disability Status Scale, spasticity, and functional abilities. Eligible patients will return for a baseline evaluation, will initiate their randomly assigned study medication, and will return after one and three months for re-evaluation. The type and severity of any adverse events will be recorded using standard definitions. Participants will be instructed to call between visits to inform the investigators regarding any adverse events they experience. Follow-up will continue until all adverse events resolve or stabilize.
|
Multiple Sclerosis
|
multiple sclerosis
| null | 2
|
arm 1: Memantine 10 mg bid arm 2: Placebo
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: matched tablets bid intervention 2: 10 mg bid
|
intervention 1: placebo intervention 2: memantine
| 1
|
Rochester | New York | United States | -77.61556 | 43.15478
| 0
|
NCT00638027
|
[
3
] | 421
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
The purpose of this study is to determine whether gabapentin enacarbil (XP13512/GSK1838262), hereafter referred to as GEn is effective in the treatment of neuropathic pain associated with diabetic peripheral neuropathy(DPN)
|
This is a dose-response study of XP13512 compared with concurrent placebo control and LYRICA (pregabalin), in subjects with neuropathic pain associated with DPN. Three doses of XP13512 (1200 mg/day, 2400 mg/day and 3600 mg/day) are being evaluated for the management of neuropathic pain associated with DPN. Approximately 392 subjects from 70 to 80 participating sites in the US will be randomized to receive either XP13512 at the above mentioned doses, placebo or pregabalin (300mg/day).
|
Neuropathy, Diabetic
|
Peripheral Diabetic Neuropathy (PDN) Neuropathic Pain
| null | 5
|
arm 1: Placebo arm 2: Pregabalin 300mg/day (positive control), maintenance treatment 14 weeks arm 3: gabapentin enacarbil 1200mg/day, maintenance treatment 14 weeks arm 4: gabapentin enacarbil 2400mg/day, maintenance treatment 14 weeks arm 5: gabapentin enacarbil 3600mg/day, maintanance treatment 14 weeks
|
[
2,
5,
0,
0,
0
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: placebo intervention 2: gabapentin enacarbil 1200mg/day intervention 3: gabapentin enacarbil 2400mg/day intervention 4: gabapentin enacarbil 3600mg/day intervention 5: pregabalin 300mg/day
|
intervention 1: Placebo intervention 2: GEn 1200mg/day intervention 3: GEn 2400mg/day intervention 4: GEn 3600mg/day intervention 5: Pregabalin
| 90
|
Alabaster | Alabama | United States | -86.81638 | 33.24428
Birmingham | Alabama | United States | -86.80249 | 33.52066
Dothan | Alabama | United States | -85.39049 | 31.22323
Hoover | Alabama | United States | -86.81138 | 33.40539
Jasper | Alabama | United States | -87.27751 | 33.83122
Muscle Shoals | Alabama | United States | -87.66753 | 34.74481
Northport | Alabama | United States | -87.57723 | 33.22901
Tuscaloosa | Alabama | United States | -87.56917 | 33.20984
Mesa | Arizona | United States | -111.82264 | 33.42227
Peoria | Arizona | United States | -112.23738 | 33.5806
Tempe | Arizona | United States | -111.90931 | 33.41477
Hot Springs | Arkansas | United States | -93.05518 | 34.5037
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Anaheim | California | United States | -117.9145 | 33.83529
Concord | California | United States | -122.03107 | 37.97798
Escondido | California | United States | -117.08642 | 33.11921
Fresno | California | United States | -119.77237 | 36.74773
Huntington Park | California | United States | -118.22507 | 33.98168
La Jolla | California | United States | -117.2742 | 32.84727
Los Gatos | California | United States | -121.97468 | 37.22661
Mission Viejo | California | United States | -117.672 | 33.60002
Newport Beach | California | United States | -117.92895 | 33.61891
Northridge | California | United States | -118.53675 | 34.22834
Oxnard | California | United States | -119.17705 | 34.1975
Riverside | California | United States | -117.39616 | 33.95335
San Diego | California | United States | -117.16472 | 32.71571
Santa Ana | California | United States | -117.86783 | 33.74557
Santa Monica | California | United States | -118.49138 | 34.01949
Temecula | California | United States | -117.14836 | 33.49364
Walnut Creek | California | United States | -122.06496 | 37.90631
Westlake Village | California | United States | -118.80565 | 34.14584
Brandon | Florida | United States | -82.28592 | 27.9378
Clearwater | Florida | United States | -82.8001 | 27.96585
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
Fort Myers | Florida | United States | -81.84059 | 26.62168
Hallandale | Florida | United States | -80.14838 | 25.9812
Hollywood | Florida | United States | -80.14949 | 26.0112
New Port Richey | Florida | United States | -82.71927 | 28.24418
Ocala | Florida | United States | -82.14009 | 29.1872
Ormond Beach | Florida | United States | -81.05589 | 29.28581
Pembroke Pines | Florida | United States | -80.22394 | 26.00315
St. Petersburg | Florida | United States | -82.67927 | 27.77086
Tallahassee | Florida | United States | -84.28073 | 30.43826
Atlanta | Georgia | United States | -84.38798 | 33.749
Decatur | Georgia | United States | -84.29631 | 33.77483
Marietta | Georgia | United States | -84.54993 | 33.9526
Roswell | Georgia | United States | -84.36159 | 34.02316
Chicago | Illinois | United States | -87.65005 | 41.85003
Libertyville | Illinois | United States | -87.95313 | 42.28308
Evansville | Indiana | United States | -87.55585 | 37.97476
Evansville | Indiana | United States | -87.55585 | 37.97476
Wichita | Kansas | United States | -97.33754 | 37.69224
Rockville | Maryland | United States | -77.15276 | 39.084
Wellesley Hills | Massachusetts | United States | -71.27867 | 42.30843
Kalamazoo | Michigan | United States | -85.58723 | 42.29171
Olive Branch | Mississippi | United States | -89.82953 | 34.96176
Kansas City | Missouri | United States | -94.57857 | 39.09973
St Louis | Missouri | United States | -90.19789 | 38.62727
St Louis | Missouri | United States | -90.19789 | 38.62727
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
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Flushing | New York | United States | -73.81736 | 40.76538
New York | New York | United States | -74.00597 | 40.71427
North Massapequa | New York | United States | -73.46207 | 40.70093
Rochester | New York | United States | -77.61556 | 43.15478
Staten Island | New York | United States | -74.13986 | 40.56233
Greensboro | North Carolina | United States | -79.79198 | 36.07264
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Salisbury | North Carolina | United States | -80.47423 | 35.67097
Toledo | Ohio | United States | -83.55521 | 41.66394
Norman | Oklahoma | United States | -97.43948 | 35.22257
Eugene | Oregon | United States | -123.08675 | 44.05207
Medford | Oregon | United States | -122.87559 | 42.32652
Levittown | Pennsylvania | United States | -74.82877 | 40.15511
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Greer | South Carolina | United States | -82.22706 | 34.93873
Mt. Pleasant | South Carolina | United States | -79.86259 | 32.79407
Kingsport | Tennessee | United States | -82.56182 | 36.54843
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
Alexandria | Virginia | United States | -77.04692 | 38.80484
Richmond | Virginia | United States | -77.46026 | 37.55376
Weber City | Virginia | United States | -78.28389 | 37.75514
Spokane | Washington | United States | -117.42908 | 47.65966
Spokane | Washington | United States | -117.42908 | 47.65966
Tacoma | Washington | United States | -122.44429 | 47.25288
Vancouver | Washington | United States | -122.66149 | 45.63873
| 0
|
NCT00643760
|
[
2
] | 25
|
RANDOMIZED
|
CROSSOVER
| 9OTHER
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to assess whether a cross-over type study design in post-traumatic neuropathic patients can be used to assess the activity of potential analgesic agents
|
Methodology study to evaluate a cross-over study design in post-traumatic neuropathic pain patients.
|
Nerve Pain
| null | 2
|
arm 1: None arm 2: None
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: Oral, 75mg or 150mg capsules, BID intervention 2: Oral, matched capsules, BID
|
intervention 1: Pregabalin (Lyrica) intervention 2: Placebo
| 5
|
Calgary | Alberta | Canada | -114.08529 | 51.05011
Hamilton | Ontario | Canada | -79.84963 | 43.25011
Sarnia | Ontario | Canada | -82.40407 | 42.97866
Jönköping | N/A | Sweden | 14.15618 | 57.78145
Linköping | N/A | Sweden | 15.62157 | 58.41086
| 0
|
NCT00654940
|
|
[
4
] | 339
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 2MALE
| false
|
This study investigates the safety and efficacy of a new dosage form of Vardenafil, an orodispersible tablet (ODT), and compares it to the safety and efficacy of a placebo (inactive) tablet in the treatment of erectile dysfunction. After a 4-week unmedicated phase, patients will receive Vardenafil ODT or matching placebo for 12 weeks. Safety will be determined by laboratory and other evaluations. Efficacy will be determined by the results of different questionnaires and the patient diary that will be used.
| null |
Erectile Dysfunction
|
Erectile Dysfunction
| null | 2
|
arm 1: Vardenafil 10 mg orodispersible tablet (ODT) taken on demand (PRN), approximately one hour before start of sexual activity, no more than one dose per day. arm 2: Matching placebo tablet taken on demand (PRN), approximately one hour before start of sexual activity, no more than one dose per day.
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Subjects will receive 12 weeks of PRN (on demand) treatment with Vardenafil 10 mg orodispersible tablet (ODT) intervention 2: Subjects will receive 12 weeks of PRN (on demand) treatment with matching placebo tablet
|
intervention 1: Vardenafil ODT (STAXYN, BAY38-9456) intervention 2: Placebo
| 40
|
Chandler | Arizona | United States | -111.84125 | 33.30616
Mesa | Arizona | United States | -111.82264 | 33.42227
Mesa | Arizona | United States | -111.82264 | 33.42227
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Tempe | Arizona | United States | -111.90931 | 33.41477
Irvine | California | United States | -117.82311 | 33.66946
National City | California | United States | -117.0992 | 32.67811
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
Aventura | Florida | United States | -80.13921 | 25.95648
Jacksonville | Florida | United States | -81.65565 | 30.33218
Pembroke Pines | Florida | United States | -80.22394 | 26.00315
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Great Neck | New York | United States | -73.72846 | 40.80066
New York | New York | United States | -74.00597 | 40.71427
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Columbus | Ohio | United States | -82.99879 | 39.96118
Levittown | Pennsylvania | United States | -74.82877 | 40.15511
Norristown | Pennsylvania | United States | -75.3399 | 40.1215
Spokane | Washington | United States | -117.42908 | 47.65966
Bondi Junction | New South Wales | Australia | 151.24723 | -33.89275
St Leonards | New South Wales | Australia | 151.19836 | -33.82344
Adelaide | South Australia | Australia | 138.59863 | -34.92866
Melbourne | Victoria | Australia | 144.96332 | -37.814
Nedlands | Western Australia | Australia | 115.8073 | -31.98184
Perth | Western Australia | Australia | 115.8614 | -31.95224
London | Ontario | Canada | -81.23304 | 42.98339
Oakville | Ontario | Canada | -79.68292 | 43.45011
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Chicoutimi | Quebec | Canada | -71.06369 | 48.41963
Greenfield Park | Quebec | Canada | -73.46223 | 45.48649
Montreal | Quebec | Canada | -73.58781 | 45.50884
Montreal | Quebec | Canada | -73.58781 | 45.50884
Guadalajara | Jalisco | Mexico | -103.34749 | 20.67738
México, D. F. | Mexico City | Mexico | -99.12766 | 19.42847
Mérida | Yucatán | Mexico | -89.62318 | 20.967
México D. F. | N/A | Mexico | N/A | N/A
México, D. F. | N/A | Mexico | -103.57339 | 22.76088
| 0
|
NCT00655629
|
[
4
] | 40
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| null |
The purpose of this study is to assess the effectiveness and safety of oral pancrelipase MT in the treatment of adult and pediatric/adolescent cystic fibrosis (CF) patients with clinical symptoms of exocrine pancreatic insufficiency (EPI).
|
This is a randomized, placebo-controlled, double-blind withdrawal, multicenter study to evaluate the effectiveness of pancrelipase MT capsules compared with placebo in the treatment of adult (\>18 to 60 years of age) and children/adolescent (7 to \<18 years of age) patients with CF and who require pancreatic enzyme replacement therapy (PERT) to control clinical symptoms of EPI and steatorrhea (excess fat in the feces). The study has 3 phases: a screening phase, an open-label (run-in) phase, and a double-blind withdrawl phase. The study including the screening phase will be approximately 28 days in length. In the screening phase, patients will begin a high-fat diet and will take pancrelipase MT10.5 or MT21 capsules (or a combination of both) orally with meals (or snacks) to optimize digestion based on clinical signs and symptoms. In the open-label phase patients will continue taking their optimal dose of study drug. After a minimum of 3 days in the open-label treatment phase, an inpatient 72-hour stool collection period for fecal fat determination will be performed. Patients with a coefficient of fat absorption (COA)-fat of 80% or greater who have completed at least 6 days on a controlled high-fat diet will be eligible for the double-blind withdrawal phase of the study and will be randomly assigned to receive placebo or pancrelipase MT. After a minimum of 1 day on double-blind treatment and with the presence of deteriorating clinical signs and symptoms, patients will be admitted to the clinic to begin a second 72-hour inpatient stool collection period. Effectiveness evaluations will be performed throughout the study and consist of stool collection for determination of COA-fat and coefficient of protein absorption (COA-protein), stool diary, nutrition worksheet, and Clinical Global Impression-Severity of illness (CGI-S), Clinical Global Impression-Change (CGI-C), and Global Assessment of Change (GAC) scales. Signs and symptoms exhibited during the study will be monitored and will include the presence or absence of diarrhea, abdominal pain, nausea, vomiting, bloating, and a description of stool changes. Safety will be montitored during the study by evaluating adverse events and findings from clinical laboratory tests, vital signs measurements, and physical examinations. The study hypothesis is that the study drug will be more effective than placebo as measured by the change in the coefficient of fat absorption (COA-fat) in adults and pediatric/adolescent patients with EPI secondary to CF. Pancrelipase MT10.5 or MT21 capsules (or a combination of both) will be taken orally with meals (or snacks) within the recommended ranges of pancreatic enzyme therapy as recommended by the CF Foundation and up to a maximum 10,000 lipase units per kilogram \[kg\] per day. All patients will take pancrelipase MT for 6 days in the screening phase and for approximately 6 to 10 days in the open-label phase; patients will take pancrelipase MT or placebo for 4 to 7 days in the double-blind phase.
|
Exocrine Pancreatic Insufficiency Steatorrhea Malabsorption Syndromes Cystic Fibrosis
|
Exocrine pancreatic insufficiency Steatorrhea Malabsorption syndromes Cystic fibrosis Pediatrics Adult Pancrelipase
| null | 2
|
arm 1: Pancrease MT 10.5 or MT 21 Pancrease MT capsules for maximum dose of 10 000 lipase units / Kg / day arm 2: Placebo for Pancrease MT 10.5 or MT 21 Capsules with Pancrease MT excipients without the active enzymes
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Pancrease MT capsules for maximum dose of 10,000 lipase units / Kg / day intervention 2: Capsules with Pancrease MT excipients without the active enzymes
|
intervention 1: Pancrease MT 10.5, or MT 21 intervention 2: Placebo for Pancrease MT 10.5 or MT 21
| 11
|
Long Beach | California | United States | -118.18923 | 33.76696
Los Angeles | California | United States | -118.24368 | 34.05223
Orlando | Florida | United States | -81.37924 | 28.53834
Louisville | Kentucky | United States | -85.75941 | 38.25424
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Long Branch | New Jersey | United States | -73.99236 | 40.30428
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cleveland | Ohio | United States | -81.69541 | 41.4995
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
| 0
|
NCT00662675
|
[
3,
4
] | 140
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The current study is designed to test the long-term (12-month) safety and efficacy of LCP-AtorFen, a combination of atorvastatin and fenofibrate, in patients with dyslipidemia
|
POPULATION:
Subjects with mixed dyslipidemia (non-HDL cholesterol \> 130 mg/dL and TG ≥ 150 mg/dL and ≤ 500 mg/dL) who completed the double-blind study (LCP-AtorFen-2001; NCT00504829), met the enrollment criteria (all of the inclusion criteria and none of the exclusion criteria), and elected to enter the open-label extension study.
STUDY DESIGN AND DURATION:
This is a 52-week, open-label, single-treatment arm with 8 visits (Weeks 0, 4, 8, 12, 24, 36, 48 and 52). A maximum of approximately 200 subjects will enter this open-label safety and efficacy extension study from the LCP AtorFen-2001 double-blind study. All subjects enrolled in this study will receive open-label LCP-AtorFen combination therapy. Visit 1 of the extension study corresponds to the last visit of the double-blind study (Visit 6 or Week 12).
|
Dyslipidemia
|
LCP-AtorFen Non-HDL cholesterol Triglycerides HDL cholesterol LDL cholesterol Atorvastatin Fenofibrate
| null | 1
|
arm 1: Open-label LCP-AtorFen
|
[
0
] | 1
|
[
0
] |
intervention 1: All subjects will be assigned to receive open-label LCP-AtorFen combination therapy for 52 weeks. Subjects will take a single oral dose of study drug in the evening without regard to meals.
|
intervention 1: LCP-AtorFen
| 1
|
Chicago | Illinois | United States | -87.65005 | 41.85003
| 0
|
NCT00664859
|
[
3
] | 134
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
This study assesses inhaled corticosteroid plus montelukast compared with inhaled corticosteroid therapy alone for treatment of patients with chronic asthma.
|
During this study, all patients will receive mometasone (powder, 220 mcg once-daily, for approximately 6 weeks). In a crossover manner, eligible patients will also receive montelukast (powder, 1 mg once-daily, for approximately 2 weeks) followed by placebo; or will receive placebo followed by montelukast. The order of when each of these 2 treatments are added to the mometasone will be randomized.
|
Asthma
| null | 2
|
arm 1: mometasone arm 2: montelukast followed by placebo; or placebo followed by montelukast.
|
[
1,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: mometasone (inhalation powder, 220 mcg once-daily, for approximately 6 weeks) intervention 2: montelukast (inhalation powder, 1 mg once-daily, for approximately 2 weeks) intervention 3: Placebo (Placebo once-daily, for approximately 2 weeks)
|
intervention 1: Comparator: mometasone intervention 2: Comparator: montelukast intervention 3: Comparator: placebo (unspecified)
| 0
| null | 0
|
NCT00666679
|
|
[
4
] | 877
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
This is a short-term study to evaluate the efficacy, safety, and tolerability of escitalopram in adult patients (18 to 65 years of age) with moderate to severe depression. Patients completing the study may be eligible to enter a long-term open-label extension study with escitalopram.
| null |
Major Depressive Disorder
|
Depression Major Depressive Disorder Escitalopram
| null | 3
|
arm 1: Escitalopram low dose arm 2: Escitalopram high dose arm 3: Placebo
|
[
1,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: Escitalopram low dose, oral administration, once daily dosing for 8 weeks. intervention 2: Placebo, oral administration, once daily dosing for 8 weeks intervention 3: Escitalopram high dose, oral administration, once daily dosing for 8 weeks
|
intervention 1: Escitalopram intervention 2: Placebo intervention 3: Escitalopram
| 45
|
Phoenix | Arizona | United States | -112.07404 | 33.44838
Arcadia | California | United States | -118.03534 | 34.13973
Encino | California | United States | -118.50119 | 34.15917
Garden Grove | California | United States | -117.94145 | 33.77391
Irvine | California | United States | -117.82311 | 33.66946
Los Alamitos | California | United States | -118.07256 | 33.80307
Denver | Colorado | United States | -104.9847 | 39.73915
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Bradenton | Florida | United States | -82.57482 | 27.49893
Jacksonville | Florida | United States | -81.65565 | 30.33218
Orlando | Florida | United States | -81.37924 | 28.53834
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Atlanta | Georgia | United States | -84.38798 | 33.749
Newton | Kansas | United States | -97.34504 | 38.04668
Overland | Kansas | United States | N/A | N/A
Baltimore | Maryland | United States | -76.61219 | 39.29038
Glen Burnie | Maryland | United States | -76.62469 | 39.16261
Rockville | Maryland | United States | -77.15276 | 39.084
Okemos | Michigan | United States | -84.42747 | 42.72226
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Omaha | Nebraska | United States | -95.94043 | 41.25626
Cherry Hill | New Jersey | United States | -75.03073 | 39.93484
Clementon | New Jersey | United States | -74.98294 | 39.8115
Brooklyn | New York | United States | -73.94958 | 40.6501
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
Staten Island | New York | United States | -74.13986 | 40.56233
The Bronx | New York | United States | -73.86641 | 40.84985
Canton | Ohio | United States | -81.37845 | 40.79895
Dayton | Ohio | United States | -84.19161 | 39.75895
Portland | Oregon | United States | -122.67621 | 45.52345
Media | Pennsylvania | United States | -75.38769 | 39.91678
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Charleston | South Carolina | United States | -79.93275 | 32.77632
Memphis | Tennessee | United States | -90.04898 | 35.14953
Memphis | Tennessee | United States | -90.04898 | 35.14953
Austin | Texas | United States | -97.74306 | 30.26715
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Woodstock | Vermont | United States | -72.51843 | 43.62424
Richmond | Virginia | United States | -77.46026 | 37.55376
Bellevue | Washington | United States | -122.20068 | 47.61038
Seattle | Washington | United States | -122.33207 | 47.60621
| 0
|
NCT00668525
|
[
5
] | 35
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
This study will look at the safety of using the study medicine for a long time. It will see if the germs get used to the medicine, making it not work as well, if it's used by people with gum disease for a long time.
|
The objective of this study is to evaluate the changes in populations of minocycline-resistant bacteria after long-term use of minocycline HCl microspheres, 1 mg in subjects with moderate-to-severe chronic periodontitis. This will be assessed through monitoring the total number and proportion of minocycline-resistant bacteria and the identity of minocycline-resistant species within a panel of 40 representative periodontal species in saliva and subgingival plaque.
|
Periodontitis
|
chronic periodontitis, antibiotic resistance
| null | 2
|
arm 1: Minocycline HCl microspheres arm 2: No drug intervention
|
[
0,
4
] | 1
|
[
0
] |
intervention 1: At Baseline and all interim visits, a single unit dose of 1mg minocycline HCl (with approximately 3mg PGLA) will be professionally administered subgingivally into periodontal pockets at each site exhibiting a PD ≥ 5mm.
|
intervention 1: Minocycline HCl microspheres
| 1
|
Boston | Massachusetts | United States | -71.05977 | 42.35843
| 0
|
NCT00668746
|
[
0
] | 8
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 9OTHER
| 1SINGLE
| true
| 1FEMALE
| false
|
The goal of this series of challenge studies is to examine the impact of menstrual cycle phase on cortical GABA response to administration of agents with either direct (benzodiazepines) or indirect (progesterone, fluoxetine) GABA modulating properties. While the impact of these agents on cortical GABA levels in women with premenstrual dysphoric disorder (PMDD) is of interest, this study is designed primarily for those women without a psychiatric illness.
| null |
Healthy
|
menses women healthy controls Healthy females with regular menstrual cycles
| null | 3
|
arm 1: Zolpidem will be administered twice to each participant; once in the follicular and luteal phases of the menstrual cycle. arm 2: Progesterone will be administered twice to each participant; once in both the follicular and luteal phases of the menstrual cycle. arm 3: Fluoxetine will be administered twice to each participant; once in both the follicular and luteal phases of the menstrual cycle.
|
[
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: Fluoxetine 20 mg by mouth in the follicular and luteal phase of the menstrual cycle per participant. intervention 2: Zolpidem 10 mg by mouth in the follicular and luteal phase of the menstrual cycle per participant. intervention 3: Progesterone 800 mg by mouth will be administered to each participant once in the follicular and luteal phases of the menstrual cycle.
|
intervention 1: Fluoxetine intervention 2: Zolpidem intervention 3: Progesterone
| 1
|
New Haven | Connecticut | United States | -72.92816 | 41.30815
| 0
|
NCT00676026
|
[
4
] | 93
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
This protocol will compare 24 hour glucose control for subject taking saxagliptin and metformin extended release (XR) versus metformin XR alone
| null |
Type 2 Diabetes
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Tablets, Oral, 5mg, once daily, 4 weeks intervention 2: Tablets, Oral, 0 mg, once daily, 4 weeks
|
intervention 1: Saxagliptin intervention 2: Placebo
| 27
|
Phoenix | Arizona | United States | -112.07404 | 33.44838
Escondido | California | United States | -117.08642 | 33.11921
Irvine | California | United States | -117.82311 | 33.66946
Redlands | California | United States | -117.18254 | 34.05557
Santa Ana | California | United States | -117.86783 | 33.74557
Tustin | California | United States | -117.82617 | 33.74585
Blue Ridge | Georgia | United States | -84.32409 | 34.86397
Roswell | Georgia | United States | -84.36159 | 34.02316
Kalamazoo | Michigan | United States | -85.58723 | 42.29171
New York | New York | United States | -74.00597 | 40.71427
Portland | Oregon | United States | -122.67621 | 45.52345
San Antonio | Texas | United States | -98.49363 | 29.42412
Midvale | Utah | United States | -111.89994 | 40.61106
Martínez | Buenos Aires | Argentina | -58.51679 | -34.49397
Holon | N/A | Israel | 34.77918 | 32.01034
Jerusalem | N/A | Israel | 35.21633 | 31.76904
Kfar Saba | N/A | Israel | 34.90694 | 32.175
Ẕerifin | N/A | Israel | 34.84852 | 31.95731
Milan | N/A | Italy | 12.59836 | 42.78235
Aguascalientes | Aguascalientes | Mexico | -102.2843 | 21.88262
Monterrey | Nuevo León | Mexico | -100.31721 | 25.68435
Cebu City | N/A | Philippines | 123.89071 | 10.31672
Marikina City | N/A | Philippines | 121.1133 | 14.6481
Ponce | Puerto Rico | Puerto Rico | -66.62398 | 18.01031
Lund | Sweden | Sweden | 13.19321 | 55.70584
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Huddinge | N/A | Sweden | 17.98192 | 59.23705
| 0
|
NCT00683657
|
|
[
2,
3
] | 60
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| true
|
Assess whether transbuccal fentanyl provides more rapid relief of orthopedic pain, than does the comparator Percocet
|
Patients will be initially deemed eligible for study consideration if, after MGH ED nursing triage, an X-ray is ordered for suspected isolated extremity injury and the triage acuity level is "Minor". Study staff (physicians) will monitor the ED registration and triage areas to assess whether triaged patients are potentially eligible.
For ED patients with minor isolated injuries, X-rays are often ordered from triage, where there is a supervising physician (or nurse practitioner) available to examine patients and direct care. Either at triage (for patients undergoing care at that location) or when patients are moved to the ED's Minor Surgery area, the supervising healthcare provider will be approached immediately after that individual's evaluation of the patient, and before any pain medication is administered, to begin the process of eligibility ascertainment.
If the provider agrees that the patient may be a candidate for the study, the next step will be for the provider to ask the patient if study staff may approach to discuss the trial.
If the patient agrees to have study staff approach to discuss the trial, study personnel (all EM resident or Attending-level physicians) will be introduced by healthcare providers to potential subjects. Study staff will then converse with the patients about the study's aims, methodology, and risks, confirming eligibility and determining if patients will consent to participate.
Patients who are approached, but who are determined to be ineligible, will have no data recorded, other than their age and race/ethnicity and the reason they were ineligible.
If eligible patients provide written consent in the manner and form dictated by Partners guidelines, the study procedures will commence.
For eligible patients who do not give consent, study physicians will emphasize that patient care will be unaffected by their decision. No further contact will occur between study staff and those patients. No identifying information about such patients will be recorded, but their age and race/ethnicity will be recorded. (Recording this information will allow for subsequent assessment for selection bias, and will also help search for patterns in patient types refusing analgesia trial participation.)
The actual medication administration will involve the following steps:
1. Patients participating in the study will be identified and placed in a "room" (stretcher or actual ED room) in the MGH ED's Minor Multipurpose (MIMP) area;
2. RNs will obtain the study medication pairs (buccal tablet + oral tablet) from the computerized medication storage area - RNs will take the next-numbered medication pair from the MGH Research Pharmacy-prepared drug packaging;
3. Actual medications will be administered by a licensed physician (a study co-investigator, EM resident or Attending physician at MGH), who is not the co-investigator monitoring the patient for endpoint assessment - the physician administering the medication/placebo will inform neither the patient nor the clinical or study staff, the identity of the medication/placebo pair given.
Patients will be monitored by a study physician co-investigator physically present with the patient, for a total of 120 minutes after administration of medication. They will be asked q-5-minutes, through 60 minutes, to rate their pain and degree of nausea, as well as to describe any adverse reactions to the medication. Both pain and nausea levels will be recorded using 10-point scales. Use of such scales is common in the pain literature, and is an emerging tool for evaluation of nausea.1,2 Data collection for analgesia efficacy will cease after 60 minutes, but patients will be monitored for at least another 60 minutes to maximize safety; patients will be assessed for discharge suitability by treating clinicians/nurses in the same fashion as other ED patients who receive opioids.
Vital signs (respiratory rate, blood pressure, heart rate, pulse oximetry) will be monitored for the two hours of the study. Continuous pulse oximetry will be used during the first study hour, and q5-minute spot-check pulse oximetry will be used during the second study hour; pulse oximetry monitoring will be changed to continuous mode during the second study hour if any spot-check reading falls below 98%. Other (non-pulse oximetry) vital signs will be monitored q5-minutes during the first study hour, and q15-minutes during the second study hour. These vital signs monitoring parameters represent the minimum for study subjects; treating clinicians or study staff physicians can increase the frequency of vital signs monitoring at their discretion. Any study subject not admitted to the hospital, will be discharged under the care of a responsible adult.
At the conclusion of the data collection period, patients will be asked if they would want to receive the same medication in the future. Other than a 24-hour telephone call (made only if patients agree), intended to assess for delayed problems such as nausea/vomiting, there will be no other study procedures or interventions.
|
Pain, Fracture, Sprain
|
Emergency Department acute
| null | 2
|
arm 1: Intervention Group:
Subject receives:
1. placebo oral/swallowed pill
2. Fentanyl (Fentora) 100mcg rapidly dissolving transbuccal tablet arm 2: Active Comparator Group:
Subject receives:
1. Oxycodone/APAP (Percocet) 5/325 mg oral/swallowed pill
2. Lansoprazole 15 mg (Prevacid) comparator rapidly dissolving transbuccal tablet
|
[
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Fentanyl rapid dissolving tablet 100mcg intervention 2: lansoprazole 15mg rapidly dissolving tablet intervention 3: Oxycodone 5/325 mg tablet
|
intervention 1: Fentanyl intervention 2: Lansoprazole intervention 3: Oxycodone
| 1
|
Boston | Massachusetts | United States | -71.05977 | 42.35843
| 0
|
NCT00685295
|
[
4
] | 459
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to demonstrate the efficacy of Adapalene 0.1% / Benzoyl Peroxide (quoted as BPO) 2.5% Gel associated with Doxycycline Hyclate 100 mg Tablets compared to Adapalene 0.1% /Benzoyl Peroxide 2.5% Vehicle Gel associated with Doxycycline Hyclate 100 mg Tablets, in the treatment of severe acne vulgaris. The safety of the two treatment regimens will also be evaluated.
|
Further to this study, eligible Subjects with at least good Global Assessment of Improvement at Week 12 will be randomized in a maintenance study (SPR.29075)
|
Severe Acne Vulgaris
|
Acne
| null | 2
|
arm 1: Adapalene-BPO + Doxycyline arm 2: Vehicle + Doxycycline
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Adapalene BPO Gel: Topical to the face, once daily in the evening Doxycycline Hyclate: Oral, 1 tablet once daily in the morning. Both during 12 weeks. intervention 2: Vehicle Gel: Topical to the face, once daily in the evening; Doxycycline Hyclate: Oral, 1 tablet once daily in the morning. Both during 12 weeks.
|
intervention 1: Adapalene BPO Gel associated with Doxycyline Hyclate intervention 2: Vehicle Gel associated with Doxycycline Hyclate
| 34
|
Oceanside | California | United States | -117.37948 | 33.19587
San Diego | California | United States | -117.16472 | 32.71571
Denver | Colorado | United States | -104.9847 | 39.73915
Longmont | Colorado | United States | -105.10193 | 40.16721
Miami | Florida | United States | -80.19366 | 25.77427
Snellville | Georgia | United States | -84.01991 | 33.85733
Chicago | Illinois | United States | -87.65005 | 41.85003
Evansville | Indiana | United States | -87.55585 | 37.97476
Overland Park | Kansas | United States | -94.67079 | 38.98223
Louisville | Kentucky | United States | -85.75941 | 38.25424
Detroit | Michigan | United States | -83.04575 | 42.33143
Fort Gratiot | Michigan | United States | N/A | N/A
Fridley | Minnesota | United States | -93.26328 | 45.08608
Omaha | Nebraska | United States | -95.94043 | 41.25626
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Stony Brook | New York | United States | -73.14094 | 40.92565
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Warren | Ohio | United States | -80.81842 | 41.23756
Hazleton | Pennsylvania | United States | -75.97465 | 40.95842
Hershey | Pennsylvania | United States | -76.65025 | 40.28592
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Arlington | Texas | United States | -97.10807 | 32.73569
Austin | Texas | United States | -97.74306 | 30.26715
College Station | Texas | United States | -96.33441 | 30.62798
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
Webster | Texas | United States | -95.11826 | 29.53773
Barrie | Ontario | Canada | -79.66634 | 44.40011
North Bay | Ontario | Canada | -79.46633 | 46.3168
Windsor | Ontario | Canada | -83.01654 | 42.30008
Québec | Quebec | Canada | -71.21454 | 46.81228
Aibonito | N/A | Puerto Rico | -66.266 | 18.13996
Carolina | N/A | Puerto Rico | -65.95739 | 18.38078
| 0
|
NCT00688064
|
[
3
] | 360
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL administered with 5 micrograms tiotropium bromide solution for inhalation, delivered by the Respimat inhaler, once daily for four weeks in patients with chronic obstructive pulmonary disease (COPD).
| null |
Pulmonary Disease, Chronic Obstructive
| null | 4
|
arm 1: BI 1744 CL low dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation arm 2: BI 1744 CL medium dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation arm 3: BI 1744 CL high dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation arm 4: tiotropium bromide; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation
|
[
0,
0,
0,
0
] | 3
|
[
0,
0,
1
] |
intervention 1: BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation intervention 2: tiotropium bromide; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation intervention 3: None
|
intervention 1: BI 1744 CL/tiotropium bromide fixed dose combination intervention 2: tiotropium bromide intervention 3: Respimat® Inhaler
| 37
|
Riverside | California | United States | -117.39616 | 33.95335
San Diego | California | United States | -117.16472 | 32.71571
Wheat Ridge | Colorado | United States | -105.07721 | 39.7661
Clearwater | Florida | United States | -82.8001 | 27.96585
DeLand | Florida | United States | -81.30312 | 29.02832
Tampa | Florida | United States | -82.45843 | 27.94752
Coeur d'Alene | Idaho | United States | -116.78047 | 47.67768
Edina | Minnesota | United States | -93.34995 | 44.88969
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Saint Charles | Missouri | United States | -90.48123 | 38.78394
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Charleston | South Carolina | United States | -79.93275 | 32.77632
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Killeen | Texas | United States | -97.7278 | 31.11712
New Braunfels | Texas | United States | -98.12445 | 29.703
Richmond | Virginia | United States | -77.46026 | 37.55376
Spokane | Washington | United States | -117.42908 | 47.65966
Tacoma | Washington | United States | -122.44429 | 47.25288
Morgantown | West Virginia | United States | -79.9559 | 39.62953
Winnipeg | Manitoba | Canada | -97.14704 | 49.8844
Mississauga | Ontario | Canada | -79.6583 | 43.5789
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Sainte-Foy | Quebec | Canada | -71.29217 | 46.78139
Sherbrooke | Quebec | Canada | -71.89908 | 45.40008
Saskatoon | Saskatchewan | Canada | -106.66892 | 52.13238
Berlin | N/A | Germany | 13.41053 | 52.52437
Erfurt | N/A | Germany | 11.03283 | 50.9787
Gauting | N/A | Germany | 11.37703 | 48.06919
Halle | N/A | Germany | 11.97947 | 51.48158
Neuruppin | N/A | Germany | 12.80311 | 52.92815
Rüdersdorf | N/A | Germany | 13.78631 | 52.46927
Weinheim | N/A | Germany | 8.66697 | 49.54887
| 0
|
NCT00696020
|
|
[
2
] | 76
|
RANDOMIZED
|
SINGLE_GROUP
| 1PREVENTION
| 3TRIPLE
| true
| 2MALE
| false
|
This is a 28-day, single-center, double-blind, placebo-controlled inpatient study of the administration of risperidone alone or in combination with mifepristone in healthy adult male volunteers to determine the average change in absolute weight at Day 28 compared to baseline.
|
This is a 28-day, single-center, double-blind, placebo-controlled inpatient study of the administration of risperidone alone or in combination with mifepristone in healthy adult male volunteers. The primary study objective is to determine the mean change in absolute weight at Day 28 compared to baseline in normal healthy male volunteers treated with risperidone plus mifepristone or risperidone alone. The secondary study objectives are to determine the mean percent change in baseline body weight; and the proportion of subjects that gain less than 5% and less than 7% of their baseline body in the treatment groups.
|
Healthy
|
healthy weight gain anti-psychotic risperidone mifepristone mitigation weight loss
| null | 3
|
arm 1: risperidone plus mifepristone daily for 28 days arm 2: risperidone plus mifepristone-matched placebo daily for 28 days arm 3: risperidone-matched placebo plus mifepristone daily for 28 days
|
[
0,
2,
2
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: risperidone daily for 28 days intervention 2: mifepristone daily for 28 days intervention 3: risperidone-matched placebo daily for 28 days intervention 4: mifepristone-matched placebo daily for 28 days
|
intervention 1: Risperidone intervention 2: Mifepristone intervention 3: Risperidone-matched placebo intervention 4: Mifepristone-matched placebo
| 1
|
Mumbai | N/A | India | 72.88261 | 19.07283
| 0
|
NCT00698022
|
[
2,
3
] | 61
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the safety, pharmacokinetics and pharmacodynamics of TA-7284 orally administered once daily for 15 days (1 day followed by a 1 day washout period and then 14 consecutive days). Dose escalation design is utilized in this study, and dose escalation of TA-7284 will be starting with 25 mg (step 1). Subsequent doses of 100 mg (step 2), 200 mg (step 3) and 400 mg (step 4) are planned after review of the tolerance and PK of the previous step.
| null |
Type 2 Diabetes Mellitus
|
Diabetes TA-7284
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Patients will receive single ascending dose of TA-7284 in each step (4 doses planned: 25, 100, 200 and 400 mg), once daily, 15 days (1 day followed by a 1 day washout period and then 14 consecutive days) intervention 2: Patients will receive placebo tablets in each step, once daily, 15 days (1 day followed by a 1 day washout period and then 14 consecutive days)
|
intervention 1: TA-7284 intervention 2: Placebo of TA-7284
| 1
|
Hachiōji | Tokyo-to | Japan | 139.32389 | 35.65583
| 0
|
NCT00707954
|
[
3
] | 141
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL administered with 5 microgram tiotropium bromide solution for inhalation, delivered by the Respimat® inhaler, once daily for four weeks in patients with chronic obstructive pulmonary disease (COPD).
| null |
Pulmonary Disease, Chronic Obstructive
| null | 2
|
arm 1: BI 1744 CL low dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation arm 2: BI 1744 CL medium dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation
|
[
0,
0
] | 2
|
[
0,
1
] |
intervention 1: BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation intervention 2: None
|
intervention 1: BI 1744 CL plus tiotropium bromide intervention 2: Respimat® Inhaler
| 24
|
Clearwater | Florida | United States | -82.8001 | 27.96585
Tampa | Florida | United States | -82.45843 | 27.94752
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Killeen | Texas | United States | -97.7278 | 31.11712
Spokane | Washington | United States | -117.42908 | 47.65966
Brussels | N/A | Belgium | 4.34878 | 50.85045
Brussels | N/A | Belgium | 4.34878 | 50.85045
Edegem | N/A | Belgium | 4.44504 | 51.15662
Ghent | N/A | Belgium | 3.71667 | 51.05
Leuven | N/A | Belgium | 4.70093 | 50.87959
Mississauga | Ontario | Canada | -79.6583 | 43.5789
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Ste-Foy | Quebec | Canada | N/A | N/A
Berlin | N/A | Germany | 13.41053 | 52.52437
Berlin | N/A | Germany | 13.41053 | 52.52437
Berlin | N/A | Germany | 13.41053 | 52.52437
Bruchsal | N/A | Germany | 8.59804 | 49.12426
Gelnhausen | N/A | Germany | 9.18742 | 50.20164
Großhansdorf | N/A | Germany | 10.28333 | 53.66667
Hamburg | N/A | Germany | 9.99302 | 53.55073
Tübingen | N/A | Germany | 9.05222 | 48.52266
Wiesloch | N/A | Germany | 8.69846 | 49.29504
| 0
|
NCT00720499
|
|
[
3
] | 102
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The purpose of this pilot study is to compare the effects (effectiveness and safety)of an intranasal corticosteroid (fluticasone furoate nasal spray \[FFNS\]) with a placebo nasal spray for the treatment of irritant (non-allergic) rhinitis.
| null |
Rhinitis, Allergic, Perennial
|
Adolescents Irritant(non-allergic)rhinitis Adults GW685698 Air Pollution
| null | 2
|
arm 1: Fluticasone Furoate Nasal Spray 110mcg intranasally once daily arm 2: Matching placebo nasal spray intranasally once daily
|
[
1,
2
] | 2
|
[
0,
10
] |
intervention 1: Fluticasone furoate nasal spray 110mcg intranasally once daily for 4 weeks intervention 2: Matching placebo nasal spray intranasally once daily for 4 weeks
|
intervention 1: Fluticasone Furoate Nasal Spray intervention 2: Placebo Nasal Spray
| 5
|
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Chiang Mai | N/A | Thailand | 98.98468 | 18.79038
Khon Kaen | N/A | Thailand | 102.833 | 16.44671
| 0
|
NCT00730756
|
[
4
] | 457
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the safety and efficacy of 2.5 mg and 10 mg vortioxetine, once daily (QD), in adults with generalized anxiety disorder.
|
Participants in this study will be randomly assigned to receive either 2.5 mg or 10 mg of vortioxetine or a placebo once daily for an eight week treatment period.
Participants will be seen weekly during the first 2 weeks of treatment, and then every 2 weeks up to the end of the 8-week treatment period. Total commitment time is up to 12 weeks.
|
Generalized Anxiety Disorder
|
Generalized Anxiety Disorder Mood Disorder Affective Disorder Anxiety Disorder Drug Therapy
| null | 3
|
arm 1: Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks. arm 2: Vortioxetine 2.5 mg encapsulated tablets, orally, once daily for up to 8 weeks. arm 3: Vortioxetine 10 mg encapsulated tablets, orally, once daily for up to 8 weeks.
|
[
2,
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Encapsulated vortioxetine immediate-release tablets intervention 2: Vortioxetine placebo-matching capsules
|
intervention 1: Vortioxetine intervention 2: Placebo
| 40
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Anaheim | California | United States | -117.9145 | 33.83529
Cerritos | California | United States | -118.06479 | 33.85835
Costa Mesa | California | United States | -117.91867 | 33.64113
Orange | California | United States | -117.85311 | 33.78779
Redlands | California | United States | -117.18254 | 34.05557
Cromwell | Connecticut | United States | -72.64537 | 41.5951
Norwich | Connecticut | United States | -72.07591 | 41.52426
Hockessin | Delaware | United States | -75.6966 | 39.78761
Fort Myers | Florida | United States | -81.84059 | 26.62168
Jacksonville | Florida | United States | -81.65565 | 30.33218
Lady Lake | Florida | United States | -81.92286 | 28.91749
Miami | Florida | United States | -80.19366 | 25.77427
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Libertyville | Illinois | United States | -87.95313 | 42.28308
Valparaiso | Indiana | United States | -87.06114 | 41.47309
Overland Park | Kansas | United States | -94.67079 | 38.98223
Prairie Village | Kansas | United States | -94.63357 | 38.99167
Boston | Massachusetts | United States | -71.05977 | 42.35843
Braintree | Massachusetts | United States | -71.00215 | 42.20384
Pittsfield | Massachusetts | United States | -73.24538 | 42.45008
St Louis | Missouri | United States | -90.19789 | 38.62727
Cherry Hill | New Jersey | United States | -75.03073 | 39.93484
Fresh Meadows | New York | United States | -73.79347 | 40.73482
New York | New York | United States | -74.00597 | 40.71427
Olean | New York | United States | -78.42974 | 42.07756
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Columbus | Ohio | United States | -82.99879 | 39.96118
Middleburg Heights | Ohio | United States | -81.81291 | 41.36144
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Emmaus | Pennsylvania | United States | -75.49685 | 40.53954
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Reading | Pennsylvania | United States | -75.92687 | 40.33565
North Charleston | South Carolina | United States | -79.97481 | 32.85462
Nashville | Tennessee | United States | -86.78444 | 36.16589
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
Midlothian | Virginia | United States | -77.64916 | 37.50598
Waukesha | Wisconsin | United States | -88.23148 | 43.01168
| 0
|
NCT00731120
|
[
3
] | 60
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The purpose of this study is to assess the safety and efficacy of a single dosage strength of GW685698/GW642444 in subjects with Chronic Obstructive Pulmonary Disease (COPD).
| null |
Pulmonary Disease, Chronic Obstructive
|
Chronic Obstructive Pulmonary Disease Novel Dry Powder Inhaler Chronic Obstructive Pulmonary Disease (COPD) GW685698/GW642444
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: GW685698/GW642444
|
intervention 1: GW685698/GW642444
| 9
|
Bergen | N/A | Norway | 5.32415 | 60.39299
Elverum | N/A | Norway | 11.56231 | 60.88191
Fredrikstad | N/A | Norway | 10.9298 | 59.2181
Sandvika | N/A | Norway | 13.59125 | 64.46377
Trondheim | N/A | Norway | 10.39506 | 63.43049
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Luleå | N/A | Sweden | 22.15465 | 65.58415
Lund | N/A | Sweden | 13.19321 | 55.70584
Stockholm | N/A | Sweden | 18.06871 | 59.32938
| 0
|
NCT00731822
|
[
4
] | 255
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
The purpose of this study is to determine whether topical application of PEP005 is effective for the treatment of actinic keratoses.
| null |
Actinic Keratoses
|
Peplin Actinic keratosis PEP005
| null | 2
|
arm 1: PEP005 (ingenol mebutate) Gel arm 2: Vehicle gel
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: two day treatment intervention 2: two day treatment
|
intervention 1: PEP005 (ingenol mebutate) Gel intervention 2: Vehicle gel
| 20
|
Mesa | Arizona | United States | -111.82264 | 33.42227
Denver | Colorado | United States | -104.9847 | 39.73915
Kissimmee | Florida | United States | -81.41667 | 28.30468
Orange Park | Florida | United States | -81.70648 | 30.16607
Ormond Beach | Florida | United States | -81.05589 | 29.28581
Newnan | Georgia | United States | -84.79966 | 33.38067
Snellville | Georgia | United States | -84.01991 | 33.85733
Plainfield | Indiana | United States | -86.39944 | 39.70421
Detroit | Michigan | United States | -83.04575 | 42.33143
South Delran | New Jersey | United States | N/A | N/A
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Rochester | New York | United States | -77.61556 | 43.15478
Cleveland | Ohio | United States | -81.69541 | 41.4995
Portland | Oregon | United States | -122.67621 | 45.52345
Portland | Oregon | United States | -122.67621 | 45.52345
Germantown | Tennessee | United States | -89.81009 | 35.08676
Goodlettsville | Tennessee | United States | -86.71333 | 36.32311
College Station | Texas | United States | -96.33441 | 30.62798
Benowa | Queensland | Australia | 153.38583 | -28.0077
Victoria Park | Western Australia | Australia | 115.90525 | -31.97619
| 0
|
NCT00742391
|
[
4
] | 204
|
RANDOMIZED
|
PARALLEL
| 4SUPPORTIVE_CARE
| 2DOUBLE
| false
| 0ALL
| false
|
Effective postoperative pain control to promote improved healing, faster patient mobilization, shortened hospital stays, and reduced healthcare costs.
|
Effective postoperative pain control is a critical element in patient recovery, as the majority of patients may experience significant pain, particularly in the first few days following surgery. Appropriate postoperative pain management contributes to improved healing, faster patient mobilization, shortened hospital stays, and reduced healthcare costs.
|
Hemorrhoids
|
hemorrhoids
| null | 2
|
arm 1: 100 mg Bupivacaine HCl (e.g., Marcaine with epinephrine 1:200,000) is the reference-listed drug for bupivacaine and contains the same active, local anesthetic as SKY0402.
A single dose of study drug was administered intraoperatively (at the end of surgery) via local infiltration. arm 2: 300 mg SKY0402 in a 40-mL injection volume.
A single dose of study drug was administered intraoperatively (at the end of surgery) via local infiltration.
|
[
1,
5
] | 2
|
[
0,
0
] |
intervention 1: 100 mg Bupivacaine HCl intervention 2: Single administration 300 mg SKY0402 in a 40-mL injection volume
|
intervention 1: Bupivacaine HCl intervention 2: SKY0402
| 20
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Montgomery | Alabama | United States | -86.29997 | 32.36681
Pasadena | California | United States | -118.14452 | 34.14778
San Clemente | California | United States | -117.61199 | 33.42697
San Diego | California | United States | -117.16472 | 32.71571
Orlando | Florida | United States | -81.37924 | 28.53834
Springfield | Illinois | United States | -89.64371 | 39.80172
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Louisville | Kentucky | United States | -85.75941 | 38.25424
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
Greenville | North Carolina | United States | -77.36635 | 35.61266
Cleveland | Ohio | United States | -81.69541 | 41.4995
Kingsport | Tennessee | United States | -82.56182 | 36.54843
Bellaire | Texas | United States | -95.45883 | 29.70579
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
Tacoma | Washington | United States | -122.44429 | 47.25288
| 0
|
NCT00744848
|
[
4
] | 245
|
RANDOMIZED
|
PARALLEL
| 4SUPPORTIVE_CARE
| 2DOUBLE
| false
| 0ALL
| false
|
The primary objective is to demonstrate that SKY0402 is superior when compared to bupivacaine HCl in the management of postoperative pain for patients undergoing total knee arthroplasty.
|
The primary objective is to demonstrate the superiority of SKY0402, compared with bupivacaine HC1, with respect to the extent and duration of the analgesic effect achieved by a single intraoperative administration of the study drug via local infiltration in subjects undergoing total knee arthroplasty (TKA).
The secondary objectives are to evaluate additional efficacy parameters and characterize the safety profile of SKY0402 in comparison with bupivacaine HCl.
|
Postoperative Pain
|
Total knee arthroplasty Pain Analgesia
| null | 2
|
arm 1: Single dose of 200 mg bupivacaine HCl administered intraoperatively via local infiltration arm 2: Single dose of 600 mg SKY0402 (study drug) administered intraoperatively via local infiltration
|
[
1,
5
] | 2
|
[
0,
0
] |
intervention 1: 200 mg bupivacaine HCl intervention 2: 600 mg SKY0402 (study drug).
|
intervention 1: Bupivacaine HCl intervention 2: SKY0402
| 19
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Mobile | Alabama | United States | -88.04305 | 30.69436
Montgomery | Alabama | United States | -86.29997 | 32.36681
Sun City West | Arizona | United States | -112.34127 | 33.66198
La Jolla | California | United States | -117.2742 | 32.84727
Laguna Hills | California | United States | -117.71283 | 33.61252
Laguna Hills | California | United States | -117.71283 | 33.61252
Los Angeles | California | United States | -118.24368 | 34.05223
Decatur | Georgia | United States | -84.29631 | 33.77483
Chicago | Illinois | United States | -87.65005 | 41.85003
New York | New York | United States | -74.00597 | 40.71427
Greenville | North Carolina | United States | -77.36635 | 35.61266
Raleigh-Durham | North Carolina | United States | N/A | N/A
Columbus | Ohio | United States | -82.99879 | 39.96118
Altoona | Pennsylvania | United States | -78.39474 | 40.51868
Johnstown | Pennsylvania | United States | -78.92197 | 40.32674
Jackson | Tennessee | United States | -88.81395 | 35.61452
Grapevine | Texas | United States | -97.07807 | 32.93429
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00745290
|
[
4
] | 427
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| true
| 0ALL
| false
|
This is a randomized, double-blind, placebo-controlled, parallel-group study of armodafinil and placebo treatment in healthy subjects with excessive sleepiness associated with jet lag disorder.
| null |
Excessive Sleepiness
| null | 3
|
arm 1: armodafinil - dosage of 50 mg/day arm 2: armodafinil - dosage of 150 mg/day arm 3: matching placebo
|
[
0,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: 50 mg/day orally, once daily in the morning for 3 days intervention 2: 150 mg/day orally, once daily in the morning for 3 days intervention 3: placebo tablets, once daily in the morning for 3 days
|
intervention 1: armodafinil intervention 2: armodafinil intervention 3: placebo
| 4
|
Atlanta | Georgia | United States | -84.38798 | 33.749
Crestview | Kentucky | United States | -84.41744 | 39.02534
New York | New York | United States | -74.00597 | 40.71427
Columbia | South Carolina | United States | -81.03481 | 34.00071
| 0
|
NCT00758498
|
|
[
3
] | 20
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
A national, prospective single arm phase II study investigating the pharmacokinetics and safety of the 2% TD1414 cream when applied 3 times daily for 7 days to adult patients with impetigo or Secondarily Infected Traumatic Lesions (SITL). A total of 20 patients will be enrolled.
| null |
Secondarily Infected Traumatic Lesions (SITL) Impetigo
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Application 3 times daily for 7 days
|
intervention 1: 2% TD1414 Cream
| 1
|
College Station | Texas | United States | -96.33441 | 30.62798
| 0
|
NCT00758862
|
|
[
3
] | 86
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to determine if MSDC-0160 is effective in the treatment of Type 2 diabetes.
| null |
Type 2 Diabetes Mellitus
| null | 4
|
arm 1: Microcrystaline cellulose once daily arm 2: Pioglitazone 45 mg once daily arm 3: MSDC-0160 90 mg once daily arm 4: MSDC-0160 220 mg once daily
|
[
2,
1,
0,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Once daily, oral intervention 2: Once daily, oral intervention 3: Once daily, oral intervention 4: Once daily, oral
|
intervention 1: Placebo intervention 2: Pioglitazone intervention 3: MSDC-0160 90 mg intervention 4: MSDC-0160 220 mg
| 8
|
Los Angeles | California | United States | -118.24368 | 34.05223
Miami Gardens | Florida | United States | -80.2456 | 25.94204
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Kalamazoo | Michigan | United States | -85.58723 | 42.29171
Greenville | South Carolina | United States | -82.39401 | 34.85262
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
| 0
|
NCT00760578
|
|
[
0
] | 14
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the effectiveness and safety of Daytrana® in the treatment of attention deficit hyperactivity disorder (ADHD) in adults who have abused stimulants in the past. Daytrana® is a stimulant medication that has been approved by the Food and Drug Administration for the treatment of ADHD in children over the age of 6 years old.
|
Methylphenidate and amphetamines are considered to be the first line of treatment for ADHD in children (Biederman et al, 1997). Although treating children and adolescents with stimulants does not appear to increase the risk of substance use disorders (Wilens et al, 2003), little is known about the abuse of prescription stimulants in adults with ADHD. A review of the literature on the abuse potential of methylphenidate in animals and humans found that methylphenidate produced reinforcing, discriminative-stimulus, and subjective effects similar to amphetamines or cocaine (Kollins et al, 2001). Although the abuse rates of methylphenidate and other stimulant medications used for the treatment of ADHD have not been empirically established, significant concern exists so that regulatory mandates are enforced to control distribution, and some physicians may be reluctant to use stimulants in patients with drug abuse histories. The introduction of a methylphenidate patch is an important advancement, as the patch formulation should increase compliance while minimizing abuse potential, making it an attractive treatment option in the large population of individuals who have a history of previous drug misuse. The primary aim of this study is to assess the efficacy of the methylphenidate patch in adult individuals with ADHD who have abused stimulants in the past. It is hypothesized that the methylphenidate patch will be efficacious in reducing ADHD symptoms in this population.
|
Adult Attention Deficit Hyperactivity Disorder (ADHD)
|
Attention Deficit Hyperactivity ADHD
| null | 1
|
arm 1: Methylphenidate patch
|
[
5
] | 1
|
[
0
] |
intervention 1: Subjects will be provided with a 7-day supply of medication at each study visit. The dose will be flexible and will be titrated based on effect and tolerability. Unless a subject is experiencing side effects, the dose will be increased if a 25% reduction in ADHD symptoms as determined by the WRAADDS is not obtained. A proposed dosing schedule is as follows: Week 1: 12.5 cm2, Week 2: 18.75 cm2, Week 3: 25 cm2, Week 4: 37.5 cm2. The dose may be decreased as needed for tolerability.
|
intervention 1: Daytrana (methylphenidate patch)
| 1
|
Charleston | South Carolina | United States | -79.93275 | 32.77632
| 0
|
NCT00780208
|
[
5
] | 9
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This study will examine whether combined use of an antidepressant medication and the medication nimodipine reduces risk of depression relapse in patients with vascular depression.
|
Depressed elderly patients often show signs of cerebrovascular disease, commonly known as a stroke. Some scientists theorize that having cerebrovascular disease may affect depression in older adults in one of three ways: by causing depression, by making it more likely that people who have been depressed have a relapse, or by maintaining certain depressive symptoms in those already depressed. The combination of depression and cerebrovascular disease in older adults is referred to as vascular depression and is associated with psychomotor slowing, functional impairment, and cognitive impairment. Additionally, the likelihood of improvement or remission is lower in vascular depression and is more difficult to treat over time.
Nimodipine (NIM) is FDA approved to reduce incidence and severity of problems with blood flow resulting from a particular type of stroke. In addition to improving blood flow in the brain following a stroke, NIM also protects neurons from injury or degeneration and has cognitive and functional benefits. These positive effects of NIM may make it useful for treatment of vascular depression. In a previous study of people with vascular depression, pairing NIM with the antidepressant fluoxetine showed greater improvements in depression treatment outcomes, higher likelihood of full remission, and less incidence of depression recurrence than using fluoxetine alone. This study will examine whether pairing NIM with other antidepressants will reduce recurrence of vascular depression.
Participation in this study will last 56 weeks and will be divided into two phases. In the first phase, participants will receive antidepressant medication without NIM. Participants will begin taking escitalopram but may be switched to duloxetine or have lorazepam added to their regimen, depending on individual treatment effectiveness and side effects. The first phase will last between 6 and 24 weeks, ending when the individual participant either responds to medication or experiences 24 weeks of nonresponse. During the first phase, participants will attend weekly study visits, during which researchers will assess medication effectiveness and monitor side effects.
At the beginning of the second phase, participants will be randomly assigned to receive either NIM or a placebo in addition to continuing with the antidepressant medication already helping them. Participants will take NIM or the placebo for 8 months, undergoing weekly study visits for the first month and monthly study visits for the last 7 months. During these visits, researchers will monitor the participants' health and reactions to their medications. After 4, 16, and 32 weeks, an EKG test will be performed, and after 16 and 32 weeks, cognitive and physical tests will be performed again. After the 8 months, participants will attend three weekly study visits while their use of medication is lowered and then ended.
For information on a related study, please follow this link:
http://clinicaltrials.gov/show/NCT00177424
|
Depression
|
Depressive Disorder, Major Cerebrovascular Disorders Risk Factors Nimodipine
| null | 1
|
arm 1: In Phase 1, all participants will be placed on antidepressant medication. In Phase 2, participants will continue with their antidepressant medication and also receive receive either nimodipine or placebo.
|
[
5
] | 2
|
[
0,
0
] |
intervention 1: Nimodipine will be initiated at one, 30-mg tablet three times a day for 1 week, increased to 2 tablets three times a day for 1 week, and then increased to three tablets three times a day for the remaining 30 weeks of the study. Participants who cannot tolerate the maximum dose of 270 mg/day will be maintained at the highest tolerable dose. intervention 2: Placebo will be given in doses matching those of nimodipine.
|
intervention 1: Nimodipine intervention 2: Placebo
| 1
|
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
| 0
|
NCT00781326
|
[
4
] | 3
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The primary objective of the study was to evaluate the immunogenicity of Avonex® (interferon beta-1a) 30 mcg when administered subcutaneously (SC) to interferon-naïve participants with relapsing multiple sclerosis. The secondary objective of this study was to evaluate the safety and tolerability of Avonex® 30 mcg when administered SC to interferon-naïve subjects with relapsing MS.
| null |
Multiple Sclerosis
|
Multiple Sclerosis - Relapsing
| null | 1
|
arm 1: Avonex 30 mcg given subcutaneously, once weekly, for 18 months.
|
[
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: BG9418 (interferon beta 1-a)
| 2
|
Detroit | Michigan | United States | -83.04575 | 42.33143
Dallas | Texas | United States | -96.80667 | 32.78306
| 0
|
NCT00784836
|
[
4
] | 707
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
To demonstrate the efficacy of ciclesonide HFA applied as a nasal aerosol (160 μg and 80 μg) once daily compared to placebo in subjects with SAR.
|
This is a randomized, double blind, placebo controlled, parallel group, multicenter study to demonstrate the efficacy of ciclesonide HFA applied as a nasal aerosol (160 μg and 80 μg) once daily compared to placebo in subjects with SAR. This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.
|
Seasonal Allergic Rhinitis
|
SAR
| null | 3
|
arm 1: 80 mcg Ciclesonide once daily arm 2: 160 mcg Ciclesonide once daily arm 3: Placebo once daily
|
[
0,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: 80 mcg Ciclesonide HFA Inhaler once daily (one actuation per nostril) intervention 2: 160 mcg Ciclesonide HFA Inhaler once daily (one actuation per nostril) intervention 3: Placebo HFA Inhaler once daily (one actuation per nostril)
|
intervention 1: 80 mcg Ciclesonide intervention 2: 160 mcg Ciclesonide intervention 3: Placebo
| 4
|
Austin | Texas | United States | -97.74306 | 30.26715
Kerrville | Texas | United States | -99.14032 | 30.04743
New Braunfels | Texas | United States | -98.12445 | 29.703
San Antonio | Texas | United States | -98.49363 | 29.42412
| 0
|
NCT00790023
|
[
3
] | 38
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study was to determine the pharmacokinetics (PK), safety and clinical response following a single dose of either 30 mg/kg IR (Immediate Release) or 60 mg/kg ER (Extended Release) formulation in pediatric subjects 6 months to 6 years of age inclusive.
| null |
Acute Otitis Media
|
azithromycin, pharmacokinetics, pediatrics
| null | 2
|
arm 1: 60 mg/kg azithromycin ER (Extended Release)arm arm 2: 30 mg/kg azithromycin IR (Immediate Release) arm
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: subjects taken 60 mg/kg azithromycin ER intervention 2: subjects taken 30 mg/kg azithromycin IR (Immediate Release)
|
intervention 1: 60 mg/kg azithromycin ER intervention 2: 30 mg/kg azithromycin IR
| 2
|
San José | Provincia de San José | Costa Rica | -84.08489 | 9.93388
San José | Provincia de San José | Costa Rica | -84.08489 | 9.93388
| 0
|
NCT00796224
|
[
3,
4
] | 231
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
Aim of this study is to evaluate the efficacy and safety of a range of doses of tamsulosin hydrochloride as treatment in children with an elevated detrusor leak point pressure associated with a known neurological deficit
| null |
Bladder, Neurogenic
|
tamsulosin pediatric neurogenic bladder
| null | 4
|
arm 1: Participants received matching placebo to tamsulosin hydrochloride via opened capsules every day for 14 weeks arm 2: Participants received 0.001 - 0.002 mg/kg tamsulosin hydrochloride via opened capsules every day for 14 weeks arm 3: Participants received 0.002 - 0.004 mg/kg tamsulosin hydrochloride via opened capsules every day for 14 weeks arm 4: Participants received 0.004 - 0.008 mg/kg tamsulosin hydrochloride via opened capsules every day for 14 weeks
|
[
2,
0,
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Oral intervention 2: Oral
|
intervention 1: tamsulosin hydrochloride intervention 2: Placebo
| 52
|
Los Angeles | California | United States | -118.24368 | 34.05223
Tampa | Florida | United States | -82.45843 | 27.94752
St Louis | Missouri | United States | -90.19789 | 38.62727
Buffalo | New York | United States | -78.87837 | 42.88645
Tarrytown | New York | United States | -73.85875 | 41.07621
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Akron | Ohio | United States | -81.51901 | 41.08144
Ghent | N/A | Belgium | 3.71667 | 51.05
Santo André | N/A | Brazil | -46.53833 | -23.66389
São Paulo | N/A | Brazil | -46.63611 | -23.5475
Berlin | N/A | Germany | 13.41053 | 52.52437
Deggendorf | N/A | Germany | 12.96068 | 48.84085
Essen | N/A | Germany | 7.01228 | 51.45657
Hamburg | N/A | Germany | 9.99302 | 53.55073
Mainz | N/A | Germany | 8.2791 | 49.98419
Ahmedabad | N/A | India | 72.58727 | 23.02579
Belagavi | N/A | India | 74.50447 | 15.85212
Bengaluru | N/A | India | 77.59369 | 12.97194
Hyderabaad | N/A | India | N/A | N/A
Kochi | N/A | India | 76.26022 | 9.93988
Lucknow | N/A | India | 80.92313 | 26.83928
Ludhiana | N/A | India | 75.85379 | 30.91204
Manipal | N/A | India | 74.78333 | 13.35
Mumbai | N/A | India | 72.88261 | 19.07283
Nadiād | N/A | India | 72.86157 | 22.69385
Nagpur | N/A | India | 79.08491 | 21.14631
New Delhi | N/A | India | 77.2148 | 28.62137
Pune | N/A | India | 73.85535 | 18.51957
Pune | N/A | India | 73.85535 | 18.51957
Cagliari | N/A | Italy | 9.11917 | 39.23054
Florence | N/A | Italy | 11.24626 | 43.77925
Roma | N/A | Italy | 11.10642 | 44.99364
León | N/A | Mexico | -113.78333 | 28.51667
Puebla City | N/A | Mexico | -98.20723 | 19.04778
Manila | N/A | Philippines | 120.9822 | 14.6042
Pasig | N/A | Philippines | 121.0614 | 14.58691
Quezon City | N/A | Philippines | 121.0509 | 14.6488
Moscow | N/A | Russia | 37.61556 | 55.75222
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Bloemfontein | N/A | South Africa | 26.214 | -29.12107
Cape Town | N/A | South Africa | 18.42322 | -33.92584
Johannesburg | N/A | South Africa | 28.04363 | -26.20227
Pretoria | N/A | South Africa | 28.18783 | -25.74486
Roodepoort | N/A | South Africa | 27.8725 | -26.1625
Gwangju | N/A | South Korea | 126.91556 | 35.15472
Incheon | N/A | South Korea | 126.70515 | 37.45646
Pusan | N/A | South Korea | 128.3681 | 36.3809
Seoul | N/A | South Korea | 126.9784 | 37.566
Barcelona | N/A | Spain | 2.15899 | 41.38879
Madrid | N/A | Spain | -3.70256 | 40.4165
Málaga | N/A | Spain | -4.42034 | 36.72016
Chernivtsy | N/A | Ukraine | N/A | N/A
| 0
|
NCT00796614
|
[
0
] | 100
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 2DOUBLE
| false
| 1FEMALE
| false
|
It has been proven that tracheal tube inflated with lidocaine could decrease the post-intubation sore throat in nitrous oxide anesthesia. In the study, the investigators would like to evaluate the effect of lidocaine inflation in non-nitrous oxide anesthesia and compare the effect of tetracaine, the best mucosal local anesthetics with lidocaine.
|
The female patients receiving gynecological surgeries were divided into air, saline and 2% lidocaine and 1% tetracaine groups of 25 each using sealed envelope technique. The cuff of the endotracheal tube was inflated by the inflation medium (with the help of intracuff pressure monitoring device) to occlude the leak around the tube by the Minimal Occlusive Volume Technique. This was done by the same anaesthesiologist in all the patients. The cuff volume and pressure were then recorded. The primary outcome of the study was to evaluate the post-intubation sore throat using the visual analogue scale 6h, 24h and 48h after extubation. The secondary outcomes were incidence of complications during emergence of anesthesia and after extubation. Intra-cuff pressure monitoring was done with a pressure monitor, which consisted of the pressure gauge, three-way stopcock whose one end was attached to the pressure monitoring line. Net volume of the inflation medium was noted. Volume of the inflation medium, intra cuff pressure, duration from intubation to extubation and volume of the inflation medium withdrawn from the cuff was noted. Incidence (Yes/No) of tube intolerance, coughing on tube, restlessness, hoarseness, sore throat, breathlessness and laryngospasm were analyzed by the anaesthesiologist who did not know which group the patient belonged to.
|
Pharyngitis
|
lidocaine tetracaine tracheal intubation pharyngitis
| null | 4
|
arm 1: air was used to inflate the cuff. arm 2: Normal saline was used to inflate the cuff. arm 3: 2% lidocaine was used to inflate the cuff. arm 4: 1% tetracaine was used to inflate the cuff.
|
[
2,
2,
1,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: lidocaine: 2%, injected into the cuff to seal the space between the trachea and the tube at minimal volume intervention 2: Air injected into the cuff to seal the space between the trachea and the tube at minimal volume intervention 3: tetracaine: 1%, injected into the cuff to seal the space between the trachea and the tube at minimal volume intervention 4: 0.9% Normal saline injected into the cuff to seal the space between the trachea and the tube at minimal volume
|
intervention 1: 2% lidocaine intervention 2: placebo intervention 3: 1% tetracaine intervention 4: N.S
| 1
|
Chengdu | Sichuan | China | 104.06667 | 30.66667
| 0
|
NCT00798018
|
[
5
] | 24
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The primary objective of this study is to investigate the initial antibiotic effects in the treatment of bacterial conjunctivitis symptoms in subjects one year of age and older.
| null |
Bacterial Conjunctivitis
|
Bacterial Conjunctivitis
| null | 2
|
arm 1: Vigamox Ophthalmic Solution (Moxifloxacin 5mg/mL) arm 2: Balanced Salt Solution
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Moxifloxacin 5mg/mL 3 times daily for 7 days intervention 2: Balanced Saline Solution for 3 doses, then Moxifloxacin 5mg/mL 3 times daily for 7 days
|
intervention 1: Vigamox Ophthalmic Solution intervention 2: BSS placebo
| 1
|
Fort Worth | Texas | United States | -97.32085 | 32.72541
| 0
|
NCT00798577
|
[
3
] | 53
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the relative efficacy of JNJ- 39220675 and pseudoephedrine compared to placebo (medication with no active ingredients) in participants with allergic rhinitis (inflammation of the nose due to exposure to allergens such as pollen, dust or animal hair).
|
This is a randomized (the study drug is assigned by chance), single-dose, single-blind (a clinical trial in which the person giving the treatment, but not the participant, knows which treatment the participant is receiving), double-dummy, placebo-controlled, three-treatment period, cross-over (participants may receive different interventions sequentially during the trial) study of JNJ-39220675 in participants with allergic rhinitis. The duration of study will be 20-64 days per participant. The study consists of 2 parts: Screening (that is, 30 days before study commences on Day 1) and Treatment (consists of single-dose of either JNJ-39220675 solution \[10 milligram\], Pseudoephedrine tablet \[60 milligram\] or Placebo, in subsequent three-treatment periods, each separated with washout period of 6 days). All the eligible participants will be randomly assigned to 1 of the 6 treatment sequences. Participants will be given dose approximately 2 hours before entry into the environmental exposure chamber where they will be exposed to ragweed pollen for 8 hours. Efficacy will primarily be evaluated by measurement of nasal congestion that will be assessed through nasal cavity geometry that is, minimal cross-sectional area of nasal cavity by Acoustic rhinometry. Participants' safety will be monitored throughout the study.
|
Allergic Rhinitis
|
Allergy Rhinitis Allergic Rhinitis JNJ-39220675 Pseudoephedrine
| null | 6
|
arm 1: Single-dose of JNJ-39220675 will be administered as 1 milliliter (ml) of 10 milligram/milliliter (mg/ml) solution orally along with placebo tablet in first treatment period; after that in second treatment period, single-dose of 1 ml placebo solution will be administered orally along with 60 milligram (mg) pseudoephedrine tablet; and then single-dose of 1 ml placebo solution will be administered orally along with placebo tablet in third treatment period. A washout period of at least 6 days will be maintained between each treatment period. arm 2: Single-dose of JNJ-39220675 will be administered as 1 ml of 10 mg/ml solution orally along with placebo tablet in first treatment period; after that, in second treatment period, single-dose of 1 ml placebo solution will be administered orally along with placebo tablet; and then single-dose of 1 ml placebo solution will be administered orally along with 60 mg pseudoephedrine tablet in third treatment period. A washout period of at least 6 days will be maintained between each treatment period. arm 3: Single-dose of 1 ml placebo solution will be administered orally along with placebo tablet in first treatment period; after that, in second treatment period, single-dose of JNJ-39220675 will be administered as 1 ml of 10 mg/ml solution orally along with placebo tablet; and then single-dose of 1 ml placebo solution will be administered orally along with 60 mg pseudoephedrine tablet in third treatment period. A washout period of at least 6 days will be maintained between each treatment period. arm 4: Single-dose of 1 ml placebo solution will be administered orally along with placebo tablet in first treatment period; after that, in second treatment period, single-dose of 1 ml placebo solution will be administered orally along with 60 mg pseudoephedrine tablet; and then single-dose of JNJ-39220675 will be administered as 1 ml of 10 mg/ml solution orally along with placebo tablet in third treatment period. A washout period of at least 6 days will be maintained between each treatment period. arm 5: Single-dose of 1 ml placebo solution will be administered orally along with 60 mg pseudoephedrine tablet in first treatment period; after that, in second treatment period, single-dose of JNJ-39220675 will be administered as 1 ml of 10 mg/ml solution along with placebo tablet; and then single-dose of 1 ml placebo solution will be administered orally along with placebo tablet in third treatment period. A washout period of at least 6 days will be maintained between each treatment period. arm 6: Single-dose of 1 ml placebo solution will be administered orally along with 60 mg pseudoephedrine tablet in first treatment period; after that, in second treatment period, single-dose of 1 ml placebo solution will be administered orally along with placebo tablet; and then single-dose of JNJ-39220675 will be administered as 1 ml of 10 mg/ml solution orally along with placebo tablet in third treatment period. A washout period of at least 6 days will be maintained between each treatment period.
|
[
0,
0,
0,
0,
0,
0
] | 3
|
[
10,
0,
0
] |
intervention 1: Single-dose of 1 milliliter (ml) placebo solution will be administered orally and/or placebo tablet orally in one of the treatment periods. intervention 2: Single-dose of JNJ-39220675 will be administered as 1 ml of 10 milligram/milliliter solution orally in one of the treatment periods. intervention 3: Single-dose of 60 milligram pseudoephedrine tablet will be administered orally in one of the treatment periods.
|
intervention 1: Placebo intervention 2: JNJ-39220675 intervention 3: Pseudoephedrine
| 1
|
Mississauga | Ontario | Canada | -79.6583 | 43.5789
| 0
|
NCT00804687
|
[
3
] | 3
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
To review safety and effectiveness of two doses compared to current standard of care.
|
Evaluate the efficacy of intercostal nerve block using SKY0402 compared to epidural bupivacaine HCl in subjects undergoing posterolateral thoracotomy. The primary outcome metric for this will be the amount of rescue PCA fentanyl administered for breakthrough pain during the first 72 hours.
|
Postoperative Pain
|
Pain postoperative thoracotomy
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
1,
0
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: Bupivacaine, 15 mg/mL via epidural PLUS single total administration of 75mg SKY0402 (25 mg to each of three segments) in 4 mL volume each for a total of 12 mL via nerve block (intercostal) intervention 2: Bupivacaine, 15 mg/mL via epidural PLUS single total administration of 150 mg (50 mg to each of three segments) in 4 mL volume each for a total of 12 mL via nerve block (intercostal) intervention 3: Bupivacaine, 15 mg/mL per epidural PLUS administration of 4 mL Placebo to each of three nerves for a total of 12 mL (intercostal) intervention 4: Fentanyl via PCA intervention 5: Bupivacaine via epidural
|
intervention 1: Low Dose SKY0402 intervention 2: High Dose SKY0402 intervention 3: Placebo intervention 4: Fentanyl via PCA intervention 5: Bupivacaine via epidural
| 5
|
Pasadena | California | United States | -118.14452 | 34.14778
Orlando | Florida | United States | -81.37924 | 28.53834
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
Tacoma | Washington | United States | -122.44429 | 47.25288
| 0
|
NCT00807209
|
[
4
] | 506
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to determine if one allergy medication (0.15% azelastine hydrochloride) is more effective than Placebo alone
| null |
Seasonal Allergic Rhinitis
| null | 2
|
arm 1: Placebo arm 2: 0.15% azelastine hydrochloride
|
[
2,
1
] | 2
|
[
0,
0
] |
intervention 1: Placebo intervention 2: 0.15% azelastine hydrochloride 822 mcg
|
intervention 1: Placebo intervention 2: 0.15% azelastine hydrochloride
| 7
|
Austin | Texas | United States | -97.74306 | 30.26715
Austin | Texas | United States | -97.74306 | 30.26715
New Braunfels | Texas | United States | -98.12445 | 29.703
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
Waco | Texas | United States | -97.14667 | 31.54933
| 0
|
NCT00824473
|
|
[
5
] | 89
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The purpose of this study is to determine whether Nesiritide is more effective than nitroglycerin in modifying inflammatory and neurohormonal biomarkers without renal toxicity when proper infusion duration is administered.
|
No additional details provided
|
Acute Decompensated Heart Failure
|
Natriuretic peptides BNP Heart Failure Nitoglycerin Biomarkers
| null | 2
|
arm 1: Nesiritide: 2 mcg/kg bolus (optional) followed by 0.01 mcg/kg/min infusion for 48 hours. arm 2: Nitroglycerin was initiated at 10 mcg/min initial starting dose titrated every 5-10 minutes until symptom relief, SBP\<or= 90 mm Hg, or up to a maximum rate of 200 mcg/min plus standard treatment.
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Bolus 2 mcg/kg followed by 0.01 mcg/kg/min intervention 2: 5-10 mcg/min titrating per protocol based on blood pressure
|
intervention 1: Nesiritide intervention 2: Nitroglycerin
| 1
|
Inglewood | California | United States | -118.35313 | 33.96168
| 0
|
NCT00842023
|
[
0
] | 10
|
RANDOMIZED
|
CROSSOVER
| 7BASIC_SCIENCE
| 0NONE
| false
| 0ALL
| false
|
Glutathione is normally present at high (millimolar) levels in blood and plays an important role in the body's defense against oxidative stress, that is, against the damage caused to the body by reactive oxygen species produced by the metabolism of most nutrients, including glucose. Glutathione is a small peptide made from 3 amino acids, glutamate, cysteine, and glycine.
This study is looking at how blood sugar levels may affect the way glutathione is made and used by the body. Since glutathione is continuously synthesized and broken down, the amount of glutathione present in blood depends on the balance between its rate of synthesis and its rate of use.
In earlier studies, the investigators found that in poorly controlled diabetic teenagers, glutathione was low, not because its production was decreased, but because it was used at an excessive rate. In this study, the investigators want to determine how short-term changes in blood sugar levels affect glutathione levels. This will help improve our understanding of how diabetes affects metabolism.
|
Adolescents with uncomplicated T1D will receive two, 5-hour infusions of deuterium-labeled cysteine on 2 separate days, a few weeks apart, while blood glucose will be maintained, using intravenous insulin infusion:
* in the hyper-glycemic range (200-250 mg/dL) on one study day, and
* near normoglycemia (80-140 mg/dL) on the other study day.
The order of the study days will be randomized.
We will determine whether the level of blood glucose at the time of study affects blood glutathione concentration, and, if so, whether this is associated with changes in the fractional rate of glutathione synthesis, as determined from the incorporation of labeled cysteine into blood glutathione over the course of the 5-hr infusion of labeled cysteine.
|
Diabetes Mellitus, Type 1
|
Glutathione
| null | 2
|
arm 1: 80-140 mg/dL arm 2: 200-250 mg/dL
|
[
0,
0
] | 2
|
[
10,
0
] |
intervention 1: L-\[3,3-2H2\]cysteine intervention 2: Regular insulin, IV, as needed to maintain blood glucose in near-normoglycemic range (80-140 mg/dL) or hyperglycemic range (200-250 mg/mL) during metabolic studies
|
intervention 1: Cysteine isotope infusion at normoglycemia vs hyperglycemia intervention 2: Regular Insulin
| 1
|
Jacksonville | Florida | United States | -81.65565 | 30.33218
| 0
|
NCT00858897
|
[
5
] | 50
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 2MALE
| false
|
Men treated with neoadjuvant luteinizing hormone-releasing hormone (LHRH)-agonists such as leuprolide and goserelin for prostate cancer will become hypogonadal due to hormonal suppression and demonstrate increased bone turnover and consequent bone loss at the hip and spine. This bone loss can be prevented by treatment with 35 mg/week of risedronate.
|
A 6-month randomized, double-blind, placebo-controlled trial was conducted, including 40 men aged ≥ 55 years receiving LHRH-agonist treatment for 6 months for locally advanced prostate cancer. Bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip was measured every 6 months. In addition, bone turnover markers including N-telopeptide, serum C-telopeptide and procollagen peptide, and 25-OH vitamin D and intact parathyroid hormone were measured at baseline and at 6 months.
|
Prostate Cancer
|
Non-metastatic
| null | 2
|
arm 1: 35 mg by mouth every week as directed arm 2: Calcium and vitamin D
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 35 mg/week by mouth intervention 2: One tablet by mouth every week as directed
|
intervention 1: risedronate intervention 2: Placebo risedronate oral tablet
| 1
|
Farmington | Connecticut | United States | -72.83204 | 41.71982
| 0
|
NCT00859027
|
[
5
] | 64
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
To demonstrate that the combination formulation of Moxifloxacin/Dexamethasone Eye Drop is effective and safe for the prevention of postoperative inflammation as a consequence of cataract extraction surgery.
| null |
Cataract
|
Cataract
| null | 1
|
arm 1: Vigadexa (moxifloxacin 0.5% and dexamethasone 0.1%) eye drops
|
[
0
] | 1
|
[
0
] |
intervention 1: 1 drop every 6 hours into the study eye
|
intervention 1: Vigadexa (moxifloxacin 0.5% and dexamethasone 0.1%) eye drops
| 1
|
Fort Worth | Texas | United States | -97.32085 | 32.72541
| 0
|
NCT00870103
|
[
4
] | 116
|
RANDOMIZED
|
CROSSOVER
| null | 2DOUBLE
| true
| 0ALL
| false
|
Randomized, placebo-controlled double-blind, crossover design study; 116 subjects randomized on Day 1 to obtain 98 completed subjects. Study will be composed of a 7-day period of therapy with randomized active or placebo treatment with a subsequent 6-8 day washout period, followed by a second 7-day period of double-blind therapy with the other agent. Ambulatory blood pressure measurement will be performed beginning on Day 7 of each treatment period following administration of the study drug.
| null |
Blood Pressure Human Experimentation
| null | 2
|
arm 1: Phenylephrine HCl Extended Release tablets 30 mg arm 2: Placebo
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Phenylephrine HCl Extended-Release tablets 30 mg taken twice daily (12 hours apart) for 7 days. intervention 2: Placebo taken twice daily (12 hours apart) for 7 days.
|
intervention 1: Phenylephrine Hydrochloride (HCl) Extended-Release tablets 30 mg intervention 2: Placebo
| 0
| null | 0
|
NCT00874120
|
|
[
2
] | 14
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| true
| 0ALL
| true
|
This purpose of this study is to measure the concentrations of two anti-epileptic drugs (Eslicarbazepine acetate and oxcarbazepine) and their metabolites in the cerebrospinal fluid and blood plasma of healthy subjects and also to assess how these drugs are tolerated.
| null |
Partial Epilepsy
|
Partial Epilepsy Eslicarbazepine acetate Pharmacokinetics Tolerability
| null | 2
|
arm 1: Eslicarbazepine acetate (ESL) 600 mg QD morning from Day 1-3 and 1200 mg ESL QD morning from Day 4-9 arm 2: Oxcarbazepine 300 mg BID from Day 1-3 and oxcarbazepine 600mg BID from Day 4-9
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: Oral administration 600 mg QD morning from Day 1-3 and 1200 mg from Day 4-9 intervention 2: Oxcarbazepine 300 mg BID from Day 1-3 (morning and evening) and oxcarbazepine 600mg BID from Day 4-9 (morning and evening, only morning dose on Day 9)
|
intervention 1: Eslicarbazepine acetate intervention 2: Oxcarbazepine
| 1
|
Antwerp | N/A | Belgium | 4.40026 | 51.22047
| 0
|
NCT00900237
|
[
5
] | 51
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| false
|
Urinary urgency is a key symptom of overactive bladder syndrome (OAB) and may be more bothersome to a patient than the symptom of urinary frequency. Unfortunately, controversy continues to surround the term 'urgency' and there is no good tool to evaluate the severity of urgency. This fact has constrained the performance of clinical research in this field. The cause of urinary urgency is not fully understood and may vary from patient to patient.
Although clinicians regularly obtain measures of bladder sensation during cystometry, little attention has been paid to the patient experience of urinary urgency. In this study, the researchers will use a non-significant risk device (i.e., an Urgeometer) to measure urinary urgency in women with overactive bladder.
|
At baseline, a small catheter is placed inside the participant's bladder. The bladder is filled with sterile water through the catheter. As the bladder is filled, the participant is asked to rate their urinary urgency using the Urgeometer. The Urgeometer lever marks a continuous scale from 0 'no urge at all' to 100 'maximum urge which you can tolerate'. The testing is stopped once the bladder is filled. To minimize the chance of infection, participants receive one dose of oral antibiotics prior to the bladder testing.
Following completion of the bladder test, participants will take 10mg solifenacin succinate (VesicareR) daily for 30 days. Afterward, participants repeat the bladder test. The change in participants' maximal tolerated cystometric capacity (MCC) will be measured in milliliters and used to evaluate the effectiveness of the drug.
|
Overactive Bladder Syndrome
|
Bladder Urinary Urgency Solifenacin Vesicare(R)
| null | 1
|
arm 1: The intervention for this study is 10mg daily solifenacin. Patients with overactive bladder syndrome will take this study drug for 30 days.
|
[
0
] | 1
|
[
0
] |
intervention 1: Participants take 10mg daily solifenacin succinate for 30 days
|
intervention 1: Solifenacin Succinate
| 1
|
Maywood | Illinois | United States | -87.84312 | 41.8792
| 0
|
NCT00909428
|
[
0
] | 23
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to find out if a medication that increases levels of a brain chemical called acetylcholine will improve balance and reduce falls in patients with parkinson's disease who have the problem of very poor balance and are frequently falling or nearly falling on a daily basis. Donepezil, a drug approved for the treatment of Alzheimer's dementia, will reduce falls in subjects with Parkinson's disease and balance impairment.
|
This trial is a double-blinded cross-over design comparing donepezil with placebo in 40 subjects with idiopathic Parkinson's disease who report frequent falls or near falls (\>2/week). The purpose of this study is to find out if a medication that increases levels of a brain chemical called acetylcholine will improve balance and reduce falls in patients with parkinson's disease who have the problem of very poor balance and are frequently falling or nearly falling on a daily basis. Donepezil, a drug approved for the treatment of Alzheimer's dementia, will reduce falls in subjects with Parkinson's disease and balance impairment.
|
Parkinson's Disease
|
parkinsons disease falling
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: donepezil, 5 mg, capsule, once a day, 3 weeks intervention 2: sugar pill, one capsule, once a day, 3 weeks
|
intervention 1: Donepezil intervention 2: Sugar Pill (placebo)
| 0
| null | 0
|
NCT00912808
|
[
0
] | 10
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The study doctor will give EVOLENCE® mixed with Lidocaine to people in this study to see if it effectively reduces pain while injecting and works to correct nasolabial wrinkles.
The product being used in this study is EVOLENCE®, which is currently marketed in the United States for the cosmetic correction of soft tissue contour deficiencies (including wrinkles), and been approved by the U.S. Food and Drug Administration (FDA).
|
The aim of this study is to determine if the admixture of lidocaine can effectively be used to mediate pain relief during the injection of EVOLENCE® while achieving cosmetic correction.
|
Aging Pain
|
wrinkles dermal filler collagen soft tissue augmentation lidocaine aesthetic
| null | 2
|
arm 1: Assess injection pain severity for a one time 1.0 mL injection of Evolence with 0.2 ml of topical anesthetic, applied 30 minutes prior to injection, to the left nasolabial fold of each participant . arm 2: Assess injection pain severity for a one time 1.0 mL injection of Evolence mixed with 0.18 mL of 2% lidocaine (0.3% final lidocaine-HCl) in the right nasolabial fold of each participant.
|
[
0,
0
] | 3
|
[
1,
1,
0
] |
intervention 1: Injectable collagen intervention 2: admix anesthetic intervention 3: None
|
intervention 1: Evolence intervention 2: Lidocaine intervention 3: topical anesthetic
| 1
|
Bradenton | Florida | United States | -82.57482 | 27.49893
| 0
|
NCT00929071
|
[
5
] | 99
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will examine whether the administration of galantamine is effective for improvement of attention and more effective for patients with serious disturbance of attention by administering galantamine to patients with Alzheimer's dementia and performing an attention test on baseline, week 4 and 12.
|
This is an open label (all people know the identity of the intervention), multi-center, prospective study investigating the effect of galantamine on the attention of Alzheimer's dementia patients. The objectives of this study include the evaluation of the relationship between change in attention after 4 weeks of galantamine administration and to investigate the effect of study drug after 12 weeks administration (the difference in the improvement of attention after the administration of galantamine). The secondary objective of this study is to clarify the causal relationship between improvement of attention and activities of daily living (ADL). The design of this study is prospective, open-label, multi-center study. Study populations are probable Alzheimer's dementia patients diagnosed by NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association), DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria. The efficacy of study drug will be assessed by evaluating cognitive function, attention and behavioral symptoms before and after the treatment using the following assessment tools: ADAS-K-cog11 (Alzheimer's Disease Assessment Scale - cognitive subscale), computerized attention test and activities of daily living. Safety evaluations include adverse event monitoring and clinical lab tests. The patient is administered oral galantamine 8 mg/day for the first 4 weeks and then 16 mg/day. The dose of galantamine is increased up to 24 mg if tolerated.
|
Alzheimer's Disease
|
Alzheimer's disease Galantamine Dementia
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Orally administered Galantamine 8 mg/day for the first 4 weeks. Thereafter the dose will be increased to 16 mg/day. If tolerated, the dose of galantamine can be increased up to 24 mg/day.
|
intervention 1: Galantamine
| 0
| null | 0
|
NCT01054976
|
[
5
] | 103
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the efficacy and safety of Transdermal Therapeutic System (TTS)-fentanyl D-Trans (transdermal patch containing a drug that is put on the skin so the drug will enter the body through the skin) treatment in cancer participants of Korea with inadequately controlled pain by non-narcotic analgesics (drug used to control pain) and participant's satisfaction.
|
This is an open-label (all people know the identity of the intervention), single-arm, multicenter (conducted in more than one hospital or medical school team work on a medical research study), prospective (study following participants forward in time) study conducted to assess the efficacy and safety of TTS-fentanyl D-trans in cancer participants of Korea with inadequately controlled pain by non-narcotic analgesics and for participant's satisfaction. The participants will receive the initial dose of TTS-fentanyl D-trans patch releasing 12 micrograms per hour (12 mcg/hr) of fentanyl and will be increased by 12 mcg/hr or 25 mcg/hr, every 3 days depending on the participant's pain control. Efficacy will primarily be evaluated by participant's satisfaction with pain treatment. Participant's safety will be monitored throughout the study.
|
Pain; Cancer
|
Pain; Cancer TTS-Fentanyl D-trans Durogesic D-trans
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Fentanyl D-trans will be applied as transdermal patch releasing drug at the rate of 12.5 microgram per hour (mcg/hr) for 3 days with a dose ranging from 12 mcg/hr to 50 mcg/hr.
|
intervention 1: Fentanyl D-trans
| 0
| null | 0
|
NCT01060124
|
[
4
] | 223
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The purpose of this study was to allow the continuation of everolimus treatment in patients who have completed the core study (NCT00170885) and to collect long-term safety, tolerability, and efficacy data in a group of patients treated with the upper everolimus target levels plus very low dose cyclosporin in comparison with the standard everolimus target levels plus low dose cyclosporin in patients with renal transplantation.
| null |
Transplantation Infection
|
immunosuppression kidney transplantation everolimus safety
| null | 2
|
arm 1: Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study. arm 2: Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
|
[
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: The dose of everolimus for each patient was adjusted to achieve the target everolimus blood level range. Everolimus blood trough level was measured 5 days after any dose adjustment to verify that the blood level was within the desired target level range. intervention 2: The dose of cyclosporine for each patient was adjusted to achieve the target cyclosporine blood level. Cyclosporine dose adjustments were based on drug blood level determined from whole blood samples taken 2 hours (± 10 min) after the morning dose. intervention 3: The dose of cyclosporine for each patient was adjusted to achieve the target cyclosporine blood level. Cyclosporine dose adjustments were based on drug blood level determined from whole blood samples taken 2 hours (± 10 min) after the morning dose.
|
intervention 1: Everolimus 0.25 and 0.75 mg tablets intervention 2: Cyclosporine very low dose (150-300 ng/mL) microemulsion intervention 3: Cyclosporine low dose (350-500 ng/mL) microemulsion
| 0
| null | 0
|
NCT01276457
|
[
3
] | 51
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| true
| 0ALL
| false
|
The goal of this study is to determine whether a study medication (d-cycloserine) improves the ability of older adults to perform on tests of neuropsychological functioning. Tests of neuropsychological functioning assess attention, memory, and executive functioning skills (for example, problem-solving, planning and organizing skills). It was hypothesized that participants who received study medication would perform better on neuropsychological tests than would participants who received the sugar pill.
|
Accumulating data support the augmenting effects of d-cycloserine (DCS) when combined with exposure-based treatment for anxiety disorders. Additional research is needed to determine whether DCS facilitates other forms of cognitive processing (e.g., attention, memory, executive functioning) that are involved in cognitive behavioral therapies which do not rely on extinction as a mechanism of action. This question is particularly important among older adults who have experienced normal age-related declines in cognitive functioning, which may interfere with their ability to benefit from cognitive-behavioral therapies. The aim of the current study was to determine the cognitive enhancing effects of DCS on neuropsychological test performance among healthy older adults. It was hypothesized that participants who received d-cycloserine would demonstrate superior performance on neuropsychological tests than would participants who received placebo.
|
Treatment Placebo
|
d-cycloserine geriatric neuropsychology cognition cognitive-enhancer aging neuropsychological functioning
| null | 2
|
arm 1: 250 mg d-cycloserine arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: single oral administration of 250 mg d-cycloserine intervention 2: Single oral administration 250 mg Sugar Pill
|
intervention 1: d-cycloserine intervention 2: Sugar Pill
| 1
|
Hartford | Connecticut | United States | -72.68509 | 41.76371
| 0
|
NCT01361633
|
[
2
] | 46
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This clinical trial is designed to determine the safety, tolerability, pharmacokinetics and pharmacodynamic effects of escalating doses of CP 751,871 given in combination with docetaxel in patients with non-hematologic malignancies for whom docetaxel is a reasonable treatment option.
| null |
Advanced Non-Hematologic Malignancies
|
non-hematologic cancer advanced solid tumors prostrate cancer
| null | 1
|
arm 1: None
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: CP-751,871 was given intravenously \[IV\] every 3 weeks in escalating doses ranging from 0.1 mg/kg up to 20 mg/kg.
Standard doses of Docetaxel were given every 3 weeks with CP-751,871. Study therapy was continued until disease progression, lack of tolerability for up to 17 cycles (approximately 1 year). intervention 2: Docetaxel up to 75 mg/m\^2 was administered intravenously \[IV\] on Day 1 of each 3-week dosing cycle.
|
intervention 1: CP-751,871 intervention 2: Docetaxel
| 1
|
Sutton | Surrey | United Kingdom | -0.2 | 51.35
| 0
|
NCT01653158
|
[
5
] | 80
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the efficacy and safety of long acting injectable microspheres of risperidone in participants with schizophrenia (psychiatric disorder with symptoms of emotional instability, detachment from reality, often with delusions and hallucinations, and withdrawal into the self), schizophreniform or schizoaffective disorders (disorders in which there is a loss of ego boundaries or a gross impairment in reality testing with delusions or prominent hallucinations).
|
This is an open-label (all people know the identity of the intervention), longitudinal (participants are followed over time with continuous or repeated monitoring of risk factors or health-outcomes), non-randomized (a clinical trial in which the participants are not assigned by chance to different treatment groups), single-center study to evaluate the efficacy and safety of long acting microspheres of risperidone in adult participants with schizophrenia, schizophreniform or schizoaffective disorders. The duration of this study will be 12 months and duration of treatment will be 6 months. The study will include 4 visits: Baseline, and 3 follow-up visits including Week 4, 12 and 26. All eligible participants will be treated with risperidone 25 milligram (mg) intramuscular injection (injection of a substance into a muscle) for every two weeks up to 6 months. Participants with persistent symptoms and/or requiring higher doses of antipsychotics (agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect) will be initiated with higher doses of risperidone. Doses will be adjusted according to the response of the treatment. Efficacy and safety of the participants will be primarily evaluated by Positive and Negative Syndromes Scale (PANSS) and Extrapyramidal Symptom Rating Scale (ESRS), respectively. Participants' quality of life and safety will be monitored throughout the study.
|
Schizophrenia Schizophreniform Disorder Schizoaffective Disorder
|
Schizophrenia Schizophreniform Disorder Schizoaffective Disorder Risperidone Risperdal consta
| null | 1
|
arm 1: Risperidone 25 milligram (mg) will be given as intramuscular injection for every 2 weeks up to 6 months. Participants with persistent symptoms and/or requiring higher doses of antipsychotics will be administered higher doses of risperidone. Doses will be adjusted as per Investigator's discretion.
|
[
0
] | 1
|
[
0
] |
intervention 1: Risperidone 25 milligram (mg) will be given as intramuscular injection for every 2 weeks up to 6 months. Participants with persistent symptoms and/or requiring higher doses of antipsychotics will be administered higher doses of risperidone. Doses will be adjusted as per Investigator's discretion.
|
intervention 1: Risperidone
| 0
| null | 0
|
NCT01855074
|
[
4
] | 36
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will investigate the efficacy and safety of CellCept (1.5-2g/day po), in combination with a standard care regimen of cyclosporine A (trough level 150-200ng/mL) and steroids, in patients receiving a heart transplant. The anticipated time on study treatment is 24 weeks.
| null |
Heart Transplantation
| null | 1
|
arm 1: Participants received mycophenolate mofetil (MMF) 1.0 grams (g), orally (PO), twice daily (BID) from within 24 hours of transplantation through Week 24. Participants also received an initial loading dose of cyclosporine A (CsA) 4 to 6 milligrams per kilogram (mg/kg) within 48 hours of transplantation, adjusted thereafter to a blood trough concentration of 150 to 300 nanograms per milliliter (ng/mL) through Week 24. Participants also received corticosteroids as per the practice of each participating center.
|
[
0
] | 3
|
[
0,
0,
0
] |
intervention 1: 1.0 g PO BID intervention 2: Initial loading dose of 4 to 6 mg/kg within 48 hours of transplantation, adjusted thereafter to a blood trough concentration of 150 to 300 ng/mL intervention 3: As per the practice of each participating center
|
intervention 1: mycophenolate mofetil (MMF) intervention 2: cyclosporine A (CsA) intervention 3: corticosteroids
| 3
|
Beijing | N/A | China | 116.39723 | 39.9075
Fuzhou | N/A | China | 119.30611 | 26.06139
Shanghai | N/A | China | 121.45806 | 31.22222
| 0
|
NCT02091414
|
|
[
2
] | 30
|
RANDOMIZED
|
CROSSOVER
| 7BASIC_SCIENCE
| 0NONE
| true
| 0ALL
| false
|
Determine bioequivalence, safety and tolerability of guaifenesin extended-release 600 mg (Mucinex® SE) compared to an immediate-release syrup reference product in normal healthy subjects.
| null |
Healthy Subjects
| null | 2
|
arm 1: Single dose of Mucinex® SE extended-release 600 mg bi-layer tablet taken with 240 mL of water after an overnight fast arm 2: Vicks Cough Syrup for Chesty Coughs 200 mg every 4 hours taken with 240 mL of water after an overnight fast
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Single dose of Mucinex® SE extended-release 600 mg bi-layer tablet intervention 2: Vicks Cough Syrup for Chesty Coughs 15 mL (200 mg guaifenesin q4h) immediate release (IR) syrup
|
intervention 1: Mucinex® SE intervention 2: Vicks Cough Syrup for Chesty Coughs
| 0
| null | 0
|
NCT03644095
|
|
[
3
] | 33
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This is an open-label extension to study 49653/461, to assess the long-term safety of rosiglitazone (extended release tablets) in subjects with mild to moderate Alzheimer's Disease.
| null |
Alzheimer's Disease
|
Alzheimer's Disease Rosiglitazone
| null | 1
|
arm 1: Extended Release Tablets
|
[
0
] | 1
|
[
0
] |
intervention 1: Extended Release Tablets
|
intervention 1: rosiglitazone
| 7
|
Litchfield Park | Arizona | United States | -112.35794 | 33.49337
Phoenix | Arizona | United States | -112.07404 | 33.44838
Sun City | Arizona | United States | -112.27182 | 33.59754
Belmont | Massachusetts | United States | -71.17867 | 42.39593
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Durham | North Carolina | United States | -78.89862 | 35.99403
Montreal | Quebec | Canada | -73.58781 | 45.50884
| 0
|
NCT00381238
|
[
3
] | 100
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
CE-224,535 is known to block a chemical that acts as a gateway to some of your immune cells. Blocking this gateway prevents the cells from pushing out 2 chemicals called IL-1 and IL-18 that are known to cause some of the inflammation seen in rheumatoid arthritis. It is hoped that taking this drug will reduce the symptoms of rheumatoid arthritis
| null |
Arthritis, Rheumatoid
|
rheumatoid arthritis DMARD methotrexate
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 500 mg po BID intervention 2: no active ingredient
|
intervention 1: CE-224,535 intervention 2: Placebo
| 27
|
Mesa | Arizona | United States | -111.82264 | 33.42227
DeBary | Florida | United States | -81.30868 | 28.88305
Lake Mary | Florida | United States | -81.31784 | 28.75888
Tampa | Florida | United States | -82.45843 | 27.94752
Avon | Indiana | United States | -86.39972 | 39.76282
New Orleans | Louisiana | United States | -90.07507 | 29.95465
New Orleans | Louisiana | United States | -90.07507 | 29.95465
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Frederick | Maryland | United States | -77.41054 | 39.41427
Columbia | Missouri | United States | -92.33407 | 38.95171
Columbia | Missouri | United States | -92.33407 | 38.95171
Reno | Nevada | United States | -119.8138 | 39.52963
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Spokane | Washington | United States | -117.42908 | 47.65966
Providencia | Santiago, RM | Chile | -70.60454 | -33.43107
Česká Lípa | N/A | Czechia | 14.53764 | 50.68551
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Mexico | D.F. | Mexico | -98.43784 | 18.88011
Krakow | N/A | Poland | 19.93658 | 50.06143
Poznan | N/A | Poland | 16.92993 | 52.40692
Poznan | N/A | Poland | 16.92993 | 52.40692
Incheon | N/A | South Korea | 126.70515 | 37.45646
Pusan | N/A | South Korea | 128.3681 | 36.3809
Santiago de Compostela | A Coruña | Spain | -8.54569 | 42.88052
A Coruña | N/A | Spain | -8.396 | 43.37135
Madrid | N/A | Spain | -3.70256 | 40.4165
| 0
|
NCT00628095
|
[
3
] | 4
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The purpose of this study is to evaluate the feasibility of giving four weekly doses of Rituximab (anti-CD20 antibody) in the treatment of children with refractory neuroblastoma associated opsoclonus-myoclonus. Patients must have continued symptoms of opsoclonus, myoclonus and or ataxia despite surgical resection and a minimum of one month of steroid therapy. Evaluations include clinical symptoms of opsoclonus-myoclonus and ataxia as well as detailed evaluation of learning and development.
|
Opsoclonus-myoclonus ataxia syndrome (OMS) is a rare immune mediated paraneoplastic syndrome that occurs in approximately 2 to 3% of children with neuroblastoma. Children with neuroblastoma associated opsoclonus-myoclonus tend to have a favorable prognosis from the standpoint of the cure of their cancer. Unfortunately,approximately two-thirds of this subgroup of patients are left with long term sequellae of the syndrome, including residual symptoms of opsoclonus, myoclonus, ataxia, learning difficulties and disturbance of sleep and mood.
Multiple lines of evidence indicate an immune mechanism to this rare disorder. This includes occurence of OMS in the post-infectious state, aggressive lymphocytic infiltration of the tumor in children with OMS, and documented responses to therapries that act through suppression of the immune system.
The current study utilizes four weekly doses of anti-CD 20 antibody (rituximab) to treat children with refractory OMS. Refractory disease is defined as continued symptoms of OMS despite surgical resection of the tumor and a minimum of one month of steroid therapy.
All patients have baseline OMS evaluation and detailed neurocognitive testing with all studies being repeated at the completion of the four weekly infusions. OMS testing is repeated at Month 3. OMS testing and detailed neurocognitive testing is conducted at 6 months intervals until 2 years from the initial infusion.
The goal of the study is to utilize this novel therapy to improve long term neurologic and neurodevelopmental outcome in children with refratory neuroblastoma associated opsoclonus-myoclonus.
|
Neuroblastoma Opsoclonus-myoclonus
|
neuroblastoma Opsoclonus-myoclonus rituximab
| null | 1
|
arm 1: Single Arm
|
[
5
] | 1
|
[
0
] |
intervention 1: 4 weekly doses of IV rituxan at 375 mg/m2 on days 1, 8, 15 and 22
|
intervention 1: anti-CD20 (Rituximab)
| 0
| null | 0
|
NCT00202930
|
[
3
] | 415
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
This trial was conducted in Europe,Asia and Africa. Study participants were randomised evenly to treatment with semaglutide (0.1 mg QW - 1.6 mg QW, 6 treatment arms, placebo or liraglutide (1.2 mg QD, or 1.8 mg QD).Treatment allocation to semaglutide or placebo was double-blind, whereas liraglutide treatment was administered open-label.Primary efficacy parameter was HbA1c and the treatment duration was 12 weeks.
| null |
Diabetes Diabetes Mellitus, Type 2
| null | 14
|
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None arm 14: None
|
[
0,
0,
0,
0,
0,
0,
2,
2,
2,
2,
2,
2,
0,
0
] | 13
|
[
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] |
intervention 1: 0.1 mg, once weekly, s.c. injection intervention 2: 0.2 mg, once weekly, s.c. injection intervention 3: 0.4 mg, once weekly, s.c. injection intervention 4: 0.8 mg, once weekly, s.c. injection intervention 5: 0.8 mg with titration, once weekly, s.c. injection intervention 6: 1.6 mg with titration, once weekly, s.c. injection intervention 7: 0.1 mg, once weekly, s.c. injection intervention 8: 0.2 mg, once weekly, s.c. injection intervention 9: 0.4 mg, once weekly, s.c. injection intervention 10: 0.8 mg with titration, once weekly, s.c. injection intervention 11: 1.6 mg, once weekly, s.c. injection intervention 12: 1.2 mg with titration, once daily, s.c. injection intervention 13: 1.8 mg with titration, once daily, s.c. injection
|
intervention 1: semaglutide intervention 2: semaglutide intervention 3: semaglutide intervention 4: semaglutide intervention 5: semaglutide intervention 6: semaglutide intervention 7: placebo intervention 8: placebo intervention 9: placebo intervention 10: placebo intervention 11: placebo intervention 12: liraglutide intervention 13: liraglutide
| 77
|
Gratwein | N/A | Austria | 15.31667 | 47.11667
Graz | N/A | Austria | 15.45 | 47.06667
Innsbruck | N/A | Austria | 11.39454 | 47.26266
Mödling | N/A | Austria | 16.28921 | 48.08605
Vienna | N/A | Austria | 16.37208 | 48.20849
Vienna | N/A | Austria | 16.37208 | 48.20849
Vienna | N/A | Austria | 16.37208 | 48.20849
Vienna | N/A | Austria | 16.37208 | 48.20849
Plovdiv | N/A | Bulgaria | 24.75 | 42.15
Rousse | N/A | Bulgaria | 25.9534 | 43.84872
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Varna | N/A | Bulgaria | 27.91667 | 43.21667
Helsinki | N/A | Finland | 24.93545 | 60.16952
Imatra | N/A | Finland | 28.75242 | 61.17185
Mikkeli | N/A | Finland | 27.27227 | 61.68857
Oulu | N/A | Finland | 25.46816 | 65.01236
Tampere | N/A | Finland | 23.78712 | 61.49911
Turku | N/A | Finland | 22.26869 | 60.45148
Dommartin-lès-Toul | N/A | France | 5.91005 | 48.66949
La Rochelle | N/A | France | -1.15222 | 46.16308
Montpellier | N/A | France | 3.87635 | 43.61093
Narbonne | N/A | France | 3.00141 | 43.18396
Vénissieux | N/A | France | 4.88593 | 45.69706
Bad Lauterberg im Harz | N/A | Germany | 10.47031 | 51.63272
Falkensee | N/A | Germany | 13.0927 | 52.56014
Hamburg | N/A | Germany | 9.99302 | 53.55073
Ludwigshafen | N/A | Germany | 9.06138 | 47.81663
Marburg | N/A | Germany | 8.77069 | 50.80904
Münster | N/A | Germany | 7.62571 | 51.96236
Pohlheim | N/A | Germany | N/A | N/A
Budapest | N/A | Hungary | 19.04045 | 47.49835
Debrecen | N/A | Hungary | 21.62444 | 47.53167
Gyula | N/A | Hungary | 21.28333 | 46.65
Pécs | N/A | Hungary | 18.23083 | 46.0725
Szekszárd | N/A | Hungary | 18.70905 | 46.35014
Hyderabad | Andhra Pradesh | India | N/A | N/A
Chennai | Tamil Nadu | India | 80.27847 | 13.08784
Chennai | N/A | India | 80.27847 | 13.08784
Hyderabad | N/A | India | 78.45636 | 17.38405
Catanzaro | N/A | Italy | 16.60086 | 38.88247
Chieti | N/A | Italy | 14.16494 | 42.34827
Florence | N/A | Italy | 11.24626 | 43.77925
Milano (MI) | N/A | Italy | 12.59836 | 42.78235
Napoli | N/A | Italy | 14.5195 | 40.87618
Perugia | N/A | Italy | 12.38878 | 43.1122
Belgrade | N/A | Serbia and Montenegro | N/A | N/A
Pretoria | Gauteng | South Africa | 28.18783 | -25.74486
Durban | KwaZulu-Natal | South Africa | 31.0292 | -29.8579
Cape Town | Western Cape | South Africa | 18.42322 | -33.92584
Almería | N/A | Spain | -2.45974 | 36.83814
Gijón | N/A | Spain | -5.66152 | 43.53573
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Seville | N/A | Spain | -5.97317 | 37.38283
Valencia | N/A | Spain | -0.37966 | 39.47391
Bern | N/A | Switzerland | 7.44744 | 46.94809
Geneva | N/A | Switzerland | 6.14569 | 46.20222
Lausanne | N/A | Switzerland | 6.63282 | 46.516
Sankt Gallen | N/A | Switzerland | 9.37477 | 47.42391
Antalya | N/A | Turkey (Türkiye) | 30.69556 | 36.90812
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Istanbul | N/A | Turkey (Türkiye) | 28.94966 | 41.01384
Addlestone | N/A | United Kingdom | -0.49353 | 51.37135
Bath | N/A | United Kingdom | -2.36172 | 51.3751
Bexhill-on-Sea | N/A | United Kingdom | 0.47095 | 50.85023
Bradford | N/A | United Kingdom | -1.75206 | 53.79391
Dundee | N/A | United Kingdom | -2.97489 | 56.46913
Guildford | N/A | United Kingdom | -0.57427 | 51.23536
Hull | N/A | United Kingdom | -0.33525 | 53.7446
Inverness | N/A | United Kingdom | -4.22398 | 57.47908
Llanelli | N/A | United Kingdom | -4.16191 | 51.68195
Sheffield | N/A | United Kingdom | -1.4659 | 53.38297
Trowbridge | N/A | United Kingdom | -2.20861 | 51.31889
| 0
|
NCT00696657
|
|
[
3
] | 7
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
The purpose of this study is to determine whether the CollaRx Bupivacaine Implant (bupivacaine sponge) is safe and effective in reducing the amount of narcotic pain medication needed to control pain during the first 24 hours after gastrointestinal (GI) surgery.
|
Gastrointestinal (GI) surgery encompasses a range of surgical procedures that involve abdominal incision. Gastrointestinal surgery may be performed to treat an abdominal aortic aneurysm, ulcerative colitis, Crohn's disease, gallbladder disease, bile duct disease and morbid obesity. Although less invasive laparoscopic procedures are performed when warranted, open abdominal surgery is required for certain indications and for more complicated or advanced cases.
Bupivacaine is a local anesthetic (pain medicine) that has an established safety profile. Collagen is a protein that is found in all mammals. The CollaRx Bupivacaine implant is a thin flat sponge made out of collagen that comes for cow tendons and contains bupivacaine. When inserted into a surgical site, the collagen breaks down and bupivacaine is released at the site but very little is absorbed into the blood stream. The high levels of bupivacaine at the surgical site may result in less pain for several days after surgery.
This study will compare the amount of narcotic pain medication required after surgery in patients who receive the CollaRx Bupivacaine implant or a plain collagen sponge.
|
Pain, Postoperative
|
Gastrointestinal surgery Post operative pain
| null | 2
|
arm 1: Either three or four 5x5-cm bupivacaine sponges implanted at 2 sites within the surgical field (1) over the abdominal viscera and under the fascia prior to closing the fascia and (2) in the subcutaneous tissue just under the skin incision. arm 2: Either three or four 5x5-cm placebo sponges implanted at 2 sites within the surgical field (1) over the abdominal viscera and under the fascia prior to closing the fascia and (2) in the subcutaneous tissue just under the skin incision.
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: placebo
|
intervention 1: Bupivacaine Collagen Sponge intervention 2: Placebo
| 1
|
Albany | New York | United States | -73.75623 | 42.65258
| 0
|
NCT00661466
|
[
4
] | 1,912
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
This is a 26-week study in subjects with type 2 diabetes currently sub-optimally controlled by diet and exercise or with non-thiazolidinedione antihyperglycemic monotherapy. The total duration of a subject's participation will be approximately 30 weeks, including a 2-week placebo run-in period, a 26-week double-blind treatment period, and a 2-week post-treatment follow-up period.
| null |
Type 2 Diabetes Mellitus
|
Type 2 Diabetes Mellitus
| null | 4
|
arm 1: None arm 2: Rivoglitazone 1.0 mg arm 3: Rivoglitazone 1.5 mg arm 4: Pioglitazone 45 mg
|
[
2,
0,
0,
1
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: 45 mg over-encapsulated tablet administered orally, once daily intervention 2: Rivoglitazone-matching placebo administered as a tablet orally, once daily or a pioglitazone-matching placebo administered as an over-encapsulated tablet orally, once daily capsule intervention 3: 1.0 mg tablet administered orally, once daily intervention 4: 1.5 mg tablet administered orally, once daily
|
intervention 1: Pioglitazone intervention 2: Placebo intervention 3: Rivoglitazone intervention 4: Rivoglitazone
| 183
|
Anniston | Alabama | United States | -85.83163 | 33.65983
Birmingham | Alabama | United States | -86.80249 | 33.52066
Hoover | Alabama | United States | -86.81138 | 33.40539
Muscle Shoals | Alabama | United States | -87.66753 | 34.74481
Hot Springs | Arkansas | United States | -93.05518 | 34.5037
Jonesboro | Arkansas | United States | -90.70428 | 35.8423
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Buena Park | California | United States | -117.99812 | 33.86751
Garden Grove | California | United States | -117.94145 | 33.77391
Huntington Park | California | United States | -118.22507 | 33.98168
Los Angeles | California | United States | -118.24368 | 34.05223
Paramount | California | United States | -118.15979 | 33.88946
Sacramento | California | United States | -121.4944 | 38.58157
San Diego | California | United States | -117.16472 | 32.71571
Walnut Creek | California | United States | -122.06496 | 37.90631
West Covina | California | United States | -117.93895 | 34.06862
West Hills | California | United States | -118.64398 | 34.19731
Denver | Colorado | United States | -104.9847 | 39.73915
Delray Beach | Florida | United States | -80.07282 | 26.46146
Jacksonville | Florida | United States | -81.65565 | 30.33218
Merritt Island | Florida | United States | -80.69 | 28.359
Miami | Florida | United States | -80.19366 | 25.77427
Pembroke Pines | Florida | United States | -80.22394 | 26.00315
Tampa | Florida | United States | -82.45843 | 27.94752
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Boise | Idaho | United States | -116.20345 | 43.6135
Chicago | Illinois | United States | -87.65005 | 41.85003
Evansville | Indiana | United States | -87.55585 | 37.97476
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Wichita | Kansas | United States | -97.33754 | 37.69224
Madisonville | Kentucky | United States | -87.49889 | 37.3281
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Slidell | Louisiana | United States | -89.78117 | 30.27519
Springfield | Massachusetts | United States | -72.58981 | 42.10148
Portage | Michigan | United States | -85.58 | 42.20115
Southfield | Michigan | United States | -83.22187 | 42.47337
St Louis | Missouri | United States | -90.19789 | 38.62727
Voorhees Township | New Jersey | United States | -74.49062 | 40.4795
Syracuse | New York | United States | -76.14742 | 43.04812
Morehead City | North Carolina | United States | -76.72604 | 34.72294
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
Cleveland | Ohio | United States | -81.69541 | 41.4995
Delaware | Ohio | United States | -83.06797 | 40.29867
Lyndhurst | Ohio | United States | -81.48873 | 41.52005
Marion | Ohio | United States | -83.12852 | 40.58867
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
Beaver | Pennsylvania | United States | -80.30478 | 40.69534
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
Cleveland | Tennessee | United States | -84.87661 | 35.15952
Kingsport | Tennessee | United States | -82.56182 | 36.54843
New Tazewell | Tennessee | United States | -83.59963 | 36.44258
Carrollton | Texas | United States | -96.89028 | 32.95373
Conroe | Texas | United States | -95.45605 | 30.31188
Corpus Christi | Texas | United States | -97.39638 | 27.80058
Dallas | Texas | United States | -96.80667 | 32.78306
El Paso | Texas | United States | -106.48693 | 31.75872
Garland | Texas | United States | -96.63888 | 32.91262
Irving | Texas | United States | -96.94889 | 32.81402
Midland | Texas | United States | -102.07791 | 31.99735
San Antonio | Texas | United States | -98.49363 | 29.42412
Richmond | Virginia | United States | -77.46026 | 37.55376
Olympia | Washington | United States | -122.90169 | 47.04491
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Loma Verde | Buenos Aires | Argentina | -58.40383 | -35.27401
Zárate | Buenos Aires | Argentina | -59.02423 | -34.09584
San Vicente | Córdoba Province | Argentina | -65.43037 | -31.85375
Feldkirch | N/A | Austria | 9.6 | 47.23306
Graz | N/A | Austria | 15.45 | 47.06667
Vienna | N/A | Austria | 16.37208 | 48.20849
Santiago | Providencia | Chile | -70.64827 | -33.45694
Santiago | N/A | Chile | -70.64827 | -33.45694
Temuco | N/A | Chile | -72.59738 | -38.73628
Horní Město | N/A | Czechia | 17.21112 | 49.90845
Karlovy Vary | N/A | Czechia | 12.87117 | 50.23271
Prague | N/A | Czechia | 14.42076 | 50.08804
Ústí nad Labem | N/A | Czechia | 14.03227 | 50.6607
Vysoký Les | N/A | Czechia | 16.29415 | 49.76585
Zlín | N/A | Czechia | 17.67065 | 49.22645
Znojmo | N/A | Czechia | 16.0488 | 48.8555
Aschaffenburg | N/A | Germany | 9.15214 | 49.97704
Augsburg | N/A | Germany | 10.89851 | 48.37154
Bad Oeynhausen | N/A | Germany | 8.80365 | 52.20699
Berlin | N/A | Germany | 13.41053 | 52.52437
Bosenheim | N/A | Germany | 7.91382 | 49.84472
Dortmund | N/A | Germany | 7.466 | 51.51494
Dresden | N/A | Germany | 13.73832 | 51.05089
Friedrichsthal | N/A | Germany | 7.09622 | 49.32786
Giessen | N/A | Germany | 8.67554 | 50.58727
Halle | N/A | Germany | 11.97947 | 51.48158
Hamburg | N/A | Germany | 9.99302 | 53.55073
Kippenheim | N/A | Germany | 7.8251 | 48.29564
Mainz | N/A | Germany | 8.2791 | 49.98419
Rehlingen | N/A | Germany | 10.22092 | 53.10572
Riesa | N/A | Germany | 13.29168 | 51.30777
Saarbrücken | N/A | Germany | 7.00982 | 49.23262
Saarlouis | N/A | Germany | 6.75154 | 49.31366
Siegen | N/A | Germany | 8.02431 | 50.87481
Wiesbaden | N/A | Germany | 8.24932 | 50.08258
Balatonfüred | N/A | Hungary | 17.87187 | 46.96188
Békéscsaba | N/A | Hungary | 21.1 | 46.68333
Budapest | N/A | Hungary | 19.04045 | 47.49835
Debrecen | N/A | Hungary | 21.62444 | 47.53167
Eger | N/A | Hungary | 20.37329 | 47.90265
Gyula | N/A | Hungary | 21.28333 | 46.65
Kaposvár | N/A | Hungary | 17.8 | 46.36667
Szentes | N/A | Hungary | 20.2608 | 46.65834
Hyderabad | Andhra Pradesh | India | N/A | N/A
Vijayawada | Andhra Pradesh | India | 80.6466 | 16.50745
Visakhapatnam | Andhra Pradesh | India | 83.20161 | 17.68009
Vasanth Nagar | Bangalore | India | 77.59444 | 12.99182
Mylapore | Chennai | India | 80.27083 | 13.02917
Shāstri Nagar | Ghaziabad | India | 80.34791 | 25.46445
Ahmedabad | Gujarat | India | 72.58727 | 23.02579
Gandhinagar | Gujarat | India | 72.68333 | 23.21667
Karnāl | Haryana | India | 76.98448 | 29.69197
Sarwa C. | Jaipur | India | 74.58557 | 23.22418
Bangalore | Karnataka | India | 77.59369 | 12.97194
Belagavi | Karnataka | India | 74.50447 | 15.85212
Mangalore | Karnataka | India | 74.85603 | 12.91723
Kochi | Kerala | India | 76.26022 | 9.93988
Indore | Madhya Pradesh | India | 75.8333 | 22.71792
Mumbai | Maharashtra | India | 72.88261 | 19.07283
Dhantoli | Nagpur | India | 78.45874 | 21.26384
Rāmdaspeth | Nagpur | India | 79.0756 | 21.12993
Jaipur | Rajasthan | India | 75.78781 | 26.91962
Coimbatore | Tamil Nadu | India | 76.96612 | 11.00555
Aligarh | Uttar Pradesh | India | 78.07464 | 27.88145
Daugavpils | N/A | Latvia | 26.53333 | 55.88333
Kuldīga | N/A | Latvia | 21.95721 | 56.97399
Liepāja | N/A | Latvia | 21.01085 | 56.50474
Riga | N/A | Latvia | 24.10589 | 56.946
Cuernavaca | Morelos | Mexico | -99.23075 | 18.9261
Monterrey | Nuevo León | Mexico | -100.31721 | 25.68435
Metepec | Toluca | Mexico | -99.60175 | 19.25934
Mérida | Yucatán | Mexico | -89.62318 | 20.967
Aguascalientes | N/A | Mexico | -102.2843 | 21.88262
Durango | N/A | Mexico | -104.65756 | 24.02032
Puebla City | N/A | Mexico | -98.20723 | 19.04778
La Victoria | Lima region | Peru | -76.39095 | -12.98028
Magdalena del Mar | Lima region | Peru | -77.06319 | -12.09346
San Juan de Miraflores | Lima region | Peru | -76.96914 | -12.15991
San Martín de Porres | Lima region | Peru | -77.43306 | -11.10028
Monterrico | Sucro Lima | Peru | -73.59202 | -12.82484
Lima | N/A | Peru | -77.02824 | -12.04318
Villa Fontana | Carolina | Puerto Rico | -65.9735 | 18.40439
Rio Piedras | N/A | Puerto Rico | -66.04989 | 18.39745
San Juan | N/A | Puerto Rico | -66.10572 | 18.46633
Arad | N/A | Romania | 21.31667 | 46.18333
Brasov | N/A | Romania | 25.60613 | 45.64861
Bucharest | N/A | Romania | 26.10626 | 44.43225
Satu Mare | N/A | Romania | 22.86255 | 47.79926
Târgu Mureş | N/A | Romania | 24.55747 | 46.54245
Belgrade | N/A | Serbia | 20.46513 | 44.80401
Kragujevac | N/A | Serbia | 20.91667 | 44.01667
Niš | N/A | Serbia | 21.90333 | 43.32472
Subotica | N/A | Serbia | 19.66667 | 46.1
Zemun | N/A | Serbia | 20.40116 | 44.8458
Bratislava | N/A | Slovakia | 17.10674 | 48.14816
Lučenec | N/A | Slovakia | 19.66708 | 48.33249
Moldava nad Bodvou | N/A | Slovakia | 20.99957 | 48.61428
Nové Mesto nad Váhom | N/A | Slovakia | 17.8309 | 48.75763
Považská Bystrica | N/A | Slovakia | 18.42169 | 49.12153
Žilina | N/A | Slovakia | 18.73941 | 49.22315
Johannesburg | N/A | South Africa | 28.04363 | -26.20227
Port Elizabeth | N/A | South Africa | 25.61494 | -33.96109
Dnipro | N/A | Ukraine | 35.04066 | 48.46664
Kharkiv | N/A | Ukraine | 36.25475 | 49.98177
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Lviv | N/A | Ukraine | 24.02324 | 49.83826
Simferopol | N/A | Ukraine | 34.11079 | 44.95719
Edmonton | London | United Kingdom | -0.05798 | 51.62561
Sunbury-on-Thames | Middlesex | United Kingdom | -0.41817 | 51.40424
Addlestone | Surrey | United Kingdom | -0.49353 | 51.37135
Wakefield | West Yorks | United Kingdom | -1.49768 | 53.68331
Swindon | Wiltshire | United Kingdom | -1.78116 | 51.55797
Chippenham | N/A | United Kingdom | -2.12472 | 51.46
| 0
|
NCT00484198
|
[
4
] | 331
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This is a Phase III, multicenter, open-label extension, single-group study in male and female outpatients with mild-to-moderate Alzheimer's disease (AD) who have completed AVA105640. All subjects will receive rosiglitazone extended-release (RSG XR) 4mg once daily for the first 4 weeks of the study followed by 8mg RSG XR. Subject participation will last until one of 5 conditions applies. After a 52-week open-label treatment phase, subjects will attend a final Follow-Up Visit 6 weeks after the end of treatment. The primary objective of this study is to evaluate the long-term safety and tolerability of RSG XR in subjects with mild-to-moderate AD who have completed AVA105640. The secondary objective of this study is to explore further the long-term efficacy of RSG XR in terms of cognitive function and overall clinical response as a function of apolipoprotein E (APOE) e4 allele status
| null |
Alzheimer's Disease
|
open-label extension tolerability Alzheimer's disease Rosiglitazone extended-release (XR) safety cognition BRL-049653
| null | 1
|
arm 1: Rosiglitazone XR
|
[
0
] | 1
|
[
0
] |
intervention 1: experimental drug
|
intervention 1: Rosiglitazone XR
| 70
|
Palo Alto | California | United States | -122.14302 | 37.44188
Deerfield Beach | Florida | United States | -80.09977 | 26.31841
Hialeah | Florida | United States | -80.27811 | 25.8576
Melbourne | Florida | United States | -80.60811 | 28.08363
Plantation | Florida | United States | -80.23184 | 26.13421
Tampa | Florida | United States | -82.45843 | 27.94752
Centerville | Ohio | United States | -84.15938 | 39.62839
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Nashville | Tennessee | United States | -86.78444 | 36.16589
Graz-Eggenberg | N/A | Austria | N/A | N/A
Hall in Tirol | N/A | Austria | 11.51667 | 47.28333
Plovdiv | N/A | Bulgaria | 24.75 | 42.15
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Viña del Mar | Región de Valparaíso | Chile | -71.55183 | -33.02457
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
Santiago | Región Metro de Santiago | Chile | -70.64827 | -33.45694
Guangzhou | Guangdong | China | 113.25 | 23.11667
Beijing | N/A | China | 116.39723 | 39.9075
Beijing | N/A | China | 116.39723 | 39.9075
Shanghai | N/A | China | 121.45806 | 31.22222
Shanghai | N/A | China | 121.45806 | 31.22222
Shanghai | N/A | China | 121.45806 | 31.22222
Tianjin | N/A | China | 117.17667 | 39.14222
Zagreb | N/A | Croatia | 15.97798 | 45.81444
Tallinn | N/A | Estonia | 24.75353 | 59.43696
Tallinn | N/A | Estonia | 24.75353 | 59.43696
Tallinn | N/A | Estonia | 24.75353 | 59.43696
Tartu | N/A | Estonia | 26.72509 | 58.38062
Ellwangen | Baden-Wurttemberg | Germany | 10.13173 | 48.96164
Tübingen | Baden-Wurttemberg | Germany | 9.05222 | 48.52266
Günzburg | Bavaria | Germany | 10.27695 | 48.45599
Munich | Bavaria | Germany | 11.57549 | 48.13743
Nuremberg | Bavaria | Germany | 11.07752 | 49.45421
Unterhaching | Bavaria | Germany | 11.61564 | 48.06598
Bad Homburg | Hesse | Germany | 8.61816 | 50.22683
Achim | Lower Saxony | Germany | 9.0263 | 53.01416
Hanover | Lower Saxony | Germany | 9.73322 | 52.37052
Schwerin | Mecklenburg-Vorpommern | Germany | 11.41316 | 53.62937
Schwerin | Mecklenburg-Vorpommern | Germany | 11.41316 | 53.62937
Baesweiler | North Rhine-Westphalia | Germany | 6.18874 | 50.90964
Bochum | North Rhine-Westphalia | Germany | 7.21648 | 51.48165
Cologne | North Rhine-Westphalia | Germany | 6.95 | 50.93333
Duisburg | North Rhine-Westphalia | Germany | 6.76516 | 51.43247
Jülich | North Rhine-Westphalia | Germany | 6.36267 | 50.92149
Dresden | Saxony | Germany | 13.73832 | 51.05089
Dresden | Saxony | Germany | 13.73832 | 51.05089
Berlin | N/A | Germany | 13.41053 | 52.52437
Berlin | N/A | Germany | 13.41053 | 52.52437
Berlin | N/A | Germany | 13.41053 | 52.52437
Hamburg | N/A | Germany | 9.99302 | 53.55073
Hamburg | N/A | Germany | 9.99302 | 53.55073
Athens | N/A | Greece | 23.72784 | 37.98376
Thessaloniki | N/A | Greece | 22.93086 | 40.64361
Pécs | N/A | Hungary | 18.23083 | 46.0725
Szeged | N/A | Hungary | 20.14824 | 46.253
Saltillo | Coahuila | Mexico | -100.97963 | 25.42595
Monterrey | Nuevo León | Mexico | -100.31721 | 25.68435
Mexico | N/A | Mexico | -98.43784 | 18.88011
Auckland | N/A | New Zealand | 174.76349 | -36.84853
Lima | N/A | Peru | -77.02824 | -12.04318
Pasig | N/A | Philippines | 121.0614 | 14.58691
San Juan | N/A | Puerto Rico | -66.10572 | 18.46633
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
Seongnam-si | N/A | South Korea | 127.13778 | 37.43861
Seoul | N/A | South Korea | 126.9784 | 37.566
West of Scotland Science Park, Glasgow | N/A | United Kingdom | -4.25763 | 55.86515
| 0
|
NCT00550420
|
[
3
] | 61
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is the evaluate the safety and tolerability of repeat dosing of the combination of inhaled GSK233705 and GW642444 administered once-daily in subjects with COPD.
| null |
Pulmonary Disease, Chronic Obstructive
|
COPD long-acting beta agonist Emphysema Chronic Bronchitis Chronic Obstructive Pulmonary Disease (COPD) bronchodilator long acting muscarinic antagonist
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: matching placebo intervention 2: The combination of the long-acting muscarinic antagonist GSK233705 and the long acting beta agonist GW642444 in a single inhaler.
|
intervention 1: Placebo intervention 2: GSK233705/GW642444
| 12
|
Mobile | Alabama | United States | -88.04305 | 30.69436
Wheat Ridge | Colorado | United States | -105.07721 | 39.7661
Biddeford | Maine | United States | -70.45338 | 43.49258
St Louis | Missouri | United States | -90.19789 | 38.62727
Summit | New Jersey | United States | -74.36468 | 40.71562
Medford | Oregon | United States | -122.87559 | 42.32652
Erie | Pennsylvania | United States | -80.08506 | 42.12922
Greenville | South Carolina | United States | -82.39401 | 34.85262
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Johnson City | Tennessee | United States | -82.35347 | 36.31344
San Antonio | Texas | United States | -98.49363 | 29.42412
Spokane | Washington | United States | -117.42908 | 47.65966
| 0
|
NCT00749411
|
[
4
] | 750
|
NON_RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 0NONE
| true
| 0ALL
| null |
The purpose of this trial is to assess if the rate of febrile reactions following the co-administration of a booster dose of pneumococcal conjugate vaccines with standard infant vaccines is lowered when paracetamol is given prophylactically and to assess the impact of pneumococcal conjugate vaccine on pneumococcal and H. influenzae nasopharyngeal carriage compared to control group receiving meningococcal conjugate vaccine (GSK134612).
This protocol posting deals with objectives \& outcome measures of the booster phase. The objectives \& outcome measures of the primary phase are presented in a separate protocol posting (NCT number = NCT00370318).
|
The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
|
Infections, Streptococcal
|
Streptococcus Pneumoniae Vaccines Meningococcal disease Carriage Prophylactic antipyretic Safety Pneumococcal vaccine Fever Pneumococcal disease Immunogenicity Meningococcal vaccine Booster vaccination
| null | 5
|
arm 1: Subjects were vaccinated with 3 primary vaccination doses of Synflorix™ vaccine with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa along with prophylactic antipyretic treatment. arm 2: Subjects were vaccinated with 3 primary vaccination doses of Synforix™ vaccine without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment arm 3: Subjects were vaccinated with 3 primary vaccination doses of Synforix™ vaccine without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study (before the implementation of the protocol amendment) at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment. arm 4: Subjects were vaccinated with 3 primary vaccination doses of Synforix™ vaccine without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study (after the implementation of the protocol amendment) at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment. arm 5: Age-matched pneumococcal vaccine unprimed group receiving a single dose of Mencevax™ vaccine co-administered with Infanrix™ hexa vaccine.
|
[
0,
0,
0,
0,
1
] | 4
|
[
2,
2,
2,
0
] |
intervention 1: 1 intramuscular injection. intervention 2: 1 intramuscular injection. intervention 3: 1 intramuscular injection. intervention 4: Body weight of \< 7 kg: none; Body weight of ≥ 7 kg to \< 9 kg : 3 suppositories of 125 mg to be administered at 8h intervals after vaccination. Body weight of ≥ 9 kg: 4 suppositories of 125 mg to be administered at 6h intervals after vaccination.
|
intervention 1: Pneumococcal conjugate vaccine GSK1024850A. intervention 2: Infanrix hexa. intervention 3: Meningococcal vaccine GSK134612. intervention 4: Paracetamol.
| 10
|
Brno | N/A | Czechia | 16.60796 | 49.19522
Hradec Králové | N/A | Czechia | 15.83277 | 50.20923
Jindřichův Hradec | N/A | Czechia | 15.00301 | 49.14404
Náchod | N/A | Czechia | 16.16289 | 50.4167
Ostrava | N/A | Czechia | 18.28204 | 49.83465
Pardubice | N/A | Czechia | 15.77659 | 50.04075
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Znojmo | N/A | Czechia | 16.0488 | 48.8555
| 0
|
NCT00496015
|
[
5
] | 9
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to compare the pharmacokinetic parameters and safety of Advate rAHF-PFM versus Recombinate rAHF in well described previously treated patients with severe hemophilia A (factor VIII level \< 1%).
| null |
Hemophilia A
| null | 2
|
arm 1: Advate rAHF-PFM arm 2: Recombinate rAHF
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Infusion of 50 +/- 5 IU/kg bodyweight intervention 2: Infusion of 50 +/- 5 IU/kg bodyweight
|
intervention 1: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) intervention 2: Recombinant Factor VIII (rAHF)
| 1
|
Bonn | N/A | Germany | 7.09549 | 50.73438
| 0
|
NCT00666406
|
|
[
3
] | 62
|
RANDOMIZED
|
CROSSOVER
| 1PREVENTION
| 1SINGLE
| false
| 0ALL
| true
|
This study will examine whether the experimental drug R115777 (Tipifarnib) can shrink or slow the growth of plexiform neurofibromas in children and young adults with neurofibromatosis type 1 (NF1) and determine what side effects are related to treatment. Plexiform tumors arise from nerves; the only effective treatment is surgical removal. Often, however, not all the tumors can be removed, because of their number or location.
Patients with NF1 have a reduced amount of the protein neurofibromin. Neurofibromin is thought to help control the activity of another protein, called ras, which regulates cell growth. Too little neurofibromin, therefore, may allow for uncontrolled cell growth and tumor formation. R115777 interferes with the function of the ras and other proteins. In test tube and animal studies, R115777 has blocked the growth of cancer cells. This study will examine whether the drug is effective against plexiform tumors.
Patients with NF1 and progressive plexiform neurofibromas between 3 and 25 years of age may be eligible for this study. Patients whose tumors can be successfully removed surgically may not participate in this study. Candidates are screened with a medical history and physical and eye examinations, blood and urine tests, and magnetic resonance imaging (MRI). Photographs are taken of tumors visible on the body surface.
Study participants are randomly assigned to receive either R115777 or placebo (an inactive substance). They take R115777 or placebo tablets every 12 hours for 21 days, followed by a 7-day rest period. This constitutes one 28-day treatment cycle. Treatment continues for as long as the tumors remain stable or shrink and side effects are tolerable. The treatment is switched (for example, from placebo to R115777) or stopped if the tumors grow or if side effects become unacceptable. Patients (or their parents) keep a record of side effects.
For the first 3 treatment cycles, patients have a physical examination and blood tests every other week. Blood tests are also done before starting treatment, and at one time point after at least 14 days of treatment to measure the effect of R115777 on proteins in blood cells. A blood sample is obtained before starting treatment and before cycles 4, 7 and 10 and then after every 6 cycles to measure the level of a substance called nerve growth factor. The analysis of nerve growth factor is used to determine if it can predict which patients might be at risk of developing side effects from R115777.
|
R115777 (Tipifarnib) is a farnesyltransferase inhibitor that blocks the post-translational isoprenylation of ras and other farnesylated proteins. The ras proteins are integral in cell signaling pathways, and farnesylation is essential for the function of both mutant and non-mutant ras proteins. Patients with neurofibromatosis type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, and there are no standard treatment options, other than surgery, available for these tumors. Neurofibromin, which is the product of the NF1 gene, contains a domain with significant homology to ras GTPase-activating proteins (GAP). Although NF1 patients lack germline ras mutations, the decreased levels of neurofibromin have been shown to be associated with a constitutively activated ras-GTP status. Thus, upstream inhibition of ras farnesylation may inhibit growth of tumors in NF1 patients. A randomized, cross-over, double-blinded, placebo-controlled pediatric phase II trial of oral R115777 will be performed in children and young adults with NF1, who have progressive, plexiform neurofibroma(s) to determine the effect of this novel anticancer drug on the rate of growth of neurofibromas. The endpoint of the trial is time to progression. R115777 will be administered orally at a dose of 200 mg/m(2) twice daily for cycles of 21 days followed by a 7 day rest period based on the results of our prior pediatric phase I trial.
|
Neurofibroma, Plexiform Neurofibromatosis Type I
|
Surrogate Markers 3-Dimensional Magnetic Resonance Imaging (MRI) Natural History of Neurofibromatosis Type 1 (NF1) Tumor Tissue Bank Neurofibromatosis NF1 Neurofibromatosis Type 1 Plexiform Neurofibroma Neurofibroma
|
Prot_SAP_ICF_000.pdf:
CTEP Protocol No:
T-99-0090
CC Protocol No: 01-C-0222
Amendment: J
Revised:
4/21/09
IRB Approval Date:
1
A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled
Trial of the Farnesyltransferase Inhibitor R115777 in Pediatric Patients with
Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Coordinating Center:
Pediatric Oncology Branch, NCI
Principal Investigator:
Brigitte Widemann, M.D.* (POB, NCI)
NIH Associate Investigators:
Frank M. Balis, M.D. (POB, NCI)
Beth Fox, M.D. (POB, NCI)
Kathy Warren, M.D. (NOB, NCI)
Andy Gillespie, R.N. (ND, CC)
Eva Dombi, MD (POB, NCI)**
Nalini Jayaprakash, (POB, NCI)
Diane Cole, (POB, NCI)
Seth Steinberg, Ph.D. (BDMB, DCS, NCI)
Nicholas Patronas, M.D. (DR, CC)**
Maria Tsokos, M.D., (Laboratory of Pathology, NCI)**
Pamela Wolters, Ph.D. (HAMB, NCI)
Staci Martin, Ph.D. (HAMB, NCI)
Jeffrey Solomon, (NIH and Sensor Systems, Inc.)
Non-NIH Associate Investigators:
Wanda Salzer, M.D. **
Keesler Air Force Base, Biloxi, Mississippi)
81st MDOS/SGOC 301 Fisher Street, Room 1A132 Keesler
AFB, MS 39534-2519
Phone: 228-377-6524
E-mail: wanda.salzer@keesler.af.mi
Bruce R. Korf, M.D., Ph.D. **
Chair, Department of Genetics
Univeristy of Alabama at Birmingham
1530 3rd Ave. S.
Birmingham, AL 35294
Phone: (205)-934-9411, Fax: (205)-934-9488
E-mail: bkorf@uab.edu
David H. Gutmann, M.D., Ph.D. **
Department of Neurology
Washington University School of Medicine
St. Louis Children’s Hospital
Box 8111, 660 S. Euclid Avenue
St. Louis, MO 63110
Phone: (314)-632-7149, Fax: (314)-362-9462
E-mail: gutmannd@neuro.wustl.edu
4/21/2009
T-99-0090, 01-C-0222
2
Arie Perry, M.D. **
Division of Neuropathology
Washington University School of Medicine
Campus Box 8111, 660 S. Euclid Avenue
St. Louis, MO 63110
Phone: (314) 362-9130, Fax: (314) 362-4096
E-mail: aperry@pathology.wustl.edu
M. Watson, M.D., Ph.D. **
Division of Laboratory Medicine/Box 8118
Alvin J. Siteman Cancer Center/Box 8100
Washington University School of Medicine
660 S. Euclid Avenue, St. Louis, MO 63110
Phone: (314)-454-7919, Fax: (314)-454-5525
E-mail: watsonm@labmed.wustl.edu
Margaret Wallace, Ph.D.
Associate Professor, Pediatric Genetics
University of Florida
Box 100296, 1600 SW Archer Road
Gainesville, FL 32610-0296
Phone: (352) 392-3055; Fax: (352) 392-3051
E-mail: peggyw@cmg.health.ufl.edu
David Muir, Ph.D.
Associate Professor
Pediatric Neurology & Neuroscience
Box 100296, JHMHC
University of Florida, College of Medicine
Gainsville, FL 32610
Phone: (352)-392-0312; Fax: (352) 392-9520
E-mail: muir@ufbi.ufl.edu
Participating Institution:
Johns Hopkins Oncology Center (M1011)
Responsible Investigator:
IRB contact:
Pharmacy contact:
Robert J. Arceci, M.D., Ph.D.
Bunting-Blaustein Cancer Research Building
1650 Orleans Street, 2M51
Baltimore, MD 21231
Phone: 410-502-7518, Fax: 410-955-8897
E-mail: arcecro@jhmi.edu
Monica Carlton
550 N. Broadway, Room 1121
Baltimore, MD 21287
Phone 410-955-0350, Fax: 410-614-1328
Pauline Newman
600 N. Wolfe Street
Baltimore, MD 21205
CMSC 209 Pediatric Pharmacy
Phone: 410-955-5926, Fax: 410-955-0283
E-mail: pnewman@JHH.Pharmacy
4/21/2009
T-99-0090, 01-C-0222
3
Participating Institution:
Children’s Hospital of Philadelphia, PA (M1257)
Responsible Investigator:
IRB contact:
Pharmacy contact:
Jean Belasco, M.D.
34th and Civic Center Blvd, Philadelphia, PA 19104
Phone: (215) 590-2848, Fax: (215) 590-4183
E-mail: belasco@email.chop.edu
Carol Sazama
The Children’s Hospital of Philadelphia
1st floor Abramson Building
3517 Civic Center Boulevard
Philadelphia, PA 19104-4399
Phone: 215-590-2830
E-mail: sazama@email.chop.edu
Betsy Bickert, Pharm D.
4th floor pharmacy, 4th floor main building
34th & Civic Center Boulevard
Philadelphia, PA 19104
Phone: 215-590-3833
E-mail: bickert@email.chop.edu
Participating Institution:
Responsible Investigator:
IRB contact:
Pharmacy contact:
SUNY Upstate Medical University, NY (M1303)
Ronald Dubowy, M.D.
Department of Pediatrics – 5C
750 E Adams Street, Syracuse, NY 13210
Phone: (315) 464-5294; Fax: (315) 464-7238
E-mail: dubowyr@upstate.edu
Karen Bilynsky, RN, CCRA
SUNY Upstate Medical University, NY
Department of Pediatrics 5C 750 E Adams Street,
Syracuse, NY 13210
Phone: 315-464-7601, Fax: 315-464-7515
E-mail: bilynskk@upstate.edu
Andrea Allen
SUNY Upstate Medical University, NY
Department of Pharmacy 5C 750 E Adams Street,
Syracuse, NY 13210
Phone: 315-464-4210, Fax: 315-464-4314
E-mail: allena@upstate.edu
Participating Institution:
Responsible Investigator:
IRB contact:
Texas Children's Hospital, Houston, TX (M1060)
Susan, M. Blaney, M.D.
Division of Hematology/Oncology, 6621 Fannin Street,
Texas Children's Hospital, CC 1410.00,
Houston, TX 77030
Phone: 832-822-1482; Fax: 832-825-4299
E-mail: sblaney@bcm.tmc.edu
Stacey Berg M.D., Kay Motil, M.D.
Baylor College of Medicine
One Baylor Plaza S108
4/21/2009
T-99-0090, 01-C-0222
4
Pharmacy contact:
Houston, TX 77030
Phone: 713-798-6970
E-mail: sberg@txccc.org, kmotil@bcm.tmc.edu
Renee A. Robinson RPh
Texas Children’s Hospital
Pharmacy department MC 2-2510
6621 Fannin Street
Houston, TX 77030
Phone: 713-770-3899
E-mail rarobins@txccc.org
Participating Institution:
Responsible Investigators:
IRB contact:
Pharmacy contact:
The Children’s Hospital, Dana-Farber Cancer Institute,
Boston, MA (M1034)
Mark W. Kieran, MD, PhD
Director, Pediatric Medical Neuro-Oncology
Dana-Farber Cancer Institute
44 Binney Street, Boston, MA, 02115
Phone: (617) 632-4907; Fax: (617) 632-4248
E-mail: mark_kieran@dfci.harvard.edu
Jessica Jacobs, Protocol Administrator
Protocol Administration Office
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
Phone: 617-632-5737, Fax: 617-632-2686
E-mail: Jessica_Jacobs@dfci.harvard.edu
Peter Blanding
Clinical Pharmacist-Pediatric Clinic
Department of Pharmacy L-2
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
Phone 617-632-3785, Fax: 617-632-4410
E-mail: peter_blanding@dfci.harvard.edu
Participating Institution:
Responsible Investigator:
IRB contact:
St. Louis Children’s Hospital, St. Louis, MO (M1123)
Allison King, M.D.
Washington University School of Medicine
St. Louis Children’s Hospital
660 S. Euclid Avenue
Campus Box 8116
St. Louis, MO 63110
Phone: (314)-286-1170, Fax: (314)-454-2780
E-mail: king_a@kids.wustl.edu
Kirsten Cady
Washington University School of Medicine
660 S. Euclid Avenue
4/21/2009
T-99-0090, 01-C-0222
5
Pharmacy contact:
Campus Box 8056
St. Louis, MO 63110
Phone: 314-362-7773, Fax: 314-747-0232
E-mail: kcady@im.wustl.edu
Melissa Heigham, RPh
Investigational Pharmacist
St. Louis Children’s Hospital
One Children’s Place 8W25
St. Louis, MO 63110
Phone: 314-454-2361, fax: 314-454-2441
E-mail: mheigham@bjc
Participating Institution:
Responsible Investigator:
IRB contact:
Pharmacy contact:
Children’s Hospital Los Angeles, CA (M1118)
Jonathan L. Finley, M.D., Ch.B.
Childrens Hospital Los Angeles
4650 Sunset Blvd, Mail Stop 54
Los Angeles, CA 90027
Phone 323-906-8147,
Fax: (323)-660-7128
E-mail: jfinlay@chla.usc.edu
Rhonda Crutcher
4650 Sunset Blvd, Mailstop 54
Los Angeles, CA 90027
Phone: 323-660-2450 ext. 5701, Fax: 323-671-1585
E-mail: rcrutcher@chla.usc.edu
John Pech, MS
4650 Sunset Blvd, Mailstop 44
Los Angeles, CA 90027
Phone: 323-660-2450 ext. 5989, Fax: 323-664-0326
E-mail: jpech@chla.usc.edu
Participating Institution:
Responsible Investigator:
IRB Contact:
Pharmacy Contact:
Cincinnati Children’s Hospital (FWA 00002988)
John Perentesis, M.D.
Division, Hematology/Oncology ML 7015
Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave.
Cincinnati, Ohio 45229
Phone: 513-636-8241, Fax: 513-636-3459
E-mail: john.perentesis@cchmc.org
Irwin Light, M.D.
Cincinnati Children’s Hospital Medical Center
229 Erkenbrecher Ave. ML 5020
Cincinnati, Ohio 45229
Phone: 513-636-8039, Fax: 513-636-3959
E-mail: Irwin.light@cchmc.org
Denise Lagory, RPh
Investigational Pharmacy
Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave ML 1011
4/21/2009
T-99-0090, 01-C-0222
6
Cincinnati, Ohio 45229
Phone: 513-636-3016, Fax: 513-636-2740
E-mail: denise.lagory@cchmc.org
Participating Institution:
Responsible Investigator:
IRB contact:
Pharmacy contact:
Children’s Memorial Hospital, Chicago, IL (M1484)
Stewart Goldman, M.D.
Children’s Memorial Hospital
2300 Children’s Plaza, Box # 30
Chicago, IL 60614
Phone: (773)-880-3270, Fax: (773)-880-3053
E-mail: sgoldman@nwu.edu
Gary Dennison, IRB Manager
Joel Frader, M.D., IRB Chair
Children’s Memorial Institute for Education and
Research, Office of Research Administration
Institutional Review Board
2300 Children’s Plaza, Box # 205
Chicago, IL 60614
Phone: 773-880-8116
Susan Berg, R.Ph. (Hem/Onc Pharmacy)
Marianne Chan, PharmD., Director Pharmacy Services
Children’s Memorial Hospital
2300 Children’s Plaza, Box 74
Chicago, IL 60614
Phone: 773-880-4471
Participating Institution:
Responsible Investigator:
IRB Contact:
Pharmacy Contact:
Hospital for Sick Children in Toronto (T3859)
Douglas J. Hyder, M.D.
Hospital for the Sick Children
555 University Ave.
Toronto, ON M5G 1X8
Phone: 416-813-7758
Fax: 416-813-8024
E-mail: douglas.hyder@sickkids.ca
Melvin Freedman, M.D.
Chair, Research Ethics Board
Hospital for Sick Children
555 University Ave.
Toronto, ON M5G 1X8
Phone: 416-813-6152
Fax: 416-813-5327
E-mail: melvin.freedman@sickkids.ca
Darcy Nicksy
Research Support Pharmacist
555 University Ave.
Toronto, ON M5G 1X8
Phone: 416-813-7605
4/21/2009
T-99-0090, 01-C-0222
7
Fax: 416-813-7886
E-mail: darcy.nicksy@sickkids.ca
Participating Institution:
Responsible Investigator:
IRB Contact:
Pharmacy Contact:
University of Alabama at Birmingham (M1149)
Alyssa Reddy, MD
1600 7th Ave. South
ACC 512
Birmingham, AL 35233
Phone: (205) 939-9285, Fax: (205) 975-6377
E-mail: areddy@peds.uab.edu
Sheila Moore
Director, UAB Institutional Review Board
Administration Building, Room 470
701 20th Street, South
Birmingham, AL 35294
Phone: (205) 934-3789
E-mail: smoore@provost.uab.edu
Kathleen (Keen) Blair
Investigational Study Pharmacist
1600 7th Ave., South
Birmingham, AL 35233
Phone: (205) 939-5918, Fax: (205) 939-9934
E-mail: keen.blair@chsys.org
Participating Institution:
Responsible Investigator:
IRB Contact:
Pharmacy Contact:
Klinikum Nord, Hamburg, Germany (FWA 00003228)
Victor-F. Mautner M.D.
Klinikum Nord
Langenhorner Chaussee 560
D-22419 Hamburg, Germany
Phone: 040-5271-2872, Fax: 040-5271-462
E-mail: VRGes@aol.com
Helga Hinzmann
Ethik-Kommission der Ärztekammer Hamburg
Heinrich-Hertz-Str. 125
D-22083 Hamburg, Germany
Phone: 040-22802-517, Fax: 040-22802-597
E-mail: Helga.heinzmann@aerztekammer-hamburg.de
Gerhard Mützelburg
Apotheke Niedersachsenhaus
Heimfelder Str. 43
D-21075 Hamburg, Germany
Phone: 040-7905325, Fax: 040-7906678
Trial Sponsor:
Cancer Therapy Evaluation Program (CTEP), NCI
Study Drug:
R115777 (IND. #58359)
Supplied by:
CTEP
* Pharmacology & Experimental Therapeutics Section
4/21/2009
T-99-0090, 01-C-0222
8
Pediatric Oncology Branch, NCI
10 Center Drive, MSC 1920
Building 10, Room 13C103
Bethesda, MD 20892-1920
Phone: (301) 496-7387/Fax: (301) 480-8871
E-mail: Bw42y@nih.gov
**Not responsible for direct patient care related to this trial
PROPRIETARY and CONFIDENTIAL
This protocol contains confidential information that should only be disclosed to those persons responsible for execution and
organization of the trial and on condition that all such persons agree not to further disseminate it.
4/21/2009
T-99-0090, 01-C-0222
9
PRECIS
R115777 is a farnesyltransferase inhibitor that blocks the post-translational
isoprenylation of ras and other farnesylated proteins. The ras proteins are integral in cell
signaling pathways, and farnesylation is essential for the function of both mutant and
non-mutant ras proteins. Patients with neurofibromatosis type 1 (NF1) have an
increased risk of developing tumors of the central and peripheral nervous system, and
there are no standard treatment options, other than surgery, available for these tumors.
Neurofibromin, which is the product of the NF1 gene, contains a domain with
significant homology to ras GTPase-activating proteins (GAP). Although NF1 patients
lack germline ras mutations, the decreased levels of neurofibromin have been shown to
be associated with a constituitively activated ras-GTP status. Thus, upstream inhibition
of ras farnesylation may inhibit growth of tumors in NF1 patients. A randomized,
cross-over, double-blinded, placebo-controlled pediatric phase II trial of oral R115777
will be performed in children and young adults with NF1, who have progressive,
plexiform neurofibroma(s) to determine the effect of this novel anticancer drug on the
rate of growth of neurofibromas. The endpoint of the trial is time to progression.
R115777 will be administered orally at a dose of 200 mg/m2 twice daily for cycles of 21
days followed by a 7 day rest period based on the results of our prior pediatric phase I
trial.
4/21/2009
T-99-0090, 01-C-0222
10
TABLE OF CONTENTS
PRECIS ........................................................................................................................................................................9
1.0
INTRODUCTION ...........................................................................................................................................12
1.1
OBJECTIVES ...................................................................................................................................................12
1.2
BACKGROUND AND RATIONALE ....................................................................................................................13
1.2.1
Introduction...........................................................................................................................................13
1.2.2
Inhibition of Post-Translational Farnesylation.....................................................................................13
1.2.3
Preclinical Antitumor Activity of R115777 ...........................................................................................14
1.2.4
Toxicology of R115777..........................................................................................................................15
1.2.5
Phase I Clinical Trials of R115777 in Adults........................................................................................16
1.2.6
Phase I Clinical Trials of R115777 in Children....................................................................................17
1.2.7
Clinical Pharmacokinetics of R115777 in adults and children.............................................................19
1.2.8
Proposed Pediatric Phase II Trial of R115777.....................................................................................20
2.0
ENROLLMENT PROCEDURES ..................................................................................................................24
2.1
ELIGIBILITY CRITERIA ...................................................................................................................................24
2.1.1
Inclusion Criteria ..................................................................................................................................24
2.1.2
Exclusion Criteria .................................................................................................................................27
2.2
PRE-TREATMENT EVALUATION (SEE APPENDIX 7)........................................................................................27
3.0
IMPLEMENTATION OF STUDY ................................................................................................................29
3.1
STUDY DESIGN ..............................................................................................................................................29
3.1.1
Randomized Design...............................................................................................................................29
3.1.2
Patient Registration and Randomization...............................................................................................29
3.1.3
Dosing Schedule and Prescribing .........................................................................................................30
3.1.4
Monitoring Time to Progression and Response ....................................................................................31
3.1.5
Definition of Tumor Progression...........................................................................................................31
3.1.6
Tissue Procurement...............................................................................................................................31
3.1.7
Establishment of tumor cell lines and tissue bank.................................................................................32
3.1.8
FPTase Activity in PBMC .....................................................................................................................32
3.1.9
Nerve Growth Factor (NGF).................................................................................................................32
3.1.10
Monitoring Toxicity............................................................................................................................32
3.2
DRUG ADMINISTRATION................................................................................................................................32
3.3
MODIFICATIONS FOR TOXICITY .....................................................................................................................33
3.4
ON STUDY EVALUATION (SEE APPENDIX 7) ..................................................................................................34
3.5
CONCURRENT THERAPY.................................................................................................................................36
3.6
OFF STUDY CRITERIA ....................................................................................................................................36
3.7
POST-STUDY EVALUATION............................................................................................................................37
4.0
SUPPORTIVE CARE .....................................................................................................................................37
5.0
DATA COLLECTION AND EVALUATION...............................................................................................38
5.1
DATA COLLECTION........................................................................................................................................38
5.1.1
Case Report Forms................................................................................................................................38
5.2
RESPONSE CRITERIA......................................................................................................................................39
5.3
TOXICITY CRITERIA.......................................................................................................................................40
5.4
STATISTICAL CONSIDERATIONS .....................................................................................................................40
5.4.1
Subject Accrual .....................................................................................................................................40
5.4.2
Statistics and Feasibility .......................................................................................................................40
5.5
MULTI-INSTITUTIONAL GUIDELINES..............................................................................................................42
5.5.1
IRB Approvals .......................................................................................................................................42
5.5.2
Amendments and Consents....................................................................................................................42
5.5.3
Patient Registration...............................................................................................................................42
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5.5.4
Data Collection and Toxicity Reporting................................................................................................42
5.5.5
Data and Center Audits.........................................................................................................................43
6.0
HUMAN SUBJECTS PROTECTIONS.........................................................................................................43
6.1
RATIONALE FOR SUBJECT SELECTION............................................................................................................43
6.2
PARTICIPATION OF CHILDREN........................................................................................................................43
6.3
EVALUATION OF BENEFITS AND RISKS/DICOMFORTS......................................................................................43
6.4
RISK/BENEFIT ANALYSIS.................................................................................................................................44
6.5
CONSENT AND ASSENT PROCESS AND DOCUMENTATION ................................................................................44
6.6
HANDLING OF RESEARCH SAMPLES...............................................................................................................45
7.0
DATA REPORTING.......................................................................................................................................45
7.1
PATIENT REGISTRATION AND RANDOMIZATION ............................................................................................46
7.2
CASE REPORT FORMS ....................................................................................................................................46
7.3
SAFETY REPORTING.......................................................................................................................................46
7.3.1
Adverse Events ......................................................................................................................................46
7.3.2
Adverse Event Reporting.......................................................................................................................47
7.4
ASSURANCES .................................................................................................................................................50
7.5
IRB APPROVALS............................................................................................................................................50
7.6
PATIENT DATA REPORTING AND AUDITS.......................................................................................................50
8.0
PHARMACEUTICAL INFORMATION......................................................................................................50
8.1
R115777 AND PLACEBO ................................................................................................................................50
8.2
DRUG ORDERS, TRANSFERS, RETURNS, ACCOUNTABILITY / EMERGENCY UNBLINDING ................................59
9.0
CLINICAL TRIALS AGREEMENT (CTA).................................................................................................60
10.0
REFERENCES...............................................................................................................................................62
11.0
APPENDICES................................................................................................................................................64
APPENDIX 1: PROTOCOL FOR REQUIRED PRE STUDY AND ON STUDY MRI STUDIES .............................................64
APPENDIX 2: PATHOLOGY ANALYSIS OF PLEXIFORM NEUROFIBROMAS ...................................................................72
APPENDIX 3: INSTRUCTIONS FOR TISSUE ACQUISITION OF DISCRETE AND PLEXIFORM NEUROFIBROMAS.................77
APPENDIX 4: INSTRUCTIONS FOR SHIPMENT OF TUMOR BIOPSIES.............................................................................79
APPENDIX 5: PROCEDURE PBMC SEPARATION FOR FARNESYLTRANSFERASE ACTIVITY........................................81
APPENDIX 6: DETERMINATION OF NERVE GROWTH FACTOR..................................................................................83
APPENDIX 7: REQUIRED STUDY EVALUATIONS.......................................................................................................85
APPENDIX 8 A: ELIGIBILITY CHECKLIST FOR PROTOCOL........................................................................................87
APPENDIX 8 B: BLINDED PATIENT ON-STUDY FORM ..............................................................................................89
APPENDIX 9A: PROGRESSION CHECKLIST FOR PROTOCOL......................................................................................91
APPENDIX 9 B: BLINDED PATIENT CROSSOVER / OFF-STUDY FORM.......................................................................92
APPENDIX 10: ROADMAP FOR PATIENT REGISTRATION AND CROSSOVER ..............................................................94
APPENDIX 11A: PATIENT DIARY FOR R115777/PLACEBO.......................................................................................96
APPENDIX 11 B: PILL COUNT CASE REPORT FORM .................................................................................................98
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1.0
INTRODUCTION
1.1
OBJECTIVES
PRIMARY STUDY OBJECTIVES:
1.1.1 To assess the effect of R115777, administered on a chronic oral schedule
(21 days on followed by 7 days rest), on the time to disease progression in
children and young adults with neurofibromatosis type 1 (NF1) and
progressive plexiform neurofibromas.
1.1.2 To define the objective response rate of progressive plexiform
neurofibromas to R115777.
1.1.3 To describe and define the toxicities of R115777, administered on a chronic
oral schedule (21 days on followed by 7 days rest), in pediatric patients
and young adults.
SECONDARY STUDY OBJECTIVES:
1.1.4 To measure the level of farnesylprotein transferase (FPTase) activity in
tumor specimens and peripheral blood mononuclear cells obtained from
patients treated on this trial, and to assess the value of FPTase activity as a
surrogate marker for the antiproliferative effect of R115777.
1.1.5 To assess the value of three-dimensional MRI (3D-MRI) and uni-
dimensional MRI (1D-MRI) data analysis in the evaluation of plexiform
neurofibromas, and to compare both to conventional two-dimensional
MRI (2D-MRI) data analysis.
1.1.6 To analyze tumor specimens from patients with NF1 treated with R115777
for the level of expression of N-ras, K-ras, and H-ras, and to correlate the
level of expression and the ras mutation status with the efficacy of
R115777.
1.1.7 To analyze tumor specimens from patients treated on this trial, for NF1
gene mutations in the GAP related domain, and to correlate these findings
with the antiproliferative effect of R115777.
1.1.8 To establish tumor cell lines from tumor specimens (plexiform
neurofibromas and discrete neurofibromas) obtained from patients treated
on this trial.
1.1.9 To contribute tumor specimens obtained on this trial to an already
existing tissue bank. Tumor samples from plexiform neurofibromas will
undergo a central pathology review including a detailed morphologic,
ultrastructural and immunohistochemical analysis. Tumor cell lines and
tumor samples will be made available to the scientific community, after
obtaining IRB approval in order to collect more information on the
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pathology, genetics, and cell biology of plexiform and discrete
neurofibromas.
1.1.10 To determine circulating levels of nerve growth factor from blood samples
at various time points during treatment with R115777/placebo, and to
correlate levels of NGF with the development of clinical neurotoxicity
from R115777.
1.1.11 To assess the quality of life of patients treated with R115777 or placebo
using the newly developed National Institutes of Health (NIH) Impact of
Pediatric Illness (IPI) Scale, which assesses the impact of disease and
treatment on children’s behavior, and to evaluate the ability of this new
assessment tool to measure changes in a child’s quality of life.
1.2
BACKGROUND AND RATIONALE
1.2.1 INTRODUCTION
Neurofibromatosis 1 (NF1) is a common autosomal dominant, progressive genetic
disorder with an incidence of 1:3000 (>80,000 persons affected in The United States).
NF1 is characterized by diverse, progressive cutaneous, neurological, skeletal and
neoplastic manifestations with no standard drug treatment options available. Patients
with NF1 have an increased risk of developing tumors of the central and peripheral
nervous system including plexiform neurofibromas (27%)[10] optic gliomas gliomas
(15-20%), pheochromocytomas (1%),[1] malignant peripheral nerve sheath tumors (5%),
and neurofibrosarcomas (6%).[5, 17] Plexiform neurofibromas are nerve sheath tumors
that grow along the length of nerves and involve multiple branches of a nerve. They
are a major source of morbidity, causing disfigurement, impairment of nerve function,
and in some cases development of malignant peripheral nerve sheath tumors.
Neurofibromin, the NF1 gene product, contains a domain with significant
homology to ras GTPase-activating proteins (GAP).[1, 8, 14] The ras proteins are
integral in cell signaling pathways, and activation of ras leads to cell proliferation.
GAPs catalyze the hydrolysis of ras-GTP (the active form of ras) to ras-GDP and lead to
ras inactivation. Patients with NF1 have decreased levels of neurofibromin, which is
associated with an activated ras-GTP status. Agents directed at inhibiting ras, therefore,
are a rational choice for trials of potential therapeutic agents in patients with NF1 and
progressive plexiform neurofibromas.
1.2.2 INHIBITION OF POST-TRANSLATIONAL FARNESYLATION
Farnesylation is a post-translational modification in which a farnesyl isoprene
group is added to a number of cellular proteins by the enzyme, farnesyl-protein
transferase (FPTase). The ras family of G proteins is one of the classes of proteins that
are modified by FPTase. H-, K-, and N-ras are 21 kDa guanine nucleotide-binding
proteins that control a multitude of cell signaling events.[2, 22] Mutant ras genes have
the ability to transform cells into a malignant phenotype, and ras mutations have been
observed in approximately 30% of all human cancers.[21] Patients with NF1 do not
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14
have germline ras mutations. However, tumor cell lines established from malignant
schwannomas of NF1 patients have been shown to have a constituitively activated ras-
GTP status. Neurofibromin, which is the product of the NF1 gene, contains a domain
that shows significant homology to ras GTPase-activating proteins (GAP).[8] In these
cell lines, there are normal levels of GAP, but decreased levels of neurofibromin,
supporting the role of the NF1 gene as a tumor suppressor gene. Advances in the
understanding of ras oncoprotein function suggest novel points for anti-tumor
intervention. Ras is synthesized as a cytosolic precursor that ultimately localizes to the
cytoplasmic face of the plasma membrane after a series of post-translational
modifications. The first obligatory step in this series of post-translational modifications
is the addition of a farnesyl moiety. This modification is essential for ras function.[13]
FPTase appears to be an appropriate biochemical target for the development of
inhibitors of post-translational processing of ras resulting in prevention of ras-mediated
cellular transformation[4, 7, 16, 19].
1.2.3 PRECLINICAL ANTITUMOR ACTIVITY OF R115777
R115777 is a potent and selective non-peptidomimetic inhibitor of FPTase both in
vitro and in vivo. In several preclinical studies, R115777 was shown to inhibit the
growth of H-ras, K-ras and N-ras transformed tumors.[6]
In intact tumor cells in culture, R115777 produced antiproliferative effects at
nanomolar concentrations. The proliferation of NIH 3T3 stably transfected with the
activated T24 H-ras oncogene (T24 cells) was inhibited by R115777 with an IC50 of 1.7
nM. Inhibition of p21 ras farnesylation was observed in T24 cells in the same
concentration range which inhibited cell proliferation. In LoVo cells and HCT116 cells,
two human colon cancer cell lines transformed by an activated K-rasB oncogene,
R115777 inhibited cell proliferation with IC50's of 16 and 22 nM, respectively. In intact
CAPAN-2 human pancreatic cancer cells, which bear a K-rasB mutation, R115777
inhibited cell proliferation with an IC50 of 16 nM.
Although FPTase inhibitors were developed to treat tumors with ras mutations, it
has been shown in established cell lines that FPTase inhibitors also inhibit tumors
without ras mutations, including breast, colon, prostate, epidermoid, Ewing’s sarcoma
and rhabdomyosarcoma. Peptidomimetic FPTase inhibitors inhibit the growth of the
Ewing’s sarcoma cell line RD-ES, which does not contain a ras mutation.[24]
Patients with neurofibromatosis type 1 (NF1) do not have germline ras mutations.
However, tumor cell lines established from malignant schwannomas of NF1 patients
have been shown to have a constituitively activated ras GTP status. The growth of the
malignant schwannoma cell line, ST88-14, derived from a patient with NF1 was
inhibited by a bisubstrate analog FPTase inhibitor in a concentration-dependent
manner.[27]
In nude mice bearing subcutaneous T24 cell tumors, R115777 administered orally
(BID) at doses of 6.25, 12.5 and 25 mg/kg inhibited the growth of tumors by 56%, 84%
and 86%, respectively after 15 days of treatment. In nude mice bearing the K-rasB
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15
transformed LoVo human colon tumors, R115777 administered orally (BID) at doses of
25, 50 and 100 mg/kg inhibited tumor growth by 11%, 68% and 81%, respectively after
32 days of treatment. In nude mice bearing subcutaneous CAPAN-2 tumors, R115777
administered orally (BID) significantly inhibited tumor growth at doses of 50 and 100
mg/kg. A 56% reduction of final tumor weight was observed at the 50 mg/kg dose
level and a 76% reduction of final tumor volume was observed at the 100 mg/kg dose
level.
1.2.4 TOXICOLOGY OF R115777
The toxicity profile of R115777 has been well characterized in animals. In a one-
month repeat-dose pilot toxicity study in rats, five males and five females per dosage
group were dosed orally by gavage with R115777 at doses 0, 5, 20 and 80 mg/kg/day.
Rats dosed at 5 mg/kg showed no adverse effects. At 20 mg/kg, a minimal decrease in
body weight gain and slight atrophic and degenerative histological changes in the nasal
epithelium were the only effects observed. Dosing at 80 mg/kg resulted in sedation,
ptosis, salivation and in a decrease in body weight. Hematological examination
revealed slight decreases in the number of white blood cells (decrease in lymphocytes
and eosinophils).
A one-month pilot study was conducted in Beagle dogs. Doses of 0, 2.5, 10 and 40
mg/kg were given orally to two males and two females per dosage group. Dosing at
2.5 mg/kg resulted in a slightly decreased weight of the testes, histologically confirmed
by slight atrophy. At 10 mg/kg, changes consisted of a decrease in platelets in one dog
and a decreased weight of the testes. Dosing at 40 mg/kg resulted in the death of all
four dogs within 15 days. Vomiting, diarrhea and decreased food consumption and
body weight were noted. Hematological changes were characterized by marked
leucopenia, thrombocytopenia, an increase in activated partial thromboplastin time, and
a slight decrease in hematocrit and hemoglobin. Biochemistry revealed decreases in
sodium, potassium, chloride, inorganic phosphate and gamma glutamyltransferase
while increases in total protein, cholesterol, phospholipids, blood urea nitrogen, total
bilirubin and alkaline phosphatase were observed. Histological examination in most
dogs given 10 mg/kg and in all dogs given 40 mg/kg revealed atrophy of the
hematopoietic tissue with signs of mitotic arrest (e.g., bone marrow, thymus, lymph
nodes, mucosa-associated lymphoid tissue and spleen). As a consequence of the severe
thrombocytopenia, systemic hemorrhage was seen in the intestine, mesentery,
hematopoietic system, lung, brain, adrenals, skeletal muscle, vagina and subcutaneous
tissue. In a toxicity study with recovery in Beagle dogs, oral doses of 10 mg/kg and 40
mg/kg were administered daily until hematological changes occurred. Two dogs per
group were tested. Leukopenia and thrombocytopenia were noted after four and seven
days in both dogs, after which dosing was stopped. Within 14 days after dosing was
stopped, complete hematological recovery was observed. Histological examination of
the testes indicated moderate atrophy. Slight lymphoid depletion in the mesenteric
lymph node and the gut associated lymphoid tissue were also seen in the male.
Examination of three bone marrow biopsies, taken at different times during the study,
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revealed distinct regeneration of the hematopoietic tissue. The degree of atrophy
ranged from severe atrophy with marked loss of early precursors at the end of dosing to
slight atrophy and increase in blast cells at the end of recovery.
Dose dependent lens opacities have been observed after 1 month of dosing of 60
mg/kg in male Wistar rats (2 out of 30 rats), in 10 mg/kg dosed females (1 out of 20
rats), in 40 mg/kg dosed females (13 out of 19 rats) and in 60 mg/kg dosed females (26
out of 28 rats). Changes consisted of localized or diffuse (sub)capsular opacification at
the posterior pole of the lens. The degree of opacification and the area involved was
never so extended as to make visualization of the fundus difficult. This effect was not
observed in dogs receiving chronic administration of R115777
1.2.5
PHASE I CLINICAL TRIALS OF R115777 IN ADULTS
Solid tumor trials: In the first adult phase I trial (R115777-USA-1), oral R115777
was administered initially as a solution, then as capsules every 12 hours for 5 days, and
repeated every 2 weeks.[28] Doses were escalated from 25 mg q12h to 1300 mg q12h.
An MTD was not reached in this trial. One of six patients on the 1300 mg dose level
developed dose-limiting grade 3 peripheral neuropathy, described as severe burning in
the lower extremities, oral cavity and vaginal area. The pain resolved within 24 hours of
stopping R115777. This patient had a history of prior mild peripheral neuropathy
attributed to paclitaxel therapy. Non-dose-limiting toxicities (non-DLT) observed at the
800 and 1300 mg dose levels were fatigue and an increase in serum creatinine. Nausea
and vomiting were observed more frequently with the oral solution than with the
capsules, but were observed with the capsule formulation at the 800 and 1300 mg dose
levels. Myelosuppression was mild.
A phase I trial of oral R115777 on a q12h for 21 day schedule followed by a 7 day
rest period was performed at the Fox Chase Cancer Center (R115777-USA-3). At doses
>300 mg q12h, dose-limiting myelosuppression was observed. In addition, some
patients experienced fatigue and weakness.
Two additional adult phase I trials were performed in Europe (R115777-BEL-7,
R115777-BEL-2) to evaluate the safety, pharmacokinetics and define and MTD of
R115777, when administered for 4 weeks and continuously for 3 months or more,
respectively. Reversible grade III diarrhea was reported in a single patient from the
Netherlands treated at a dose 300 mg bid. Grade II hypokalemia and grade II renal
insufficiency was observed in one patient. After stopping study medication
hypokalemia and renal insufficiency decreased to grade I.
On the continuous dosing phase I trial R1157777 was administered at doses from
50 mg to 500 mg BID.[23] Dose limiting toxicities (DLT) toxicities were grade 4
neutropenia (1 pt each at 400 and 500 mg), grade 3 thrombocytopenia (1 patient at 500
mg), and sensory and motor peripheral neuropathy grade 3 (at 500 mg). The
neuropathy was not completely reversible in all patients. One patient developed grade
3 skin hypersensitivity at 150 mg BID. The MTD was 300 mg BID. One partial remission
was seen in a patient with non-small cell lung cancer.
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A phase II study of R115777 in patients with advanced breast cancer was recently
completed.[12] R115777 was administered continuously at a dose of 400 mg BID to six
patients, and because of dose-limiting neutropenia on this schedule, at a reduced dose
of 300 mg BID to the subsequent 21 patients. Sixteen patients had received prior
chemotherapy. Toxicities in the 21 patients included grade 3 to 4 neutropenia (29%),
grade 3 thrombocytopenia (11%), grade 2 to 3 paresthesias/numbness (26%) after a
median of 10 weeks on therapy, grade 2 to 3 diarrhea (11%), skin rash (11%), and
fatigue (28%). Confirmed partial responses (PR) were seen in 3 patients (12%). The
abstract did not describe the time frame for recovery from R115777 associated toxicities
or if patients fully recovered from neurotoxicity.
A phase I trial of the combination of oral R115777 with gemcitabine,[20] in which
gemcitabine was administered at a fixed dose of 1000 mg/ m2 i.v. on days 1, 8, and 15
every 4 weeks, and R115777 was administered continuously at doses ranging from 100
to 300 mg q12h was also performed. The MTD of R1157777 on this trial is 200 mg q12h,
and neutropenia was the DLT.
A sensory peripheral neuropathy manifesting with pain, tingling, numbness and
dysesthesias was observed in more than 50% of 19 adult patients who were treated in
Europe on a trial of continuous administration of R115777 at a dose of 350 mg twice
daily. The neuropathy was only observed in patients who received doses of R115777
>200 mg q12h, and who had received the drug for >12 weeks duration. Peripheral
neuropathy had not previously been observed on the intermittent schedule, but there
were not as many patients on the intermittent schedule who had prolonged therapy.
The neuropathy was reversible in all patients after discontinuation of R115777.
Leukemia trial: A phase I trial of R115777 in adult patients with refractory
leukemias was conducted at the University of Maryland.17 Patients received oral
R115777 q12h for up to 21 days at doses ranging from 100 to 1200 mg for 21 days
followed by a 1-2 week rest period. Thirty patients with refractory leukemias (22 AML,
5ALL, 3 CML in blast crisis) were enrolled. Reversible myelosuppression was observed
at doses ≥ 600 mg q12h. Reversible polydipsia and paresthesias were observed at the
900 mg dose level. Dose-limiting neurotoxicity manifesting with confusion, ataxia and
vision changes was observed in 3/3 patients entered at the 1200 mg dose level within 48
hours of starting R115777. These toxicities resolved completely within 72 hours of
stopping R115777. Responses (2 CR, 7 PR) were observed at all dose levels. Inhibition
of FPTase was > 80% at dose levels ≥ 300 mg q12h. Inhibition of farnesylation of lamin
A and heat shock protein HDJ2 was observed in 4/4 and 6/6 patients at the 600 mg
dose level, respectively. The MTD was 900 mg q12h, which is 3-fold higher than the
MTD in adults with solid tumors.
1.2.6
PHASE I CLINICAL TRIALS OF R115777 IN CHILDREN
Solid Tumor Phase I: The Pediatric Oncology Branch, Texas Children's Cancer
Center, and the Children Hospital of Cincinnati are currently completing a collaborative
pediatric phase I trial of R115777 in patients with refractory solid tumors or patients
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with neurofibromatosis type 1 (NF1) and progressive neurofibromas (R115777-USA-6).
The MTD was initially determined on a q12h for 21 days schedule followed by a 7-day
rest. The MTD determined on the 21 day schedule was then administered on a
continuous dosing schedule (28 day cycles with no rest period). No dose escalation on
the continuous dosing schedule was planned. Thirty-six patients (23 with refractory
solid tumors, 13 with NF1) were entered on the 21 day dosing schedule, and six patients
(2 with refractory solid tumors, 4 with NF1) on the continuous dosing schedule. Four
dose levels were studied: 150 mg/m2/dose (n=4), 200 mg/m2/dose (21-day schedule,
n=13; continuous dosing, n=6), 275 mg/m2/dose (n=12), and 375 mg/m2/dose (n=7).
Non dose-limiting toxicities included myelosuppression, rash, nausea, diarrhea,
abdominal pain, and fatigue. Observed dose limiting toxicities are shown in the table
below:
Dosel Level
(mg/m2/dose)
Pts
(n)
Pts DLT
(n)
Dose-limiting toxicities
(grade)
21 day schedule followed by 7 days rest
150
4
200
13
2
1 Seizure (3), 1 Platelets (4)
275
12
3
2 Platelets (3)+ANC (4), 1 diarrhea (3)
375
7
4
2 Rash (3), 1 ANC (4) +
hypofibrinogenemia (3), 1 Nausea,
Vomiting, Diarrhea (3)
Continuous dosing schedule with no rest
200
6
1
Rash (3)
The seizure was observed on day 21 of treatment in one patient with
adrenocortical carcinoma and no prior history of seizures. MRI of the head showed
diffuse white matter changes, which improved on a follow-up scan. All dose-limiting
toxicities resolved after discontinuation of R115777. The MTD determined for patients
with NF1 and refractory solid tumors combined was 200 mg/ m2/dose q12h on both
schedules
Four patients with NF1 continue to receive R115777 on the 21 day schedule after a
median of 19 (range 18-23) cycles, and 3 patients with NF1 continue to receive R115777
on the continuous dosing schedule after a median of 11 cycles (range 4-13). Peripheral
neuropathy has not been observed in this trial. However, because of the development of
peripheral neuropathy in adults, who were treated on the continuous dosing schedule,
the 21 day schedule followed by a 7 day rest period will be used in future trials with
R115777.
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Leukemia Phase I: A phase I trial of R115777 for children with refractory
leukemias is ongoing. Twenty children with refractory ALL (n=11), AML (n=8), or
JMML (n=1) were treated. Overall, R115777 has been well tolerated. At the starting
dose (300 mg/m2 q12h po x 21 d, repeated q28 d), 3 of 6 evaluable patients had grade 3
adverse events (AE), which included rash (n=1), hyperbilirubinemia (n=1),
hyperbilirubinemia and AST (n=1). The dose was de-escalated to 200 mg/m2, and 2 of
6 evaluable patients developed grade 3 AE, which included mucositis (n=1),
hyperbilirubinemia (n=1). Two of the three patients who developed grade 3
hyperbilirubinemia, had a history of hyperbilirubinemia during the days preceding
treatment with R115777, but normal or grade 1 bilirubin immediately prior to R115777.
After discontinuation of R115777, bilirubin remained elevated in one patient, continued
to increase in one patient, and decreased to grade 1 toxicity in one patient. The
relationship of the study drug to this AE, and of the dose of study drug to this AE are
thus unclear.
The protocol was amended to only allow entry of patients with normal liver function
tests at trial entry (normal bilirubin, AST, and ALT). Currently, the 300 mg/m2 dose
level is expanded to enroll up to 12 evaluable patients.
1.2.7
CLINICAL PHARMACOKINETICS OF R115777 IN ADULTS AND CHILDREN
Pharmacokinetic analysis of plasma samples from 19 patients treated on an adult
phase I trial with R115777 revealed:
• R115777 is rapidly absorbed after oral administration (time to peak was
approximately 2-4 hours). The bioavailability of the capsules increased when
given after a meal.
• The concentrations of R115777 decline biphasically with an initial, dominant half-
life of about 2-3 hours and with a median terminal T1/2 of about 6 hours;
• Over the dosage range studied to date the pharmacokinetics of R115777 appear
to be linear;
• The average accumulation ratio of R115777 was calculated at 1.1, and therefore
minimal accumulation is expected on the q12 hr dosing regimen.
• In healthy human adults plasma protein binding of R115777 was very high, with
a free fraction of 0.66-0.77%.
• In human hepatocytes glucuronidation of R115777 at the imidazole nitrogen was
the major metabolic pathway.
Pharmacokinetic analysis of oral R115777 has also been performed on plasma
samples from 30 children (median age 13 years, age range 5 to 17 years) treated on our
pediatric phase I trial. In general the pharmacokinetics of R1157777 are similar in adults
and children. Preliminary observations regarding the plasma pharmacokinetics of
R115777 in pediatric patients are:
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• R115777 is rapidly absorbed after oral administration: The average time to peak
concentration was 2.7 hours (range 1.0 –8.0 hours);
• The Average terminal half-life was 6.8 hours (range 2.8-16.7 hours) The
determination of T1/2 was limited by the 36-hr sampling and highly dependent
on the ability to quantify low concentrations of R115777 in the terminal phase;
• Over the dosage range studied to date the pharmacokinetics of R115777 appear
to be linear: The average AUC increased from 4318 ng•h/ml (± 1763) at the 150
mg/ m2 dose level to 13536 ng•h/ml (± 7831) at the 375 mg/ m2 dose level. The
Cmax increased from 1034 ng/ml (± 566) at the 150 mg/ m2 dose level to 2433
ng/ml (± 730) at the 375 mg/ m2 dose level.
• Minimal accumulation is expected on the q12 hr dosing regimen.
1.2.8
PROPOSED PEDIATRIC PHASE II TRIAL OF R115777
Patients with NF1 are at increased risk of developing a variety of benign and
malignant tumors of the central and peripheral nervous system. Plexiform
neurofibromas occur with the highest frequency, and are associated with considerable
morbidity. Management of plexiform neurofibromas is generally surgical. However,
up to 44% of tumors progress after the first surgery, most commonly in patients
younger than ten years of age with head and neck tumors that could not be completely
resected.[18] There is no other standard treatment modality for patients with
progressive plexiform neurofibromas.
Neurofibromas do not follow a classical oncology model, in which tumor growth
occurs unchecked unless therapy is provided. Rather, neurofibroma growth can be
unpredictable, including periods of rapid growth and others of quiescence. Some
neurofibromas remain static indefinitely after a period of active growth. This erratic
behavior can make it difficult to document the effectiveness of a potential treatment.
A “Natural History Protocol” (Principal Investigator Dr. Bruce Korf) is currently
open to patients with NF1 with the main goal to provide data on the growth rate of
neurofibromas. Patients entered on this study do not receive treatment for their disease,
but are followed closely clinically and by serial MRI’s. Volumetric MRI analysis is
evaluated for it’s value in determining the growth rate of plexiform neurofibromas.
Results from this study will prove very valuable for the design of treatment protocols,
but are not available to this time point.
This trial will be a randomized, cross-over, double-blinded, placebo-controlled
pediatric phase II trial of oral R115777 in children and young adults with NF1 who have
progressive plexiform neurofibroma(s). Each patient will serve as his/her own control
for the primary endpoint of time to progression. After documentation of progressive
disease on the first treatment, patients will be crossed over to receive R115777 (if
placebo was first given) or placebo (if R115777 was first given). The first treatment that
a patient is randomized to receive (either placebo or R115777) is defined as “phase A”,
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and the second treatment (either placebo or R115777), is defined as “phase B”. This trial
design is ethical, because alternative designs without placebo control could bias
observation, and there is no standard treatment to which R115777 may be compared. In
addition, each patient will receive study medication provided there is disease
progression, and therefore may derive benefit from the trial.
R115777 or placebo will be administered twice daily for 21 days followed by a 7
day rest period between cycles. The dose of R115777 for this trial will be 200
mg/m2/dose every 12 hours, the MTD on the intermittent dosing schedule on the
pediatric phase I trial.
Imaging and measurement of plexiform neurofibromas: Tumor response criteria
that are used for cancers are based on one-dimensional (1-D) and two-dimensional (2-
D) tumor measurements (Therasse et al., 2000; Estey et al, 1986). These methods have
limited value in the assessment of treatment outcome for plexiform neurofibromas,
which are frequently large, have a complex (non-spherical) shape, and have a slow,
erratic growth pattern. In order to reproducibly quantify the size of these complex
lesions and detect small changes in the size over time, we used MR imaging
characteristics of plexiform neurofibromas to develop an automated method of lesion
detection and volume measurement. Short T1-Inversion Recovery (STIR) MR images,
on which plexiform neurofibromas are bright lesions compared with normal
surrounding tissue, were used to develop a program for automated image analysis
within
MEDx
(v3.41)
software
(Sensor Systems, Inc. Sterling, VA).
Reproducibility and inter-observer
variability
of
this
automated
method were determined by 2
observers who quantified volumes
for plexiform neurofibromas of the
orbit
(n=2),
face/neck
(n=3),
abdomen (n=1), and pelvis (n=3) on
three different days. For each MR
image (Figure 1A), the tumor is
roughly
outlined
manually
including a rim of low signal
intensity normal tissue (Figure 1B).
The program then performs a histogram analysis of signal intensity pixel by pixel and a
threshold that distinguishes high signal intensity tumor from normal tissue is defined
(Figure 1C). Tumor contours are then determined using a gradient image, connected
component analysis and automatic edge following operation (Figure 1D). There is an
option for re-analysis of MR images using an average or selected threshold. Tumor
volume is calculated by summing the results from all images based on the resulting 2-D
contours and slice thickness; and a report is generated.
Figure 1: Axial MRI of pelvic plexiform
neurofibroma. Steps of automated volumetric
analysis A-D.
A
B
D
C
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For comparison, plexiform neurofibroma volume was also determined by manually
tracing the tumor borders on each MR image. The results of application of the
automated method are shown in the table below.
Observer 1
Observer 2
Mean tumor volume ml, median (range)
291 (80.9-1581)
290 (75.7-1603)
Inter-day CV %, median (range)
3.6 (0.7-6.0)
1.6 (0.6-5.6)
Median (range) % difference in volume between
observers
6.4 (1.4 – 11.9)
Correlation automated vs. manual method, R
0.999
0.999
This automated volumetric MRI analysis is applicable to most plexiform neurofibromas,
has excellent intra- and inter-observer reproducibility and agrees with volumes
determined by manual tumor tracing. This method is used in the currently ongoing
phase II trial of the farnesyltransferase inhibitor R115777 and in the phase I trial of
pirfenidone for children with NF1 and plexiform neurofibromas to assess changes in
tumor size, and in both clinical trials tumor progression is defined as an increase in
tumor volume by ≥20%.
This volume increase corresponds to much smaller changes in 1-D, or 2-D
measurements as outlined in the table below.
Phase II R117555
Response Criteria
RECIST
Diameter, 2r
WHO
Product, (2r)2
Volume, 4/3Πr3
Disease progression (Increase)
20
44
73
12
25
40
6
13
20
Shaded areas show current criteria used to define disease progression by RECIST,
WHO, and the ongoing R115777 NF1 phase II trial
3D-MRI analysis will be evaluated against conventional 2D-MRI and 1D-MRI
analysis for its reproducibility in the assessment of disease status of plexiform
neurofibromas. Tumor response will therefore also be assessed using 1D-MRI data
analysis. Each patient will undergo MRI imaging of all known disease prior to entry on
each phase of the study. At the time of study entry the extent of the progressive
plexiform neurofibroma(s) will be determined, and followed for response using 1D-,
2D-, and 3D-MRI (appendix 1).
In order to enhance the knowledge about the molecular basis of NF1, and to
develop surrogate markers for tumor response, this study will attempt to obtain
biopsies from easily accessible discrete neurofibromas or superficial plexiform
neurofibromas from all eligible patients prior to entry to treatment, and if feasible at a
later time point during treatment on each arm of the study. Discrete neurofibromas
undergo a natural history, beginning as small growing lesions, and maturing into static
lesions. It is possible that the biology of these lesions differ, and hence might yield
different results in studies of ras expression, ras mutations and FPTase activity.
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However, they may still prove valuable as surrogates. Furthermore, it is anticipated
that some patients may require surgery during their treatment on this trial, either for
complications of NF1 or for other unrelated medical reasons, and attempts will be made
to obtain tumor biopsies at this time. Tumor biopsies are invasive procedures, and
patients may refuse to undergo biopsies and still be eligible for the study.
Tumor samples obtained on this study will be contributed to an already existing
tumor tissue bank, and samples obtained from plexiform neurofibromas will undergo a
central pathology review including a detailed morphologic, ultrastructural and
immunohistochemical analysis (Appendix 2, 3, 4). All tumor samples will be used to
establish tumor cell lines (Appendix 3, 4). Tumor samples obtained prior to study
entry, and once at steady state on treatment during each study phase (“A”, “B”), will be
used for molecular biological studies (FPTase activity), expression of N-ras, K-ras, and
H-ras, ras mutations, and NF1 gene mutations in the GAP related domain.
Peripheral blood mononuclear cells and tumor specimens obtained at various time
points during the trial will also be used to measure the level of farnesyl-protein
transferase (FPTase) activity in order to determine the value of FPTase activity as a
surrogate marker of tumor response (Appendix 5).
The contribution of tumor specimens to a central tissue repository will provide
valuable resources for ongoing as well as future studies aimed at investigating the
molecular pathogenesis of NF1 tumors, and may allow for the development of
predictive markers (clinical or molecular) to identify individuals at risk for cancer
development. The identification of at risk individuals will have significant impact on
our management and evaluation of individuals with this common inherited
predisposition to cancer syndrome.
Recently the development of chemotherapy induced peripheral neuropathy has
been correlated with circulating levels of nerve growth factor [3]. Patients who received
neurotoxic agents experienced a decrease in circulating levels of NGF, which correlated
with the development and severity of peripheral neuropathy. Peripheral neuropathy
has been observed in adult patients after ≥12 weeks of chronic dosing. This trial will
therefore attempt to measure NGF at various time points during treatment with
R115777 and placebo, and to correlate levels with the development of neuropathy
(Appendix 6).
The quality of life of patients treated with R115777 or placebo on this study will be
assessed using the National Institutes of Health (NIH) Impact of Pediatric Illness (IPI)
Scale. This questionnaire was developed to assess the effects of chronic illness and
treatment on the everyday behavior of children. It assesses adaptive behavior,
emotional functioning, physical status and central nervous system symptoms. This
questionnaire has not been completely validated, and means and standard deviations
for different subgroups of patients on the scale and subscales are not available yet.
Without normative data on this scale for patients with NF1, and having a relatively
small sample size in the protocol, it may be difficult to analyze the data as an outcome
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24
measure for this particular study. Attempts will be made to compare the quality of life
of patients while they receive treatment with placebo or R115777. The IPI scale should
be administered to all patients ≥6 years and ≤ 18 years of age and their primary
caregiver prior to the start of therapy. This questionnaire will not be administered to
patients > 18 years. This assessment consists of an age-appropriate questionnaire and
generally takes less than 30 minutes to complete. Patients between the ages of 6 and 10
years of age should be administered the IPI-Young Child form; patients between 11 and
18 years of age should be administered the IPI-Older Child/Adolescent form; the
patient’s primary caregiver should receive the IPI-Parent Form.
2.0 ENROLLMENT PROCEDURES
2.1
ELIGIBILITY CRITERIA
2.1.1 INCLUSION CRITERIA
2.1.1.1 Age: ≥3 years and ≤25 years of age
2.1.1.2 Diagnosis: Patients with NF1 and progressive plexiform neurofibromas
that have the potential to cause significant morbidity, such as (but not limited to) head
and neck lesions that could compromise the airway or great vessels, brachial or lumbar
plexus lesions that could cause nerve compression and loss of function, lesions that
could result in major deformity (e.g., orbital lesions), lesions of the extremity that cause
limb hypertrophy or loss of function, and painful lesions. Histologic confirmation of
tumor is not necessary in the presence of consistent clinical and radiographic findings,
but should be considered if malignant degeneration of a plexiform neurofibroma is
clinically suspected. In addition to plexiform neurofibroma(s), all study subjects must
have at least one other diagnostic criteria for NF1 listed below (NIH Consensus
Conference[9]):
1. Six or more café-au-lait spots (≥0.5 cm in prepubertal subjects or ≥1.5 cm
in postpubertal subjects)
2. Freckling in the axilla or groin
3. Optic glioma
4. Two or more Lisch nodules
5. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
thinning of long bone cortex)
6. A first degree relative with NF1
In this study a plexiform neurofibroma is defined as a neurofibroma that has
grown along the length of a nerve and may involve multiple fascicles and branches. A
spinal plexiform neurofibroma involves two or more levels with connection between
the levels or extending laterally along the nerve.
2.1.1.3 Measurable disease: Patients must have measurable plexiform
neurofibroma(s). For the purpose of this study a measurable lesion will be defined as a
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25
lesion of at least 3 cm measured in one dimension. There must be evidence of recurrent
or progressive disease as documented by an increase in size or the presence of new
plexiform neurofibromas on MRI. Progression at the time of study entry is defined as:
• A measurable increase of the plexiform neurofibroma (≥ 20% increase in the volume,
or a ≥ 13% increase in the product of the two longest perpendicular diameters, or a ≥
6% increase in the longest diameter) over the last two consecutive scans (MRI or
CT), or over the time period of approximately one year prior to evaluation for this
study.
• Patients who underwent surgery for a progressive plexiform neurofibroma will be
eligible to enter the study after the surgery, provided the plexiform neurofibroma
was incompletely resected and is measurable.
2.1.1.4 Prior therapy: Patients with NF1 are eligible at the time of recurrence or
progression of inoperable plexiform neurofibroma.
A surgical consultation should be obtained prior to enrollment on the study to
evaluate if tumor resection is a feasible option. Patients will only be eligible if complete
tumor resection is not feasible, or if a patient with a surgical option refuses surgery.
Since there is no standard effective chemotherapy for patients with NF1 and
progressive plexiform neurofibromas, patients may be treated on this trial without
having received prior therapy.
Patients must have recovered from the toxic effects of all prior therapy before
entering this study. The Cancer Therapy Evaluation Program Common Toxicity
Criteria (CTC) Version 2.0 will be used for toxicity assessment. A copy of the CTC
version 2.0 can be downloaded from the CTEP home page at http://ctep.cancer.gov.
Recovery is defined as a toxicity grade <2, unless otherwise specified in the Inclusion
and Exclusion Criteria.
Patients must have had their last dose of radiation therapy at least six weeks
prior to study entry, and their last dose of chemotherapy at least four weeks prior to
study entry. Patients who received G-CSF after the prior cycle of chemotherapy must
be off G-CSF for at least one week prior to entering this study.
2.1.1.5 Performance Status: Patients should have a life expectancy of at least 12
months and an ECOG performance score of 0, 1, or 2 (see below). Patients who are
wheelchair bound because of paralysis should be considered “ambulatory” when they
are up in their wheel chair.
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ECOG Performance Status
Score Clinical Status
0
Asymptomatic
1
Symptomatic, fully ambulatory
2
Symptomatic, in bed < 50% of the day
3
Symptomatic, in bed > 50% of the day but not bedridden
4
Bedridden
2.1.1.6 Hematologic Function: Patients must have an absolute granulocyte count
≥1,500/µL , a hemoglobin ≥ 9.0 gm/dl, and a platelet count ≥150,000/µL at study entry,
and a normal fibrinogen.
2.1.1.7 Hepatic Function: Patients must have a bilirubin within normal limits
and SGPT ≤ 2x upper limit of normal. Patients with Gilbert syndrome are excluded
from the requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10% of the
general
population,
and
is
characterized
by
mild,
chronic
unconjugated
hyperbilirubinemia in the absence of liver disease or overt hemolysis).
2.1.1.8 Renal Function: Patients must have an age-adjusted normal serum
creatinine (see table below) OR a creatinine clearance ≥ (70 mL/min/1.73 m2) .
Age
(Years)
Maximum Serum Creatinine
(mg/dl)
≤ 5
0.8
5 < age ≤ 10
1.0
10 < age ≤ 15
1.2
> 15
1.5
2.1.1.9 Informed Consent: All patients or their legal guardians (if the patients is
<18 years old) must sign an IRB approved document of informed consent (screening
protocol) prior to performing studies obtained exclusively to determine patient
eligibility. After confirmation of patient eligibility all patients or their legal guardians
must sign the protocol specific informed consent to document their understanding of
the investigational nature and the risks of this study before any protocol related studies
are performed (other than the studies which were performed to determine patient
eligibility). When appropriate pediatric patients will be included in all discussion. Per
institutional guidelines, age appropriate assent forms for children from 7 through 12
years, and for children may be developed and, when appropriate, will be signed by the
pediatric patients in order to obtain written assent.
2.1.1.10 Durable Power of Attorney (DPA): All patients ≥18 years of age will be
offered the opportunity to assign DPA so that another person can make decisions about
their medical care if they become incapacitated or cognitively impaired.
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2.1.1.11 Ability to undergo MRI examinations.
2.1.2 EXCLUSION CRITERIA
2.1.2.1 Pregnant or breast feeding females are excluded, because the toxic effects
and pharmacology of R115777 in the fetus and newborn are unknown.
2.1.2.2 Clinically significant unrelated systemic illness (serious infections or
significant cardiac, pulmonary, hepatic or other organ dysfunction) which in the
judgment of the Principal or Associate Investigator would compromise the patient’s
ability to tolerate R115777 or are likely to interfere with the study procedures or results.
2.1.2.3 Prior treatment with >1 prior myelosuppressive chemotherapy regimen.
2.1.2.4 An investigational agent within the past 30 days.
2.1.2.5 Evidence of an optic glioma, malignant glioma, malignant peripheral
nerve sheath tumor or other cancer requiring treatment with chemotherapy or radiation
therapy.
2.1.2.6 Ongoing radiation therapy, chemotherapy, hormonal therapy directed at
the tumor, or immunotherapy.
2.1.2.7 Inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity and response to therapy.
2.1.2.8 Prior treatment with R115777.
2.2
PRE-TREATMENT EVALUATION (SEE APPENDIX 7)
Pre-treatment blood tests should be performed within 2 weeks prior to enrollment
on the trial unless otherwise stated. The evaluation required prior to starting treatment
phase “A” and “B” is listed in table form in Appendix 7.
2.2.1 History and Physical Examination: Complete history (including prior and
concurrent therapy), physical examination including documentation of measurable
disease, performance status, and signs and symptoms. A complete neurologic
examination should be performed and focus on signs of sensory peripheral neuropathy.
Height, weight and body surface area must be recorded. History and physical
examination will be documented in case report forms as outlined Section 5.1.1. The BSA
should be calculated from the average of 3 repeated measurements of weight and
height on the same day using the formula below or a formula used at a participating
institution:
BSA = Weight (kg)0.425 • Height (cm)0.725
139.315
2.2.2 PHOTOGRAPHY: When possible, plexiform neurofibromas that are visible on
the body surface should be photographed prior to treatment with R115777 and placebo.
A size marker should be taped to the skin in the field of view when appropriate, and
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the plexiform neurofibroma should be photographed so that it fills the frame. Frontal
and side images will be taken, as appropriate. Copies of photographs should be sent to
the study coordinator, identified by the subject ID number, date, and treatment phase
(“A” or “B”) and treatment cycle number.
2.2.3 HEMATOLOGY: Complete blood counts, differential, platelet count, PT, PTT
and fibrinogen.
2.2.4 CHEMISTRIES: Electrolytes (including calcium, phosphorus and magnesium),
creatinine, SGPT, and bilirubin.
2.2.5 URINALYSIS
2.2.6 URINE PREGNANCY TEST: For all females of child-bearing potential.
2.2.7 RADIOGRAPHIC EVALUATION (APPENDIX 1): MRI scan of the progressing
plexiform neurofibroma(s) within 2 weeks prior to enrollment on study. In addition, if
possible, MRI scan of all known additional, measurable plexiform neurofibroma(s)
within 2 weeks of enrollment on study. The progressing plexiform neurofibroma(s) will
be identified as index lesion(s), and will be studied by 3-D MRI. Should there be more
than 3 progressing plexiform neurofibromas, the three most clinically relevant
plexiform neurofibromas will be followed by 3-D MRI analysis. The imaging protocol
outlined in Appendix 1 will be used each time MRI examinations are performed to
assess the effect to R115777.
2.2.8 OPHTHALMOLOGIC EVALUATION: Ophthalmologic examination prior to or
within the first three days of starting treatment with R115777 or placebo, including
visual fields if the patient is able to cooperate with the exam and examination of the lens
for opacifications.
2.2.9
TISSUE
PROCUREMENT:
In
patients
with
easily
accessible
discrete
neurofibromas or superficial plexiform neurofibromas, who consent to the procedure,
biopsies will be performed prior to the first dose of treatment at study entry. In
addition, attempts will be made to obtain tumor specimens from any patients requiring
surgery for complications of their tumors or for unrelated medical problems. Peripheral
blood mononuclear cells for FPTase assay (Section 2.2.10, Appendix 5) should be
obtained at the same time as biopsy whenever possible. As this is an invasive
procedure, patients may refuse biopsy and still be eligible for the study.
Kits will be supplied for handling and shipping of tumor specimens. To obtain a
kit, please call Ms. Andy Gillespie at (301) 402-1848 seven days prior to the planned
surgery (Appendix 3, Appendix 4). Two kits will be sent by FedEx to arrive several
days prior to the surgical procedure. Included in the kits will be all media and tubes
needed for shipment. Procedures for tissue handling and shipment are provided in
Appendices 3 and 4, respectively.
2.2.10 FARNESYL-PROTEIN TRANSFERASE (FPTase) ACTIVITY IN PERIPHERAL BLOOD
MONONUCLEAR CELLS (PBMC): Peripheral blood mononuclear cells (PBMC) will be
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collected pretreatment. The activity of FPTase will be measured in these samples as a
surrogate for tumor FPTase inhibition. If the patient has consented to a tumor biopsy,
PBMCs should be obtained at the same time as the biopsy (Section 2.2.9). PBMC should
be separated from 20 ml of heparinized blood (10 ml in children ≤10 kg) as described in
Appendix 5.
2.2.11 NERVE GROWTH FACTOR (NGF): A blood sample will be collected
pretreatment. NGF levels will be correlated with the development of clinical
neurotoxicity (Appendix 6).
2.2.12 QUALITY OF LIFE (QOL) ASSESSMENT: The National Institutes of Health
(NIH) Impact of Pediatric Illness (IPI) Scale, which assesses the impact of disease and
treatment on children’s behavior, should be administered to all patients ≥ 6 ≤ 18 years of
age and their primary caregiver prior to the start of therapy. This assessment consists of
an age-appropriate questionnaire and generally takes less than 30 minutes to complete.
Patients between the ages of 6 and 10 years of age should be administered the IPI-
Young Child form; patients between 11 and 18 years of age should be administered the
IPI-Older Child/Adolescent form; the patient’s primary caregiver should receive the
IPI-Parent Form. This questionnaire will not be administered to patients > 18 years.
3.0 IMPLEMENTATION OF STUDY
3.1 STUDY DESIGN
3.1.1 RANDOMIZED DESIGN
This is a randomized, cross-over, double-blinded, placebo-controlled pediatric
phase II trial of oral R115777 in children and young adults with NF1 who have
progressive plexiform neurofibroma(s). Patients will be randomized to either receive
R115777 or placebo first. After documentation of progressive disease on the first
treatment, patients will be crossed over to receive R115777 (if placebo was first given) or
placebo (if R115777 was first given). The first treatment that a patient is randomized to
receive (either placebo or R115777) is defined as “phase A”, and the second treatment
(either placebo or R115777), is defined as “phase B”. There should be a 2 week washout
period, during which no drug is administered, when crossing over from the first (phase
A) to the second (phase B) treatment. The treatment cycle number will reset to “1” when
the patient crosses over from “phase A” to “phase B”. For study purposes “arm 1” is
defined as treatment with R115777 first followed by placebo, and “arm 2” is defined as
treatment with placebo first followed by R115777.
3.1.2 PATIENT REGISTRATION AND RANDOMIZATION
Patients must be registered by contacting Ms. Andy Gillespie at the Pediatric
Oncology Branch (POB) (phone number, 301-402-1848, e-mail: gillesan@mail.nih.gov).
When registering a patient, information about all entry criteria (e.g., laboratory results)
must be available to allow for verification of eligibility. Dr. Brigitte Widemann (phone
number: 301-496-7387, e-mail: bw42y@nih.gov) or Dr. Frank Balis (phone number 301-
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496-0085, e-mail balisf@mail.nih.gov) must also be contacted to discuss the patient prior
to entry on study. The completed Eligibility Checklist (Appendix 8A) and the Blinded
Patient On Study Form (Appendix 8B) must be faxed to the (POB) c/o Ms. Andy
Gillespie (Fax: 301-480-8871). All patients will be registered with Orkand (phone: 301-
402-1732, fax: 301-480-0757) by the POB research nurse. Orkand will notify the POB
research nurse and the Pharmaceutical Management Branch (PMB), CTEP, NCI of the
patient’s ID number using the completed Blinded Patient On Study Form (Appendix
8B). The POB research nurse will notify the registering site of the patient’s ID number
and, based on notification by Orkand, the PMB will ship drug for that specific patient
ID number to the registering site (see section 8.0). After patient registration the POB
research nurse will also ship a module with the necessary materials to administer the
quality of life assessment, and the required tests outlined in Appendix 5, 6, and 7 to the
participating institution. The POB research nurse must also be notified when the patient
progresses after “phase A” (i.e., crossover notification to the PMB) and when the patient
progresses after “phase B” (i.e., off-study notification to Orkand and PMB) by faxing the
completed Progression Checklist (Appendix 9A) and the Blinded Patient Crossover/Off
Study Form (Appendix 9B) to the Pediatric Oncology Branch (c/o Andy Gillespie) at
(301) 480-8871. The POB research nurse will notify the PMB when a patient progresses
on treatment “phase A”, and Orkand and the PMB when a patient progresses on
treatment “phase B” using the completed Blinded Patient Crossover/Off Study Form
(Appendix 9B). A “roadmap” for the patient registration process is shown in Appendix
10.
3.1.3 DOSING SCHEDULE AND PRESCRIBING
R115777 or placebo will be administered orally q12h for 21 days followed by a 7
day rest period between cycles (28-day treatment cycle). The patient’s prescriptions
must include the patient ID number (e.g., 01C0222-01), the patient initials (e.g. ABC =
first three letters of patient’s last name), the phase (i.e., “Phase A” or “Phase B”), the
body surface area (in m2), and the dose (i.e.___ mg po q12h). “Phase A” will be defined
as the treatment after initial randomization until documentation of progressive disease.
“Phase B” will be defined as the treatment after the patient is crossed over to receive
R115777 (if placebo was first given) or placebo (if R115777 was first given). The dosage
of R115777 will be 200 mg/m2/dose (see dosing table in section 3.2). Patients will
continue on therapy until they meet one of the off-study criteria (Section 3.6). There
should be a 2 week washout period, during which no drug is administered, when
crossing over from “Phase A” to “Phase B”. Patients or their guardians will keep a diary
to document the intake of each dose of R115777 and potential side effects (Appendix
11A). Each institutional pharmacy will ensure quality control procedures for R115777
and placebo allocation, and will use the Pill Count Case Report Form (Appendix 11B)
for dispensing the boxes, and for counting the dispensed and returned tablets. The
tearoff labels from boxes will also be attached on this form. The patient diary and the
Pill Count Case Report Form should be reviewed with the patient’s family after
completion of every three treatment cycles, and drug should be accounted for at this
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time (Appendix 11A/B). These diaries and copies of the Pill Count Case Report Form
will be forwarded to Ms. Andy Gillespie (Pediatric Oncology Branch, NCI, FAX: 301-
480-8871, Phone: 301-402-1848) after completion of every 3 treatment cycles.
3.1.4 MONITORING TIME TO PROGRESSION AND RESPONSE
This phase II trial is designed to determine the time to tumor progression and
response rate with R115777 in patients with NF1 and progressive plexiform
neurofibromas. The primary endpoint will be time to progression. Each patient will
undergo MRI imaging of all known disease prior to entry on study. At the time of study
entry one to three progressing plexiform neurofibroma(s) will be identified as index
lesion(s), and followed for progression and response using 1D-, 2D-, and 3D-MRI.
Results obtained with 1D-MRI and 3D-MRI analysis will be compared to conventional
2D-MRI analysis for their ease and reproducibility. The imaging protocol outlined in
Appendix 1 will be used each time MRI scans are performed to assess response to
R115777. MRI scans are performed prior to cycles 1, 4, 7, 10, and then after every 6
cycles on each study phase. If a patient is removed from a study phase because of
clinical evidence of disease progression, the MRI scans should be repeated if they had
not been performed within the past 4 weeks.
3.1.5 DEFINITION OF TUMOR PROGRESSION
• A ≥ 20% increase in the volume (by 3D-MRI) of at least one of the index plexiform
neurofibromas compared to the pretreatment volume measured prior to the start of
the current treatment phase.
• Appearance of new discrete dermal neurofibroma(s) does not qualify for disease
progression.
• Worsening of existing symptoms or the appearance of new symptoms that persist
for more than 7 days and that are felt to be definitely related to plexiform
neurofibroma should be evaluated by repeating the MRI. Patients should not be
classified as having progressive disease solely on the basis of new or increased
symptoms without discussing the case with the protocol Principal Investigator.
• Patients with other evidence of disease progression than outlined above should also
be discussed with the Principal Investigator.
3.1.6 TISSUE PROCUREMENT
This study will attempt to obtain biopsies from easily accessible discrete
neurofibromas or superficial plexiform neurofibromas from all eligible patients prior to
the start of treatment, and if feasible at a later time point during treatment (at steady
state, between day 15-21 on cycle 1) on each treatment phase. In addition, attempts will
be made to obtain tumor specimens from any patients requiring surgery for
complications of their tumors or for unrelated medical problems (Appendices 3 and 4).
Peripheral blood mononuclear cells for FPTase activity (Section 3.1.8, Appendix 5)
should be collected at the same time as the biopsy.
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The following studies will be performed with tumor specimens (Appendices 2, 3,
4): (1) FPTase activity, (2) expression of N-ras, H-ras, and K-ras, and (3) ras mutations,
and (4) NF1 mutations in the GAP related domain, (5) establishment of tumor cell lines,
and (6) detailed immunohistochemical analysis (plexiform neurofibromas only).
Findings will be correlated with response to treatment with R115777. It is hypothesized
that ras mutations will be rare, germline NF1 mutations will be found in all tumors, and
additional NF1 mutations will be found in many cases.
3.1.7 ESTABLISHMENT OF TUMOR CELL LINES AND TISSUE BANK
Attempts will be made to establish tumor cell lines from tumor specimens from
patients treated on this trial. The tissue bank and pathology review will be open to use
by the scientific community, provided IRB approval for research questions not
addressed by this protocol is obtained, in order to collect more information on the
pathology, genetics, and cell biology of plexiform neurofibromas.
3.1.8 FPTASE ACTIVITY IN PBMC
FPTase activity will be assessed in PBMCs pretreatment and once between days 15
and 21 of treatment (steady state) on cycle #1 of each treatment phase (“A” and “B”) as
a surrogate marker for the effect of R115777 (Appendix 5). PBMCs should be obtained
at the same time as tumor biopsies in patients who consent to a biopsy.
3.1.9 NERVE GROWTH FACTOR (NGF)
A blood sample will be collected pretreatment, and then prior to cycles 4, 7, 10,
and then after every six cycles on treatment phase (“A” and “B”). NGF levels will be
correlated with the development of clinical neurotoxicity (Appendix 6).
3.1.10 MONITORING TOXICITY
The hematologic and non-hematologic toxicities of R115777 will be monitored and
recorded throughout treatment with R115777 or placebo. (Appendix 1 and Sections 3.4
and 3.7). The Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC)
Version 2.0 will be used for toxicity assessment. A copy of the CTC version 2.0 can be
downloaded from the CTEP home page at http://ctep.cancer.gov (Section 5.3).
3.2
DRUG ADMINISTRATION
R115777 or placebo in 50 mg tablets will be manufactured by Janssen
Pharmaceuticals and supplied by CTEP, NCI under IND #58359. Tablets will be
administered orally immediately after a meal every 12 hours for 21 days followed by a 7
day rest period (28 day cycles). The dose of R115777or placebo will be 200 mg/m2
every 12 hours, and is based on the maximum tolerated dose on the intermittent dosing
schedule from the pediatric phase I trial. See Section 2.2.1 for calculation of BSA. Each
patient’s dose will be rounded to the nearest 50 mg according to the following dosing
table:
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BSA (m2)
R115777 / Placebo
(mg po q12h)
R115777 / Placebo
(# of 50 mg tablets po q12h)
0.00 - 0.37
50
1
0.38 - 0.62
100
2
0.63 - 0.87
150
3
0.88 - 1.12
200
4
1.13 - 1.37
250
5
1.38 +
300
6
Tablets may be crushed for easier consumption in young children.
R115777/placebo should be re-taken if vomiting occurs within 30 minutes of
taking the dose.
Patients who have to undergo an elective major surgical procedure (not to include
the biopsy of discrete neurofibromas requested on this protocol) should stop taking
study drug one week before the surgery, and are allowed to resume study drug 2 weeks
after surgery, provided they have recovered from the procedure.
3.3
MODIFICATIONS FOR TOXICITY
Patients who experience grade 2 toxicity (CTC v. 2) related to R115777 or placebo
should have R115777/placebo withheld until the toxicity resolves (grade ≤1) and then
restarted at the same dose level. If the grade 2 toxicity recurs, the R115777/placebo
dose should be withheld again until the toxicity resolves (grade ≤1) and then reduced
by 50 mg per dose. For patients with a BSA ≤0.37 the dose will be reduced to 50 mg
once daily. If the grade 2 toxicity recurs the patient should be taken off protocol. If a
grade 2 toxicity persists for >10 days off therapy, the patient should be discussed with
the PI.
Patients who experience grade 3 or 4 toxicity related to R115777 or placebo should
have their dose withheld. If the toxicity returns to grade ≤1 within 10 days, patients
may resume R115777/placebo at a dose reduced by 50 mg per dose. For patients with a
BSA ≤0.37 the dose will be reduced to 50 mg once daily. If the toxicity persists at grade
≥2 for >10 days without administration of R115777/placebo or the grade 3 or 4 toxicity
recurs at the lower dose level, the patient should be removed from the study (see
Section 3.6.2).
If the toxicity warrants, the physician can determine whether the patient is
receiving R115777 or placebo (unblind the study) by calling Dr. Brigitte Widemann
(301) 496-7387 or Dr. Frank Balis (301) 496-0085. These physicians can also be reached
through (301) 496-7704 or the NIH page operator (301) 496-1211 (see section 8.2.5).
Pediatric Oncology Branch staff will require the protocol number (i.e., ‘T99-0090’), the
patient’s ID number (e.g., ‘00-C0222-01’), the phase (i.e., ‘A’ or ‘B’), and the patient’s
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initials (first three letters of last name, eg., ‘ABC’) to unblind the patient. The unblinded
patient must be removed from the study.
3.4
ON STUDY EVALUATION (SEE APPENDIX 7)
3.4.1 HISTORY & PHYSICAL EXAMINATION: Every 2 weeks during the first 3 cycles
on each treatment phase (“A”, “B”). Physical exam should include assessment of
performance status (documentation if changed from baseline), measurement of visible
or palpable neurofibroma, height, weight and body surface area prior to every
treatment cycle. A complete neurologic examination should be performed and focus on
signs of sensory peripheral neuropathy. After cycle 3 perform prior to each cycle.
History and physical examination will be documented in case report forms as outlined
Section 5.1.1.
3.4.2 PHOTOGRAPHY: When possible, plexiform neurofibromas that are visible on
the body surface should be photographed prior to treatment cycle 1, 4, 7, 10, and then
after every 6 cycles on each treatment phase (“A”, “B”). A size marker should be taped
to the skin in the field of view when appropriate, and the plexiform neurofibroma will
be photographed so that it fills the frame. Frontal and side images will be taken, as
appropriate. Copies of photographs identified by the patient ID number, date,
treatment phase (“A” or “B”), and treatment cycle should be sent to:
Andy Gillespie, R.N.
Pediatric Oncology Branch, NCI
10 Center Drive, MSC 1928
Bldg. 10/Rm. 13N240
Bethesda, MD 20892-1928
3.4.3 LABORATORY ASSESSMENT (see Appendix 7). Laboratory studies will be
documented in case report forms as outlined Section 5.1.1.
Hematology: During the first 3 cycles of treatment on each treatment phase (“A”,
“B”), obtain complete blood count, differential and platelet count every other week
(more frequent monitoring may be performed if the ANC <1,000/mm3 or platelet count
<50,000/mm3). During subsequent cycles complete blood count, differential, and
platelet count will be obtained prior to each cycle. PT, PTT and fibrinogen will be
obtained prior to each treatment cycle on each treatment phase.
Chemistries: During the first 3 cycles of treatment on each treatment phase (“A”,
“B”), obtain electrolytes, creatinine, calcium, magnesium, phosphorus, SGPT, and
bilirubin every other week. During subsequent cycles these tests should be performed
prior to each treatment cycle.
Urinalysis: Prior to treatment cycle 1, 4, 7, 10, and then q 6 cycles on each
treatment phase (“A”, “B”).
3.4.4 RADIOGRAPHIC EVALUATION: Evaluate the index lesions by MRI prior to cycle
1 on treatment phase “A”, and prior to cycle 4, 7, 10, and then after every 6 cycles on
each treatment phase (“A”, “B”). The protocol outlined in Appendix 1 will be used each
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time MRI examinations are performed to assess progression or response to R115777 or
placebo. In patients with clinical suspicion of disease progression MRI analysis should
be performed earlier using the protocol outlined in Appendix 1. At the time of disease
progression on treatment phase “A”, if possible, a MRI scan of all known measurable
plexiform neurofibromas in addition to the index lesions should be performed, in order
to have a new baseline prior to treatment phase “B” (Appendix 1).
3.4.5 OPHTHALMOLOGIC EVALUATION: Prior to or within the first three days of
starting treatment phase “A”, and prior to or within the first 3 weeks of starting
treatment phase “B”. Exam should include visual fields if the patient is able to
cooperate with the exam and examination of the lens for opacifications.
3.4.6 TISSUE PROCUREMENT: In patients with easily accessible discrete
neurofibromas or superficial plexiform neurofibromas, who consent to the procedure,
biopsies will be performed prior to the first dose of treatment on phase “A”, and if
feasible at one steady state time point on each treatment phase (“A”, “B”) (between day
15-21 on cycle #1) of treatment. In addition, attempts will be made to obtain tumor
specimens from any patients requiring surgery for complications of their tumors or for
unrelated medical problems. Peripheral blood mononuclear cells for FPTase assay
(Section 3.4.7, appendix 5) should be obtained at the same time as biopsy whenever
possible. As this is an invasive procedure, patients may refuse biopsy and still be
eligible for the study.
Two kits will be supplied for handling and shipping of tumor specimens. To
obtain the kits, please call Ms Andy Gillespie (301)-402-1848. Kits will be sent by FedEx
to arrive several days prior to the surgical procedure. Included in the kits will be all
media and tubes needed for shipment. Procedures for tissue handling and shipment are
provided in Appendices 3 and 4, respectively.
3.4.7 FPTase ACTIVITY IN PBMC: PBMC should be collected pretreatment, and once
between days 15 and 21 of treatment (steady state) on cycle #1 of each treatment phase
(“A” and “B”). If the patient has consented to a tumor biopsy, PBMCs should be
obtained at the same time as the biopsy (Section 3.4.6). PBMC should be separated from
20 ml of blood (10 ml in children ≤10 kg) as described in Appendix 5.
3.4.8 NERVE GROWTH FACTOR: A blood sample will be collected pretreatment, and
prior to cycles 4, 7, 10, and then after every six cycles on each treatment phase (“A”,
“B”). Nerve growth factor levels will be correlated with the development of clinical
neurotoxicity (Appendix 6).
3.4.9 QUALITY OF LIFE (QOL) ASSESSMENT: The National Institutes of Health (NIH)
Impact of Pediatric Illness (IPI) Scale, which assesses the impact of disease and
treatment on children’s behavior, should be administered to all patients ≥6 years to 18
years of age and their primary caregiver prior to the start of therapy, and then prior to
cycles 4, 7, 10, and then after every 6 cycles on each treatment phase. This questionnaire
has not been completely validated, and means and standard deviations for different
subgroups of patients on the scale and subscales are not available yet. This assessment
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consists of an age-appropriate questionnaire and generally takes less than 30 minutes to
complete. Patients between the ages of 6 and 10 years of age should be administered
the IPI-Young Child form; patients between 11 and 18 years of age should be
administered the IPI-Older Child/Adolescent form; the patient’s primary caregiver
should receive the IPI-Parent Form. This questionnaire will not be administered to
patients > 18 years. Patient and parent response forms should be photocopied after
completion and copies sent to Ms. Andy Gillespie, Pediatric Oncology Branch, NCI,
FAX: (301)-480-8871, Building 10, Room 13N240, 10 Center Drive, Bethesda, MD 20892-
1928 within 2 weeks of completion of the cycle of therapy. Any questions regarding the
administration of the IPI Scale should be addressed to Pam Wolters, Ph.D. at phone:
301-496-0561, e-mail: pw34m@nih.gov.
3.5
CONCURRENT THERAPY
Other cancer chemotherapy, radiation therapy, immunotherapy, or investigational
agents can not be administered to patients receiving R115777 or placebo.
Alternative Therapy: Oral vitamin or nutritional supplements may be used if
approved by the patient’s primary physician, and should be recorded in the patient’s
history and diary.
Pharmacokinetic data suggest that H2 antagonists and proton pump inhibitors do
not alter the exposure to R115777 to a clinically significant extent. Patients may use
proton pump inhibitors or H2 antagonists during the treatment portion of this study.
However, patients should be instructed to use antacids (Mg- or Al-containing
formulations) AT LEAST 2 hours before or after intake of the oral study drug.
3.6
OFF STUDY CRITERIA
3.6.1 ADMINISTRATIVE: A patient may be taken off the study for the following non-
medical or administrative reasons:
• Patient refusal of further treatments (reasons must be noted on the patient’s CRF).
• It is deemed in the best interest of the patient. In this instance the Principal
Investigator should be notified and the reasons for withdrawal should be noted in
the CRF.
• Serious protocol violation as determined by the PI or representative from CTEP.
3.6.2 TOXICITY: Recurrent grade 3 or 4 toxicity after dose reduction or persistent
toxicity grade ≥2 for >10 days without administration of drug that is considered
primarily related to study drug (Section 3.3). Persistent (>10 days) grade 2 toxicity
should be discussed with the PI prior to removing the patient from the study. The
protocol Principal Investigator and CTEP should be notified immediately in the event of
severe or life-threatening toxicity (Dr. Brigitte Widemann, 301-496-7387, 301-496-1211
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page operator, and CTEP, Investigational Drug Branch (301) 230-2330 (recorder after
hours).
If toxicity necessitates unblinding the study drug for a patient, the patient should
be removed from the study.
3.6.3 TUMOR PROGRESSION: Any patient with clinical or radiographic evidence of
progressive disease (see Section 3.1.5) on treatment “phase A”, as documented by 3D-
MRI, following any treatment cycle will be switched to treatment “phase B” (from
R115777 to placebo or vice versa). After disease progression on both treatment phases,
patients will be removed from study (see Sections 3.1.5 and 5.2). The POB research
nurse must be notified when the patient progresses after “phase A” (crossover
notification to PMB) and when the patient progresses after “phase B” (i.e., off-study
notification to Orkand and PMB) by faxing the completed Tumor Progression Checklist
and the Crossover / Off-Study Form (Appendix 9A/B) to the Pediatric Oncology
Branch (c/o Andy Gillespie) at (301) 480-8871.
3.6.4 The development of a concurrent serious medical condition that might
preclude or contraindicate the further administration of R115777.
3.7
POST-STUDY EVALUATION
The following tests and procedures should be performed, if possible, at the time a
patient comes off study regardless of the reason for coming off study, unless the test or
procedure has been performed in the past 6 weeks (2 weeks for physical examination
and laboratory assessment).
3.7.1 HISTORY & PHYSICAL EXAMINATION (including a neurologic exam,
performance status, and measurement of visible or palpable tumor lesions).
3.7.2 PHOTOGRAPHS of visible lesions (See Section 3.4.2)
3.7.3 LABORATORY ASSESSMENT
Complete blood count, differential and platelet count, PT, and PTT.
Electrolytes, creatinine, calcium, magnesium, phosphorus, SGPT, bilirubin.
Urinalysis.
3.7.4 MRI Scan of the index lesions and any other progressing lesions using the
protocol outlined in Appendix 1.
4.0 SUPPORTIVE CARE
GENERAL: Appropriate antibiotics, blood product support, antiemetics and general
supportive care will be used as indicated.
HEMATOPOIETIC GROWTH FACTORS: Hematopoietic growth factors (e.g., EPO, G-CSF,
GM-CSF) should not be administered except to those patients with either grade 4
neutropenia and blood culture positive septicemia, or grade 4 neutropenia of ≥7 days
duration.
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5.0 DATA COLLECTION AND EVALUATION
5.1 DATA COLLECTION
The POB, NCI will coordinate data collection and supply the data to the trial
sponsor (CTEP) via the CDUS online system. Data will also be entered into the NCI
Center for Cancer Research (CCR) C3D database. Documentation and date of IRB
approval must be provided to CTEP and the POB, NCI prior to initial patient entry
from each institution. The completed Eligibility Checklist and On-Study Form
(Appendix 8 A/B) must be faxed to Ms. Andy Gillespie at (301) 480-8871 prior to
patient entry onto the trial. The completed Tumor Progression Checklist and Crossover
/ Off-Study Form (Appendix 9A/B) must be faxed to Ms. Andy Gillespie at the time a
patient has documented tumor progression on treatment phase “A” and on treatment
phase “B”.
5.1.1 CASE REPORT FORMS
Case Report Forms have been developed by the POB. CRFs should be completed
after each patient evaluation and submitted within 2 weeks of completion of each
evaluation to:
Pediatric Oncology Branch, NCI
c/o Ms. Andy Gillespie
FAX: (301) 480-8871
Bldg. 10/Rm. 13N240
10 Center Drive, MSC 1928
Bethesda, MD 20892-1928
The following forms should be submitted to the POB:
ELIGIBILITY CHECKLIST AND BLINDED PATIENT ON STUDY FORM (APPENDIX 8 A/B): To
be completed at study entry and forwarded to Ms. Andy Gillespie (301) 480-8871
(Phone, 301-402-1848)
PROGRESSION CHECKLIST AND BLINDED PATIENT CROSSOVER / OFF-STUDY FORM
(Appendix 9A/B): To be completed and forwarded to Ms. Andy Gillespie (301) 480-
8871 (Phone, 301-402-1848) when a patient progresses on treatment phase “A” and “B”.
PATIENT DIARIES AND PILL COUNT CASE REPORT FORM (APPENDIX 11A/B): Patients or
their guardians will keep a diary to document the intake of each dose of R115777 or
placebo and potential side effects (Appendix 11A). Each pharmacy will use the Pill
Count Case Report Form (Appendix 11B). The completed diaries and Pill Count Case
Report Forms will be forwarded to Ms. Andy Gillespie after every three treatment
cycles at (301) 480-8871 (Phone, 301-402-1848).
MRI STUDIES (Appendix 1): A copy of the MRI protocol used to obtain the baseline
MRI study should be Faxed to Ms. Andy Gillespie within 1 week of obtaining the MRI
study. MRI studies should be submitted electronically or on CD or optical disk to the
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NCI POB within 1 week of obtaining the study. The institutional radiology report for
each study should be faxed to Ms. Andy Gillespie within 1 week.
QOL ASSESSMENT (NIH IPI SCALE) FORMS: Patient and parent response forms
should be photocopied after completion and copies sent to Ms. Andy Gillespie,
Pediatric Oncology Branch, NCI, FAX: (301)-480-8871, Building 10, Room 13N240, 10
Center Drive, Bethesda, MD 20892-1928 within 2 weeks of completion of the cycle of
therapy. Any questions regarding the administration of the IPI Scale should be
addressed to Pam Wolters, Ph.D. at phone: 301-496-0561, e-mail: pw34m@nih.gov.
LABORATORY STUDIES: Results of laboratory studies requested per protocol should
be faxed to Ms. Andy Gillespie within 1 week of performing the study.
Protocol violations should be directly reported to Dr. Brigitte Widemann (phone:
301-496-7387, fax: 301-480-8871, e-mail: bw42y@nih.gov).
Patients will be identified in all data collection forms and on photographs only by
their initials and study number in an effort to maintain patient confidentiality. All
patient documents, including informed consent and case report forms, will be kept in
designated offices, in locked file cabinets with access only to personnel involved in the
clinical trial. The NCI Center for Cancer Research (CCR) C3D electronic database is
password protected and allow access only to persons directly involved in the clinical
trial. All documents will be stored for at least 2 years after the drug has received
marketing approval, or after the decision has been made not to market the drug.
5.2 RESPONSE CRITERIA
Response is assessed at the time that follow-up 3D-MRI scans are performed (prior
to cycles 4, 7, 10, then q6 cycles). For the purpose of determining the level of response
(complete, partial, minor, etc.) measurements from the follow-up scans are compared to
the tumor size in the pretreatment MRI scan using 3D data analysis. Response
determined using 3D-MRI volumetric analysis will be compared with 2D- and 1D-MRI
measurements.
COMPLETE RESPONSE (CR): A complete resolution of all measurable or palpable soft
tissue tumors for ≥ 4 weeks and no appearance of new lesions.
PARTIAL RESPONSE (PR): A ≥50% reduction in the sum of the volume of all index
lesions for ≥4 weeks.
MINOR RESPONSE (MR): A ≥25% but <50% reduction in the sum of the volume of all
index lesions for ≥4 weeks.
STABLE DISEASE (SD): A <20% increase, and < 25% decrease in the sum of the
volume of all index lesions for ≥4 weeks.
PROGRESSIVE DISEASE (PD):
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• A ≥ 20% increase in the volume (by 3D-MRI) of at least one of the index plexiform
neurofibromas compared to the pretreatment volume measured prior to the start of
the current treatment phase.
• The appearance of new discrete subcutaneous neurofibromas does not qualify for
disease progression.
• Worsening of existing symptoms or the appearance of new symptoms that persist
for more than 7 days and that are felt to be definitely related to the plexiform
neurofibroma should be evaluated by repeating the MRI. Patients should not be
classified as having progressive disease solely on the basis of new or increased
symptoms without discussing the case with the protocol Principal Investigator.
• Patients with other evidence of disease progression than outlined above should also
be discussed with the Principal Investigator.
5.3 TOXICITY CRITERIA
Toxicity will be graded according to the CTEP Expanded Common Toxicity
Criteria, version 2. The Cancer Therapy Evaluation Program Common Toxicity Criteria
(CTC) Version 2.0 will be used for toxicity assessment. A copy of the CTC version 2.0
can be downloaded from the CTEP home page (http://ctep.cancer.gov).
5.4 STATISTICAL CONSIDERATIONS
5.4.1 SUBJECT ACCRUAL
Subjects of both genders, from all racial and ethnic groups are eligible for this trial
if they meet the criteria outlined in Section 2.1. To date, there is no information that
suggests differences in drug metabolism or disease response among racial or ethnic
groups or between the genders, indicating that results of the trial will be applicable to
all groups. Most plexiform neurofibroma grow out of proportion to somatic growth for
a period of time during childhood, but reach a plateau by the end of puberty. Efforts
will be made to extend the accrual to a representative population, but in a phase II
study with limited accrual, a balance must be struck between patient safety
considerations and limitations on the number of individuals exposed to potentially
toxic or ineffective treatments on the one hand and the need to explore gender, racial,
and ethnic aspects of clinical research on the other. If differences in outcome that
correlate to gender, age, racial, or ethnic identity are noted, accrual may be expanded or
additional studies may be performed to investigate those differences more fully.
5.4.2 STATISTICS AND FEASIBILITY
The primary objective of the study is to determine whether R115777 (“drug”) is
able to increase the time to progression of patients who have NF1 with progressive
plexiform neurofibromas. The study will be conducted as a crossover, two-arm
randomized, double-blind, placebo controlled trial. After being randomized to drug or
placebo, patients will be followed until progression. Once patients have progressed
(documented by MRI), they will be crossed over to receive the placebo if they originally
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received drug, and drug if they originally received placebo. Because the time until
crossover is dependent on time until progression, this differs from a classic crossover
study, in which patients are followed on both treatment arms for a predetermined fixed
period of time, evaluated, given a wash-out period, and then followed identically on the
other agent. As such, results from the first placebo vs. drug period will be used to
determine sample size, and will constitute the primary endpoint of time to disease
progression. The natural history of the growth rate and range of plexiform
neurofibromas is not well known. In addition to the analysis of time to disease
progression on the first treatment phase, a paired comparison of the first and second
treatment phase (each patient will serve as his/her own control) will be performed
using appropriate non parametric methods. This analysis will also help provide
additional information on the differences in the natural history of NF1, and also address
the effect of other variables, for example age differences, which may impact on the
growth rate of plexiform neurofibromas.
Because the estimate of time to progression for patients eligible for this trial is
approximately 6 months, it would be desirable to increase this time to 12 months. A
one-tailed hypothesis will be used since it would only be considered interesting to see
the improvement of drug compared to placebo. With 80% power and a one-tailed
alpha=0.05, in order to detect a difference in median time to progression (during the
first part of the trial) between the two arms of 6 vs. 12 months, 30 patients per arm are
required (60 total) assuming 36 months of accrual and 12 months of additional follow-
up following entry of the last patient. Kaplan-Meier analysis using log-rank statistics
will be used to perform the required evaluation. We plan to replace patients who were
diagnosed with a malignant peripheral nerve sheath tumor (MPNST) after enrolling on
study, as these patients will not be evaluable for the primary outcome measure, which
is time to progression of progressive plexiform neurofibromas. For this reason we will
increase the accrual ceiling to 63 patients
Randomization of patients between the two study arms will be performed
centrally by Orkand (See Section 3.1.1, 3.1.2). With more than one institution
participating, it is expected that 20 patients per year can be entered onto the trial, with
an expected accrual period of 3 years.
This trial will be monitored by the NCI/DCS Data Safety and Monitoring Board.
Due to the projected accrual rate, it is expected that 3 interim evaluations and a final
evaluation will take place at each of 4 consecutive annual meetings of the DSMB. Using
the O’Brien-Fleming approach, if the p-values at the following evaluations are less than
or equal to those tabled below, then the trial would be declared to have a statistically
significant result; no further accrual would be required once such a determination has
been made.
Evaluation #
Threshold p-Value
(one-tailed)
1
0.00005
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2
0.0039
3
0.0184
4 (FINAL)
0.0412
In addition, if, at any annual evaluation, a conditional power analysis indicates that
there is a minimal chance of declaring a significant advantage to drug with the addition
of the remaining planned patients based on results to date and the hypothesized results,
then the DSMB may choose to close the study to further accrual.
Time to progression between the two study arms will be compared separately for
the two periods of the cross-over study; initial treatment and second (crossover)
treatment. Both comparisons will be reported in order to describe the effect of drug on
this endpoint. In addition, because each patient will have received both placebo and
drug, comparisons of time to progression can be undertaken between both treatment
conditions, employing methodology for paired subject data in order to further interpret
the findings.
The quality of life of patients treated with R115777 and placebo on this study will
be assessed using the National Institutes of Health (NIH) Impact of Pediatric Illness
(IPI) Scale (Section 1.2.8), and scores of patients will be compared using the paired t-test.
5.5
MULTI-INSTITUTIONAL GUIDELINES
5.5.1 IRB APPROVALS
The PI from each participating institution will provide the Study Coordinator
with a copy of the initial IRB protocol approval and the yearly IRB continuing
reviews, and the Study Coordinator will submit these to the NCI IRB.
Registration will be halted at a participating institution if a current continuing
approval is not on file at the NCI IRB.
5.5.2 AMENDMENTS AND CONSENTS
The PI from each participating institution will provide the Study
Coordinator with a copy of IRB approval of all amendments to the
protocol or consent, and the Study Coordinator will submit these
institutional reviews to the NCI IRB.
5.5.3 PATIENT REGISTRATION
All patients entered at the POB, NCI will be registered with the DCS
Central Office (ORKAND). The completed eligibility checklist and On-
Study Form (Appendix 8 A/B) must be FAXed to the POB prior to
enrollment on the trial.
5.5.4 DATA COLLECTION AND TOXICITY REPORTING
The trial is being sponsored by CTEP and monitored through the CDUS
system. Case report forms developed by the Pediatric Oncology Branch
will be used for submitting clinical data to the coordinating center and this
data will be entered into the NCI CCR C3D database. Data must be
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submitted to the Coordinating Center within 2 weeks of completing each
treatment cycle while the patient is on treatment. All adverse events from
participating institutions will be submitted to the NCI IRB by the Study
Coordinator.
5.5.5 DATA AND CENTER AUDITS
The trial will be audited by the trial sponsor CTEP for compliance and
safety. In addition, the NCI CCR will audit this trial via contract for
compliance and safety. Volumetric MRI analysis will be used to
determine the primary study endpoint, which is disease progression. The
volumetric analysis for all measurements will be performed centrally at
the NCI, POB with Dr. N. Patronas serving as the responsible
neuroradiologist for this trial.
6.0 HUMAN SUBJECTS PROTECTIONS
6.1 RATIONALE FOR SUBJECT SELECTION
Neurofibromatosis type 1 is a genetic disorder and the incidence of the disease in
the various racial and ethnic groups may vary. This may impact on our ability to recruit
sufficient numbers of patients within each group to this trial. Subject accrual in regards
to gender, and racial and ethnic groups is described in Section 5.4.1. None of these
groups are being excluded from participation in the trial. Females who are pregnant or
breast feeding will not be eligible for entry onto the trial because of the potential and
unknown risks that R115777 could pose to the fetus or newborn. This trial is designed
to determine the activity of R115777 in childhood with NF1 and plexiform
neurofibromas and, therefore, children will be entered onto this research trial. Patients
who are ≥18 years will be offered the opportunity to assign DPA prior to study entry.
6.2
PARTICIPATION OF CHILDREN
This trial is designed to study the effect of R115777 on time to disease progression
in children and young adults with progressive plexiform neurofibromas. Therefore
children who meet eligibility criteria for this trial will be entered in the study. Children
will be evaluated and cared for by physicians trained in pediatrics and pediatric
oncology, and will be followed in the Pediatric Oncology Branch clinic.
6.3 EVALUATION OF BENEFITS AND RISKS/DICOMFORTS
This trial will be a randomized, cross-over, double-blinded, placebo-controlled
pediatric phase II trial of oral R115777 in children and young adults with NF1 who have
progressive plexiform neurofibroma(s). Each patient will serve as his/her own control
for the primary endpoint of time to progression. Because of the unpredictable nature of
tumor growth in NF1, alternative designs without placebo control could bias
observation, and there is no standard treatment to which R115777 may be compared. In
addition, each patient will receive study medication provided there is disease
progression, and therefore may derive benefit from the trial. R115777 is a
farnesyltransferase inhibitor. It was designed to inhibit the farnesylation of ras and
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44
therefore inhibit the activity of mutated ras proteins. However, it may also be useful for
other mutations upstream from the farnesylation of ras, such as is found in patients
with NF1. Since neurofibromin, the product of the NF1 gene, is decreased in tumors
from patients with NF1, and since this is associated with a constituitively activated ras
protein, R115777 is a rational therapeutic approach for patients with plexiform
neurofibromas. The potential benefit from participation in this trial is the stabilization
or reduction in the size of the tumor(s), relief of symptoms caused by the tumor(s), and
prolongation of life. The primary risk to the subjects from participation in this trial is
from R115777 toxicity (primarily myelosuppression). Toxicities from R115777 are
outlined in Section 1.2.5, 1.2.6, and 8.1.9 and have been reversible when they occur. The
attempt will be made to obtain tumor biopsies from easily accessible tumor nodules at
several time points during the study to answer study related research questions. Tumor
samples will be contributed to a central tissue repository, and will be made available to
researchers who obtain IRB approval to study additional research questions. Samples
will be identified by a code number that can be traced to the patient only by contacting
the trial coordinating center. However, as the tumor sample is linked to the patient’s
name, a small risk persists that unauthorized persons could gain access to information.
Some testing may eventually reveal information that, could result in discrimination
with health or life insurance or employment. We believe that these risks are minimal
since it is already known that patients enrolled on the study have neurofibromatosis.
All research results will be kept confidential. Patients who do not give permission for
tumor biopsies will still be eligible for the treatment part of this study. Patients also
have the right to withdraw the tumor specimen from the tissue repository at any time.
6.4 RISK/BENEFIT ANALYSIS
The primary objective of this phase II trial is to define the time to progression of
plexiform neurofibromas treated with R115777 or placebo, and thus patients entered on
the trial will be treated with therapeutic intent and response to the therapy will be
closely monitored. Therefore, this protocol involves greater than minimal risk to
children, but presents the potential for direct benefit to individual subjects. Although
patients will be treated with placebo, the risk of placebo is minimal and no other
standard therapy is available. In addition, all patients will receive R115777, provided
there is disease progression on the first treatment phase.
6.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The investigational nature and objectives of this trial, the procedures and
treatments involved and their attendant risks and discomforts and benefits, and
potential alternative therapies will be carefully explained to the patient or the patient’s
parents or guardian if he/she is a child, and a signed informed consent document will
be obtained. The investigators have received a waiver from the IRB to allow only one
parent to sign the informed consent to enter a child on the protocol. Because many
patients must travel to the clinical site from long distances at substantial expense,
requiring both parents to be present for the consent process could be a financial
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45
hardship for many families. Consent will be obtained by the PI or an associate
investigator on the trial. Where deemed appropriate by the clinician and the child’s
parents or guardian, the child will also be included in all discussions about the trial.
Age appropriate assent forms for children from 7 through 12 years, and for children
from 13 through 17 years have been developed and will be signed by the pediatric
patients in order to obtain written assent. This is a multi-institutional trial, and the NCI
as coordinating center will require evidence of local IRB approval of the protocol prior
to allowing for accrual of patients at that institution. This trial will be conducted in
compliance with the protocol, Good Clinical Practice (GCP) and the applicable
regulatory requirements.
6.6 HANDLING OF RESEARCH SAMPLES
This study is conducted at and coordinated by the Pediatric Oncology Branch, NCI.
Sample labeling, collection and initial processing will be conducted as outlined in the
study Section 3.4 6, 3.4.7, and 3.4.8, as well as in Appendices 2 to 6. Tumor samples sent
to the central tissue procurement facility at Washington University will be handled as
described in Section 3.4.6 and in Appendix 2. Should tumor sample be left after
completion of research studies described in the protocol, prospective approval from the
IRB with oversight of the tissue bank will be obtained prior to performing additional
studies. This is also described in the informed consent. Blood samples sent to the NCI
for analysis of farnesyltransferase activity (Section 3.4.7, Appendix 5), or for nerve
growth factor analysis (Section 3.4.8, Appendix 6) will be stored in designated
monitored freezers at -70°C or -20°C as indicated in the protocol in the Pharmacology &
Experimental Therapeutics Section (PETS) Laboratory, POB, NCI on 1 West. Samples
will identified by protocol specific patient ID number, and will be tracked using the
PETS
pharmacokinetics
filemaker
database.
Samples
will
be
analyzed
for
farnesyltransferase activity and nerve growth factor at the NCI, POB and be considered
the responsibility of Brigitte Widemann, MD. Once analyzed for studies outlined in this
protocol any remaining samples will be stored by the POB, NCI until the study is
complete, and the manuscript describing the study has been accepted for
publication. At this point remaining samples will be destroyed. The study will remain
open and status reported to the NCI IRB until all samples have been analyzed, reported
or destroyed. Unintentional loss or destruction of any samples will be reported to the
NCI IRB as part of annual continuing reviews. Any use of samples not outlined in
Sections 3.4.7 and 3.4.8 or in Appendices 5 and 6 will require prospective NCI IRB
review and approval.
7.0 DATA REPORTING
Unless otherwise stated, all forms should be submitted to:
Andy Gillespie , R.N.
Pediatric Oncology Branch, National Cancer Institute
Building 10/Room 13N240, 10 Center Drive
Bethesda, MD 20892
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46
Phone (301) 402-1848
FAX (301) 480-8871
7.1 PATIENT REGISTRATION AND RANDOMIZATION
See Section 3.1.2 and Appendix 10. The eligibility checklist is in Appendix 8 A/B.
7.2
CASE REPORT FORMS
The POB will provide Case Report Forms for recording relevant clinical data for
each patient entered on the trial (Section 5.1). The Progression Checklist (Appendix
9A/B) must be submitted before patients can be crossed over from phase A to phase B
(see Appendix 10). Patient diaries and Pill Count Case Report Forms (Appendix
11A/B) should be provided to patients and their families and submitted after
completion with the label from the patient’s prescription attached after completion of
every 3 treatment cycles.
7.3
SAFETY REPORTING
7.3.1 ADVERSE EVENTS
Adverse events are any unfavorable and unintended sign (including an abnormal
laboratory finding) symptom or disease temporally associated with the use of a medical
treatment or procedure regardless of whether it is considered related to the medical
treatment or procedure (attribution of unrelated, unlikely, possible, probable or
definite).
Life-threatening adverse events are any adverse event that places the patient or
subject, in view of the investigator at an immediate risk of death from the reaction.
Serious adverse events are any adverse event occurring at any dose that result in
any of the following outcomes: Death, a life-threatening adverse event, inpatient
hospitalization or prolongation of existing hospitalization, a persistent or significant
disability/incapacity, a congenital anomaly/birth defect, and other medically
significant events.
Unexpected adverse events are any adverse events, which are not listed in the
Agent Specific Adverse Event List (ASAEL) which is a subset of the Comprehensive
Adverse Events and Potential Risks List (CAEPR).
Expected adverse events are those events listed in the Agent Specific Adverse
Event List (ASAEL) which is a subset of the Comprehensive Adverse Events and
Potential Risks List (CAEPR) (Section).
All observed or volunteered adverse events, regardless of treatment group or
suspected causal relationship to study drug, will be recorded on the Adverse Event
page(s) of the case report form. Events involving adverse drug reactions, illnesses with
onset during the study, or exacerbation of pre-existing illnesses should be recorded.
Objective test findings (e.g., electrocardiogram changes, abnormal laboratory test
results) that result in a change in study drug dosage should also be recorded.
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Adverse events should be graded according to the CTEP Common Toxicity
Criteria version 2, which can be downloaded from http://ctep.cancer.gov. Next it will
be determined if the adverse event is related to the medical treatment (attribution). If so,
it will be determined whether the adverse event is expected or unexpected. Using the
guidelines outlined in Section 7.3.2 adverse events will then be reported to the NCI
using a routine report (CDUS), and if required, the Adverse Event Expedited Reporting
System (AdEERS), an electronic system for expedited submission of adverse event
reports, in addition to the CDUS.
The adverse event page will contain information if the reported event was
expected or unexpected, and if the reported toxicity is included in the informed consent.
A justification will be provided on the adverse event page if the observed toxicity in not
included in the informed consent. For all adverse events, the investigator must pursue
and obtain information adequate both to determine the outcome of the adverse event
and to assess whether it meets the criteria for classification as a serious adverse event
requiring immediate notification to the sponsor. Follow-up of the adverse event, even
after the date of therapy discontinuation, is required if the adverse event or its sequelae
persist. Follow-up is required until the event or its sequelae resolve or stabilize at a level
acceptable to the investigator and sponsor.
7.3.2 ADVERSE EVENT REPORTING
The NCI/DCTD requirements for reporting Adverse Events (AE) will be followed.
All serious adverse events, and the adverse events outlined in the table below
regardless of attribution require expedited reporting.
Expedited AE reporting for this study must use AdEERS (Adverse Event
Expedited
Reporting
System),
accessed
via
the
CTEP
home
page
(http://ctep.cancer.gov). The reporting procedures to be followed are presented in the
“CTEP, NCI Guidelines: Adverse Event Reporting Requirements” which can be
downloaded from the CTEP home page (http://ctep.cancer.gov).
In the rare occurrence when Internet connectivity is lost, an AE report may be
submitted using CTEP's Adverse Event Expedited Report-Single Agent or Multiple
Agent paper template (available at http://ctep.cancer.gov) and faxed to 301-230-0159.
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497, only when
Internet connectivity is disrupted. Once Internet connectivity is restored, an AE report
submitted on a paper template or a 24-hour notification phoned in must be entered
electronically into AdEERS by the original submitter at the site.
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Phase 2 and 3 Trials utilizing an Agent under a CTEP IND: AdEERS Reporting
Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of the
Investigational Agent
Grade 1
Grade 2
Grade 2
Grade 3
Grade 3
Grades
4 & 5
2
Grades
4 & 5
2
Unexpected
Expected
Unexpected
and
Expected
Unex-
pected
Expected
with
Hospitali-
zation
without
Hospitali-
zation
with
Hospitali-
zation
without
Hospitali-
zation
Unex-
pected
Expected
Unrelated
Unlikely
Not
Required
Not
Required
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
10
Calendar
Days
Possible
Probable
Definite
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
10
Calendar
Days
10
Calendar
Days
Not
Required
24-Hour;
5 Calendar
Days
10
Calendar
Days
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last
dose of treatment with an agent under a CTEP IND require reporting as follows:
AdEERS 24-hour notification followed by complete report within 5 calendar days for:
•
Grade 4 and Grade 5 unexpected events
AdEERS 10 calendar day report:
•
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
•
Grade 5 expected events
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is
required as outlined in the table.
December 15, 2004
Note: All deaths on study must be reported using expedited reporting regardless of
causality. Attribution to treatment or other cause should be provided.
•
Expedited AE reporting timelines defined:
¾ “24 hours; 5 calendar days” – The investigator must initially report the AE via
AdEERS within 24 hours of learning of the event followed by a complete
AdEERS report within 5 calendar days of the initial 24-hour report.
¾ “10 calendar days” - A complete AdEERS report on the AE must be submitted
within 10 calendar days of the investigator learning of the event.
•
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates
hospitalization (or prolongation of existing hospitalization) must be reported
regardless of attribution and designation as expected or unexpected with the
exception of any events identified as protocol-specific expedited adverse event
reporting exclusions.
•
Any event that results in persistent or significant disabilities/incapacities,
congenital anomalies, or birth defects must be reported via AdEERS if the event
occurs following treatment with an agent under a CTEP IND.
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•
Use the NCI protocol number and the protocol-specific patient ID provided
during trial registration on all reports.
•
The Comprehensive Adverse Events and Potential Risks List (CAEPR), the
Agent Specific Adverse Event List (ASAEL), and a list of toxicities with yet
undetermined relationship to R115777 can be found in the protocol in Section
8.1.11.
A list of all known toxicities can be found in the protocol document (Section 8) or
consent form.
Reactions judged definitely not treatment related should not be reported.
However, a report should be submitted if there is reasonable suspicion of drug effect.
Hospitalizations for procedures judged definitely not treatment related do not require
expedited reporting.
All reportable adverse events (as defined above), regardless of treatment group
or suspected relationship to study drug, must be reported to:
Brigitte Widemann, M.D.
Pediatric Oncology Branch
10 Center Drive, 10-CRC, Room 1-5750
Bethesda, MD 20892
Phone: (301) 496-7387
FAX: (301) 402-0575
E-mail: bw42Y@nih.gov
All serious adverse events (as defined in Section 7.3) for NCI patients must be
reported to the Institutional Principal Investigator, Dr. Brigitte Widemann, M.D.,
within 7 days (see contact information above).
The NCI Protocol PI will report to the NCI-IRB:
• All serious adverse events (SAEs) that are not in the consent form, but are
possibly, probably or definitely related to the research. A SAE is defined as an
untoward medical occurrence that
o resulted in a death;
o was life-threatening;
o required or prolonged hospitalization;
o caused persistent or significant disability/incapacity;
o resulted in congenital anomalies or birth defects; or
o required intervention to prevent permanent impairment or death.
• All other deaths that occur within 30 days of receiving R115777/placebo.
• All grade 3 and 4 (CTC v3) events that are not in the consent and that are
possibly, probably or definitely related to the research.
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Reports must be received by the NCI-IRB within 7 days of notification of the event.
Forms for submission of an AE to CTEP/NCI/DCTD and the POB/NCI can be
obtained from the CTEP website at http://ctep.cancer.gov.
The NCI POB will distribute Adverse Event Expedited Reports distributed by
CTEP to responsible Investigators at participating sites.
7.4 ASSURANCES
Each participating institution is required to maintain a current Multiple Project
Assurance in order to participate in government-sponsored Group research. The files
will be copied or made available for review by authorized persons as required for
conduct of this trial.
7.5 IRB APPROVALS
As the coordinating center for this clinical trial, the POB will be responsible for
verifying Institutional Review Board (IRB) approval of the protocol. Each participating
institution must provide a copy of their IRB approval to the POB before that center can
enter and register a patient on study. The participating institutions must also provide
the POB with a copy of documentation that the protocol has undergone yearly IRB
review and a copy of IRB approvals for any protocol amendments.
7.6 PATIENT DATA REPORTING AND AUDITS
Clinical data from patients treated on this trial will be submitted to the POB on the
provided case report forms and will be entered into the CCR C3D database by POB data
managers/research nurses. The study will be monitored by Clinical Data Update
Systems (CDUS) version 1.1. Cumulative CDUS data will be submitted quarterly to
CTEP by electronic means. Reports are due to CTEP Jan 31, April 30, July 31, and
October 31. 3-D MRI analysis for assessing the volume of plexiform neurofibromas will
be performed centrally. The NCI Clinical Trials Monitoring Service (CTMS) may
independently audit selected charts on patients who are treated on this trial. Selected
patient charts to be audited must be sent to the POB from participating institutions. In
addition, the NCI CCR will audit this trial via contract for compliance and safety.
8.0 PHARMACEUTICAL INFORMATION
8.1 R115777 AND PLACEBO
R115777 with matching placebo will be provided to study participants free-of-
charge by the Janssen Research Foundation and distributed by the Pharmaceutical
Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), Division of
Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).
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Note that this study involves a crossover from R115777 to placebo (Arm 1) or
from placebo to R115777 (Arm 2). The medication for the first phase (initial
randomization) will be labeled as “Phase A”, and the medication for the second
phase (crossover randomization) will be labeled as “Phase B”, regardless of which
arm the patient is randomized to. When dispensing the medication, please be certain
that the physician has specified on the prescription (1) the patient ID number [e.g.,
‘01C0222-01’]; (2) the patient initials [e.g., ‘ABC’ = first three letters of the patient’s
last name]; (3) the phase [i.e., “Phase A” or “Phase B”]; (4) the body surface area [in
m2]; and (5) the dose [i.e., “___mg po q12h”]. Check to be certain that the patient ID
number and phase specified on the patient’s box(es) of medication correspond to the
patient ID number and phase specified on the patient’s prescription. If the patient
ID number or phase is missing from the patient’s prescription, you must contact the
physician!
R115777 (NSC 702818 / IND #58359) and matching placebo will be supplied in
blister packages in a cardboard box. Each box will contain 70 – 50mg tablets and will be
sealed with a tamper-evident seal. Each box will be labeled with:
• the protocol number (i.e., ‘T99-0090’)
• the patient ID number (e.g., ‘01C0222-01’ where ‘01C0222’ represents the NIH
Clinical Center protocol number and ‘01’ represents a patient sequence number
assigned at registration)
• the patient initials (e.g., ‘ABC’ = first three letters of the patient’s last name)
• a blank line for the patient’s name
• the phase (i.e., ‘Phase A’ or ‘Phase B’)
• the agent identification (i.e., ‘R115777 50mg or Placebo’)
• the number of tablets (i.e., ‘70 tablets’)
• administration instructions (i.e., ‘Take ___ tablets every 12 hours after meals.’)
• storage instructions (i.e., ‘Store at controlled room temperature [59° to 77° F].
Protect from moisture.’)
• emergency contact instructions
• a Julian date
At the time the box is dispensed to the patient, the pharmacist should enter the
patient’s name and the number of tablets (based on the patient’s BSA / prescribed dose)
in the spaces provided.
BSA
(m2)
R115777 / Placebo
(mg po q12h)
R115777 / Placebo
(# of 50 mg tablets po
q12h)
3-cycle supply
(# of boxes of 70 tablets
provided)
0.00 - 0.37
50
1
2
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0.38 - 0.62
100
2
4
0.63 - 0.87
150
3
6
0.88 - 1.12
200
4
8
1.13 - 1.37
250
5
9
1.38 +
300
6
11
The Julian date indicates the day the box was labeled and shipped and is
composed of the last two digits of the calendar year (e.g., 2001 = 01, 2002 = 02) and a
day count (e.g., January 1 = 001, December 31 = 365). For example, a box labeled and
shipped on January 1, 2001 would have a Julian date of ‘01001’ and a box labeled and
shipped on December 31, 2002 would have a Julian date of ‘02365’. The Julian date will
be used by PMB for recalls. When a lot expires, PMB will determine the last date the
expired lot was shipped and will recall all boxes (i.e., both R115777 and placebo)
shipped on or before that date thus eliminating any chance of breaking the blind.
8.1.1 CHEMICAL NAME: R115777 is a methyl-quinolone. The full chemical name is
(R)-6-[amino(4-chlorophenyl) (1-methyl –1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-
1-methyl-2(1H)-quinolinone.
8.1.2 CHEMICAL STRUCTURE:
Cl
N
O
NH 2
N
N
Cl
CH 3
H 3C
8.1.3 MOLECULAR FORMULA: C27H22Cl2N4O
8.1.4 MOLECULAR WEIGHT: 489.4
8.1.5 FORMULATION: Supplied as a film-coated compressed tablet containing
either 50mg of R115777 (active) or 0 mg of R115777 (placebo) with lactose,
unmodified maize starch, hypromellose, microcrystalline cellulose, crospovidone,
colloidal silicon dioxide, and magnesium stearate. The coating contains
hypromellose, propylene glycol, titanium dioxide, and talc.
8.1.6 STORAGE: Store at room temperature (59° to 77° F) and protect from
moisture.
8.1.7 STABILITY: Shelf life surveillance studies are ongoing.
8.1.8 ROUTE OF ADMINISTRATION: Oral. The bioavailability of the tablet
increases under the influence of a meal. Based on these findings, it is advised to
administer the tablets of R115777 immediately after a meal. The tablets may be
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53
crushed if a patient is unable to swallow the intact tablet; however, the entire tablet
must be administered.
8.1.9 Dose: For this protocol, the dose of R115777 is 200mg/m2 (rounded to the
nearest 50mg) orally after meals every 12 hours for 21 days followed by a 7 day rest
period for a cycle length of 28 days. Cycles are repeated until the patient progresses.
8.1.10 Drug Interactions: Pharmacokinetic data suggest that H2 antagonists and
proton pump inhibitors do not alter the exposure to R115777 to a clinically
significant extent. Patients may use proton pump inhibitors or H2 antagonists during
the treatment portion of this study. However, patients should be instructed to use
antacids (Mg- or Al-containing formulations), e.g., Maalox or Mylanta AT LEAST 2
hours before or after intake of the oral study drug.
8.1.11 KNOWN TOXICITIES:
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single,
complete list of reported and/or potential adverse events (AE) associated with an agent
using a uniform presentation of events by body system. In addition to the
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in
a separate column and is identified with bold and italicized text. This subset of AEs
(ASAEL) contains events that are considered ‘expected’ for expedited reporting
purposes only. Refer to the “CTEP, NCI Guidelines: Adverse Event Reporting
Requirements” http://ctep.cancer.gov/reporting/adeers.html for further clarification.
Frequency is provided based on 2702 patients. Below is the CAEPR for R115777.
Version 2.0, March 2, 2009
Adverse Events with Possible
Relationship to Tipifarnib (R115777)
(CTCAE 3.0 Term)
[n= 2702]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
Agent Specific Adverse Event
List
(ASAEL)
BLOOD/BONE MARROW
Hemoglobin
Hemoglobin
Leukocytes (total WBC)
Leukocytes (total WBC)
Lymphopenia
Neutrophils/granulocytes
(ANC/AGC)
Neutrophils/granulocytes
(ANC/AGC)
Platelets
Platelets
CARDIAC GENERAL
Hypotension
CONSTITUTIONAL SYMPTOMS
Fatigue (asthenia, lethargy,
malaise)
Fatigue (asthenia, lethargy,
malaise)
Fever (in the absence of neutropenia, where
neutropenia is defined as ANC <1.0 x
10e9/L)
Fever (in the absence of
neutropenia, where neutropenia
is defined as ANC <1.0 x 10e9/L)
Insomnia
DERMATOLOGY/SKIN
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Photosensitivity
Photosensitivity
Rash/desquamation
Rash/desquamation
GASTROINTESTINAL
Anorexia
Anorexia
Constipation
Constipation
Dehydration
Diarrhea
Diarrhea
Heartburn/dyspepsia
Heartburn/dyspepsia
Mucositis/stomatitis
(functional/symptomatic) - Select
Mucositis/stomatitis
(functional/symptomatic) - Select
Nausea
Nausea
Vomiting
Vomiting
HEMORRHAGE/BLEEDING
Hemorrhage, CNS
Hemorrhage, pulmonary/upper respiratory -
Nose
Petechiae/purpura (hemorrhage/bleeding
into skin or mucosa)
INFECTION
Febrile neutropenia (fever of unknown
origin without clinically or
microbiologically documented
infection)(ANC <1.0 x 10e9/L, fever >=38.5
degrees C)
Infection (documented clinically or
microbiologically) with Grade 3 or 4
neutrophils (ANC <1.0 x 10e9/L) - Select
Infection (documented clinically
or microbiologically) with Grade
3 or 4 neutrophils (ANC <1.0 x
10e9/L) - Select
Infection with normal ANC or Grade 1 or 2
neutrophils - Select
Infection with normal ANC or
Grade 1 or 2 neutrophils - Select
Infection with unknown ANC - Select
Infection with unknown ANC -
Select
LYMPHATICS
Edema: limb
METABOLIC/LABORATORY
Bilirubin (hyperbilirubinemia)
Bilirubin (hyperbilirubinemia)
Creatinine
Creatinine
Lipase
Lipase
Potassium, serum-low (hypokalemia)
Potassium, serum-low
(hypokalemia)
NEUROLOGY
Confusion
Confusion
Dizziness
Dizziness
Neuropathy: sensory
Neuropathy: sensory
Somnolence/depressed level of
consciousness
PAIN
Pain - Abdomen NOS
Pain - Abdomen NOS
Pain - Chest/thorax NOS
Pain - Head/headache
Pain - Head/headache
Pain - Pain NOS
PULMONARY/UPPER RESPIRATORY
Cough
Dyspnea (shortness of breath)
Dyspnea (shortness of breath)
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RENAL/GENITOURINARY
Renal/Genitourinary - Other (Renal
insufficiency)
Renal/Genitourinary - Other
(Renal insufficiency)
1
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This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal
Investigators at the time of revision. The current version can be obtained by contacting:
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included
in the e-mail.
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Also reported on tipifarnib (R115777) trials but with the relationship to tipifarnib (R115777) still
undetermined:
ALLERGY/IMMUNOLOGY – Allergic rhinitis (including sneezing, nasal stuffiness, postnasal
drip)
BLOOD/BONE MARROW – Blood/Bone Marrow – Other (leukocytosis)
CARDIAC ARRHYTHMIA – Palpitations; Supraventricular and nodal arrhythmia ‐ Atrial
fibrillation; Supraventricular and nodal arrhythmia ‐ Sinus tachycardia; Supraventricular and
nodal arrhythmia ‐ Supraventricular tachycardia; Ventricular arrhythmia ‐ Ventricular
tachycardia
CARDIAC GENERAL – Cardiopulmonary arrest, cause unknown (non‐fatal); Left ventricular
systolic dysfunction
COAGULATION – PTT (Partial Thromboplastin Time)
CONSTITUTIONAL SYMPTOMS – Rigors/chills; Sweating (diaphoresis); Weight loss
DERMATOLOGY/SKIN – Dry skin; Hair loss/alopecia (scalp or body); Pruritus/itching
ENDOCRINE – Hot flashes/flushes
GASTROINTESTINAL – Dry mouth/salivary gland (xerostomia); Flatulence; Gastrointestinal –
Other (polydipsia); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation);
Obstruction, GI ‐ Small bowel NOS; Taste alteration (dysgeusia)
HEMORRHAGE/BLEEDING – Hematoma; Hemorrhage, GI ‐ Oral cavity; Hemorrhage, GI –
Upper GI NOS
HEPATOBILIARY/PANCREAS – Liver dysfunction/failure (clinical)
INFECTION – Opportunistic infection associated with >=Grade 2 Lymphopenia
LYMPHATICS – Lymphatics ‐ Other (localized lymphadenopathy)
METABOLIC/LABORATORY – Alkaline phosphatase; ALT, SGPT (serum glutamic pyruvic
transaminase); AST,SGOT (serum glutamic oxaloacetic transaminase); Amylase; Calcium,
serum‐high (hypercalcemia); Glucose, serum‐high (hyperglycemia); Magnesium, serum‐low
(hypomagnesemia); Potassium, serum‐high (hyperkalemia); Sodium, serum‐low
(hyponatremia); Triglyceride, serum‐high (hypertriglyceridemia)
MUSCULOSKELETAL/SOFT TISSUE – Muscle weakness, generalized or specific area (not
due to neuropathy)
NEUROLOGY – Ataxia (incoordination); Extrapyramidal/involuntary movement/restlessness;
Memory impairment; Mood alteration – Agitation; Mood alteration ‐ Anxiety; Mood alteration ‐
Depression; Neuropathy: motor; Psychosis (hallucinations/delusions); Seizure; Syncope
(fainting); Tremor
OCULAR/VISUAL– Dry eye syndrome; Ocular/Visual ‐ Other (abnormal vision)
PAIN – Pain ‐ Back; Pain ‐ Bladder; Pain ‐ Bone; Pain ‐ Joint; Pain ‐ Muscle
PULMONARY/UPPER RESPIRATORY – Hiccoughs (hiccups, singulitus); Hypoxia;
Pneumonitis/pulmonary infiltrates; Voice changes/dysarthria (e.g., hoarseness, loss or alteration
in voice, laryngitis)
RENAL/GENITOURINARY – Urine color change
VASCULAR – Phlebitis (including superficial thrombosis); Thrombosis/thrombus/embolism
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Note: Tipifarnib (R115777) in combination with other agents could cause an exacerbation of any
adverse event currently known to be caused by the other agent, or the combination may result
in events never previously associated with either agent.
8.2 DRUG
ORDERS,
TRANSFERS,
RETURNS,
ACCOUNTABILITY
/
EMERGENCY
UNBLINDING
Questions about drug orders, transfers, returns, or accountability should be
addressed to the PMB by calling (301) 496-5725 Monday through Friday between
8:30am and 4:30pm Eastern Time.
8.2.1 DRUG ORDERS: No starter supplies will be available for this study. Orkand
will notify the PMB (see Section 3.1.2 and Appendix 8A/B) when a patient is registered
by the Pediatric Oncology Branch research nurse. Using the “On-Study Form” in
Appendix 8B, Orkand will provide the protocol number (i.e., T99-0090), the patient ID /
sequence number (e.g., ‘01C0222-01’), the patient initials (e.g., ‘ABC’ = first three letters
of the patient’s last name), and the patient’s BSA (in m2). Based on the patient’s BSA,
the PMB will ship an initial three month patient-specific supply (see table in Section 8.1)
for “Phase A” to the registering site.
Two months after the initial request (i.e., one month before needed), clinical sites
may reorder an additional three month supply by completing an NCI Clinical Drug
Request form and faxing it to the PMB at 301-480-4612. The NCI Clinical Drug Request
form is available on the CTEP home page (http://ctep.cancer.gov) or by calling the PMB
at 301-496-5725. The patient ID number (e.g., ‘01C0222-01’) and patient initials (e.g.,
‘ABC’) should be entered in the “Patient or Special Code” field. In addition, the
patient’s BSA must be provided. All drug orders should be shipped directly to the
physician responsible for treating the patient.
When the patient progresses on Phase A, the Pediatric Oncology Branch research
nurse will notify the PMB (see Section 3.1.2 and Appendix 9A/B). Based on the
patient’s BSA, the PMB will again ship an initial three month patient-specific supply
(see table in Section 8.1) for Phase B to the registering site. Any remaining supplies for
Phase A should be returned immediately on receipt of supplies for “Phase B” (see
Section 8.2.3).
8.2.2 DRUG TRANSFERS: Boxes MAY NOT be transferred from one patient to
another patient or from one protocol to another protocol. All other transfers (e.g., a
patient moves from one participating center to another participating center, the
principal investigator at a participating center changes, etc) must be approved in
advance by the PMB. To obtain an approval for transfer, investigators should complete
and submit to the PMB (fax number 301-480-4612) a Transfer Investigational Agent
Form available on the CTEP home page http://ctep.cancer.gov, or by calling the PMB
at 301-496-5725. The patient ID number (e.g., ‘01C0222-01’) and patient initials (e.g.,
‘ABC’) should be entered in the “Received on NCI Protocol No.” and the “Transferred
to NCI Protocol No.” fields in addition to the protocol number (i.e., T99-0090).
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8.2.3 DRUG RETURNS: All unused drug supplies should be returned to the PMB.
When it is necessary to return study drug (e.g., sealed boxes remaining when a patient
completes the first blinded treatment phase, sealed boxes remaining when a patient
completes the second blinded treatment phase, expired boxes recalled by the PMB),
investigators should return the study drug to the PMB using the NCI Return Agent
Form available on the CTEP home page http://ctep.cancer.gov, or by calling the PMB
at 301-496-5725. The patient ID number (e.g., ‘01C0222-01’) and patient initials (e.g.,
‘ABC’) should be entered in the “Lot No. and Sample No.” field.
8.2.4 DRUG ACCOUNTABILITY: The investigator, or a responsible party designated
by the investigator, must maintain a careful record of the receipt, disposition, and
return of all drugs received from the PMB using the NCI Investigational Agent
Accountability Record available on the CTEP home page http://ctep.cancer.gov, or by
calling the PMB at 301-496-5725. A separate NCI Investigational Agent Accountability
Record must be maintained for each patient on this protocol. The patient ID number
(e.g., ‘01C0222-01’) and the phase (i.e., “Phase A” or “Phase B”) should be entered in the
“Patient’s ID No.” field.
8.2.5 EMERGENCY UNBLINDING: In the event of an emergency, call Dr. Brigitte
Widemann (301-496-7387) or Dr. Frank Balis (301-496-0085). These physicians can also
be reached through 301-496-7704 or through the NIH Page Operator at 301-496-1211.
Pediatric Oncology Branch staff will require the protocol number (i.e., T99-0090), the
patient ID number (e.g., ‘01C0222-01), the patient initials (e.g., ‘ABC’), and the phase
(i.e., ‘Phase A’ or ‘Phase B’) to unblind the patient.
9.0 CLINICAL TRIALS AGREEMENT (CTA)
The agent(s) (hereinafter referred to as “Agent”, R115777, used in this protocol
is/are provided to the NCI under a Clinical Trials Agreement (CTA) between
Company: Janssen Pharmaceuticals (hereinafter referred to as “Collaborator(s)”) and
the NCI Division of Cancer Treatment, Diagnosis. Therefore the following
obligations/guidelines apply to the Agent(s) in this study:
1) The Agent(s) may not be used outside the scope of this protocol, nor can the
Agent(s) be transferred or licensed to any party not participating in the clinical
study. Collaborator(s) data for Agent(s) are confidential and proprietary to the
Collaborator(s) and should be maintained as such by the investigators.
2) For a clinical protocol where there is an investigational Agent used in combination
with other investigational Agent(s), each the subject of different CTAs, the access to
and use of data by each Collaborator shall be as follows (data pertaining to such
combination use shall hereinafter be referred to as “Multi-Party Data”).
a) NCI must provide all Collaborators with written notice regarding the existence
and nature of any agreements governing their collaboration with NIH, the design
of the proposed combination protocol, and the existence of any obligations which
would tend to restrict NCI’s participation in the proposed combination protocol.
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b) Each Collaborator shall agree to permit use of the Multi-Party Data from the
clinical trial by any other Collaborator to the extent necessary to allow said other
Collaborator to develop, obtain regulatory approval or commercialize its own
investigational Agent.
c) Any Collaborator having the right to use the Multi-Party Data from these trials
must agree in writing prior to the commencement of the trials that it will use the
Multi-Party
Data
solely
for
development,
regulatory
approval,
and
commercialization of its own investigational Agent.
3) The NCI encourages investigators to make data from these clinical trials fully
available to Collaborators for review at the appropriate time. Clinical trial data
developed under the CTA will be made available exclusively to Collaborator(s), the
NCI, and the FDA, as appropriate.
4) When a Collaborator wishes to initiate a data request, the request should first be
sent to the NCI, who will then notify the appropriate investigators (Group Chair for
cooperative group studies, or PI for other studies) of Collaborator’s wish to contact
them.
5) Any data provided to Collaborator(s) must be in accordance with the guidelines and
policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for
this clinical trial.
6) Any manuscripts reporting the results of this clinical trial should be provided to
CTEP for immediate delivery to Collaborator(s) for advisory review and comment
prior to submission of publication. Collaborator(s) will have 30 days from the date of
receipt for review. An additional 30 days may be requested in order to ensure that
confidential and proprietary data, in addition to Collaborator(s) intellectual property
rights, are protected. Copies of abstracts should be provided to Collaborator(s) for
courtesy review following submission, but prior to presentation at the meeting or
publication in the proceedings. Copies of any manuscript and/or abstract should be
sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI
Executive Plaza North, Room 718
Bethesda, MD 20892
Fax: 301-402-1584
The Regulatory Affairs Branch will then distribute them to Collaborator(s).
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10.0 REFERENCES
1.
Bernards A (1995) Neurofibromatosis type 1 and Ras-mediated signaling: filling
in the GAPs. Biochim Biophys Acta. 1242(1):43-59. Review. No abstract available.
2.
Bollag G, McCormick F (1992) GTPase activating proteins. Cancer Biology 3:199-
208.
3.
De Santis S, Pace A, Bove L, Cognetti F, Properzi F, Fiore M, Triaca V, Savarese
A, Simone M, Jandolo B, Manzione L, Aloe L (2000) Patients treated with antitumor
drugs displaying neurological deficits are characterized by a low circulating level of
nerve growth factor. Clinical Cancer research 6:90-95.
4.
Gibbs JB, Oliff A (1997) The potential of farnesyltransferase inhibitors as cancer
chemotherapeutics. Annu Rev Pharmacol Toxicol 37:143-166.
5.
Goldberg Y, Dibbern K, Klein J, Riccardi V, Graham J (1996) Neurofibromatosis
Type I - an update and review for the primary physician. Clinical Pediatrics :545-561.
6.
Goyen J LA, Lavrijsen K, de Coster R (1996) Investigator's Brochure R115777.
7.
Graham S (1995) Inhibitors of protein farnesylation: a new approach to cancer
chemotherapy. Exp Opin Ther Patents 5(12):1269-1285.
8.
Gutmann D, Collins F (1993) The neurofibromatosis type 1 gene product and its
protein product, neurofibromin. Neuron 10:335-343.
9.
Gutmann DH, et al. (1997) The diagnostic evaluation and multidisciplinary
management of neurofibromatosis 1 and neurofibromatosis 2. Jama. 278(1):51-57.
Review.
10.
Hudson J, et al. (1997) Novel and recurrent mutations in the neurofibromatosis
type 1 (NF1) gene. Hum Mutat. 9(4):366-367. No abstract available.
11.
James K, Eisenhauer E, Christian M, Terenziani M, Vena D, Muldal A, Therasse P
(1999) Measuring response in solid tumors: Unidimensional versus bidimensional
measurement. Journal of the National Cancer Institute 91(6):523-528.
12.
Johnston SR, Ellis PA, Houston S, Hickish T, Howes A, Palmer P, Horak I (2000)
A phase II study of the farnesyltransferase inhibitor R115777 in patients with advanced
breast cancer. New Orleans: ASCO: 83a.
13.
Kato K, Der C, Buss J (1992) Prenoids and palmitate: lipids that control the
biological activity of Ras proteins. Cancer Biology 3:179-188.
14.
Kim HA, et al. (1997) Nf1-deficient mouse Schwann cells are angiogenic and
invasive and can be induced to hyperproliferate: reversion of some phenotypes by an
inhibitor of farnesyl protein transferase. Mol Cell Biol. 17(2):862-872.
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15.
Lancet J, Rosenblatt J, Liesveld D, End D, Hovak I, Ange D, Rosell K, Petronio S,
Smith A, Karp J (2000) Use of farnesyl transferase inhibitor R115777 in relapsed and
refractory leukemias: Preliminary results of a phase I trial. New Orleans: ASCO: 3a.
16.
Leonard DM (1997) Ras farnesyltransferase: a new therapeutic target. J Med
Chem 40(19):2971-2990.
17.
Lowy D, Willumsin B (1993) Function and Regulation of Ras. Annu. Rev.
Biochem 62:851-891.
18.
Needle MN, et al. (1997) Prognostic signs in the surgical management of
plexiform neurofibroma: the Children's Hospital of Philadelphia experience, 1974-1994.
J Pediatr. 131(5):678-682.
19.
Omer CA, Kohl NE (1997) CA1A2X-competitive inhibitors of farnesyltransferase
as anti-cancer agents. Trends Pharmacol Sci 18(11):437-444.
20.
Patnik A, Eckhardt S, Itzbicka E, Hidalgo M, McCreery H, Mori M, Terada K,
Tolcher A, Smith L, Britten C, Bowden C, Bol K, Ochon L, Davidson K, Hammond L,
Schwartz G, Horak I, Gentner L, Rowinsky E (2000) A phase I and pharmacokinetic
(PK) study of the farnesyltransferase inhibitor R115777 in combination with
gemcitabine (Gem). New Orleans: ASCO: 2a.
21.
Rodenhuis S (1992) ras and human tumors. Cancer Biology 3:241-247.
22.
Satoh T, Kaziro Y (1992) Ras in signal transduction. Cancer Biology 3:169-177.
23.
Schellens JH, de Clerk G, Swart M, Palmer PA, Bol CJ, van't Veer LJ, Tan S, de
Gast GC, Beijnen JH, ten Bokkel Huinink WW (2000) Phase I and pharmaologic study
with the novel farnesyltransferase inhibitor (FTI) R115777. New Orleans: ASCO: 184a.
24.
Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A, Rosen N (1995) A
peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-
dependent and -independent growth of human tumor cell lines. Cancer Res 55(22):5302-
5309.
25.
Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan R, Rubinstein L, Verweij
J, Van Glabbeke M, Van Oosterom T, Chrisitan M, Gwyther S (2000) New guidelines to
evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92(3):205-216.
26.
Warren K, Patronas N, Aikinb A, Balis F (2000) Unidimensional (1D), Bi-
dimensional (2D), and 3-Dimensional (3D) Measurements of Childhood Brain Tumors.
New Orleans, LA: ASCO: 168a.
27.
Yan N, Ricca C, Fletcher J, Glover T, Seizinger BR, Manne V (1995)
Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant
phenotype. Cancer Res 55(16):3569-3575.
28. Zujewski J, Horak I, Bol R, et al. (2000) Phase I and pharmacokinetic study of
farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol
18(4):927-941.
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11.0
APPENDICES
APPENDIX 1: PROTOCOL FOR REQUIRED PRE STUDY AND ON STUDY MRI STUDIES
Prior to starting treatment on this study all known measurable tumors should be
imaged with MRI to obtain a baseline. Tumor spread in patients with NF1 can be very
extensive, and may not allow for all lesions to be followed using 3D-MRI.
The goal will therefore be to use 3D-MRI only to follow the progressing plexiform
neurofibroma(s) (a maximum of three lesions), which will be defined as index lesion(s).
Pre-study radiographic evaluation:
• Identify and select the progressive plexiform neurofibroma(s) (a maximum of three
lesions) for 3-D MRI evaluation based on prior imaging studies. Should there be
more than 3 progressing plexiform neurofibromas, the three most clinically relevant
plexiform neurofibromas will be followed by 3-D MRI analysis.
• Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI
acquisition protocols below.
• In addition, if possible, perform MRI of all additional measurable plexiform
neurofibroma(s).
On study radiographic evaluation:
Unless clinically indicated otherwise obtain MRI of the index lesions only as outlined in
the MRI acquisition protocol below prior to cycles 4, 7, 10, and then after every 6 cycles
on each treatment phase (“A”, “B”).
At the time of disease progression on treatment phase “A”,if possible, a MRI scan of all
known measurable plexiform neurofibromas in addition to the index lesions should be
performed, in order to have a new baseline prior to treatment phase “B”.
MRI protocols:
Depending on the location of the index lesions the Spine, Head/Neck or
Trunk/Extremities protocols outlined on the following pages will be used.
The measurement of very irregular or infiltrative neurofibromas will present major
challenges, and in some cases, it may be difficult to precisely define tumor margins. If
necessary, participating institutions may modify the MRI sequences to optimize
differentiation of tumor and surrounding tissue. Modifications should be documented
in the MRI protocols, and the same imaging protocol, and, if possible, the same MRI
scanner, should be used for all subsequent MRI studies.
Every attempt should be made to image the entire progressive plexiform
neurofibroma(s).
A written protocol for scanning each patient has to be established at the time of study
entry to allow for reproducibility of follow-up studies.
If possible, Ms. Andy Gillespie should be notified at least 24 hours prior to performing a
MRI (Fax: 301-480-8871, phone: 301-402-1848, e-mail: gillesan@mail.nih.gov).
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A copy of the MRI protocol used to acquire the baseline MRI study will be faxed to Ms.
Andy Gillespie (301-480-8871) within 24 hours of obtaining the MRI study.
MRI studies should be submitted electronically or on CD or optical disk to the NCI POB
within 1 week of obtaining the study. The institutional radiology report for each study
should be faxed to Ms. Andy Gillespie within 1 week.
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MRI PROTOCOL- SPINE
Patient ID number: _________
Note: All series except for #4 and #5 should be performed as a normal clinical scan as specified by the
radiologist. The additional Series #4 and #5 may or may not be part of the normal clinical scan sequence,
however these series are required for the NF1 study protocol and must be performed within protocol
specifications as indicated below.
1. SAGITTAL T1
LOCALIZER⎯SPINE COIL
Per normal clinical scan
2. SAGITTAL T1
Per normal clinical scan
3. SAGITTAL FSEIR
Per normal clinical scan
4. AXIAL FSEIR
Axial FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
5 mm
Skip
0
Matrix
256x256
FOV
22 cm
NEX
1
Frequency Direction
R→L
Options
Tailored RF, FC, PC, 0.75 FOV
5.
CORONAL FSEIR
Coronal FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
5 mm
Skip
0
Matrix
256x256
FOV
22 cm
NEX
1
Frequency Direction
S→I
Options
Tailored RF, FC, PC
6. AXIAL T1
Per normal clinical scan
7. AXIAL T1- POST CONTRAST
Per normal clinical scan
Date:_________ Signature (responsible MRI technician):_____________________________
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Baseline study only, fax completed form to: Ms. Andy Gillespie at: 301-480-8871 (phone: 301-402-
1848)
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MRI Protocol- Head/Neck
PATIENT ID NUMBER: _________
Note: All series except for #2 and #3 should be performed as a normal clinical scan as specified by the
radiologist. The additional Series #2 and #3 may or may not be part of the normal clinical scan sequence,
however these series are required for the NF1 study protocol and must be performed within protocol
specifications as indicated below.
1. SAGITTAL T1
Per normal clinical scan
2. AXIAL FSEIR
Axial FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
4 mm
Skip
0
Matrix
256x256
FOV
22 cm
NEX
1
Frequency Direction
A→P
Options
Tailored RF, FC, 0.75 FOV
3.
CORONAL FSEIR
Coronal FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
5 mm
Skip
0 mm
Matrix
256x192
FOV
22 cm
NEX
1
Frequency Direction
S→I
Options
Tailored RF, PC
4.
AXIAL T1
Per normal clinical scan
5.
AXIAL T1- POST CONTRAST
Per normal clinical scan
Date:_________ Signature (responsible MRI technician):_____________________________
Baseline study only, fax completed form to: Ms. Andy Gillespie at: 301-480-8871 (phone: 301-402-1848)
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MRI Protocol-Trunk/Extremities
PATIENT ID NUMBER: _________
Note: All series except for #1 and # 2 should be performed as a normal clinical scan as specified by the
radiologist. The additional Series #1 and # 2 may or may not be part of the normal clinical scan sequence,
however these series are required for the NF1 study protocol and must be performed within protocol
specifications as indicated below.
1. AXIAL PLANE-STIR
Axial Plane STIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Coil: Body
Sequence: Fast Spin Echo (Turbo) FSEIR
Echo Train Length
5
TR
6000
TE
15
TI
150
Slice Thickness
10 mm
Skip
0
Matrix
512x160
FOV
40x30
No. of Excitations/
Sequence
0.5
No. of Acquisitions
1
Saturation
None
2.
CORONAL PLANE STIR
Coronal Plane STIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Coil: Body
Sequence: Fast Spin Echo (Turbo) FSEIR
Echo Train Length
5
TR
3400
TE
15
TI
150
Slice Thickness
5 mm
Skip
0
Matrix
512x160
FOV
48x48
No. of Excitations/
Sequence
1
No. of Acquisitions
1
Saturation
None
Date:_________ Signature (responsible MRI technician):_____________________________
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Baseline study only, fax completed form to: Ms. Andy Gillespie at: 301-480-8871 (phone: 301-
402-1848)
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Data Analysis:
• All MRI data will be analyzed at the Pediatric Oncology Branch of the NCI under
guidance of Dr. N. Patronas (head neuroradiologist). The MRI data from each
scan will be processed to assess the volume of the index plexiform
neurofibroma(s). The tumor will be traced on subsequent contiguous MR slices,
the numbers summed and then multiplied by the slice thickness to obtain a
numerical volume measurement. The tumor will be identified by high signal on
the T2 images not corresponding to known normal anatomic structures and
corresponding with the course of known nerves. Each patient’s volumetric
measurement obtained from the initial MRI will serve as the baseline against
which to assess incremental changes in volume that occur during the subsequent
intervals. Volumetric measurements and 1D-, and 2D-data analysis will be done
by 2 physicians trained in 1D-, 2D-, and 3D-MRI data analysis at the Pediatric
Oncology Branch, NCI at an Image Review Workstation using MEDx software
(Sensor Systems Inc.). Dr. Nicholas Patronas, NCI, will review and confirm 1D-,
2D-, and volumetric measurements for all images obtained on the study.
Volumetric measurements will be used to determine disease progression as
outlined in Section 5.2. After review by Dr. Patronas, the Principal Investigator
will inform the Participating Investigators about the results of the MRI study by
written report.
• The results of volumetric MRI measurements will be compared with 1D- and 2D-
MRI measurements, with results of the photographic evaluation, the physical
examination and the study subject’s subjective impression following clinical
variables.
Image And Data Acquisition:
In order to perform quantitative analysis the Pediatric Oncology Branch must
receive the imaging data from the investigator sites.
Distribution of images from all participating institutions to the NCI POB will be
performed by a contractor.
The contractor will:
• Contact participating institutions to determine the best mode of electronic data
transfer
• Prepare each site for electronic data transfer via network access device, File Transfer
Protocol (ftp), optical disk or modem depending on the investigator site.
• Provide training and technical support for each site
• Ensure complete, secure and timely data transfer to the POB, NCI within 24-72
hours of obtaining the MRI study.
The Pediatric Oncology Branch will check all materials received for completeness
and will notify the site if data, images, or information are missing or incomplete.
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APPENDIX 2: PATHOLOGY ANALYSIS OF PLEXIFORM NEUROFIBROMAS
PATHOLOGICAL ANALYSIS OF PLEXIFORM NEUROFIBROMAS:
The ability to design rational therapies for plexiform neurofibromas in NF1 is
heavily dependent upon an improved understanding of the composition, biological
properties, and growth characteristics of these tumors. The cellular constituency of
plexiform neurofibromas is often complex and mixed, including Schwann cells,
fibroblasts, perineurial and dendritic/monocytic cells. The patterns are further
complicated due to the intrinsic intra-neural growth pattern as well as entrapment of
native neural elements. This complex intermingling of cellular elements has impeded
our most basic understanding of these tumors. It has also rendered molecular studies,
which require relatively pure cellular populations difficult to interpret. Therefore,
combined morphologic, immunohistochemical, and molecular studies are needed to
elucidate the histogenesis, growth patterns, and malignant evolution of these tumors.
The Plexiform Neurofibroma Analysis component consists of two parts: (1) the
central diagnostic neuropathology review with accompanying light- and electron-
microscopic effort to identify the actual cell populations comprising the tumor and (2)
immunohistochemical and FISH analysis of tumor specimens. All tissues received from
surgical biopsies and/or resections will be reviewed by Dr. Arie Perry.
With this combined approach, the range of cellular constituents and their
neoplastic properties will be carefully documented in plexiform neurofibromas. Along
with related assays being developed (see below), we will provide a better
understanding of histogenesis, growth potential, and malignant transformation of these
tumors, thus facilitating a rational approach for guiding patient management.
The detailed pathological analysis outlined below will only be performed on
biopsies of plexiform neurofibromas, from patients enrolled in the Phase II FTI study.
We expect 5-10 such samples per year.
Standard Pathological Analysis: The paraffin blocks will be sectioned and the
resulting slides will be stained with hematoxylin-and-eosin (overview). Selected blocks
with the greatest degree of tumor purity and/or foci of malignant degeneration will be
additionally stained with Masson’s trichrome (collagen and myelin), alcian blue (acid
proteoglycan), reticulin (basement membrane) and peroxidase-linked antibodies against
neurofilament protein (axons), S-100 protein (Schwann cells), vimentin (mesenchymal
elements including fibroblasts), chromogranin (entrapped or neoplastic ganglion cells),
GFAP (some Schwann cells), Leu-7 (some Schwann cells), epithelial membrane antigen
(perineurial cells), cytokeratin (epithelial differentiation), HMB-45 (melanin-containing
cells), desmin (skeletal muscle differentiation), MIB-1 (Ki-67) antigen (growth fraction =
proliferation index), collagen type IV (basement membrane), CD34 (endothelial cells
and endoneurial dendritic/monocytic cells), muscle specific actin (some perineurial
cells), and CD68 (macrophages).
Gluteraldehyde-fixed tissue will be processed into epoxy resin for high-resolution
light microscopy, and electron microscopy; ultrastructural criteria exist for the
differential identification of Schwann cells, perineurial-like cells, and endoneurial
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fibroblasts and macrophages. All the attendant microscopy will be done, and the
findings entered in the project’s database, by Dr Perry.
Investigational Neuropathology Studies: Although initial studies will focus on
routine morphologic, immunohistochemical, and ultrastructural characterization of
submitted tumors, a number of additional novel studies are currently being developed.
In this section, we propose to critically evaluate the following questions:
(1) What are the cell types present in plexiform neurofibromas?
(2) Are cell types different for plexiform neurofibromas obtained from different sites
(e.g., cranial nerve, spinal nerve, peripheral nerve)?
(3) Does proliferation index correlate with growth or molecular/cellular characteristics?
(4) What is the range of neoplastic properties commonly seen in plexiform
neurofibromas and how do these differ in benign and malignant lesions?
(5) Are there any immunohistochemical or DNA FISH markers (e.g. p53 protein
expression or gene copy number) which may predict a high risk of subsequent
tumor progression or malignant transformation in plexiform neurofibromas?
(6) Is there any correlation between tumor vascularity, which may correlate with tumor
progression in plexiform neurofibromas?
(7) Is there a correlation between MAPK activity in the tumor and FTI treatment?
Immunohistochemical analysis of tumors will include p53 protein (overexpression
due to mutation or protein stabilization common in MPNST components), Factor VIII
and vascular endothelial growth factor (highly vascular tumors) and neurofibromin
protein (antibody provided by Dr. David Gutmann, Director of the Neurofibromatosis
Clinic, Washington Univ. School of Medicine). Recently, Drs. Perry and Gutmann have
successfully applied a neurofibromin antibody to archival paraffin-embedded
astrocytomas resected from patients with NF1. A similar approach will be utilized in
our study of plexiform neurofibromas, enabling morphologic correlation and the
determination of what proportion of cells have lost expression. This will be followed by
the development of several dual-color immunohistochemical assays such as
Neurofibromin/MIB-1, Neurofibromin/p53, S-100/MIB-1, S-100/Neurofibromin, etc.
Results will determine for the first time, which cell types are actively proliferating, lack
expression of neurofibromin, and/or overexpressing p53 protein. Tumor vascularity
will be determined based on the VEGF and Factor VIII expression.
Dr. Perry has extensive experience with fluorescence in situ hybridization (FISH)
studies in paraffin embedded tumor. FISH and combined FISH/Immunohistochemistry
assays will be utilized to identify specifically which cell types have deleted the NF1
gene.
Snap-frozen specimens when available will be homogenized for Western
immunoblot analysis of ras pathway effector protein activities using activation-specific
antibodies. In these experiments, equal amounts of total protein will be analyzed by
Western blotting with phospho-MAPK and phospho-akt/PKB antibodies and
normalized to the total MAPK and akt/PKB protein levels in each tumor. Densitometry
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will be performed to quantitate the levels of MAPK and akt/PKB activation in these
tumors.
The Neuropathological Review Facility is intended to provide a resource for
consistent pathological analysis of plexiform neurofibromas. This will, in the long run,
facilitate better pathological classification of plexiform neurofibromas and permit
correlations of pathological characteristics with clinical and cellular/molecular features.
CONTRIBUTION OF TUMOR SPECIMENS TO A CENTRAL TUMOR REPOSITORY:
All tumor samples obtained on this study (obtained from biopsies of discrete
neurofibromas and plexiform neurofibromas), with the exception of the tumor sample
obtained for establishment of tumor cell lines, will be sent to the tissue procurement
facility.
Tissue Acquisition (Appendix 3): To assist in the collection of tissue specimens,
the project’s Tissue Procurement Facility will provide submitting centers with a
complete specimen shipping kit after notification by the Pediatric Oncology Branch.
This kit will be sent to the submitting institution several days before the planned tissue
resection. The kit will contain all materials and instructions for the proper collection
and shipping of specimens to the Tissue Procurement Facility. A second specimen
shipment kit for shipment of a tumor sample dedicated to the establishment of tumor
cell lines will be sent to the participating institution by the Pediatric Oncology Branch,
and also contain all materials and instructions for the proper collection and shipping of
specimens .
Tissue shipment (Appendix 4): All patient specimens (with exception of the
specimen obtained for tissue culture), and a copy of the patient consent will be sent by
overnight express courier to Dr. Mark Watson at the Tissue Procurement Facility. After
performing the local institutional evaluation and issuing a pathology report, a copy of
the pathology report, and all paraffin blocks should be sent to the tissue procurement
facility. If submission of all paraffin blocks is not possible or prohibited by participating
pathology departments, 5 unstained slides from each block will be sent instead. These
slides will then be stained and reviewed by Dr. Perry, who will then select 1 or 2
appropriate blocks to be sent for further study. Blocks will be returned to the
submitting institutions upon completion of studies or within 24 hours of written request
by the submitting institution.
Upon entry to the Tissue Procurement Facility, all specimens will be coded and
recorded in the facility database. The Tissue Procurement Facility will forward
appropriate coded specimens to Dr. Perry for centralized pathology review and other
studies described above, and to Dr. Wanda Salzer (analysis of ras expression, and NF1
mutation) and Janssen Pharmaceuticals (FPTase activity) for investigations related to
the protocol. The remainder of the specimens (including paraffin blocks) will be stored
by the Tissue Procurement Facility until needed for future research studies or recall by
the submitting institution. Figure 1 diagrams the proposed flow of information and
specimens, the coding scheme, and the residence of each data set. This is a coded,
double-broker model designed to maintain patient confidentiality while making
meaningful research studies possible. All tumor samples remain linked to the patient
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data by the study number. Only the coordinating Center (POB) will have access to the
clinical data. Communication between the central tissue repository and the POB will
use the patient study number. Communication between research laboratories and the
tissue bank will use the specimen code number. The tumor sample obtained for
establishment of tumor cell lines will be sent directly form the participating institution
to Dr. Wallace and will be identified by the patient study number.
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Figure 1: Proposed Scheme for Specimen and data exchange, and specimen and data encoding
Trial coordinating
Center: POB, NCI
Patient Identifiers
Clinical Data
Study Number
Tissue Procurement and Specimen
Bank
Delete identifiers
Maintain study number
Code specimens
Anonymize institutional path data
Participating Institution
Diagnostic block
Pathology report
Patient consent
Tumor specimens
Ship tumor specimen to
Dr. P. Wallace (tumor cell
culture).
Neuropath Review and
Database (Dr. Perry, Dr.
Gutmann)
Coded specimens
Anonymized institutional
path data
RESEARCH
LABORATORY
Coded specimens for
IRB approved research
question
Communication and data likage by study number
Communication and data
likage by specimen code
number
Communication
and data linkage
by specimen
code number
Ship tumor samples to:
Dr W. Salzer (ras analysis)
Dr. D. End (FPTase activity)
Communication and data likage
by specimen code number
Communication
and data
linkage by
study number
Communication
and data
linkage by
study number
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APPENDIX 3: INSTRUCTIONS FOR TISSUE ACQUISITION OF DISCRETE AND PLEXIFORM
NEUROFIBROMAS
Five to seven days prior to the planned tumor biopsy please notify Ms Andy Gillespie
at the POB, NCI, about the planned biopsy: Phone: 301-402-1848, Fax: 301-480-8871, e-
mail: gillesan@mail.nih.gov. To assist in the collection of tissue specimens, two
specimen shipment kits will be sent to participating institutions:
• The project’s Tissue Procurement Facility will provide submitting centers with a
specimen shipping kit for shipment of tumor samples. The kit will contain all
materials and instructions for the proper collection and shipping of specimens to the
Tissue Procurement Facility.
• The NCI, Pediatric Oncology Branch will provide submitting institutions with a
second specimen shipment kit (to ship the tumor sample for the culture of tumor
cells), which will contain all materials and instructions for proper collection.
STEPS FOR TISSUE COLLECTION ARE AS FOLLOWS:
1. To enable future molecular and biochemical analyses with the specimen, the
participating institutional pathologist must receive the tumor tissue fresh, rather
than “fixed in formalin”. After resection, the tissue should be transported from the
O.R. to the pathologist within 30 minutes. The specimen must not be placed in
formalin, but may be placed in normal saline, Ringer’s solution, or any other
physiologic buffer solution.
2. A representative and sufficiently large piece of the specimen should be fixed in
formalin for paraffin processing as per the institution’s standard policies and
procedure. Pathologists will be instructed to thoroughly sample the surgical
specimen (at least one block per centimeter in greatest dimension). This material
will be used to make the clinical diagnosis and, later, sent for central pathology
review.
3. If tissue remains, an additional piece of tissue 0.5-1 cm3 in size will be snap frozen in
liquid nitrogen or a –50oC histological bath. This material will be shipped to the
Tissue Procurement Facility on dry ice for future molecular and genetic research
studies.
4. If tissue remains, aseptically remove any capsular material and slice at least 0.5 cm3
of the tumor tissue to increase the exposed surface area. Half fill a 50 ml screw top,
conical centrifuge tube with Transport Medium (Leibovitz’s L-15 Medium with 1.0%
penicillin/streptomycin, 100U/ml) and shake vigorously to oxygenate. Label the tube
with patient’s study number. Place the slices into the medium, secure the top and
wrap with parafilm. Insulate the tube by encasing with several wraps of fine bubble
wrap. Place the package on top of a small reusable cold ice pack in a size-matching
styrofoam shipping box with cardboard outer. Tape the box lid shut. Ship by
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overnight express courier, priority delivery to Dr. Peggy Wallace, University of
Florida for culture of tumor cells.
5. If tissue still remains, 2-4 2 mm fragments, preferably from various sites
representing a spectrum of gross appearances, will be placed in the provided
gluteraldehyde container. These specimens will be used for electron microscopy
studies.
6. If tissue still remains, another representative specimen will be placed in the
provided formaldehyde container. This specimen will be embedded at the Tissue
Procurement Facility and used in the event that the submitting institution’s
specimen block is not available.
7. If tissue still remains, the remainder of the specimen will be divided into 1 cm3
segments and snap frozen as described in (3).
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APPENDIX 4: INSTRUCTIONS FOR SHIPMENT OF TUMOR BIOPSIES
Shipments should not be sent on Fridays or on the day preceeding a holiday.
Five to seven days prior to tumor resection, please call Ms Andy Gillespie at the
Pediatric Oncology Branch, NCI (phone: 301-402-1848, fax: 301-480-8871, e-mail:
gillesan@mail.nih.gov). Provide the name, phone number and shipping address of the
physician responsible for tissue acquisition.
Two shipping modules will be mailed via overnight express to the physician indicated:
At the time of resection, tissue should be IMMEDIATELY transported from the
operating room to the attending surgical pathologist. Material should be handled as
outlined in Appendix 3.
After collection the tumor sample, which will be used for establishment of a tumor cell
line, should be placed in L-15 (a tissue culture medium), identified with the patient’s
study number, and be sent on top of a small reusable cold ice pack in the specimen kit
provide by the POB, NCI immediately via FedEx to:
Margaret Wallace, Ph.D.
Professor, Molecular Genetics & Micro., and Pediatric Genetics
University of Florida
Box 100266, 1600 SW Archer Road, ARB Room R2-220
Gainesville, FL 32610-0266
Phone: (352)-392-3055
Fax: (352) 392-2042
E-mail: peggyw@ufl.edu
Please notify Dr. Wallace prior to shipment, and contact her with any questions you
may have regarding this sample.
All other tumor specimens (snap frozen tissue, tissue in glutaraldehyde, and
formaldehyde container) should be placed in the specimen kit provided by the Tissue
Procurement Facility, and shipped on dry ice to:
M. Watson, M.D., Ph.D.
Division of Laboratory Medicine / Box 8118
Alvin J. Siteman Cancer Center / Box 8100
Washington University School of Medicine
660 S. Euclid Avenue, St. Louis, MO 63110
Phone: (314)-454-7919, Fax: (314)-454-5525
Snap frozen tissue has to be maintained in the cryobath or a –70 degree freezer until it is
ready for shipment. It is very important that: (1) Tissue be frozen as soon as possible
after resection; (2) Tissue be frozen rapidly; and (3) Tissue be maintained at or below –
50 degrees until shipment.
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Please notify Dr. Watson prior to shipment, and contact him with any questions you
may have regarding these samples.
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APPENDIX 5: PROCEDURE PBMC SEPARATION FOR FARNESYLTRANSFERASE ACTIVITY
PBMC Collection Steps:
• Collect peripheral blood (20 ml in children >10 kg weight, 10 ml in children ≤10 kg
weight) in preservative free heparin (10-20 units heparin/1ml of blood).
• Place peripheral blood in polypropylene screw top tube(s).
• Label tube with: Patient initials, Patient ID number, date, treatment phase (“A”,
“B”), and day of treatment (pre, day 15-21).
Shipment Of Peripheral Blood:
• Place tube(s) in container.
• Place the container with the polypropylene tube(s) in Styrofoam box. Add a
package of wet ice in Styrofoam box, if it is expected that the ambient temperature
cannot be maintained between below 90 º Fahrenheit.
• Package sample as appropriate for biologic material.
Required PBMC samples
Date of sample collection
Pretreatment (prior to phase “A”)
Steady state on treatment phase “A” (day 15-21, cycle#1)
Steady state on treatment phase “B” (day 15-21, cycle#1)
• Ship the sample and the information requested above on the same day it was
obtained with Federal express overnight priority delivery to:
Dr. Brigitte Widemann
Pediatric Oncology Branch, NCI
10 Center Drive
1—CRC, Rm 1-5750,
Bethesda, MD 20892-1101
• Notify Dr. Widemann prior to shipment of the sample (Phone:301-496-7387, e-mail:
bw42y@nih.gov).
• Do not ship samples for delivery on a weekend or Holiday.
• Samples must be received by Dr. Widemann within 24 hours of obtaining the
sample.
PROCESSING OF SAMPLES
• After arrival at the Pediatric Oncology Branch, NCI:
• Mononuclear cells will be separated using the ficoll technique.
• The number of mononuclear cells in the specimen will be determined.
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• The samples will be processed for FPTase activity
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APPENDIX 6: DETERMINATION OF NERVE GROWTH FACTOR
All materials necessary will be provided by the POB, NCI.
Obtain exactly 3 cc of whole blood in a red top tube (pretreated with a protease
inhibitor, provided by the POB, NCI). After obtaining the sample:
• Storage for 1 hour at room temperature (15-25 °C),
• Overnight storage in the refrigerator at 2-8 °C.
• Centrifugation for 20 minutes at 2-8 °C at 2000 x g.
• Remove supernatant, and place supernatant in tube (provided by POB).
• Label tube (labels provided by POB) with patient initials, ID#, date, cycle and
treatment phase.
• Storage of samples until shipment: -20 °C.
Ship frozen samples and completed collection sheet on dry ice to:
Ms. Nalini Jayaprakash
Pediatric Oncology Branch, NCI
10 Center Drive, 10-CRC, Rm 1-3872
Bethesda, Maryland 20892-1101
Please notify Ms. Jayaprakash prior to shipping at (301) 402-6642, e-mail:
jayapran@mail.nih.gov. No shipments to arrive on Holidays or on Saturdays.
Samples can be batched for each treatment phase.
Patient initials:
Patient ID number:
Treatment
Phase
Sample
Date obtained
A
Pior to phase A
A
Pre cycle # 4
A
Pre cycle # 7
A
Pre cycle # 10
A
Pre cycle # 16*
B
Pre cycle #4
B
Pre cycle # 7
B
Pre cycle # 10
B
Pre cycle # 16*
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* And then after completion of every 6 treatment cycles.
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APPENDIX 7: REQUIRED STUDY EVALUATIONS
Prior To Starting Treatment, During, And Post Treatment for Each Study Phase (“A” and “B”):
Observation
Pretreatment
(Phase A&B)
During Cycle
(Phase A&B)
Prior to Each Cycle
(Phase A&B)
Post Study
History & physical exam
X
q 2 weeks, Cycles 1-3
X
X
Performance status
X
X (document if changed)
X
Body surface area
X
X
Photography of lesions, if
possible
X
Cycles 4, 7, 10, then q 6 cycles
X
CBC, platelets, differential
X
q 2 weeks, Cycles 1-3
X
X
PT, PTT, Fibrinogen
X
X
X
Electrolytes and creatinine
X
q 2 weeks, Cycles 1-3
X
X
Ca+2, Mg+2, PO4
X
q 2 weeks, Cycles 1-3
X
X
SGPT, bilirubin
X
q 2 weeks, Cycles 1-3
X
X
Urinalysis
X
Cycles 4, 7, 10, then q 6 cycles
X
Urine pregnancy test
Females
3D-MRI of index lesions Phase A only
Cycles 4, 7, 10, then q 6 cycles
X
Ophthalmologic examination
X
X
QOL assessment Phase A only
Cycles 4, 7, 10, then q 6 cycles
Tumor Biopsy Phase A only Between days 15-21, Cycle 1
Phase A and B
PBMC for FPTase Phase A only Between days 15-21, Cycle 1
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Nerve growth factor Phase A only
Cycles 4, 7, 10, then q 6 cycles
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APPENDIX 8 A: ELIGIBILITY CHECKLIST FOR PROTOCOL
Patient initials:
First three letters of last name:
Date of birth:
Race:
Gender:
Weight (kg):
Height (cm):
BSA
(m2):
Patient measurements:
(please average 3 heights and weights)
Institution:
Physician:
NF1 diagnostic criteria:
Plexiform neurofibroma:
≥6 Café-au-lait spots:
Freckling:
Optic glioma:
≥ 2 Lisch
nodules:
Bony dysplasia:
1st degree relative with NF1:
≥20% increase in tumor volume:
%:
≥ 13% increase in product of two
longest perpendicular diameters:
%:
Progressive plexiform
Neurofibroma
over prior two scans:
≥6% increase in longest diameter:
%:
Date of scans:
1.
2.
Tumor measurements:
cm:
cm:
Inoperable:
Yes:
No:
Measurable:
Yes:
No:
Potential for morbidity:
Yes:
No:
Location:
Recovered from tox. of prior Rx:
Yes:
No:
Date of last dose of (NA if none):
Radiation Rx:
ChemoRx:
ECOG performance score:
Life expectancy ≥12 mo:
Yes:
No:
Date CBC/Diff and coags drawn:
Hematologic parameters:
ANC:
Hgb:
Plt:
Fibrinogen:
Normal range:
Date chemistries drawn:
Liver function tests:
SGPT:
ULN:
Bili:
ULN:
Renal function:
Creat:
Normal range:
or Creat clear:
Signed informed consent:
Yes:
Date:
No:
Pregnant or breast feeding:
Yes:
No:
Date of pregnancy test:
Other significant illnesses:
Yes:
No:
DPA offered:
Yes:
No:
NA:
>1 myelosuppressive chemoRX:
Yes:
No:
Prior R115777:
Yes
:
No:
Investigational agent last 30 days:
Yes:
No:
Active MPNST or other cancer
Yes:
No:
Ongoing XRT, chemoRX, GCSF,
hormonal or immunoRx
Yes:
No:
Able to return for follow-up
Yes
No:
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Name of person completing form:
Signature/Date:
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APPENDIX 8 B: BLINDED PATIENT ON-STUDY FORM
PROTOCOL T99-0090 / 01-C-0222
A Phase II Randomized, Crossover, Double-Blind, Placebo-Controlled Trial of the
Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type I
and Progressive Plexiform Neurofibromas
Patient ID: 01C0222-___ ___
Patient Initials: ___ ___ ___
(provided by Orkand)
(CC protocol number - patient sequence number)
(first three letters of last name)
On-Study Form:
Date of Registration / On-Study Date (MM/DD/YYYY): ____ / ____ / ________
Drug Order:
NSC Number: 702818
Drug Name, Strength, Unit, Form: Phase A R115777 50mg / Placebo tablets
Quantity Ordered:
Check
One
BSA (m2)
R115777 / Placebo
(mg po q12h)
# of Boxes
(70 tablets per box)
θ
0.00 - 0.37
50
2
θ
0.38 - 0.62
100
4
θ
0.63 - 0.87
150
6
θ
0.88 - 1.12
200
8
θ
1.13 - 1.37
250
9
θ
1.38 +
300
11
Registering Physician:
Name (print): Dr. ______________________________
Institution: ________________________________________
Address (city / state): _________________________, ______
NCI Investigator Number: ___ ___ ___ ___ ___
Phone Number: ___ ___ ___ - ___ ___ ___ - ___ ___ ___ ___
Date Faxed to PMB by Orkand (MM/DD/YYYY): ____ / ____ / ________
Name of person faxing to PMB (print): ___________________________________
Signature of person faxing to PMB: ________________________________________
Phone number of person faxing to PMB: ___ ___ ___ - ___ ___ ___ - ___ ___ ___ ___
Fax to: Donna Shriner / Melizza Ford
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Pharmaceutical Management Branch, Cancer Therapy Evaluation
Program, DCTD, NCI: 301-402-4870
Questions:
Contact Donna Shriner or Melizza Ford of the Pharmaceutical Management
Branch at 301-496-5725.
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APPENDIX 9A: PROGRESSION CHECKLIST FOR PROTOCOL
To be completed when patient progresses on Phase A and Phase B
Patient initials:
First three letters of last name:
Patient ID number:
Patient measurements:
Weight (kg):
Height (cm):
BSA (m2):
Institution:
Registering physician:
Name:
Contact RN:
Name:
Phone:
Treatment phase completed:
A:
B:
Date:
Cycle number completed:
Last R115777/Placebo dose:
Date:
Location of progressive
plexiform neurofibroma(s):
Evidence for progression:
≥20% increase in tumor
volume:
Clinical progression:
Name of person completing form:
Signature/Date:
POB RN:
Date PMB notified:
Date Orkand notified:
Fax completed form to Ms Andy Gillespie at 301-480-8871, call with questions: 301-402-1848
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APPENDIX 9 B: BLINDED PATIENT CROSSOVER / OFF-STUDY FORM
PROTOCOL T99-0090 / 01-C-0222
A Phase II Randomized, Crossover, Double-Blind, Placebo-Controlled Trial of the
Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type I
and Progressive Plexiform Neurofibromas
Patient ID: 01C0222-___ ___
Patient Initials: ___ ___ ___
(CC protocol number - patient sequence number)
(first three letters of last name)
Crossover Form:
Date of Progression on Phase A / Crossover Date (MM/DD/YYYY): ___ / ____/ ____
Drug Order:
NSC Number: 702818
Drug Name, Strength, Unit, Form: Phase B R115777 50 mg / Placebo tablets
Quantity Ordered:
Check
One
BSA
(m2)
R115777 / Placebo
(mg po q12h)
# of Boxes
(70 tablets per box)
θ
0.00 - 0.37
50
2
θ
0.38 - 0.62
100
4
θ
0.63 - 0.87
150
6
θ
0.88 - 1.12
200
8
θ
1.13 - 1.37
250
9
θ
1.38 +
300
11
Off-Study Form:
Date of Progression on Phase B / Off-Study Date (MM/DD/YYYY): __ / ___ / ____
Registering Physician:
Name (print): Dr. ______________________________
Institution: ________________________________________
Address (city / state): _________________________, ______
NCI Investigator Number: ___ ___ ___ ___ ___
Phone Number: ___ ___ ___ - ___ ___ ___ - ___ ___ ___ ___
Date faxed to PMB by Pediatric Oncology Branch (MM/DD/YYYY): ___ / __ / ___
Name of person faxing to PMB (print): ___________________________________
Signature of person faxing to PMB: ________________________________________
Phone number of person faxing to PMB: ___ ___ ___ - ___ ___ ___ - ___ ___ ___ ___
Fax to:
Donna Shriner / Melizza Ford
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Pharmaceutical Management Branch Cancer Therapy Evaluation
Program, DCTD, NCI: 301-402-4870
Questions:
Contact Donna Shriner or Melizza Ford of the Pharmaceutical Management
Branch at 301-496-5725.
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APPENDIX 10: ROADMAP FOR PATIENT REGISTRATION AND CROSSOVER
PATIENT REGISTRATION
1)
Contact Dr. Brigitte Widemann (301) 496-7387 or Dr. Frank Balis (301) 496-0085, to
discuss the patient prior to entry on study. Call Ms. Andy Gillespie, RN to register
patient at (301-402-1848). FAX the completed Eligibility Checklist (Appendix 8A)
and Blinded Patient On Study Form (Appendix 8B) to the Pediatric Oncology
Branch c/o Andy Gillespie, RN at (301) 480-8871.
2)
POB RN registers patient with Orkand (phone: 301-402-1732, fax: 301-480-0757)
using the completed Eligibility Checklist (Appendix 8A) and Blinded Patient On
Study Form (Appendix 8B).
3)
Orkand notifies the POB RN and the Pharmaceutical Management Branch (PMB),
NCI, (phone; 301-496-5725, fax: 301-402-4870) of the patient’s ID number using the
Blinded Patient On Study Form (Appendix 8B).
4)
The POB RN notifies the registering site of the patient’s ID number using the
Blinded Patient On Study Form (Appendix 8B).
5)
The PMB ships drug for that ID number for “phase A” to registering site.
6)
POB ships module with necessary materials to administer quality of life
assessment and tests outlined in appendix 5, 6, and7 to participating institution.
DISEASE PROGRESSION ON “PHASE A”
1)
FAX the completed Progression Checklist (Appendix 9A) and Blinded Patient
Crossover/Off Study Form (Appendix 9B) to the Pediatric Oncology Branch c/o
Andy Gillespie, RN at (301) 480-8871.
2)
Return unused drug to the PMB (Section 8.2.3)
3)
POB RN notifies the PMB (phone: 301-496-5725, fax: 301-402-4870) using the
completed Blinded Patient Crossover/Off Study Form (Appendix 9B).
4)
PMB ships drug for that ID number for “phase B” to registering site.
DISEASE PROGRESSION ON “PHASE B”
1)
FAX the completed Progression Checklist (Appendix 9A) and the Blinded Patient
Crossover/Off Study Form (Appendix 9B) to the Pediatric Oncology Branch: Andy
Gillespie, RN at (301) 480-8871.
2)
Return unused drug to the Pharmaceutical Management Branch (Section 8.2.3)
3)
POB RN notifies Orkand (phone: 301-402-1732, fax: 301-480-0757) and the PMB
(phone: 301-496-5725, fax: 301-402-4870) using the completed Progression Checklist
(Appendix 9A) and Blinded Patient Crossover/Off Study Form (Appendix 9B).
4)
POB RN will take Patient off protocol.
EMERGENCY UNBLINDING
4/21/2009
T-99-0090, 01-C-0222
95
In the event of an emergency, call the Dr. Brigitte Widemann (301) 496-7387 or Dr.
Frank Balis (301) 496-0085. These physicians can also be reached through the NIH page
operator (301) 496-7704 or (301) 496-1211. Pediatric Oncology Branch staff will require
the protocol number (i.e., ‘T99-0090’), the patient’s ID number (e.g., ‘00-C0222-01’), the
phase (i.e., ‘A’ or ‘B’), and the patient’s initials (first three letters of last name, eg.,
‘ABC’) to unblind the patient.
4/21/2009
T-99-0090, 01-C-0222
96
APPENDIX 11A: PATIENT DIARY FOR R115777/PLACEBO
Patient initials/ID number:
Dose:
Treatment Phase:
Cycle Number:
Cycle Start Date:
Date →
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Time R115777 /Placebo dose taken* →
Indicate reason for missed doses →
SIDE EFFECTS
Nausea (see scale below)† →
Vomiting (# of times in 24 hr) →
Diarrhea (# of times in 24 hr) →
Pain, or numbness in hands/feet →
OTHER SIDE EFFECTS (list below)
→
→
→
OTHER MEDICATIONS (Name)
Dose
Frequency
Start Date
Stop Date
Reason for Use of Medication
* If you miss a dose write “M” in the box.
† Rate nausea mild if you are able to eat and drink a reasonable amount, moderate if you can eat and drink but the amount is substantially decreased, or
severe if you are unable to eat and drink.
Physicians should fax completed form to Ms Andy Gillespie at 301-480-8871, call with questions: 301-402-1848 Parent/patient initials
4/21/2009
T-99-0090, 01-C-0222
97
4/21/2009
T-99-0090, 01-C-0222
98
APPENDIX 11 B: PILL COUNT CASE REPORT FORM
PROTOCOL T99-0090 / 01-C-0222
A Phase II Randomized, Crossover, Double-Blind, Placebo-Controlled Trial of the
Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type I
and Progressive Plexiform Neurofibromas
Patient’s Institution ID#: _______________
Patient’s Name:_____________
Patient ID: 01C0222-___ ___
Patient Initials: ___ ___ ___
(CC protocol number - patient sequence number)
(first three letters of last name)
Phase: ____ Phase A ____ Phase B
Cycle: ______
Strength: ____ 50mg
(28 day cycle – 21 days on / 7 days off)
Start Date (MM/DD/YYYY): ____ / ____ / ________
Number of boxes dispensed (place additional labels on page 2 – make copies if
necessary)
______
Total number of tablets dispensed to patient (number of boxes * 70 tablets per
box) ______
End Date (MM/DD/YYYY): ____ / ____ / ________
Total number of tablets returned by patient:
______
Number of tablets taken by patient (total dispensed minus total returned)
______
Date Pill Count Form Completed (MM/DD/YYYY): ____ / ____ / ________
Name of person Completing Pill Count Form (Print): _____________________
Name of Principal Investigator (print): Dr. ______________________________
Institution: ________________________________________
Please fax completed forms to Ms. Andy Gillespie (301 480-8871) after completion of
every 3 treatment cycles.
PLACE BOX ONE LABEL HERE
PLACE BOX TWO LABEL HERE
PLACE BOX THREE LABEL HERE
(if applicable)
PLACE BOX FOUR LABEL HERE
(if applicable)
4/21/2009
T-99-0090, 01-C-0222
99
4/21/2009
T-99-0090, 01-C-0222
100
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(IF APPLICABLE)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
PLACE ADDITIONAL BOX LABEL
HERE
(if applicable)
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
MEDICAL RECORD
• Adult Patient or • Parent, for Minor Patient
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
01-C-0222
PRINCIPAL INVESTIGATOR: Brigitte Widemann, M.D.
STUDY TITLE:
A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trial of the
Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type 1 and
Progressive Plexiform Neurofibromas
Continuing Review Approved by IRB on 1/12/09
Amendment Approved by IRB on 6/5/09 (J)
Date Posted to Web: 6/27/09
Standard
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
• Adult Patient or • Parent, for Minor Patient
NIH-2514-1 (4-97)
P.A.: 09-25-0099
File in Section 4: Protocol Consent (1)
INTRODUCTION
We invite you/your child to take part in a research study at the National Institutes of Health (NIH).
First, we want you/your child to know that:
Taking part in NIH research is entirely voluntary.
You/your child may choose not to take part, or you/your child may withdraw from the study at any time. In
either case, you/your child will not lose any benefits to which you are otherwise entitled. However, to receive
care at the NIH, you/your child must be taking part in a study or be under evaluation for study participation.
You/your child may receive no benefit from taking part. The research may give us knowledge that may help
people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research
treatments they would want to receive (such as blood transfusions). If you/your child have such beliefs, please discuss
them with your NIH doctors or research team before you/your child agree to the study.
Now we will describe this research study. Before you/your child decide to take part, please take as much time as you
need to ask any questions and discuss this study with anyone at NIH, or with family, friends or your/your child’s
personal physician or other health professional.
You/your child have neurofibromatosis type I (also called NF1), and one or more tumors called plexiform neurofibroma(s)
that appear to be increasing in size over the past year and have the potential to cause serious medical problems.
Plexiform neurofibromas, which are tumors that arise from nerves, occur commonly in patients with NF1. The only
known effective treatment for plexiform neurofibromas is surgery, but many times complete surgical removal of all of the
plexiform neurofibromas is not possible, because of the number or location of the tumors.
The underlying cause of NF1 is a defective gene. Genes carry the information for the body composition and
characteristics. For example, genes determine the color of the eyes. The function of the gene, which is defective in NF1,
is to produce a protein called neurofibromin. In patients with NF1, neurofibromin is decreased, and the decrease in
neurofibromin is felt to contribute directly to tumor formation. Neurofibromin helps control the activity of another protein
called ras. Ras can be thought of as an "on/off" switch for cell growth. When ras is "on", cells grow. When ras is "off",
CONTINUATION SHEET for either:
MEDICAL RECORD
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
01-C-0222
CONTINUATION: page 2 of 7 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
the cells do not grow. Neurofibromin helps to keep ras "off". Decreased levels of neurofibromin therefore may allow for
uncontrolled cell growth and tumor formation.
Drugs that inactivate ras are being studied as a new way to treat cancer. These drugs may also provide a logical means
of controlling the tumors in patients with NF1. R115777 is a new experimental drug that interferes with the function of
the ras protein and other proteins in cells by blocking a step in the formation of these proteins. R115777 can block the
growth of cancer cells in test tubes and in animals, but we do not know yet whether it will be effective for the treatment
of plexiform neurofibromas in patients with NF1. This experimental drug has only been administered to a small number of
adult and pediatric patients with a variety of different types of cancer and NF1. We do not know if this drug will be
effective in your/your child’s plexiform neurofibromas. R115777 is not approved by the Food and Drug Administration
(FDA) for commercial use, but the FDA has permitted its use in this research study.
DESCRIPTION OF RESEARCH STUDY
The main purposes of this research study are (1) to determine if R115777 can slow down the growth rate of plexiform
neurofibromas in patients with NF1, (2) to determine if R115777 can result in shrinkage of progressive plexiform
neurofibromas, (3) to determine the types of side effects that can be produced by R115777 in children and young adults
with NF1 and (4) to study the biology of the tumors from patients with NF1.
The growth of plexiform neurofibromas can be unpredictable, including periods of rapid growth and other periods of no
measurable tumor growth. This unpredictable behavior can make it difficult to measure the effectiveness of R115777 as a
treatment for plexiform neurofibromas. In order to find out if R115777 will be helpful for patients with plexiform
neurofibromas, we will compare the effects of the drug to a placebo (a similar tablet that does not contain R115777) in
each patient who is treated on the study. Before starting any treatment we will randomly determine (determined by coin
flip) whether you/your child will initially receive either R115777 or placebo. Neither you/your child nor anyone involved in
the care of you/your child, such as the nurses and physicians at the NCI and your/your child’s doctor at home, will know
if you/your child are is receiving R115777 or the placebo.
We will follow you/your child closely throughout the study for signs of increase of the plexiform neurofibroma by regular
clinical examinations, if possible photography of visible tumors (with your permission, please see below), and MRI scans.
You/your child will be identified on photographs only by the study ID number, and photographs will be located in a
separate locked folder at the Pediatric Oncology Branch, NCI. If we find that the plexiform neurofibromas are increasing
in size, you/your child will be switched to the other treatment. For example, if you/your child were getting the placebo
first, then you/your child will be switched to R115777. As long as we find tumor growth during the initial part of the
study, at some point you/your child will receive R115777. Should the tumor be stable or decrease in size, you/your child
will continue to receive the same treatment for as long as it is well tolerated and appears to be of benefit. The treatment
will only be switched or stopped if it is not controlling the growth of the plexiform neurofibromas. You/your child will be
removed from the study when growth of the plexiform neurofibroma is noted on the second treatment phase. At that
time we will perform a thorough clinical evaluation, in addition to a MRI study, and arrange for necessary follow-up care
by your/your child’s physician. Other reasons for removal from the protocol could be if you/your child did not tolerate
R115777/placebo because of side effects of the drug, if you/your child developed another serious medical condition,
which would not allow the administration of R115777/placebo, or if you/your child were unable to comply with the
protocol. Although the design of this study is complicated, we think that it offers the best chance of determining if
R115777 is of benefit for progressive plexiform neurofibromas. A total of approximately 60 patients will be entered on this
study.
R115777 or placebo will be given by mouth in the form of tablets taken every 12 hours for 21 days followed by a 7 day
rest period (1 cycle = 28 days, 21 days drug, 7 days rest period). R115777 will be given at the highest dose, which was
CONTINUATION SHEET for either:
MEDICAL RECORD
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
01-C-0222
CONTINUATION: page 3 of 7 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
found to be well tolerated by most patients in a prior clinical trial. Each dose will be 200 mg/m2 body surface area, which
is calculated from your/your child’s height and weight. Tablets can be crushed for easier consumption, if necessary.
R115777 or placebo should be taken after a meal. This treatment will be continued, unless unacceptable side effects or
increase in the size of the plexiform neurofibromas are observed. You/your child will be examined by a doctor initially
every other week during this treatment, and will have routine blood tests performed initially every other week. The
frequency of these studies will be spread out after three cycles of treatment. MRI scans to measure the size of your/your
child’s plexiform neurofibromas will be performed periodically throughout the course of treatment. In addition to
measuring the plexiform neurofibroma in the longest dimensions, we will also determine the volume of the plexiform
neurofibroma to test if changes in the tumor volume may better reflect changes in the tumor size than standard
measurements.
We will provide you with a form on which you will record the time each dose is administered, any side effects that
you/your child experience, and any other medicines that you/your child are taking. This diary is an important part of our
monitoring of this experimental drug.
Blood samples of 2 to 4 teaspoons each will also be taken prior to the first dose of treatment, and at one time point after
at least 14 days of treatment on each study phase (R115777 or placebo) to measure the effect of R115777 on proteins in
blood cells. A blood sample of less than one teaspoon will be obtained prior to starting treatment and prior to cycles 4, 7,
10, and then after every 6 cycles on each study phase to measure the level of a substance called nerve growth factor.
The analysis of nerve growth factor will be used to determine if it can predict which patients may be at risk to develop
side effects from R115777.
Should you/your child have superficial (just under the skin) tumor nodules, we would also like to ask you/your child to
provide a piece of tumor from one of these nodules prior to the first dose of any treatment, and if feasible at one time
point after at least 14 days of treatment on each study phase (R115777 or placebo) to learn more about changes in
tumors of patients with NF1. In addition, should you/your child have to undergo surgery for a complication of your/your
child’s tumor, we would like to obtain a sample of the tumor. In this case we would only obtain the tumor sample after
the pathologist and surgeon have determined that any material necessary for clinical care has been obtained. We will
perform a detailed analysis of the tumor samples to better understand the cell components of plexiform neurofibromas,
and will attempt to grow tumor cells in culture. In addition we will analyze the tumor samples for changes in the NF1
gene and in the ras gene and ras protein. These studies may help us to better understand which patients may benefit
from the treatment with R115777. Any results from these studies will be preliminary and will require further analysis for
verification. Therefore, neither you/your child nor anyone else will be informed about results of the studies performed on
your/your child’s neurofibroma tissue.
Should any tumor sample be left over after performing the above studies, we would like to retain these samples in a
central tumor repository (storage site) at Washington University in St. Louis, Missouri. The tissue will be identified with a
code number, and will only be possible to connect with your/your child’s name through the trial coordinating center
“Pediatric Oncology Branch of the NCI” in Bethesda, MD. The tissue may be distributed to investigators to help with their
research on neurofibromatosis. There is a chance that the tumor sample you/your child are providing for this study, may
have some commercial applicability. There are no plans to provide financial compensation to you/your child, should this
occur. Any future research done with these samples will be conducted under a protocol approved by the Institutional
Review Board with oversight of the tissue bank. You/your child will not receive further notice of future uses of your/your
child’s sample, unless a future use could involve more than minimal risk to you/your child. Any results from these studies
will be preliminary and will require further analysis for verification. Therefore, neither you/your child nor anyone else will
be informed about results of the studies performed on your/your child’s neurofibroma tissue. All research results will be
kept confidential. You can decide not to allow storage of your/your child’s tumor sample at the tissue repository (please
CONTINUATION SHEET for either:
MEDICAL RECORD
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
01-C-0222
CONTINUATION: page 4 of 7 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
see below), or withdraw your/your child’s specimen from the tissue repository at any time. Please contact Dr. Brigitte
Widemann, Principal Investigator of this study, if you wish to do so.
If you decide not to have a tumor sample taken, you/your child can still participate in the treatment part of this study
(please see below). We will give you/your child a separate consent form, for the tumor biopsy that explains the
procedure and its risks more fully. If you decide not to give permission for storage of the tumor sample in the central
tumor repository, you/your child can still participate in the treatment part of the study (please see below).
In addition we would like to assess your/your child’s quality of life by giving you/your child a questionnaire, which
you/your child would complete periodically throughout the treatment course.
Should significant new findings regarding the treatment of NF1 become available during the course of this study, which
may influence your decision to continue on this study, we will provide you/your child with that information.
R115777 and placebo will be provided without charge, as will all examinations and studies performed at the NIH. The
NIH will usually not pay for physical examinations or laboratory tests required for the study, which are performed outside
of the NIH.
Please indicate below if you/your child agree or disagree to the following study procedures:
1) Regular photographs of visible tumors:
Agree: θ
Disagree: θ
Initials:
2) Obtain tumor sample(s) of superficial tumor nodules:
Agree: θ
Disagree: θ
Initials:
3) Storage of the tumor sample(s) in a central tumor repository: Agree: θ
Disagree: θ
Initials:
ALTERNATIVE APPROACHES OR TREATMENTS
You/your child will only be eligible for this trial if complete surgical removal of the progressive plexiform neurofibroma(s)
is not feasible. Alternatives to this treatment may include partial surgical removal of the plexiform neurofibroma, other
experimental therapies, or you/your child may decide not to receive any treatment at this point in time.
RISKS OR DISCOMFORTS OF PARTICIPATION
The side effects of R115777 have been studied in animals, in adult patients with cancer, and in children with cancer and
NF1. R115777 may affect several organs or tissues of your/your child’s body. The side effects most commonly observed
in adults were decrease in the bone marrow function leading to a drop in the white blood cell count (neutropenia,
granulocytopenia), platelet count, or red blood cell count, and nausea and vomiting. A decrease in white blood cells leads
to an increased risk for infections and fever including sepsis. A decrease in the platelet count can result in bleeding or
bruising and may require platelet transfusions to correct it. A decreased red blood cell count leads to anemia causing
tiredness, and may require red blood cell transfusions to correct it. Other likely side effects include loss of appetite,
diarrhea, nausea or vomiting. When R115777 was given continuously to adult patients with breast cancer (every day
without a rest period) for a time period exceeding 12 weeks, more than half of the patients developed signs of nerve
damage with pain, tingling and numbness or weakness in the hands or feet. Less frequently, R115777 caused
headaches, dehydration, skin rash, sensitivity to sunlight (photosensitivity) and peeling skin, a decrease in kidney
function (increase in serum creatinine), a decrease in the potassium level (an important chemical), reversible liver
damage, heartburn, decrease in blood pressure, irritation or sores in the lining of your mouth or esophagus or intestines,
constipation, nosebleed, fever or infection, tiny broken blood vessels under the skin and changes in a chemical called
lipase, which is required to digest food. One adult developed headaches and a defect in vision, which were reversible.
The same patient later developed a stroke, which was felt not to be related to the R115777. In adult patients with
CONTINUATION SHEET for either:
MEDICAL RECORD
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
01-C-0222
CONTINUATION: page 5 of 7 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
leukemia who received high doses of R115777 (900 to 1200 mg twice daily) increased thirst, confusion, changes in vision,
and difficulties to coordinate body movements were observed. These side effects subsided completely within a few days
after stopping R115777. Other less-frequently observed side effects include swelling of the arms and legs, dizziness,
sleepiness, pain in the belly, chest or in general, or cough or shortness of breath. One rare but serious side effect
observed was bleeding into the brain or spinal cord.
The side effects observed to date in the children and adolescents treated with R115777 are similar to those observed in
adults and include: 1) A decrease in the bone marrow function, with a drop in the white blood cell, platelet count and red
blood cell count, 2) the development of a rash which may be more pronounced in skin areas exposed to sun, and 3) the
development of nausea, vomiting, diarrhea and abdominal pain. One patient had a seizure while receiving R115777, and
one patient experienced a reversible decrease in fibrinogen (a substance important for blood clotting). Few children with
leukemia developed an increase in blood tests, which measure liver function (bilirubin, AST), with an unclear relationship
to R115777. In addition, 1 patient with leukemia developed mouth sores (mucositis). Signs of nerve damage have not
been reported in any of the children treated to date. However, this does not guarantee that children will not develop
neurologic toxicity, particularly after administration of R115777 for a long time period. All of these side effects have been
reversible.
The dose of R115777 that you/your child get was determined in a prior clinical study in pediatric patients with cancer and
NF1. This dose of R115777 was well tolerated by most patients. However, since this is a new experimental treatment,
other presently unknown side effects may occur. These side effects could potentially be serious and even fatal. You/your
child will be watched closely and the drug will be discontinued if serious side effects develop.
The risks from the blood drawing to assess the affect of R115777 in the body include the discomfort from having needle
sticks if required and a small risk of infection.
Participation in the present study may render you/your child ineligible to participate in other research studies that limit
the number or type of treatments that patients may have received, and in some cases, the types of side effects that
patients may have experienced.
Tumor Studies: You/your child will receive a separate consent form for the tumor biopsy that explains the procedure and
risks more fully. Tumor material will be obtained for research purposes on this study. With your permission, left over
tumor will be sent to a central tissue repository. Although there is no immediate plan to perform studies from any tumor
samples obtained, tumor material will be stored for possible future testing. It is expected that the tissue samples will be
stored indefinitely in the repository. The sample will be identified by a code number that can be traced to you/your child
only by contact with the trial coordinating center “Pediatric Oncology Branch, NCI” in Bethesda, MD. Neither you nor
anybody else will be informed about results of testing performed on your/your child’s blood sample or tumor tissue. Every
effort will be made to keep test results confidential. However, as the tumor and sample can be linked to your/your child’s
name, a small risk persists that unauthorized persons could gain access to the information. Some testing may eventually
reveal information that, in some cases, may result in discrimination with health or life insurance or employment. We
believe that these risks are minimal since it is already known that you/your child have neurofibromatosis.
MRI: Magnetic resonance imaging (MRI) is a standard procedure used for imaging plexiform neurofibromas. When
having a MRI, you/your child will lie motionless on a table that slides into a tunnel slightly wider than your/your child’s
body for about one hour. There is very little room in the MRI, however you/your child will easily be able to hear and
speak to research staff. As images are taken, the MRI makes loud banging noises as though it was being pounded on
the outside with a hammer. Earplugs will be offered to help reduce the noise. MRIs use powerful magnets. There are no
known or foreseeable risks associated with exposures to MRI provided no metal implanted prostheses (e.g., vascular
clamps or pacemakers; braces are not a problem) are present. Should you/your child have a metal prosthesis you/your
child may be excluded from participating in the study for your/your child’s own safety. All potential subjects will be
CONTINUATION SHEET for either:
MEDICAL RECORD
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
01-C-0222
CONTINUATION: page 6 of 7 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
screened for the presence of such prior to the examination. Some participants in the study may require sedation or
anesthesia to perform MRI. Consent for this will be obtained prior to the MRI. There are risks associated with sedation
and anesthesia, including the risk of death in rare instances.
If you/your child are a female and old enough to get pregnant, you/your child will be given a pregnancy test before
you/your child begin the treatment, in order to make sure that you/your child are not pregnant. If there is a chance that
you/your child could become pregnant during this study, you/your child should not participate in the study. If you/your
child are sexually active, you/your child must use an appropriate and effective method of birth control while you/your
child are taking part in this study. If you/your child become or are found to be pregnant while taking part in this study,
you/your child must notify one of the doctors listed on this form right away so the treatment can be discussed.
If you/your child are a male, you/your child should also use a means of birth control while taking part in this study (if
sexually active), because we do not know what effect the experimental drug may have on your/your child’s sex cells and
what effect this would have upon the development of an unborn child.
POTENTIAL BENEFITS OF PARTICIPATION
The potential benefit of this treatment with R115777 is that it may cause your/your child’s neurofibroma to stop growing
or shrink for a period of time or it may lessen the symptoms, such as pain, that are caused by the tumor. It is our intent
to benefit each subject in the trial. However, because there is not much information about the drug’s effect on plexiform
neurofibromas in humans, we do not know if you/your child will benefit from taking part in this study, although the
knowledge gained from this study may benefit others. The MRI data in this study will be analyzed by a special approach
called “volumetric MRI,” in addition to being read in a standard manner by a radiologist. The volumetric MRI approach
will provide more precise measurement of the size of plexiform neurofibromas, and therefore will give more complete and
objective information on which to base any possible future treatment decisions. Volumetric MRI is currently not available
on a routine clinical basis.
RESEARCH SUBJECT'S RIGHTS
Joining this research study is voluntary. You/your child may ask the doctors and nurses any questions about this
treatment. If you/your child decide at any time that you/your child do not want to receive this treatment any more, then
tell us (Dr. Brigitte Widemann, phone 301-496-7387, Dr. Frank Balis phone 301-496-0085, or Ms. Andy Gillespie, RN,
phone 301-402-1848) and we will discontinue it. You/your child may be eligible to receive experimental therapy other
than the drug described here, or can receive therapy consisting of symptomatic treatment only.
Your/your child’s medical record may be reviewed by qualified representatives from the National Cancer Institute, or by
representatives from the Food and Drug Administration (FDA).
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
MEDICAL RECORD
• Adult Patient or • Parent, for Minor Patient
STUDY NUMBER:
01-C-0222
CONTINUATION: page 7 of 7 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY (Continuation Sheet)
• Adult Patient or • Parent, for Minor Patient
NIH-2514-1 (12-08)
P.A.: 09-25-0099
FAX TO: (301) 480-3126
File in Section 4: Protocol Consent
OTHER PERTINENT INFORMATION
1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings,
the people who take part are not named and identified. In most cases, the NIH will not release any information about
your/your child’s research involvement without your written permission. However, if you sign a release of information
form, for example, for an insurance company, the NIH will give the insurance company information from your/your
child’s medical record. This information might affect (either favorably or unfavorably) the willingness of the insurance
company to sell you insurance.
The Federal Privacy Act protects the confidentiality of your/your child’s NIH medical records. However, you/your child
should know that the Act allows release of some information from your/your child’s medical record without your
permission, for example, if it is required by the Food and Drug Administration (FDA), members of Congress, law
enforcement officials, or other authorized people.
2. Policy Regarding Research-Related Injuries. The Clinical Center will provide short-term medical care for any
injury resulting from your/your child’s participation in research here. In general, no long-term medical care or financial
compensation for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or
the Federal Government. However, you/your child have the right to pursue legal remedy if you believe that your/your
child’s injury justifies such action.
3. Payments. The amount of payment to research volunteers is guided by the National Institutes of Health policies.
In general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of
travel and subsistence will be offered consistent with NIH guidelines.
4. Problems or Questions. If you/your child have any problems or questions about this study, or about your/your
child’s rights as a research participant, or about any research-related injury, contact the Principal Investigator, Dr.
Brigitte Widemann; Building 10, Room 13C103, Telephone:301-496-7387. Other researchers you/your child may call
are: Dr. Frank Balis, Telephone 301-496-0085; and Andy Gillespie, R.N., Telephone 301-402-1848.
You/your child may also call the Clinical Center Patient Representative at 301-496-2626.
5. Consent Document. Please keep a copy of this document in case you/your child want to read it again.
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent
B. Parent’s Permission for Minor Patient.
I have read the explanation about this study and have been given the
opportunity to discuss it and to ask questions. I hereby consent to take
part in this study.
I have read the explanation about this study and have been given the
opportunity to discuss it and to ask questions. I hereby give permission
for my child to take part in this study.
(Attach NIH 2514-2, Minor’s Assent, if applicable.)
Signature of Adult Patient/Legal Representative
Date
Signature of Parent(s)/Guardian
Date
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to participate in the study.
Signature of Parent(s)/Guardian
Date
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE
FROM JANUARY 12, 2009 THROUGH JANUARY 11, 2010.
Signature of Investigator
Date
Signature of Witness
Date
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
MEDICAL RECORD
• Attach to NIH-2514-2, Consent to Participate in a Clinical Research Study
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
01-C-0222
PRINCIPAL INVESTIGATOR: Brigitte Widemann, M.D.
STUDY TITLE:
A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trial of the
Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type 1 and
Progressive Plexiform Neurofibromas
Continuing Review Approved by IRB on 1/12/09
Amendment Approved by IRB on 6/5/09 (J)
Date Posted to Web: 6/27/09
Minor 7 thorugh 12 years of age
PATIENT IDENTIFICATION
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
NIH-2514-2 (4-97)
P.A.: 09-25-0099
File in Section 4: Protocol Consent (3)
You have an illness called neurofibromatosis type 1. We will call it NF1 for short. NF1 can cause lumps that are called
tumors to grow inside of your body and these tumors can cause pain or other problems. Sometimes the tumors can be
taken out with an operation, but if they can’t then doctors don’t have other ways to make them stop growing or make
them go away.
We are trying to find new medicines that can slow down or stop NF1 tumors from growing, and we are asking you to help
us test one of these new medicines that is called R115777. We don’t know yet whether this new medicine will work.
We can measure the size of your tumor and check to see if your tumor is growing by doing scans that can take a picture
of the inside your body without hurting you. This is called an MRI scan. You will lie down on a bed, and the bed is pushed
into a machine. This can be scary because you are in a small space and the machine makes a lot of noise. The scan
usually takes about 1 hour, and you have to lie still during the scan. Some kids need medicines to make them sleep
during the scan because it is too scary or they can’t lie still that long.
NF1 tumors don’t grow all of the time. They can grow for a while and then stop growing for a while without any
treatment. This makes it hard for us to tell if a new medicine is really working.
To find out if a new medicine works we will measure the change in the size of your tumor while you are taking pills that
have the new medicine in them, and we will also measure the change in tumor size while you are taking pills with no
medicine in them. You, your parents, and your doctors will not know whether the pills that you are taking have the
medicine or not. You may start with the pills that have the medicine first or you may start with the empty pills first. If
your tumor grows, then we will switch you to the other type of pills. If your tumor stays the same size then you will keep
taking the same pills.
You will take pills twice a day for 21 days and then you will have a break for 7 days before you start taking the pills
again. We will do the MRI scans to check the size of your tumor after every 3 months for the first year and then after
every 6 months.
The new medicine that we are testing can cause side effects, which can make you feel bad. Side effects can happen
when the new medicine effects other parts of your body than the tumor. These side effects do not happen to everyone
who takes the new medicine. In some people the medicine can make them feel sick to their stomach or throw up. It can
also cause diarrhea (watery poop), skin rash, which is red itchy bumps, make your nose bleed, or have tingling,
numbness or pain in your hands and feet. Let us know if you feel dizzy, confused, have a sore mouth, have trouble
catching your breath, have trouble going to the bathroom (poop), or have trouble going to sleep. The new medicine can
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
MEDICAL RECORD
STUDY NUMBER:
01-C-0222
CONTINUATION: page 2 of 2 pages
PATIENT IDENTIFICATION
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A
also lower your blood cells that carry oxygen to your body, fight infections, and make your blood clot when you get a cut.
It can also change how your kidneys or liver work, so we will check for all of these by doing blood tests every 2 weeks
after you start the new medicine and then every 4 weeks after you have been on the medicine for a while. We get this
blood by putting a small needle into a vein in your arm. This feels like a prick or bee sting. If the side effects happen to
you, they will go away after you stop taking the medicine. Tell your parents or your doctors if you think that you have
any of these side effects.
If this new medicine works, it may slow down or stop the growth of your tumor.
Ask your parents or your doctors or nurses if you have questions about this new medicine or the way that we are testing
it. We are asking for your permission and your parents permission before we test this new medicine on you. You can
decide not to take part in this study if you don’t want to and you can stop taking the medicine at any time, if you change
your mind.
I have had this study explained to me in a way that I understand, and I have had the chance to ask questions.
I agree to take part in this study.
Signature of Minor Patient:
Date:
Signature of Investigator:
Date:
CLINICAL RESEARCH STUDY
NIH-2514-2 (4-97)
P.A.: 09-25-0099
FAX TO: (301) 480-3126
File in Section 4: Protocol Consent
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
MEDICAL RECORD
• Attach to NIH-2514-2, Consent to Participate in a Clinical Research Study
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
01-C-0222
PRINCIPAL INVESTIGATOR: Brigitte Widemann, M.D.
STUDY TITLE:
A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trial of the
Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type 1 and
Progressive Plexiform Neurofibromas
Continuing Review Approved by IRB on 1/12/09
Amendment Approved by IRB on 6/5/09 (J)
Date Posted to Web: 6/27/09
Minor 13 through 17 years of age
PATIENT IDENTIFICATION
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
NIH-2514-2 (4-97)
P.A.: 09-25-0099
File in Section 4: Protocol Consent (4)
Introduction: We would like to invite you to take part in a research study at the National Institutes of Health (NIH).
Before you decide about taking part in the study, we want you to know why we are doing the study and if it will help you.
We also want you to know about any risks (what might go wrong) and what you will have to do. You can only be in the
study if you and your parent(s) agree.
This form gives you information about the study. Your doctor will talk to you about the study and answer questions you
have. If you would like to take part in this study, we will ask you to sign this form to show that you understand this
study. We will give you a copy of this form to keep. It is important that you know:
You do not have to join the study
You may change your mind and drop out of the study at any time
If we make important changes to the study we will tell you about it and make sure you still want to be in the study.
Purpose of the study
You have an illness called neurofibromatosis type 1 or NF1, which has caused a tumor (called plexiform neurofibroma) to
grow inside your body. This tumor may cause you pain, discomfort, or other problems as it gets larger. There are no
effective treatments other than surgery, to make these tumors go away. Because your tumor cannot be taken out
completely, we want to see if a new drug with the name R115777 will help to stop your tumor from growing, or shrink
your tumor. This drug has been given in the past to adults with other diseases than NF1, and to some children with
cancer or NF1.
Because we do not know whether this new drug will work, we are doing a study where we are giving R115777 to just a
few children and adults with NF1 and a tumor called a plexiform neurofibroma, which has shown recent growth and
cannot be completely removed by surgery.
We want to answer four questions about this new drug R115777 and NF1 tumors:
Will this new drug, R115777, slow down how fast your NF1 tumor(s) grow(s)?
Will R115777 make your NF1 tumor(s) smaller?
Does R115777 make you feel different or cause anything new to happen to you (for example, does the drug make you
feel tired or does it make your stomach upset)?
What more can we learn about NF1 tumors?
CONTINUATION SHEET for either:
MEDICAL RECORD
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
01-C-0222
CONTINUATION: page 2 of 3 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
Study plan
These are difficult questions to answer but we have written a plan or study, which we think, will help us find the answers.
We want to watch you and look at your tumors when you are taking the R115777 pills for a period of time and when you
are taking pills that don’t have the drug. The pill that does not contain R115777 looks just like the R115777 pill. This way
you, your parents, and your doctors will not know which type of pill you are taking and we will be able to find out if the
R115777 is really working. Before you take any drug, a coin will be flipped to decide if you will take the R115777 pills or
the empty pills first. You will continue to take that pill until your tumor(s) grow(s) and then you will be switched over to
the other pill and take it until your tumor(s) grow(s) once again. We will not know when you are taking the R115777 or
the empty pills.
The plan or protocol we have written explains the rules about this study. It tells us how you take the drug, when you
take the drug and how we will keep a very close eye on you while you are on our study. You will take the R115777 or
empty pills two times a day for 21 straight days and then you will stop taking the pills for 7 days in a row. You will
continue taking the R1115777 or empty pills this way until your tumors grow or you do not feel well enough to swallow
the pills. We will know when your tumors grow because after every 3 months during the first year, and then after every
6 months, you will have a MRI scan, which takes a picture of the inside of your body. To take the picture you lay down
on a bed, which slides into a large machine. It may be scary if you don’t like small places. You will need to lie still for
approximately 1 hour. The scanner is also very noisy while it is working. You may have to receive a medicine to make
you sleep while you get the scans. The medicine will be put into a vein in your arm through a small needle. It will feel
like a prick or bee sting when the needle is placed in your arm. In addition to the pictures we take, we will also look at
your blood, in the beginning every 2 weeks, and then every 4 weeks. We draw the blood from your arm by placing a
small needle into the vein in your arm, which will feel like a prick or a bee sting. Once the blood is drawn the needle is
taken out and you will be given a band-aid.
Risks or side effects:
Drugs can make you feel different or cause something new to happen to you. These are called side effects of a drug. At
the dose of R115777 you will receive, the drug has been well tolerated by a small number of children with NF1. However,
the following side effects may happen to you. Your stomach may be upset, causing some nausea or vomiting. The drug
may cause you to have diarrhea or watery bowel movements. A bumpy redness called a skin rash may appear on your
skin that can itch or your skin may become more sensitive to sunlight. R115777 may also affect your blood, which is
made up of many different parts or cells. One of them is your white blood cells, which helps your body fight germs or
infections. R115777 may lower the number of white blood cells in your body, which may cause you to have a fever or
get sick. Few adult patients who took the drug continuously without a break for more than 3 months developed pain and
tingling in the tips of the fingers and toes. All reported side effects from R115777 went away after the drug was stopped.
Less likely side effects may include difficulty having a bowel movement, heartburn, nosebleed, mouth sores, swelling of
the arms or legs, confusion or dizziness, sleepiness, pain in the chest or belly, headache, cough or having difficulty
breathing. This drug may change how your kidneys or liver work so we will check for this by doing blood tests. Should
you develop a side effect we may decide to stop the drug until the side effects go away, and then restart the drug at a
lower dose. One rare but serious side effect observed was bleeding into the brain or spinal cord.
Taking R115777 might be harmful to an unborn child. Birth control measures must be used by all females of child-
bearing age or who can become pregnant and are sexually active or by their sexual partners while in this study, such
as: Contraceptive pill or use of condom and spermicide cream. As effects of R115777 on a newborn child are unknown,
breast-feeding mothers must stop breast- feeding their child. Males who are sexually active, must also use means of
birth control while participating in the study.
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
MEDICAL RECORD
STUDY NUMBER:
01-C-0222
CONTINUATION: page 3 of 3 pages
PATIENT IDENTIFICATION
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A
Potential Benefits:
R115777 might slow down or stop the growth of your tumor or even might decrease its size. Taking part in this study will
help us to find out if R115777 works.
Alternatives to Participation
The only known effective treatment for plexiform neurofibromas is surgery. In many cases the tumor cannot be removed
completely, and in some cases surgery cannot be safely done. Participation in this study will only be offered to you if your
tumor cannot be safely removed, or if you or your parents don’t want you to have surgery.
Confidentiality
We will keep the records of this study confidential. Only people working on the study will know your name.
Please ask your doctor or research nurse any questions you might have about this study. Keep asking until you
understand. You can decide not to take part in this study if you don’t want to. Your doctors and nurses will understand
if you don’t want to participate. If you agree to go on this study, know that you can stop whenever you choose.
We are asking for your permission and your parent’s permission before we give this new medicine to you. A copy of this
form will be given to you and your parents.
By signing this form, you agree that you have talked to your doctor about the study and understand it, and want to be in
the study. You also agree that we have talked to you about the risks and benefits of the study, and about other choices.
You may drop out of the study at any time and no one will mind. Please call the Principal Investigator Dr. Brigitte
Widemann, M.D., at 301-496-7387 if you have any questions.
.
I have had this study explained to me in a way that I understand, and I have had the chance to ask questions.
I agree to take part in this study.
Signature of Minor Patient:
Date:
Signature of Investigator:
Date:
CLINICAL RESEARCH STUDY
NIH-2514-2 (4-97)
P.A.: 09-25-0099
FAX TO: (301) 480-3126
File in Section 4: Protocol Consent
| 2
|
arm 1: Patients receive oral R115777 (Tipifarnib) first followed by placebo. 200 mg/m\^2/dose BSA every 12 hours by mouth (po)on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive oral placebo first followed by R115777 (Tipifarnib). 200 mg/m\^2/dose BSA every 12 hours by mouth (po)every 12 hours on days 1-21. Courses repeat as in arm I.
|
[
0,
2
] | 2
|
[
0,
10
] |
intervention 1: Given orally, 200 mg/m\^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days intervention 2: Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.
|
intervention 1: tipifarnib intervention 2: placebo
| 12
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Los Angeles | California | United States | -118.24368 | 34.05223
Chicago | Illinois | United States | -87.65005 | 41.85003
Baltimore | Maryland | United States | -76.61219 | 39.29038
Bethesda | Maryland | United States | -77.10026 | 38.98067
Boston | Massachusetts | United States | -71.05977 | 42.35843
St Louis | Missouri | United States | -90.19789 | 38.62727
Syracuse | New York | United States | -76.14742 | 43.04812
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Houston | Texas | United States | -95.36327 | 29.76328
Hamburg | N/A | Germany | 9.99302 | 53.55073
| 0
|
NCT00021541
|
[
4
] | 167
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 1FEMALE
| false
|
Randomized, double-blind, placebo-controlled multicentre study, with parallel groups, to determine the efficacy and safety of a new low-concentration estriol formulation (ITFE-2026 0.005%) for application by vaginal route in the treatment of postmenopausal vaginal atrophy.
Primary objective:
• To evaluate the efficacy of 0.005% Estriol vaginal gel by evaluation of the change in the maturation value of the vaginal epithelium (MV) after 12 weeks of treatment.
Secondary objectives:
* To determine the variation of the vaginal pH, as well as symptoms and signs suggestive of vaginal atrophy after 12 weeks of treatment.
* To study the variation of the MV, pH and symptoms and signs suggestive of vaginal atrophy after an initial observation period of 3 weeks.
* To evaluate the safety of 0.005% Estriol vaginal gel
* To evaluate the acceptability of 0.005% Estriol vaginal gel
|
This is a randomized, double-blind, placebo-controlled multicentre study, with parallel groups, to determine the efficacy and safety of a new low-concentration estriol formulation (ITFE-2026 0.005%) for application by vaginal route in the treatment of postmenopausal vaginal atrophy.
Eligible patients were randomised in a ratio of 2:1 to 0.005% Estriol vaginal gel : placebo. Each patient was treated for 12 weeks followed by a one-month observational period. The patients attended the study centre at baseline and at 3, 8 and 12 weeks after start of treatment. Vaginal cytology was performed at baseline and at weeks 3 and 12; the vaginal pH and the signs and symptoms of vaginal atrophy were recorded at baseline and after 3 and 12 weeks of treatment. Vital signs, gynaecological exploration and changes in health and concomitant medication were documented at each visit. Transvaginal ultrasound was performed at screening and week 12. The investigators telephoned the patient approximately one month after the final visit to check if the patient had experienced any adverse events since the final visit. Two independent cytopathologists assessed the maturation value of each cytology sample at the end of the study.
|
Vaginal Atrophy
|
Postmenopausal women
| null | 2
|
arm 1: 0.005% Estriol (50 μg/g) gel for vaginal administration. Route: Vaginal by a cannula inserted deep inside the vagina Single dose: 1 g of gel Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: single application 2 times per week. arm 2: Placebo gel for vaginal administration. Route: Vaginal by a cannula inserted deep inside the vagina Single dose: 1 g of gel Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: single application 2 times per week.
|
[
0,
2
] | 2
|
[
0,
10
] |
intervention 1: Gel for vaginal application intervention 2: Gel for vaginal application
|
intervention 1: Estriol intervention 2: Placebo
| 12
|
Torrelavega | Cantabria | Spain | -4.04785 | 43.34943
Madrid | Castiglia | Spain | -3.70256 | 40.4165
Barcelona | Catalonia | Spain | 2.15899 | 41.38879
Barcelona | Catalonia | Spain | 2.15899 | 41.38879
Granada | N/A | Spain | -3.60667 | 37.18817
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Murcia | N/A | Spain | -1.13004 | 37.98704
Oviedo | N/A | Spain | -5.84476 | 43.36029
Valencia | N/A | Spain | -0.37966 | 39.47391
Valencia | N/A | Spain | -0.37966 | 39.47391
Vigo | N/A | Spain | -8.72264 | 42.23282
| 0
|
NCT04574999
|
[
3
] | 3
|
NA
|
SINGLE_GROUP
| 4SUPPORTIVE_CARE
| 0NONE
| false
| 0ALL
| null |
RATIONALE: Cyclophosphamide may help control the symptoms of autoimmune enteropathy .
PURPOSE: This phase II trial is studying how well cyclophosphamide works in treating young patients with severe autoimmune enteropathy.
|
OBJECTIVES:
Primary
* Determine the rate of treatment-free remission in young patients with severe autoimmune enteropathy treated with high-dose cyclophosphamide.
Secondary
* Determine the toxic effects of this drug in these patients.
OUTLINE: Patients receive cyclophosphamide IV over 1 hour on days 1-4. Patients then receive filgrastim (G-CSF) IV or subcutaneously once daily beginning on day 10 and continuing for 3 days or until blood counts recover.
After completion of study treatment, patients are followed periodically for up to 1½ years.
PROJECTED ACCRUAL: A total of 7-11 patients will be accrued for this study.
|
Diarrhea Gastrointestinal Complications Unspecified Childhood Solid Tumor, Protocol Specific
|
unspecified childhood solid tumor, protocol specific gastrointestinal complications diarrhea
| null | 1
|
arm 1: Young patients with severe autoimmune enteropathy receive cyclophosphamide IV over 1 hour on days 1-4. Patients then receive filgrastim (G-CSF) IV or subcutaneously once daily beginning on day 10 and continuing for 3 days or until blood counts recover
|
[
0
] | 2
|
[
2,
0
] |
intervention 1: Administered IV or subcutaneously once daily beginning on day 10 and continuing for 3 days or until blood counts recover intervention 2: Administered IV over 1 hour on days 1-4
|
intervention 1: filgrastim intervention 2: cyclophosphamide
| 1
|
Baltimore | Maryland | United States | -76.61219 | 39.29038
| 0
|
NCT00258180
|
[
3
] | 115
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
Primary
• Determine the efficacy of pralatrexate with concurrent vitamin B12 and folic acid supplementation when administered to patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)
Secondary
* Determine the safety of pralatrexate with concurrent vitamin B12 and folic acid supplementation when administered to patients with relapsed or refractory PTCL
* Determine the pharmacokinetic (PK) profile of pralatrexate when administered with vitamin B12 and folic acid supplementation
|
This is a Phase 2, single arm, non-randomized, open-label, multi-center study designed to evaluate the safety and effectiveness of pralatrexate when administered with vitamin B12 and folic acid supplementation to patients with relapsed or refractory PTCL.
Pralatrexate will be given over 3-5 minutes intravenously (IV), which means through a vein. If pralatrexate is tolerated well, the patient will receive IV injections of pralatrexate every week for 6 weeks, followed by 1 week without receiving pralatrexate. These 7 week cycles will be repeated depending on response and tolerability.
|
Peripheral T-cell Lymphoma
|
Peripheral T-cell Lymphoma T-cell Lymphoma Lymphoma PDX Pralatrexate Vitamin B12 Folic acid
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: Pralatrexate 30 mg/m2 via IV push over 3-5 minutes for 6 weeks in a 7 week cycle.
|
intervention 1: Pralatrexate Injection
| 32
|
Duarte | California | United States | -117.97729 | 34.13945
Los Angeles | California | United States | -118.24368 | 34.05223
New Haven | Connecticut | United States | -72.92816 | 41.30815
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Iowa City | Iowa | United States | -91.53017 | 41.66113
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Boston | Massachusetts | United States | -71.05977 | 42.35843
St Louis | Missouri | United States | -90.19789 | 38.62727
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Hackensack | New Jersey | United States | -74.04347 | 40.88593
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Houston | Texas | United States | -95.36327 | 29.76328
Seattle | Washington | United States | -122.33207 | 47.60621
Brussels | N/A | Belgium | 4.34878 | 50.85045
Yvoir | N/A | Belgium | 4.88059 | 50.3279
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Toronto | Ontario | Canada | -79.39864 | 43.70643
Créteil | N/A | France | 2.46569 | 48.79266
Dijon | N/A | France | 5.01667 | 47.31667
Nice | N/A | France | 7.26608 | 43.70313
Paris | N/A | France | 2.3488 | 48.85341
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
Bologna | N/A | Italy | 11.33875 | 44.49381
London | N/A | United Kingdom | -0.12574 | 51.50853
Sutton | N/A | United Kingdom | -0.2 | 51.35
| 0
|
NCT00364923
|
[
2
] | 211
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
A clinical study to determine the safety, efficacy and mechanism of action of sitagliptin alone and in combination with pioglitazone, in patients with type 2 diabetes mellitus who have inadequate glycemic (blood sugar) control.
| null |
Type 2 Diabetes Mellitus (T2DM)
|
Type 2 Diabetes Mellitus (T2DM)
| null | 4
|
arm 1: Arm 1: drug arm 2: Arm 2: active comparator arm 3: Arm 3: drug + active comparator arm 4: Arm 4: placebo comparator
|
[
0,
1,
0,
2
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: sitagliptin phosphate 100 mg as oral tablets. Each patient will be administered 1 tablet once daily. intervention 2: pioglitazone 30 mg will be supplied as oral tablets. Each patient will be administered 1 tablet once daily. intervention 3: pioglitazone 30 mg placebos will be supplied as oral tablets. Each patient will be administered 1 tablet once daily. intervention 4: sitagliptin phosphate 100 mg placebos will be supplied as oral tablets. Each patient will be administered 1 tablet once daily.
|
intervention 1: Comparator: sitagliptin phosphate intervention 2: Comparator: pioglitazone intervention 3: Comparator: placebo to pioglitazone intervention 4: Comparator: placebo to sitagliptin
| 0
| null | 0
|
NCT00511108
|
[
3
] | 192
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of the study is to determine the oral dosage of TR-701 to be used in Phase III studies in patients with complicated skin and skin structure infections.
| null |
Skin Diseases, Infectious Skin Diseases, Bacterial
|
Skin Infection Complicated Skin and Skin Structure Infection
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: oral TR-701 200 mg for 5 to 7 days intervention 2: oral TR-701 300 mg for 5 to 7 days intervention 3: TR-701 400 mg for 5 to 7 days
|
intervention 1: TR-701 200 mg intervention 2: TR-701 300 mg intervention 3: TR-701 400 mg
| 12
|
Dothan | Alabama | United States | -85.39049 | 31.22323
Chula Vista | California | United States | -117.0842 | 32.64005
Long Beach | California | United States | -118.18923 | 33.76696
Oceanside | California | United States | -117.37948 | 33.19587
Pasadena | California | United States | -118.14452 | 34.14778
San Francisco | California | United States | -122.41942 | 37.77493
San Jose | California | United States | -121.89496 | 37.33939
Columbus | Georgia | United States | -84.98771 | 32.46098
Ludowici | Georgia | United States | -81.74234 | 31.70799
Savannah | Georgia | United States | -81.09983 | 32.08354
Springfield | Illinois | United States | -89.64371 | 39.80172
Detroit | Michigan | United States | -83.04575 | 42.33143
| 0
|
NCT00761215
|
[
3
] | 113
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| true
| 0ALL
| null |
This is an exploratory study to determine effectiveness of Elidel for the treatment of seborrheic dermatitis
|
This is a 4 week study for patients 18 and older to compare the efficacy and safety of pimecrolimus cream 1% twice daily and ketaconazole cream 2 % twice daily for the treatment of seborrheic dermatitis.
|
Seborrheic Dermatitis
|
seborrheic dermatitis
| null | 2
|
arm 1: Elidel Cream to be applied twice daily for 4 weeks arm 2: Ketoconazole Cream to be applied twice daily for 4 weeks
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Elidel intervention 2: Ketoconazole Cream
| 1
|
Louisville | Kentucky | United States | -85.75941 | 38.25424
| 0
|
NCT00403559
|
[
4
] | 571
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to learn how well atazanavir (ATV) works in combination with ritonavir (RTV) or saquinavir (SQV) with tenofovir (TDF) and a nucleoside to reduce the viral load of treatment experienced subjects with human immunodeficiency virus (HIV). There is a comparison arm with lopinavir (LPV)/RTV and TDF and a nucleoside.
| null |
HIV Infections
| null | 3
|
arm 1: ATV 300 mg + RTV 100 mg + TDF 300 mg + nucleoside of choice
ATV , RTV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study arm 2: ATV 400 mg + SQV 1200 mg + TDF 300 mg + nucleoside of choice
ATV, SQV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study arm 3: LPV/RTV 400/100 mg + TDF 300 mg + nucleoside of choice
LPV/RTV twice daily, TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study
|
[
1,
1,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Active Comparator, Capsules, tablets, Oral intervention 2: Active Comparator, Capsules, tablets, Oral intervention 3: Active Comparator, Capsules, tablets, Oral
|
intervention 1: Atazanavir + ritonavir + tenofovir + nucleoside intervention 2: Atazanavir + saquinavir + tenofovir + nucleoside intervention 3: Lopinavir/ritonavir + tenofovir + nucleoside
| 29
|
San Francisco | California | United States | -122.41942 | 37.77493
Torrance | California | United States | -118.34063 | 33.83585
Boulder | Colorado | United States | -105.27055 | 40.01499
Altamonte Springs | Florida | United States | -81.36562 | 28.66111
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
Miami Beach | Florida | United States | -80.13005 | 25.79065
Orlando | Florida | United States | -81.37924 | 28.53834
Decatur | Georgia | United States | -84.29631 | 33.77483
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Boise | Indiana | United States | N/A | N/A
Wichita | Kansas | United States | -97.33754 | 37.69224
Louisville | Kentucky | United States | -85.75941 | 38.25424
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Brookline | Massachusetts | United States | -71.12116 | 42.33176
Fall River | Massachusetts | United States | -71.15505 | 41.70149
East Orange | New Jersey | United States | -74.20487 | 40.76732
Newark | New Jersey | United States | -74.17237 | 40.73566
Buffalo | New York | United States | -78.87837 | 42.88645
Manhasset | New York | United States | -73.69957 | 40.79788
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Huntersville | North Carolina | United States | -80.84285 | 35.41069
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Akron | Ohio | United States | -81.51901 | 41.08144
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
| 1
|
NCT00035932
|
|
[
4
] | 668
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The purpose of this study is to compare the safety and efficacy of tacrolimus/mycophenolate mofetil (MMF), cyclosporine/MMF and tacrolimus modified release/MMF in de novo kidney transplant recipients.
|
This was a 3 arm randomized, open-label, comparative, multi-center study in de novo kidney transplant recipients at 60 centers in the U.S., Canada and Brazil.
The study consisted of a 1-year post-transplant efficacy and safety study with a clinical continuation phase of a minimum of 2 years or until commercial availability of tacrolimus modified release, unless the Data Safety Monitoring Board or sponsor specified otherwise.
|
Kidney Transplantation
|
De Novo Kidney Transplant cyclosporine Prograf® mycophenolate mofetil tacrolimus
| null | 3
|
arm 1: Participants received a first dose of tacrolimus between 0.075 and 0.10 mg/kg twice daily, orally prior to or within 48 hours of the completion of the transplant procedure, and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study. arm 2: Participants received a first dose of tacrolimus modified release between 0.15 and 0.20 mg/kg/day, given as a single oral dose in the morning, prior to or within 48 hours following the completion of the transplant procedure, and subsequently as once daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study. arm 3: Participants received a first dose of cyclosporine between 4 to 5 mg/kg orally prior to or within 48 hours following the completion of the transplant procedure and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.
|
[
0,
1,
1
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: The target range for whole blood tacrolimus trough concentrations was 7 to 16 ng/mL for days 0 through 90, and 5 to 15 ng/mL thereafter. intervention 2: The target range for whole blood tacrolimus trough concentrations was the recommended trough concentration range for Prograf: 7 to 16 ng/mL for days 0 through 90 and 5 to 15 ng/mL thereafter. intervention 3: The target range for whole blood cyclosporine trough concentrations was 125 to 400 ng/mL for days 0 through 90, and 100 to 300 ng/mL thereafter. intervention 4: Oral
|
intervention 1: Tacrolimus Modified Release (MR) intervention 2: Tacrolimus intervention 3: cyclosporine microemulsion intervention 4: mycophenolate mofetil
| 57
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Mobile | Alabama | United States | -88.04305 | 30.69436
Loma Linda | California | United States | -117.26115 | 34.04835
Los Angeles | California | United States | -118.24368 | 34.05223
Los Angeles | California | United States | -118.24368 | 34.05223
Los Angeles | California | United States | -118.24368 | 34.05223
Los Angeles | California | United States | -118.24368 | 34.05223
Palo Alto | California | United States | -122.14302 | 37.44188
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Francisco | California | United States | -122.41942 | 37.77493
Denver | Colorado | United States | -104.9847 | 39.73915
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Gainesville | Florida | United States | -82.32483 | 29.65163
Jacksonville | Florida | United States | -81.65565 | 30.33218
Augusta | Georgia | United States | -81.97484 | 33.47097
Chicago | Illinois | United States | -87.65005 | 41.85003
Chicago | Illinois | United States | -87.65005 | 41.85003
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Lexington | Kentucky | United States | -84.47772 | 37.98869
New Orleans | Louisiana | United States | -90.07507 | 29.95465
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Boston | Massachusetts | United States | -71.05977 | 42.35843
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Detroit | Michigan | United States | -83.04575 | 42.33143
Livingston | New Jersey | United States | -74.31487 | 40.79593
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Albany | New York | United States | -73.75623 | 42.65258
Buffalo | New York | United States | -78.87837 | 42.88645
New York | New York | United States | -74.00597 | 40.71427
Valhalla | New York | United States | -73.77513 | 41.07482
Chapel Hill | North Carolina | United States | -79.05584 | 35.9132
Durham | North Carolina | United States | -78.89862 | 35.99403
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Portland | Oregon | United States | -122.67621 | 45.52345
Portland | Oregon | United States | -122.67621 | 45.52345
Harrisburg | Pennsylvania | United States | -76.88442 | 40.2737
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
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
San Antonio | Texas | United States | -98.49363 | 29.42412
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Fairfax | Virginia | United States | -77.30637 | 38.84622
Madison | Wisconsin | United States | -89.40123 | 43.07305
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Porto Alegre | N/A | Brazil | -51.23019 | -30.03283
Rio de Janeiro | N/A | Brazil | -43.18223 | -22.90642
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
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
| 1
|
NCT00064701
|
[
5
] | 501
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The purpose of this study is to compare the safety and efficacy of different induction agents (alemtuzumab, basiliximab or rabbit anti-thymocyte globulin) in renal transplant recipients treated with tacrolimus, mycophenolate mofetil (MMF) and a rapid steroid withdrawal.
|
A 2 arm (1 Active, 1 Active Control) study is to compare the safety and efficacy of different induction agents (alemtuzumab, basiliximab or rabbit anti-thymocyte globulin) in renal transplant recipients treated with tacrolimus, MMF and a rapid steroid withdrawal.
|
Kidney Transplantation
|
Treatment Effectiveness Treatment Efficacy Anti-rejection therapy Immunosuppression Therapy, antirejection Renal Transplantation Transplantation, Kidney Transplantation, Renal Grafting, Kidney
| null | 4
|
arm 1: Alemtuzumab, tacrolimus, mycophenolate mofetil and steroids; High risk patients: Panel reactive antibody ≥ 20% or re-transplant or African American arm 2: Rabbit anti-thymocyte globulin, tacrolimus, mycophenolate mofetil and steroids; High risk patients: Panel reactive antibody ≥ 20% or re-transplant or African American arm 3: Alemtuzumab, tacrolimus, mycophenolate mofetil and steroids; Low risk patients: Panel reactive antibody \< 20% and first transplant and non-African American arm 4: Basiliximab, tacrolimus, mycophenolate mofetil and steroids; Low risk patients: Panel reactive antibody \< 20% and first transplant and non-African American
|
[
0,
1,
0,
1
] | 6
|
[
0,
0,
0,
0,
0,
0
] |
intervention 1: IV intervention 2: IV intervention 3: oral intervention 4: Intravenous (IV) intervention 5: oral intervention 6: IV and/or oral
|
intervention 1: basiliximab intervention 2: rabbit anti-thymocyte globulin intervention 3: tacrolimus intervention 4: alemtuzumab intervention 5: mycophenolate mofetil intervention 6: steroids
| 29
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Los Angeles | California | United States | -118.24368 | 34.05223
Palo Alto | California | United States | -122.14302 | 37.44188
San Diego | California | United States | -117.16472 | 32.71571
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
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Miami | Florida | United States | -80.19366 | 25.77427
Tampa | Florida | United States | -82.45843 | 27.94752
Chicago | Illinois | United States | -87.65005 | 41.85003
Chicago | Illinois | United States | -87.65005 | 41.85003
Livingston | New Jersey | United States | -74.31487 | 40.79593
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Hawthorne | New York | United States | -73.79597 | 41.10732
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
Chapel Hill | North Carolina | United States | -79.05584 | 35.9132
Durham | North Carolina | United States | -78.89862 | 35.99403
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Portland | Oregon | United States | -122.67621 | 45.52345
Danville | Pennsylvania | United States | -76.61273 | 40.96342
Harrisburg | Pennsylvania | United States | -76.88442 | 40.2737
Charleston | South Carolina | United States | -79.93275 | 32.77632
San Antonio | Texas | United States | -98.49363 | 29.42412
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Madison | Wisconsin | United States | -89.40123 | 43.07305
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
| 1
|
NCT00113269
|
[
5
] | 896
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will evaluate the addition of a higher-dose induction treatment period with peginterferon (PEG-IFN) alfa-2a (Pegasys) and ribavirin prior to standard-dose treatment with PEG-IFN alfa-2a and ribavirin, compared to standard-dose treatment, in treatment-naive participants with CHC, genotype 1 infection.
| null |
Hepatitis C, Chronic
| null | 2
|
arm 1: Participants will receive 12 weeks of induction therapy with PEG-IFN alfa-2a (Pegasys), 360 micrograms (mcg) subcutaneous (SC) once weekly, along with ribavirin, 1000 or 1200 milligrams (mg) orally daily in divided doses. Thereafter, the dose of PEG-IFN alfa-2a will be reduced to 180 mcg SC once weekly and the ribavirin dose maintained for the remaining 36 weeks of treatment. arm 2: Participants will receive 48 weeks of standard therapy with PEG-IFN alfa-2a, 180 mcg SC once weekly, along with ribavirin, 1000 or 1200 mg orally daily in divided doses.
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: PEG-IFN alfa-2a will be administered once weekly for 48 weeks, at doses specified in respective arms. intervention 2: Ribavirin 1000 or 1200 mg orally daily in divided doses, with the dose determined based on body weight, for 48 weeks.
|
intervention 1: PEG-IFN alfa-2a intervention 2: Ribavirin
| 51
|
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
La Plata | N/A | Argentina | -57.95442 | -34.92126
Rosario | N/A | Argentina | -60.63932 | -32.94682
Adelaide | N/A | Australia | 138.59863 | -34.92866
Adelaide | N/A | Australia | 138.59863 | -34.92866
Bankstown | N/A | Australia | 151.03333 | -33.91667
Box Hill | N/A | Australia | 145.12545 | -37.81887
Brisbane | N/A | Australia | 153.02809 | -27.46794
Cottontree | N/A | Australia | 153.26009 | -29.09022
Darlinghurst | N/A | Australia | 151.21925 | -33.87939
Douglas | N/A | Australia | 146.75234 | -19.32394
Fitzroy | N/A | Australia | 144.97833 | -37.79839
Fremantle | N/A | Australia | 115.74557 | -32.05632
Geelong | N/A | Australia | 144.36069 | -38.14711
Greenslopes | N/A | Australia | 153.04951 | -27.50815
Kingswood | N/A | Australia | 150.72346 | -33.75614
Lismore | N/A | Australia | 153.2773 | -28.81354
Liverpool | N/A | Australia | 150.92588 | -33.91938
Liverpool | N/A | Australia | 150.92588 | -33.91938
Melbourne | N/A | Australia | 144.96332 | -37.814
Melbourne | N/A | Australia | 144.96332 | -37.814
Melbourne | N/A | Australia | 144.96332 | -37.814
Melbourne | N/A | Australia | 144.96332 | -37.814
Miranda | N/A | Australia | 151.10005 | -34.03857
Nedlands | N/A | Australia | 115.8073 | -31.98184
New Lambton Heights | N/A | Australia | 151.69364 | -32.92466
Parkville | N/A | Australia | 144.95 | -37.78333
Perth | N/A | Australia | 115.8614 | -31.95224
Sydney | N/A | Australia | 151.20732 | -33.86785
Sydney | N/A | Australia | 151.20732 | -33.86785
Sydney | N/A | Australia | 151.20732 | -33.86785
Sydney | N/A | Australia | 151.20732 | -33.86785
Victoria | N/A | Australia | N/A | N/A
Woden | N/A | Australia | N/A | N/A
Wollongong | N/A | Australia | 150.89345 | -34.424
Woolloongabba | N/A | Australia | 153.03655 | -27.48855
Calgary | Alberta | Canada | -114.08529 | 51.05011
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Mississauga | Ontario | Canada | -79.6583 | 43.5789
Montreal | Quebec | Canada | -73.58781 | 45.50884
Guadalajara | N/A | Mexico | -103.34749 | 20.67738
Guadalajara | N/A | Mexico | -103.34749 | 20.67738
Monterrey | N/A | Mexico | -100.31721 | 25.68435
Auckland | N/A | New Zealand | 174.76349 | -36.84853
Hamilton | N/A | New Zealand | 175.28333 | -37.78333
Riccarton, Christchurch | N/A | New Zealand | N/A | N/A
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Bangkok | N/A | Thailand | 100.50144 | 13.75398
Chiang Mai | N/A | Thailand | 98.98468 | 18.79038
| 1
|
NCT00192647
|
|
[
4
] | 7,554
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 2DOUBLE
| false
| 0ALL
| true
|
The purpose of this study is to determine if the combination of clopidogrel 75mg once daily (od) plus aspirin 100mg daily (recommended dose) is better than aspirin alone (100mg daily recommended dose) for preventing vascular events such as stroke and heart attack during approximately three years of follow-up in patients with atrial fibrillation associated with at least one major risk factor of vascular event such as elderly, blood pressure increase, history of stroke or transient ischemic attack or left ventricular dysfunction etc. The study will also accept patients with atrial fibrillation and unwilling to take oral anticoagulant therapy.
| null |
Atrial Fibrillation Vascular Risk
|
Atrial fibrillation Anticoagulant therapy Thromboembolic prevention
| null | 2
|
arm 1: Clopidogrel 75 mg once daily (od) plus acetylsalicyclic acid (ASA) 75 to 100 mg od recommended (dose at the investigators' discretion) arm 2: Matching placebo of clopidogrel 75 mg od plus acetylsalicyclic acid (ASA) 75 to 100 mg od recommended (dose at the investigators' discretion)
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: oral administration (tablets) intervention 2: oral administration (tablets)
|
intervention 1: clopidogrel (SR25990C) intervention 2: placebo
| 30
|
Bridgewater | New Jersey | United States | -74.64815 | 40.60079
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Macquarie Park | N/A | Australia | 151.12757 | -33.78105
Vienna | N/A | Austria | 16.37208 | 48.20849
Diegem | N/A | Belgium | 4.43354 | 50.89727
São Paulo | N/A | Brazil | -46.63611 | -23.5475
Laval | N/A | Canada | -73.692 | 45.56995
Santiago | N/A | Chile | -70.64827 | -33.45694
Prague | N/A | Czechia | 14.42076 | 50.08804
Hørsholm | N/A | Denmark | 12.50111 | 55.88098
Helsinki | N/A | Finland | 24.93545 | 60.16952
Paris | N/A | France | 2.3488 | 48.85341
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
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
Gouda | N/A | Netherlands | 4.70833 | 52.01667
Lysaker | N/A | Norway | 10.63545 | 59.90994
Warsaw | N/A | Poland | 21.01178 | 52.22977
Porto Salvo | N/A | Portugal | -9.30473 | 38.72293
Singapore | N/A | Singapore | 103.85007 | 1.28967
Midrand | N/A | South Africa | 28.118 | -25.976
Barcelona | N/A | Spain | 2.15899 | 41.38879
Bromma | N/A | Sweden | 17.94 | 59.34
Geneva | N/A | Switzerland | 6.14569 | 46.20222
Taipei | N/A | Taiwan | 121.52639 | 25.05306
Guildford Surrey | N/A | United Kingdom | N/A | N/A
| 1
|
NCT00249873
|
[
4
] | 284
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
The purpose of this study is to determine if flexibly-dosed ziprasidone is safe and effective for the treatment of adolescents (ages 13-17) with schizophrenia
|
Termination Reason: On March 24, 2009, Pfizer Inc. stopped late stage Geodon pediatric clinical trials in schizophrenia (A1281134 - placebo controlled; A1281135 - open label). As recommended by the DSMB, these studies were stopped due to lack of efficacy. No safety concerns were identified.
|
Schizophrenia
|
Adolescent Subjects With Schizophrenia
| null | 2
|
arm 1: None arm 2: None
|
[
2,
1
] | 2
|
[
0,
0
] |
intervention 1: Placebo matching the oral ziprasidone capsules of 20 mg, 40 mg, 60 mg, and 80 mg strength or matching placebo. Subjects will be dosed daily for 6 weeks using a flexible dose design with a minimal dose range of 40mg twice a day (BID) to a maximum dose range of 80 mg BID. For subjects weighing \<45 kg, the doses will range from 20 mg BID to 40 mg BID. intervention 2: Oral ziprasidone capsules of 20 mg, 40 mg, 60 mg, and 80 mg strength or matching placebo. Subjects will be dosed daily for 6 weeks using a flexible dose design with a minimal dose range of 40mg BID to a maximum dose range of 80 mg BID. For subjects weighing \<45 kg, the doses will range from 20 mg BID to 40 mg BID.
|
intervention 1: placebo intervention 2: Ziprasidone oral capsules
| 92
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
San Diego | California | United States | -117.16472 | 32.71571
Stanford | California | United States | -122.16608 | 37.42411
Aurora | Colorado | United States | -104.83192 | 39.72943
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Altamonte Springs | Florida | United States | -81.36562 | 28.66111
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
North Miami | Florida | United States | -80.18671 | 25.89009
Orange City | Florida | United States | -81.29867 | 28.94888
Tampa | Florida | United States | -82.45843 | 27.94752
Tavares | Florida | United States | -81.72563 | 28.80416
Smyrna | Georgia | United States | -84.51438 | 33.88399
Tucker | Georgia | United States | -84.21714 | 33.85455
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Des Plaines | Illinois | United States | -87.8834 | 42.03336
Oakbrook Terrace | Illinois | United States | -87.96451 | 41.85003
Schaumburg | Illinois | United States | -88.08341 | 42.03336
Pikesville | Maryland | United States | -76.72247 | 39.37427
Towson | Maryland | United States | -76.60191 | 39.4015
Towson | Maryland | United States | -76.60191 | 39.4015
Clinton Township | Michigan | United States | -82.91992 | 42.58698
Meridian | Mississippi | United States | -88.70366 | 32.36431
Bridgeton | Missouri | United States | -90.41151 | 38.767
St Louis | Missouri | United States | -90.19789 | 38.62727
Lincoln | Nebraska | United States | -96.66696 | 40.8
Omaha | Nebraska | United States | -95.94043 | 41.25626
Buffalo | New York | United States | -78.87837 | 42.88645
Buffalo | New York | United States | -78.87837 | 42.88645
Rochester | New York | United States | -77.61556 | 43.15478
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cleveland | Ohio | United States | -81.69541 | 41.4995
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Arlington | Texas | United States | -97.10807 | 32.73569
DeSoto | Texas | United States | -96.85695 | 32.58986
Plano | Texas | United States | -96.69889 | 33.01984
Bothell | Washington | United States | -122.2054 | 47.76232
Spokane | Washington | United States | -117.42908 | 47.65966
Spokane | Washington | United States | -117.42908 | 47.65966
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
West Allis | Wisconsin | United States | -88.00703 | 43.01668
Medellín | Antioquia | Colombia | -75.57151 | 6.245
Bogota | Cundinamarca | Colombia | N/A | N/A
San José | N/A | Costa Rica | -84.08489 | 9.93388
Vijaywada | Andhra Pradesh | India | N/A | N/A
Visakhapatnam | Andra Pradesh/India | India | 83.20161 | 17.68009
Ahmedabad | Guj | India | 72.58727 | 23.02579
Mangalore | Karnataka | India | 74.85603 | 12.91723
Aurangabad | Maharashtra | India | 75.34226 | 19.87757
Mumbai | Maharashtra | India | 72.88261 | 19.07283
Pune | Maharashtra | India | 73.85535 | 18.51957
Pune | Maharashtra | India | 73.85535 | 18.51957
Ludhiana | Punjab | India | 75.85379 | 30.91204
Chennai | Tamil Nadu | India | 80.27847 | 13.08784
Kubang Kerian | Kelantan | Malaysia | 102.27938 | 6.09123
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Lima | N/A | Peru | -77.02824 | -12.04318
Lima | N/A | Peru | -77.02824 | -12.04318
Kazan' | N/A | Russia | 49.12214 | 55.78874
Khotkovo, Moscow Region | N/A | Russia | 35.22634 | 53.76349
Lipetsk Region | N/A | Russia | N/A | N/A
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
Moscow | N/A | Russia | 37.61556 | 55.75222
Nizhny Novgorod | N/A | Russia | 44.00205 | 56.32867
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Saratov | N/A | Russia | 46.00861 | 51.54056
Saratov | N/A | Russia | 46.00861 | 51.54056
Tver' | N/A | Russia | 35.90057 | 56.85836
Yaroslavl | N/A | Russia | 39.87368 | 57.62987
Singapore | N/A | Singapore | 103.85007 | 1.28967
Singapore | N/A | Singapore | 103.85007 | 1.28967
Simferopol | Autonomous Republic of Crimea | Ukraine | 34.11079 | 44.95719
Dnipropetrovsk | N/A | Ukraine | 35.04066 | 48.46664
Dnipropetrovsk | N/A | Ukraine | 35.04066 | 48.46664
Donetsk | N/A | Ukraine | 37.80224 | 48.023
Kharkiv | N/A | Ukraine | 36.25475 | 49.98177
Kyiv | N/A | Ukraine | 30.5238 | 50.45466
Luhansk | N/A | Ukraine | 39.30553 | 48.56814
Lviv | N/A | Ukraine | 24.02324 | 49.83826
Odesa | N/A | Ukraine | 30.74383 | 46.48572
Poltava | N/A | Ukraine | 34.55367 | 49.58925
Vinnytsia | N/A | Ukraine | 28.46871 | 49.2322
| 1
|
NCT00257192
|
[
4
] | 517
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study compares the safety of the tobramycin solution for inhalation with the tobramycin dry powder formulation, used with a simple inhaler
| null |
Cystic Fibrosis
|
tobramycin
| null | 2
|
arm 1: Participants received four 28 mg capsules of tobramycin inhalation powder (TIP) delivered with the T-326 inhaler twice daily for 28 days followed by 28 days off therapy (one cycle) for a total of three cycles. arm 2: Participants received one 300 mg (in 5 mL) ampoule of tobramycin solution for inhalation (TOBI) delivered with a nebulizer twice daily for 28 days followed by 28 days off therapy (one cycle) for a total of three cycles.
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Tobramycin Inhalation Powder (TIP) capsules for inhalation. intervention 2: Tobramycin solution for inhalation (TOBI), supplied as 300 mg/5mL ampoules administered with a nebulizer
|
intervention 1: Tobramycin Inhalation Powder intervention 2: Tobramycin Solution for Inhalation
| 72
|
Hartford | Connecticut | United States | -72.68509 | 41.76371
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Louisville | Kentucky | United States | -85.75941 | 38.25424
Boston | Massachusetts | United States | -71.05977 | 42.35843
Lebanon | New Hampshire | United States | -72.25176 | 43.64229
Livingston | New Jersey | United States | -74.31487 | 40.79593
Long Branch | New Jersey | United States | -73.99236 | 40.30428
Morristown | New Jersey | United States | -74.48154 | 40.79677
Somerset | New Jersey | United States | -74.48849 | 40.4976
Albany | New York | United States | -73.75623 | 42.65258
Buffalo | New York | United States | -78.87837 | 42.88645
New Hyde Park | New York | United States | -73.68791 | 40.7351
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Stony Brook | New York | United States | -73.14094 | 40.92565
Syracuse | New York | United States | -76.14742 | 43.04812
Valhalla | New York | United States | -73.77513 | 41.07482
Hershey | Pennsylvania | United States | -76.65025 | 40.28592
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Burlington | Vermont | United States | -73.21207 | 44.47588
Charlottesville | Virginia | United States | -78.47668 | 38.02931
Morgantown | West Virginia | United States | -79.9559 | 39.62953
South Brisbane | N/A | Australia | 153.02049 | -27.48034
Calgary | N/A | Canada | -114.08529 | 51.05011
Hamilton | N/A | Canada | -79.84963 | 43.25011
Ste-Foy | N/A | Canada | N/A | N/A
Vancouver | N/A | Canada | -123.11934 | 49.24966
Santiago | N/A | Chile | -70.64827 | -33.45694
Baranquilla | N/A | Colombia | N/A | N/A
Bogotá | N/A | Colombia | -74.08175 | 4.60971
Medellín | N/A | Colombia | -75.57151 | 6.245
Santiago de Cali | N/A | Colombia | -76.5199 | 3.43054
Montpellier | N/A | France | 3.87635 | 43.61093
Paris | N/A | France | 2.3488 | 48.85341
Rouen | N/A | France | 1.09932 | 49.44313
Berlin | N/A | Germany | 13.41053 | 52.52437
Bochum | N/A | Germany | 7.21648 | 51.48165
Bonn | N/A | Germany | 7.09549 | 50.73438
Cologne | N/A | Germany | 6.95 | 50.93333
Essen | N/A | Germany | 7.01228 | 51.45657
Frankfurt | N/A | Germany | 10.53333 | 49.68333
Frankfurt | N/A | Germany | 10.53333 | 49.68333
Hamburg | N/A | Germany | 9.99302 | 53.55073
Hanover | N/A | Germany | 9.73322 | 52.37052
Munich | N/A | Germany | 11.57549 | 48.13743
München | N/A | Germany | 13.31243 | 51.60698
Hungary | N/A | Hungary | N/A | N/A
Kaposvár | N/A | Hungary | 17.8 | 46.36667
Haifa | N/A | Israel | 34.99928 | 32.81303
Jerusalem | N/A | Israel | 35.21633 | 31.76904
Petah Tikva | N/A | Israel | 34.88747 | 32.08707
Genoa | N/A | Italy | 8.94439 | 44.40478
Palermo | N/A | Italy | 13.3636 | 38.1166
Potenza | N/A | Italy | 15.80794 | 40.64175
Roma | N/A | Italy | 11.10642 | 44.99364
Monterrey Nuevo Leon | N/A | Mexico | N/A | N/A
Groesbeek | N/A | Netherlands | 5.93611 | 51.77667
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Barakaldo | N/A | Spain | -2.98813 | 43.29639
Barcelona | N/A | Spain | 2.15899 | 41.38879
Madrid | N/A | Spain | -3.70256 | 40.4165
Málaga | N/A | Spain | -4.42034 | 36.72016
Seville | N/A | Spain | -5.97317 | 37.38283
Valencia | N/A | Spain | -0.37966 | 39.47391
Belfast | N/A | United Kingdom | -5.92541 | 54.59682
Birmingham | N/A | United Kingdom | -1.89983 | 52.48142
Cambridge | N/A | United Kingdom | 0.11667 | 52.2
Leeds | N/A | United Kingdom | -1.54785 | 53.79648
London | N/A | United Kingdom | -0.12574 | 51.50853
Sheffield | N/A | United Kingdom | -1.4659 | 53.38297
| 1
|
NCT00388505
|
[
4
] | 222
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will investigate the efficacy and safety of a steroid avoidance regimen in comparison with steroid treatment in combination with an initially higher dose of enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine microemulsion in de novo renal transplant recipients. Patients will be randomly allocated to receive either EC-MPS or steroids in combination with EC-MPS. Patients of both treatment groups will receive monoclonal antibody induction therapy and a perioperative bolus of steroids and cyclosporine.
| null |
Renal Transplantation
|
Steroids avoidance, enteric-coated mycophenolate sodium (EC-MPS), de novo renal transplantation
| null | 2
|
arm 1: Patients received Enteric-coated Mycophenolate Sodium (EC-MPS), administered orally 2 times a day for 6 months. Patients also received cyclosporine and a dose of methylprednisolone immediately after transplantation, but did not subsequently receive oral corticosteroids for the remainder of the study. arm 2: Patients received Enteric-coated Mycophenolate Sodium (EC-MPS), administered orally 2 times a day for 6 months. Patients also received cyclosporine and a dose of methylprednisolone immediately after transplantation, and subsequently continued to receive daily oral prednisone.
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: An initial dose of 1080 mg EC-MPS was administered immediately before transplantation. Then, during the first 6 weeks post-transplantation, EC-MPS was administered at a dose of 1080 mg twice a day 12 hours apart. From week 7 until the end of the study (month 6), EC-MPS was administered at standard dose of 720 mg twice a day. intervention 2: Oral tablets
|
intervention 1: Enteric-coated mycophenolate sodium (EC-MPS) intervention 2: Prednisone
| 1
|
Poitiers | N/A | France | 0.34348 | 46.58261
| 1
|
NCT00413920
|
[
5
] | 296
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This trial is conducted in Europe, Africa and the United States of America (USA).
The aim of this trial is to compare the safety and efficacy of two different insulin treatments, the "basic" and the "advanced" treatment in type 2 diabetes.
| null |
Diabetes Diabetes Mellitus, Type 2
| null | 2
|
arm 1: Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively. arm 2: Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively.
|
[
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Treat-to-target dose titration scheme (individually adjusted dose) for a once daily injection s.c. (under the skin) intervention 2: Administered 1 - 3 times daily, at largest prandial increment, injection s.c. (under the skin) intervention 3: Administered 1 - 3 times daily, at largest meals, injection s.c. (under the skin)
|
intervention 1: insulin detemir intervention 2: insulin aspart intervention 3: insulin aspart
| 69
|
Fresno | California | United States | -119.77237 | 36.74773
Mission Viejo | California | United States | -117.672 | 33.60002
Miami | Florida | United States | -80.19366 | 25.77427
Athens | Georgia | United States | -83.37794 | 33.96095
Atlanta | Georgia | United States | -84.38798 | 33.749
Des Moines | Iowa | United States | -93.60911 | 41.60054
Lawrenceville | New Jersey | United States | -74.7296 | 40.29733
Asheville | North Carolina | United States | -82.55402 | 35.60095
Dayton | Ohio | United States | -84.19161 | 39.75895
Kettering | Ohio | United States | -84.16883 | 39.6895
Greer | South Carolina | United States | -82.22706 | 34.93873
Chattanooga | Tennessee | United States | -85.30968 | 35.04563
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
Newport News | Virginia | United States | -76.42975 | 36.98038
Richmond | Virginia | United States | -77.46026 | 37.55376
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Århus C | N/A | Denmark | N/A | N/A
Espoo | N/A | Finland | 24.6522 | 60.2052
Oulu | N/A | Finland | 25.46816 | 65.01236
Oulu | N/A | Finland | 25.46816 | 65.01236
Tampere | N/A | Finland | 23.78712 | 61.49911
Vaasa | N/A | Finland | 21.61577 | 63.096
Vantaa | N/A | Finland | 25.04099 | 60.29414
Le Creusot | N/A | France | 4.41632 | 46.80714
Nanterre | N/A | France | 2.20675 | 48.89198
Narbonne | N/A | France | 3.00141 | 43.18396
Pointe à Pitre | N/A | France | 1.98937 | 44.07984
Vénissieux | N/A | France | 4.88593 | 45.69706
's-Hertogenbosch | N/A | Netherlands | 5.30417 | 51.69917
Eindhoven | N/A | Netherlands | 5.47778 | 51.44083
Etten-Leur | N/A | Netherlands | 4.63726 | 51.57056
Hulst | N/A | Netherlands | 4.05278 | 51.28
Utrecht | N/A | Netherlands | 5.12222 | 52.09083
Woerden | N/A | Netherlands | 4.88333 | 52.085
Jessheim | N/A | Norway | 11.17515 | 60.14151
Oslo | N/A | Norway | 10.74609 | 59.91273
Sarpsborg | N/A | Norway | 11.10962 | 59.28391
Stavanger | N/A | Norway | 5.73332 | 58.97005
Tromsø | N/A | Norway | 18.95508 | 69.6489
Tønsberg | N/A | Norway | 10.40762 | 59.26754
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Belgrade | N/A | Serbia and Montenegro | N/A | N/A
Nis | N/A | Serbia and Montenegro | N/A | N/A
Johannesburg | Gauteng | South Africa | 28.04363 | -26.20227
Johannesburg | Gauteng | South Africa | 28.04363 | -26.20227
Pretoria | Gauteng | South Africa | 28.18783 | -25.74486
Cáceres | N/A | Spain | -6.37224 | 39.47649
Inca | N/A | Spain | 2.91093 | 39.7211
Madrid | N/A | Spain | -3.70256 | 40.4165
Málaga | N/A | Spain | -4.42034 | 36.72016
Mérida | N/A | Spain | -6.34366 | 38.91611
Mostoles - Madrid - | N/A | Spain | N/A | N/A
Santiago de Compostela | N/A | Spain | -8.54569 | 42.88052
Ängelholm | N/A | Sweden | 12.86219 | 56.2428
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Mölndal | N/A | Sweden | 12.01378 | 57.6554
Aberdeen | N/A | United Kingdom | -2.09814 | 57.14369
Coventry | N/A | United Kingdom | -1.51217 | 52.40656
Livingstone | N/A | United Kingdom | N/A | N/A
Llanelli | N/A | United Kingdom | -4.16191 | 51.68195
Llantrisant | N/A | United Kingdom | -3.37389 | 51.54028
Reading | N/A | United Kingdom | -0.97113 | 51.45625
Rugby | N/A | United Kingdom | -1.26417 | 52.37092
| 1
|
NCT00537303
|
|
[
4
] | 76
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to obtain information on the long-term safety, tolerability, and therapeutic benefit of extended release ropinirole XL, and to provide a mechanism for patients who participated in either Study 167 or Study 164 to continue receiving ropinirole XL if they chose to do so.
| null |
Parkinson Disease
|
ropinirole IR efficacy safety open-label long term safety; REQUIP ropinirole XL ropinirole CR Parkinson's disease
| null | 1
|
arm 1: Open label medication - Ropinirole CR
|
[
1
] | 1
|
[
0
] |
intervention 1: Active Ropinirole CR tablets of 2.0mg, 4.0mg, 8.0mg where subjects can tritrate to an stable optimum dose level of either 2.0mg, 4.0mg, 6.0mg, 8.0mg, 12mg, 16mg, 20mg, or 24mg per day.
|
intervention 1: Ropinirole XL (formerly CR)
| 10
|
Scottsdale | Arizona | United States | -111.89903 | 33.50921
Los Angeles | California | United States | -118.24368 | 34.05223
Oxnard | California | United States | -119.17705 | 34.1975
Miami | Florida | United States | -80.19366 | 25.77427
Tampa | Florida | United States | -82.45843 | 27.94752
Augusta | Georgia | United States | -81.97484 | 33.47097
Kansas City | Kansas | United States | -94.62746 | 39.11417
Edison | New Jersey | United States | -74.4121 | 40.51872
Upland | Pennsylvania | United States | -75.38269 | 39.85261
Houston | Texas | United States | -95.36327 | 29.76328
| 1
|
NCT00650104
|
[
4
] | 415
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
This study evaluated the 1 year safety, tolerability and efficacy of indacaterol against placebo in the treatment of Chronic Obstructive Pulmonary Disease (COPD) patients
| null |
COPD
|
COPD adults β2-agonist indacaterol
| null | 3
|
arm 1: Indacaterol 150 µg once-daily (o.d.) via single-dose dry-powder inhaler (SDDPI).
The short acting (beta) β2-agonist (SABA) salbutamol/albuterol was available for rescue use throughout the study. arm 2: Indacaterol 300 µg once-daily (o.d.) via single-dose dry-powder inhaler (SDDPI).
The short acting (beta) β2-agonist (SABA) salbutamol/albuterol was available for rescue use throughout the study. arm 3: Placebo once-daily (o.d.) via SDDPI.
The short acting (beta) β2-agonist (SABA) salbutamol/albuterol was available for rescue use throughout the study.
|
[
0,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Indacaterol once-daily (o.d.) via single-dose dry-powder inhaler (SDDPI) intervention 2: Placebo once-daily (o.d.) via single-dose dry-powder inhaler (SDDPI)
|
intervention 1: Indacaterol intervention 2: Placebo
| 190
|
Homewood | Alabama | United States | -86.80082 | 33.47177
Jasper | Alabama | United States | -87.27751 | 33.83122
Phoenix | Arizona | United States | -112.07404 | 33.44838
Tucson | Arizona | United States | -110.92648 | 32.22174
Pine Bluff | Arkansas | United States | -92.0032 | 34.22843
Encinitas | California | United States | -117.29198 | 33.03699
Fullerton | California | United States | -117.92534 | 33.87029
Orange | California | United States | -117.85311 | 33.78779
Riverside | California | United States | -117.39616 | 33.95335
Spring Valley | California | United States | -116.99892 | 32.74477
Fort Collins | Colorado | United States | -105.08442 | 40.58526
Golden | Colorado | United States | -105.2211 | 39.75554
Wheat Ridge | Colorado | United States | -105.07721 | 39.7661
Clearwater | Florida | United States | -82.8001 | 27.96585
Largo | Florida | United States | -82.78842 | 27.90979
Pensacola | Florida | United States | -87.21691 | 30.42131
Rockledge | Florida | United States | -80.72533 | 28.35084
South Miami | Florida | United States | -80.29338 | 25.7076
Tamarac | Florida | United States | -80.24977 | 26.21286
Tampa | Florida | United States | -82.45843 | 27.94752
Atlanta | Georgia | United States | -84.38798 | 33.749
Marietta | Georgia | United States | -84.54993 | 33.9526
Normal | Illinois | United States | -88.99063 | 40.5142
O'Fallon | Illinois | United States | -89.91121 | 38.59227
River Forest | Illinois | United States | -87.81395 | 41.89781
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Iowa City | Iowa | United States | -91.53017 | 41.66113
Iowa City | Iowa | United States | -91.53017 | 41.66113
Topeka | Kansas | United States | -95.67804 | 39.04833
Crescent Springs | Kentucky | United States | -84.58161 | 39.05145
Lexington | Kentucky | United States | -84.47772 | 37.98869
Lexington | Kentucky | United States | -84.47772 | 37.98869
Lafayette | Louisiana | United States | -92.01984 | 30.22409
Metaire | Louisiana | United States | N/A | N/A
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Biddeford | Maine | United States | -70.45338 | 43.49258
Clarkston | Michigan | United States | -83.41883 | 42.73586
Flint | Michigan | United States | -83.68746 | 43.01253
Livonia | Michigan | United States | -83.35271 | 42.36837
Troy | Michigan | United States | -83.14993 | 42.60559
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Rochester | Minnesota | United States | -92.4699 | 44.02163
Chesterfield | Missouri | United States | -90.57707 | 38.66311
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
Billings | Montana | United States | -108.50069 | 45.78329
Kalispell | Montana | United States | -114.31291 | 48.19579
Lincoln | Nebraska | United States | -96.66696 | 40.8
Omaha | Nebraska | United States | -95.94043 | 41.25626
Omaha | Nebraska | United States | -95.94043 | 41.25626
Omaha | Nebraska | United States | -95.94043 | 41.25626
Papillion | Nebraska | United States | -96.04224 | 41.15444
Henderson | Nevada | United States | -114.98194 | 36.0397
Summit | New Jersey | United States | -74.36468 | 40.71562
Elmira | New York | United States | -76.80773 | 42.0898
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Shelby | North Carolina | United States | -81.53565 | 35.29235
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Fargo | North Dakota | United States | -96.7898 | 46.87719
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Cleveland | Ohio | United States | -81.69541 | 41.4995
Columbus | Ohio | United States | -82.99879 | 39.96118
Columbus | Ohio | United States | -82.99879 | 39.96118
Marion | Ohio | United States | -83.12852 | 40.58867
Sylvania | Ohio | United States | -83.71299 | 41.71894
Thornville | Ohio | United States | -82.42015 | 39.89645
Zanesville | Ohio | United States | -82.01319 | 39.94035
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Eugene | Oregon | United States | -123.08675 | 44.05207
Medford | Oregon | United States | -122.87559 | 42.32652
Erie | Pennsylvania | United States | -80.08506 | 42.12922
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Cranston | Rhode Island | United States | -71.43728 | 41.77982
Cumberland | Rhode Island | United States | -71.43284 | 41.96677
Greenville | South Carolina | United States | -82.39401 | 34.85262
Johnson City | Tennessee | United States | -82.35347 | 36.31344
Corsicana | Texas | United States | -96.46887 | 32.09543
Dallas | Texas | United States | -96.80667 | 32.78306
El Paso | Texas | United States | -106.48693 | 31.75872
Fort Worth | Texas | United States | -97.32085 | 32.72541
San Antonio | Texas | United States | -98.49363 | 29.42412
Abingdon | Virginia | United States | -81.97735 | 36.70983
Lynchburg | Virginia | United States | -79.14225 | 37.41375
Richmond | Virginia | United States | -77.46026 | 37.55376
Bellingham | Washington | United States | -122.48822 | 48.75955
Spokane | Washington | United States | -117.42908 | 47.65966
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Rosario | N/A | Argentina | -60.63932 | -32.94682
Ajax | N/A | Canada | -79.03288 | 43.85012
Calgary | N/A | Canada | -114.08529 | 51.05011
Gatineau | N/A | Canada | -75.70164 | 45.47723
Moncton | N/A | Canada | -64.7965 | 46.09454
Montreal | N/A | Canada | -73.58781 | 45.50884
Niagara Falls | N/A | Canada | -79.06627 | 43.10012
Ottawa | N/A | Canada | -75.69812 | 45.41117
Québec | N/A | Canada | -71.21454 | 46.81228
Saint Romuald | N/A | Canada | -71.23921 | 46.75818
Saskatoon | N/A | Canada | -106.66892 | 52.13238
Sherbrooke | N/A | Canada | -71.89908 | 45.40008
St. John's | N/A | Canada | -52.70931 | 47.56494
Toronto | N/A | Canada | -79.39864 | 43.70643
Trois-Rivières | N/A | Canada | -72.5477 | 46.34515
Vancouver | N/A | Canada | -123.11934 | 49.24966
Windsor | N/A | Canada | -83.01654 | 42.30008
Winnipeg | N/A | Canada | -97.14704 | 49.8844
Augsburg | N/A | Germany | 10.89851 | 48.37154
Bad Segeberg | N/A | Germany | 10.30745 | 53.93775
Berlin | N/A | Germany | 13.41053 | 52.52437
Bielefeld | N/A | Germany | 8.53333 | 52.03333
Bonn | N/A | Germany | 7.09549 | 50.73438
Dachau | N/A | Germany | 11.43402 | 48.26
Hamburg | N/A | Germany | 9.99302 | 53.55073
Hoyerswerda | N/A | Germany | 14.23549 | 51.43787
Kaufbeuren | N/A | Germany | 10.62192 | 47.88238
Landsberg | N/A | Germany | 12.16076 | 51.52698
Leipzig | N/A | Germany | 12.37129 | 51.33962
Mainz | N/A | Germany | 8.2791 | 49.98419
München | N/A | Germany | 13.31243 | 51.60698
Oranienburg | N/A | Germany | 13.24197 | 52.75577
Oschersleben | N/A | Germany | 11.22898 | 52.03039
Potsdam | N/A | Germany | 13.06566 | 52.39886
Ratingen | N/A | Germany | 6.84929 | 51.29724
Steinfurt-Borghorst | N/A | Germany | N/A | N/A
Bangalore | N/A | India | 77.59369 | 12.97194
Chennai | N/A | India | 80.27847 | 13.08784
Coimbatore | N/A | India | 76.96612 | 11.00555
Coimbatore | N/A | India | 76.96612 | 11.00555
Hyderabaad | N/A | India | N/A | N/A
Indore | N/A | India | 75.8333 | 22.71792
Jaipur | N/A | India | 75.78781 | 26.91962
Kolkata | N/A | India | 88.36304 | 22.56263
Ludhiana | N/A | India | 75.85379 | 30.91204
Mumbai | N/A | India | 72.88261 | 19.07283
Panjim | N/A | India | 73.82624 | 15.49574
Trivandrum | N/A | India | 76.94924 | 8.4855
Bologna | N/A | Italy | 11.33875 | 44.49381
Busto Arsizio | N/A | Italy | 8.84914 | 45.61128
Catania | N/A | Italy | 15.07041 | 37.49223
Catanzaro | N/A | Italy | 16.60086 | 38.88247
Crema | N/A | Italy | 9.68176 | 45.36264
Ferrara | N/A | Italy | 11.62057 | 44.83804
Florence | N/A | Italy | 11.24626 | 43.77925
Messina | N/A | Italy | 15.55256 | 38.19394
Milan | N/A | Italy | 12.59836 | 42.78235
Pisa | N/A | Italy | 10.4036 | 43.70853
Roma | N/A | Italy | 11.10642 | 44.99364
Rozzano | N/A | Italy | 9.1559 | 45.38193
Siena | N/A | Italy | 11.33064 | 43.31822
Sottomarina | N/A | Italy | 12.29472 | 45.21389
A Coruña | N/A | Spain | -8.396 | 43.37135
Alicante | N/A | Spain | -0.48149 | 38.34517
Alzira | N/A | Spain | -0.43333 | 39.15
Barcelona | N/A | Spain | 2.15899 | 41.38879
Burgos | N/A | Spain | -3.70184 | 42.34106
Córdoba | N/A | Spain | -4.77275 | 37.89155
Girona | N/A | Spain | 2.82493 | 41.98311
Gladakano | N/A | Spain | N/A | N/A
Jerez de Frontera | N/A | Spain | N/A | N/A
Las Palmas de Gran Canaria | N/A | Spain | -15.41343 | 28.09973
Las Palmas de Gran Canarias | N/A | Spain | N/A | N/A
Lugo | N/A | Spain | -7.55602 | 43.00992
Madrid | N/A | Spain | -3.70256 | 40.4165
Málaga | N/A | Spain | -4.42034 | 36.72016
Ourense | N/A | Spain | -7.86407 | 42.33669
Oviedo | N/A | Spain | -5.84476 | 43.36029
Palma de Mallorca | N/A | Spain | 2.65024 | 39.56939
Ponferrada | N/A | Spain | -6.59619 | 42.54664
Pontevedra | N/A | Spain | -8.64435 | 42.431
Port de Sagunt | N/A | Spain | -0.21749 | 39.6622
Seville | N/A | Spain | -5.97317 | 37.38283
Valencia | N/A | Spain | -0.37966 | 39.47391
Vic | N/A | Spain | 2.25486 | 41.93012
Vila-real | N/A | Spain | -0.10087 | 39.9383
Zaragoza | N/A | Spain | -0.87734 | 41.65606
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Jönköping | N/A | Sweden | 14.15618 | 57.78145
Lidingö | N/A | Sweden | 18.13333 | 59.36667
Luleå | N/A | Sweden | 22.15465 | 65.58415
Luleå | N/A | Sweden | 22.15465 | 65.58415
Lund | N/A | Sweden | 13.19321 | 55.70584
Kartal/Istanbul | N/A | Turkey (Türkiye) | N/A | N/A
Mersin | N/A | Turkey (Türkiye) | 34.63886 | 36.81196
Yenisehir/Izmir | N/A | Turkey (Türkiye) | N/A | N/A
| 1
|
NCT00677807
|
[
4
] | 304
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to determine the safety and efficacy of vortioxetine, once daily (QD), in treating Generalized Anxiety Disorder.
|
The drug that was tested in this study is called Vortioxetine. Vortioxetine is being tested to treat anxiety in adults who have general anxiety disorder (GAD). This study looked at GAD relief in people who took vortioxetine.
The study enrolled 304 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need):
* Vortioxetine 5 mg
* Placebo (dummy inactive pill) - this was a capsule that looked like the study drug but had no active ingredient.
All participants were asked to take one capsule at the same time each day throughout the study.
This multi-center trial was conducted in the United States. The overall time to participate in this study was up to 13 weeks. Participants made 7 visits to the clinic, and were contacted by telephone 4 weeks after the last dose of study drug for a follow-up assessment.
|
Generalized Anxiety Disorder
|
Generalized Anxiety Disorder Mood Disorder Affective Disorder Anxiety Disorder Drug Therapy
| null | 2
|
arm 1: Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks. arm 2: Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
|
[
2,
0
] | 2
|
[
0,
0
] |
intervention 1: Encapsulated vortioxetine immediate-release tablets intervention 2: Vortioxetine placebo-matching capsules
|
intervention 1: Vortioxetine intervention 2: Placebo
| 33
|
Anaheim | California | United States | -117.9145 | 33.83529
Arcadia | California | United States | -118.03534 | 34.13973
Irvine | California | United States | -117.82311 | 33.66946
National City | California | United States | -117.0992 | 32.67811
Sherman Oaks | California | United States | -118.44925 | 34.15112
Upland | California | United States | -117.64839 | 34.09751
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Bradenton | Florida | United States | -82.57482 | 27.49893
Coral Gables | Florida | United States | -80.26838 | 25.72149
North Miami | Florida | United States | -80.18671 | 25.89009
St. Petersburg | Florida | United States | -82.67927 | 27.77086
Tampa | Florida | United States | -82.45843 | 27.94752
Oak Brook | Illinois | United States | -87.92895 | 41.83281
Park Ridge | Illinois | United States | -87.84062 | 42.01114
Lafayette | Indiana | United States | -86.87529 | 40.4167
Wichita | Kansas | United States | -97.33754 | 37.69224
Baltimore | Maryland | United States | -76.61219 | 39.29038
Fall River | Massachusetts | United States | -71.15505 | 41.70149
Worcester | Massachusetts | United States | -71.80229 | 42.26259
Flowood | Mississippi | United States | -90.13898 | 32.30959
Brooklyn | New York | United States | -73.94958 | 40.6501
New York | New York | United States | -74.00597 | 40.71427
The Bronx | New York | United States | -73.86641 | 40.84985
Morganton | North Carolina | United States | -81.68482 | 35.74541
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Toledo | Ohio | United States | -83.55521 | 41.66394
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Portland | Oregon | United States | -122.67621 | 45.52345
Lincoln | Rhode Island | United States | -71.435 | 41.92111
Memphis | Tennessee | United States | -90.04898 | 35.14953
Austin | Texas | United States | -97.74306 | 30.26715
San Antonio | Texas | United States | -98.49363 | 29.42412
Charleston | West Virginia | United States | -81.63262 | 38.34982
| 1
|
NCT00734071
|
[
2
] | 47
|
RANDOMIZED
|
PARALLEL
| 2DIAGNOSTIC
| 2DOUBLE
| true
| 0ALL
| null |
This study will evaluate methodologies for measuring pedal edema associated with calcium channel blockers in middle-aged and elderly subjects and patients with hypertension.
| null |
Hypertension
| null | 2
|
arm 1: amlodipine arm 2: Placebo to amlodipine
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Two 5 mg tablets amlodipine daily for 6 weeks. intervention 2: Two 5 mg tablets placebo to amlodipine daily for 6 weeks
|
intervention 1: Comparator: amlodipine besylate intervention 2: Comparator: Placebo
| 0
| null | 1
|
NCT00789321
|
|
[
2
] | 42
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| true
| 0ALL
| null |
This study will assess the bioequivalence of single oral doses of aprepitant (MK0869) to a single intravenous infusion of fosaprepitant (MK0517) and also determine the effect of food on the bioavailability of oral aprepitant.
| null |
Chemotherapy-Induced Nausea and Vomiting
| null | 4
|
arm 1: aprepitant 165 mg arm 2: aprepitant 185 mg arm 3: fosaprepitant 150 mg arm 4: aprepitant with food
|
[
1,
1,
0,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Single dose of aprepitant 165 mg tablet in the fasted state during treatment period 1,2, or 3. intervention 2: Single dose of aprepitant 185 mg tablet in the fasted state during treatment period 1, 2, or 3. intervention 3: Single dose of fosaprepitant 150 mg intravenous infusion in the fasted state during treatment period 1,2, or 3. intervention 4: Single dose of aprepitant 165 mg or 185 mg tablet in the fed state during treatment period 4.
|
intervention 1: aprepitant 165 mg intervention 2: Comparator: aprepitant 185 mg intervention 3: Comparator: fosaprepitant 150 mg intervention 4: Comparator: aprepitant with food
| 0
| null | 1
|
NCT00945321
|
|
[
4
] | 252
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study will compare the incidence of acute clinical or subclinical rejection between immunosuppression with CellCept at a starting dose of 3mg po daily with therapeutic drug monitoring and standard immunosuppression with CellCept and a fixed dose of 2g po daily, in kidney transplant recipients receiving induction by anti-IRL2, cyclosporine therapy, and early discontinuation of steroids. Patients will be randomized to one of the two treatment arms. The anticipated time on study treatment is 52 weeks.
| null |
Kidney Transplantation
| null | 2
|
arm 1: Participants received 3 grams (g) mycophenolate mofetil (MMF) tablets per os (p.o.) in divided doses (every 12 hours \[q12h\]) adapted to mycophenolic acid (MPA) by area under the curve (AUC) beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing through Week 52. In addition, induction by interleukin-2R (IL-2R) was administered at Day 0 per standard of care at the site at the investigator's discretion. At 72 hours post-transplantation, participants received cyclosporine 100-1500 nanograms (ng) per (/) milliliter (mL) from Day 0 to (-) Week 4, 800-1200 ng/mL from Week 4 - Week 12 and 500-800 ng/mL from Week 12 - Week 52. Solumedrol 500 mg intravenously (i.v.) was administered before or after the transplantation, and 0.5 milligrams (mg) per kilogram (kg) p.o. daily from Day 1 - Day 7. arm 2: Participants received 2 g MMF tablets p.o. in divided doses q12h beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing through Week 52. In addition, induction by IL-2R was administered at Day 0 per standard of care at the site at the investigators discretion. At 72 hours post-transplantation, participants received cyclosporine 100-1500 ng/mL from Day 0 - Week 4, 800-1200 ng/mL from Week 4 - Week 12 and 500-800 ng/mL from Week 12 - Week 52. Solumedrol 500 mg i.v. was administered before or after the transplantation, and 0.5 mg/kg p.o. daily from Day 1 - Day 7.
|
[
0,
1
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: 3 g p.o. in divided doses q12h beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing to Week 52, adapted to MPA by AUC on Weeks 2, 6, 12, 26, and 52 to obtain AUC0-12 of 50 milligrams (mg) multiplied by (\*) height (h)/ liter(L). intervention 2: 2 g p.o. in divided doses q12h beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing to Week 52. intervention 3: Induction by IL-2R was administered at Day 0 per standard of care at the site at the investigators discretion. intervention 4: 500 mg intravenous (i.v.) was administered before or after the transplantation, and 0.5 mg/kg p.o. daily from Day 1 to Day 7. intervention 5: 100-1500 nanograms (ng) per milliliter (mL) from Day 0 to Week 4, 800-1200 ng/mL from Week 4 to Week 12 and 500-800 ng/mL from Week 12 to Week 52
|
intervention 1: mycophenolate mofetil intervention 2: mycophenolate mofetil intervention 3: anti-IL-2R intervention 4: methylprednisolone intervention 5: cyclosporine
| 24
|
Bordeaux | N/A | France | -0.5805 | 44.84044
Brest | N/A | France | -4.48628 | 48.39029
Clermont-Ferrand | N/A | France | 3.08682 | 45.77969
Créteil | N/A | France | 2.46569 | 48.79266
Dijon | N/A | France | 5.01667 | 47.31667
La Tronche | N/A | France | 5.74629 | 45.20507
Le Kremlin-Bicêtre | N/A | France | 2.36073 | 48.81471
Lille | N/A | France | 3.05858 | 50.63297
Limoges | N/A | France | 1.24759 | 45.83362
Montpellier | N/A | France | 3.87635 | 43.61093
Nantes | N/A | France | -1.55336 | 47.21725
Nice | N/A | France | 7.26608 | 43.70313
Paris | N/A | France | 2.3488 | 48.85341
Paris | N/A | France | 2.3488 | 48.85341
Paris | N/A | France | 2.3488 | 48.85341
Paris | N/A | France | 2.3488 | 48.85341
Poitiers | N/A | France | 0.34348 | 46.58261
Rennes | N/A | France | -1.67429 | 48.11198
Salouël | N/A | France | 2.2434 | 49.86988
Strasbourg | N/A | France | 7.74553 | 48.58392
Suresnes | N/A | France | 2.22929 | 48.87143
Toulouse | N/A | France | 1.44367 | 43.60426
Tours | N/A | France | 0.70398 | 47.39484
Vandœuvre-lès-Nancy | N/A | France | 6.17114 | 48.66115
| 1
|
NCT02005562
|
|
[
4
] | 2,368
|
RANDOMIZED
|
FACTORIAL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2400 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of less than 7.0% for all patients).
SPECIFIC AIMS
A. Primary Aim
The primary aim of the BARI 2D trial is to test the following two hypotheses of treatment efficacy in 2400 patients with Type 2 diabetes mellitus and documented stable CAD, in the setting of uniform glycemic control and intensive management of all other risk factors including dyslipidemia, hypertension, smoking, and obesity:
1. Coronary Revascularization Hypothesis: a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone;
2. Method of Glycemic Control Hypothesis: with a target HbA1c level of less than 7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year mortality compared to a strategy of insulin provision.
B. Secondary Aims
The secondary aims of the BARI 2D trial include: a) comparing the death, myocardial infarction or stroke combined endpoint event rate between the revascularization versus medical therapy groups and between the insulin sensitization versus insulin provision groups; b) comparing rates of myocardial infarction, other ischemic events, angina and quality of life associated with each revascularization and hyperglycemia management strategy; c) evaluating the relative economic costs associated with the trial treatment strategies, d) exploring the effect of glycemic control strategy on the progression and mechanism of vasculopathy including changes in PAI-1 gene expression.
|
BACKGROUND:
Type 2 diabetes mellitus, which is becoming more prevalent in our society as the population ages, is one of the strongest risk factors for coronary artery disease (CAD) and consequent mortality. In addition to generating an enormous toll in human suffering, diabetes places an economic burden approaching 100 billion dollars annually on the U.S. health care system. Despite the well known dismal prognosis of diabetes complicated by angiographically documented CAD, the optimal treatment paradigm for this large group of patients has not been studied. Coronary revascularization, while increasingly used, has not been directly shown to be of additional benefit to simultaneous intensive medical management of CAD along with management of hyperglycemia, hypertension, dyslipidemia, and other risk factors. Moreover, while intensive efforts to lower HbA1c have been demonstrated to favorably affect the clinical course of Type 2 diabetes mellitus in terms of microvascular complications, the optimal hyperglycemia management strategy with regard to macrovascular outcome is not known.
These critical treatment dilemmas have motivated the development of BARI 2D, a multicenter randomized trial designed to determine in patients with Type 2 diabetes and stable CAD: 1) the efficacy of initial elective coronary revascularization combined with aggressive medical therapy, compared to an initial strategy of aggressive medical therapy alone; and 2) the efficacy of a strategy of providing more insulin (endogenous or exogenous), versus a strategy of increasing sensitivity to insulin (reducing insulin resistance), in the management of hyperglycemia, with a target HbA1c level of less than 7.0% for each strategy.
DESIGN NARRATIVE:
The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2400 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of less than 7.0% for all patients). Following confirmation of patient eligibility and provision of written consent, patients were randomized as shown below:
Number of Patients Per Treatment Assignment (N=2400 patients in total)
Stable Ischemic Heart Disease Treatment Strategy and Glycemic Control Strategy:
Revascularization and Insulin Providing (IP) N=600; Revascularization and Insulin Sensitizing (IS) N=600; Medical and Insulin Providing (IP) N=600; Medical and and Insulin Sensitizing (IS) N=600.
|
Coronary Disease Cardiovascular Diseases Heart Diseases Insulin Resistance Diabetes Mellitus Diabetes Mellitus, Non-Insulin-Dependent
| null | 4
|
arm 1: Prompt revascularization with intensive medical therapy and insulin providing glycemic control strategy arm 2: Prompt revascularization with intensive medical therapy and insulin sensitizing glycemic control strategy arm 3: Intensive medical therapy with delayed revascularization if clinically indicated and insulin providing glycemic control strategy arm 4: Intensive medical therapy with delayed revascularization if clinically indicated and insulin sensitizing glycemic control strategy
|
[
1,
1,
1,
1
] | 5
|
[
3,
3,
0,
0,
0
] |
intervention 1: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions intervention 2: Coronary Artery Bypass intervention 3: Biguanides, thiazolidinediones intervention 4: Insulin, sulfonylurea intervention 5: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
|
intervention 1: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions intervention 2: Coronary Artery Bypass intervention 3: Biguanides, thiazolidinediones intervention 4: Insulin, sulfonylurea intervention 5: ACE Inhibitors, Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers
| 0
| null | 0
|
NCT00006305
|
|
[
3
] | 103
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
Phase II trial to study the effectiveness of bortezomib in treating patients who have low-grade lymphoproliferative disorders. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth.
|
PRIMARY OBJECTIVES:
I. Determine the frequency and duration of complete and partial response rates in patients with grade I, II, or III follicular lymphoma or mantle cell lymphoma treated with bortezomib.
SECONDARY OBJECTIVES:
I. Determine the response of minimal residual disease by polymerase chain reaction (PCR) detectable or clonotypic PCR minimal residual disease in bone marrow of patients treated with this regimen.
II. Determine the time to progression and overall survival of patients treated with this regimen.
III. Determine the toxic effects of this regimen in these patients.
OUTLINE: Patients are stratified according to disease type (follicular lymphoma vs mantle cell lymphoma).
Patients receive an infusion of bortezomib over 3-5 seconds once weekly for 4 weeks. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve at least a partial response lasting at least 6 months may receive retreatment.
Patients are followed every 3 months for 1 year and then every 4 months for 2 years.
|
Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma
| null | 1
|
arm 1: Patients receive an infusion of bortezomib (dose of 1.8 mg/m2) over 3-5 seconds once weekly for 4 weeks. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve at least a partial response lasting at least 6 months may receive retreatment.
|
[
0
] | 1
|
[
0
] |
intervention 1: Given IV
|
intervention 1: bortezomib
| 1
|
New York | New York | United States | -74.00597 | 40.71427
| 0
|
NCT00023764
|
|
[
5
] | 219
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| true
|
This study will evaluate the effectiveness of switching medications in decreasing schizophrenia symptoms in individuals who are currently taking an antipsychotic medication for the treatment of schizophrenia.
|
Over the past several years, new, "atypical" antipsychotic medications have become available to treat schizophrenia with little information to guide prescribing for relatively stable outpatients.
Participants will be randomly assigned to either continue taking their current medications for schizophrenia, or to switch to a new medication. Participants assigned to switch to a new medication will begin receiving either olanzapine (Zyprexa), risperidone (Risperdal), ziprasidone (Geodon), quetiapine (Seroquel), or aripiprazole (Abilify), depending on what they are currently taking. Participants currently taking a single oral medication will switch to olanzapine, risperidone, ziprasidone, quetiapine, or aripiprazole. Participants currently taking a single conventional injectable will begin taking long-acting injectable risperidone (Risperdal Consta). Participants currently taking two antipsychotic medications will begin taking only one of the medications they are currently using. Participants will stay on their assigned treatment for 6 months, after which time the participant's prescribing psychiatrist will advise the participant on which medication should be used. Study participants are interviewed at study start and at follow-up visits for 1 year.
|
Schizophrenia
| null | 2
|
arm 1: Participants will continue taking medication prescribed at study entry: 1) either long-acting injectable haloperidol or fluphenazine, OR 2) two antipsychotic medications which might include a combination of any of the following: risperidone, olanzapine, ziprasidone, quetiapine, aripiprazole, or conventional (typical) antipsychotic medications. arm 2: Participants will change medications from medication prescribed at study entry, either: 1) long-acting injectable risperidone, OR 2) one of the two antipsychotic medications prescribed at baseline which may include any of the following: risperidone, olanzapine, ziprasidone, quetiapine, aripiprazole, or conventional (typical) antipsychotic medications.
|
[
1,
1
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: As prescribed by routine prescriber (not dictated by study protocol) intervention 2: As prescribed by routine prescriber (not dictated by study protocol) intervention 3: As prescribed by routine prescriber (not dictated by study protocol) intervention 4: As prescribed by routine prescriber (not dictated by study protocol) intervention 5: As prescribed by routine prescriber (not dictated by study protocol)
|
intervention 1: Risperidone intervention 2: Olanzapine intervention 3: Ziprasidone intervention 4: Quetiapine intervention 5: Aripiprazole
| 0
| null | 0
|
NCT00044655
|
|
[
4
] | 502
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
Long term safety study of TRAVATAN in patients with Open-angle glaucoma or ocular hypertension.
| null |
Glaucoma, Open-angle Ocular Hypertension
|
Glaucoma POAG OAG OHT
| null | 1
|
arm 1: Travoprost (0.004%)
|
[
0
] | 1
|
[
0
] |
intervention 1: Travoprost (0.004%) 1 drop each eye once daily
|
intervention 1: Travatan
| 1
|
Fort Worth | Texas | United States | -97.32085 | 32.72541
| 0
|
NCT00051168
|
[
2,
3
] | 72
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase II trial to study the effectiveness of 10-propargyl-10-deazaaminopterin in treating patients who have recurrent or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma.
|
OBJECTIVES:
* Determine the efficacy of 10-propargyl-10-deazaaminopterin, in terms of objective response rate, duration of response, and time to disease progression, in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma or Hodgkin's lymphoma.
* Determine the impact of pharmacokinetics on toxicity and drug elimination in patients treated with this drug.
* Determine the toxicity of this drug in these patients.
* Determine the effect of prior chemotherapy response duration on duration of response in patients treated with this drug.
* Correlate, if possible, the pharmacodynamics (area under the curve) of this drug with tumor response and toxicity (mucositis) in these patients.
* Correlate, if possible, intraerythrocytic folate or homocysteine levels with severity of mucositis in patients treated with this drug.
* Determine whether levels of the RFC-1 folate transporter, folylpolyglutamate synthetase, and folylpolyglutamate hydrolase are markers of response in patients treated with this drug.
OUTLINE: This is an open-label study.
Patients receive 10-propargyl-10-deazaaminopterin IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response (CR) may receive 2 additional courses beyond the CR.
PROJECTED ACCRUAL: A total of 39-72 patients (12-35 for cohort 1 and 17-37 for cohort 2) will be accrued for this study within 10-36 months.
|
Lymphoma
|
recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult Burkitt lymphoma recurrent adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma recurrent mantle cell lymphoma recurrent adult Hodgkin lymphoma recurrent grade 3 follicular lymphoma
| null | 5
|
arm 1: Pralatrexate (PDX) 135 mg/m\^2 administered as an intravenous (IV) infusion over one hour into a side arm of a running intravenous infusion of normal saline for 1/2 weeks. arm 2: PDX 30 mg/m\^2 administered as an IV infusion over 15 minutes into a side arm of a running intravenous infusion of normal saline for 3/4 weeks. arm 3: PDX 30 mg/m\^2 administered as an IV infusion over 15 minutes into a side arm of a running intravenous infusion of normal saline for 6/7 weeks. arm 4: PDX 45 mg/m\^2 administered as an IV infusion over 15 minutes into a side arm of a running intravenous infusion of normal saline for 6/7 weeks. arm 5: PDX (270 mg/m\^2) administered as an IV bolus over 3-5 minutes into a side arm of a running intravenous infusion of normal saline for 2/4 weeks.
|
[
0,
0,
0,
0,
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: pralatrexate
| 1
|
New York | New York | United States | -74.00597 | 40.71427
| 0
|
NCT00052442
|
[
3
] | 31
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Drugs used in chemotherapy such as gemcitabine and irinotecan use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.
PURPOSE: This phase II trial is studying how well giving gemcitabine together with irinotecan works in treating patients with cancer of unknown primary origin.
|
OBJECTIVES:
Primary
* Determine the response rate in patients with carcinoma of unknown primary when treated with gemcitabine and irinotecan.
* Determine the adverse event profile and tolerability of this regimen, based on the presence or absence of the UGT1A1\*28 polymorphism, in these patients. (Cohort I closed to accrual 11/17/05)
* Determine the adverse event profile and tolerability of this regimen. (Cohort II)
Secondary
* Determine the time to progression and overall survival of patients treated with this regimen.
* Correlate patterns of immunohistochemical staining with response in patients treated with this regimen.
* Correlate variation in multiple different genes, whose protein products are involved in the uptake, metabolism, and distribution of these drugs, with clinical outcomes, in terms of response and toxicity, in these patients.
* Determine primary origin of cancer of unknown primary samples by completing a 92-gene RT-PCR cancer classification assay.
* Determine whether the 92-gene assay results are correlated with clinical response to gemcitabine and irinotecan.
OUTLINE:
* Cohort I (closed to accrual 11/17/05): Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, 15, and 22. Irinotecan dose may be escalated or de-escalated after course 1 depending on toxicity. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
* Cohort II: Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Patients are followed every 3 months for 2 years.
|
Carcinoma of Unknown Primary
|
adenocarcinoma of unknown primary newly diagnosed carcinoma of unknown primary squamous cell carcinoma of unknown primary undifferentiated carcinoma of unknown primary
| null | 2
|
arm 1: Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, 15, and 22. Irinotecan dose may be escalated or de-escalated after course 1 depending on toxicity. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Given IV intervention 2: Given IV
|
intervention 1: gemcitabine hydrochloride intervention 2: irinotecan hydrochloride
| 4
|
Mason City | Iowa | United States | -93.20104 | 43.15357
Rochester | Minnesota | United States | -92.4699 | 44.02163
Lincoln | Nebraska | United States | -96.66696 | 40.8
Omaha | Nebraska | United States | -95.94043 | 41.25626
| 0
|
NCT00066781
|
[
2,
3
] | 50
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
This phase I/II trial is studying the side effects and best dose of FR901228 and to see how well it works in treating patients with recurrent high-grade gliomas. FR901228 may stop the growth of tumor cells by blocking the enzymes necessary for their growth
|
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) of FR901228 (depsipeptide) in patients with recurrent malignant gliomas who are taking enzyme-inducing antiepileptic drugs (EIAEDs). (Phase I) II. Determine the safety profile of this drug in these patients. (Phase I) III. Determine the pharmacokinetics and pharmacodynamics of this drug in these patients. (Phase I) IV. Determine the clinical efficacy of this drug, as measured by 6-month progression-free survival and objective tumor response, in these patients. (Phase II) V. Determine the safety profile of this drug when administered at the phase I MTD concurrently with or without EIAEDs in these patients. (Phase II)
OUTLINE: This is a multicenter, phase I, dose-escalation study followed by a phase II study. Patients are stratified according to study phase (I vs II), concurrent use of enzyme-inducing anti-epileptic drugs (EIAEDs) (yes vs no), histology (recurrent glioblastoma multiforme/gliosarcoma vs recurrent anaplastic glioma), pre-operative candidacy (yes vs no), and measurable/evaluable disease (yes vs no). Patients are assigned to 1 of 2 treatment groups (group A: no EIAEDs or group B: concurrent use of EIAEDs).
Phase I (group B only): Patients receive FR901228 (depsipeptide) IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of FR901228 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of up to 6 patients experience dose-limiting toxicity.
Phase II (groups A and B):
Group A (phase II): Patients receive FR901228 as in phase I at dose level 1. Group B (phase II): Patients receive FR901228 as in phase I at the MTD.
|
Adult Anaplastic Astrocytoma Adult Anaplastic Oligodendroglioma Adult Giant Cell Glioblastoma Adult Gliosarcoma Recurrent Adult Brain Tumor
| null | 2
|
arm 1: Patients receive FR901228 (romidepsin) IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Dose escalation two dose levels:
Romidepsin (depsipeptide): 13.3mg/m2 and 17.7mg/m2
Pharmacokinetics arm 2: Patients receive FR901228 (romidepsin) as in phase I at dose level 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Romidepsin (depsipeptide): 13.3mg/m2
|
[
0,
0
] | 1
|
[
0
] |
intervention 1: Given IV
|
intervention 1: depsipeptide
| 8
|
Los Angeles | California | United States | -118.24368 | 34.05223
San Francisco | California | United States | -122.41942 | 37.77493
Bethesda | Maryland | United States | -77.10026 | 38.98067
Boston | Massachusetts | United States | -71.05977 | 42.35843
New York | New York | United States | -74.00597 | 40.71427
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Houston | Texas | United States | -95.36327 | 29.76328
Madison | Wisconsin | United States | -89.40123 | 43.07305
| 0
|
NCT00085540
|
|
[
4
] | 403
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| true
| 0ALL
| false
|
The purpose of this study was to examine pharmacological and psychological interventions for smokers over 50.
|
The overall goals of this line of research were to prevent relapse to cigarette smoking, and to understand the processes related to smoking and relapse. The specific aims of the current study were to test a series of hypotheses about the efficacy and cost-effectiveness of long-term, tailored interventions in chronic, older smokers and the interaction of these interventions with gender and depression. Participants were 50 years or older and smoker 10 or more cigarettes per day. Baseline assessments includes measures of smoking behavior, nicotine dependence, depression diagnosis, demographics and life circumstances and measures of anger, depression and mood disturbance, stress, social support, health status, motivation for changed and drug and alcohol use.
|
Tobacco Use Disorder
|
Smoking cessation Tobacco
| null | 4
|
arm 1: Pharmacological Treatment - Subjects received 12 weeks of bupropion treatment and 10 weeks of nicotine replacement treatment (NRT)
Brief Counseling - The counseling intervention consisted of five 90-minute group meetings.
There was no further treatment during Weeks 12-52. arm 2: Pharmacological Treatment - Following completion of the Brief Treatment, subjects assigned to this condition would continue receiving NRT for up to 52 weeks. Subjects in this condition would be encouraged to continue NRT through Week 24. If a subject terminated NRT and resumed smoking, before Week 50, would be instructed to set a quit date and resume NRT.
Counseling Treatment - This is identical to the Brief Counseling described above. arm 3: This condition was identical to the Tailored/NRT condition except that no NRT was available after completion of the Brief Treatment. arm 4: Tailored Counseling Treatment- The primary goal of the extended treatment was to prevent relapse. Secondary goal was to encourage initiation of abstinence for those who have not attained it by Week 12, and re-initiation of abstinence after slips. Subjects would participate in the Brief Treatment followed by individual sessions. The first extended treatment counseling session would occur at Week 10. Additional sessions would be held every two weeks then every four weeks, and finally at Weeks 44 and 52. Each session would be 20-30 minutes long. Between sessions subjects would be contacted by phone for brief check-ins (5-10 minutes).
|
[
1,
0,
0,
0
] | 1
|
[
0
] |
intervention 1: Subjects receive 12 weeks of bupropion treatment and 10 weeks of nicotine replacement.
|
intervention 1: Nicotine polacrilex, Bupropion
| 1
|
San Francisco | California | United States | -122.41942 | 37.77493
| 0
|
NCT00086385
|
[
4
] | 332
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 4QUADRUPLE
| false
| 1FEMALE
| null |
This study will determine whether treatment with AMG 162 can prevent lumbar spine bone loss in both early and late postmenopausal women with osteopenia, and to further test the safety and tolerability of AMG 162 in this population.
| null |
Postmenopausal Osteoporosis
|
Osteoporosis Postmenopausal
| null | 2
|
arm 1: 60 mg/mL denosumab given day 1, month 6, month 12 and month 18 arm 2: Placebo given day 1, month 6, month 12 and month 18
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 60 mg/mL denosumab given day 1, month 6, month 12 and month 18 intervention 2: Placebo given at day 1, month 6, month 12 and month 18
|
intervention 1: AMG 162 intervention 2: Placebo
| 0
| null | 0
|
NCT00091793
|
[
3,
4
] | 30
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
This study is designed as a Phase II/III, multi-center trial, comparing two transplant strategies to determine whether non-myeloablative allogeneic Hematopoietic Stem Cell Transplantation (HSCT) will improve long-term progression-free survival compared to autologous HSCT. Recipients will be biologically assigned to the appropriate treatment arm depending on the availability of a Human Leukocyte Antigen (HLA) matched sibling.
|
BACKGROUND:
Although patients with follicular non-Hodgkin's lymphoma (NHL) typically experience a relatively indolent course, the disease is rarely curable with conventional chemotherapy. Patients with follicular NHL are usually treated only when symptoms require palliation or if bulky disease exists since no survival advantage has been shown as compared to administering conventional treatment at initial diagnosis. While most patients achieve a remission with initial chemotherapy, a continuous pattern of relapse occurs, resulting in progressively shorter remission durations. Additionally, the increased response rates conferred by anthracycline-containing regimens have not translated into improved survival and thus the median survival time of 6 to 10 years has not been significantly impacted over the last decade.
DESIGN NARRATIVE:
The overall study design is a comparison of two treatment arms determined by biologic assignment, based on the availability of an HLA-matched sibling, in patients diagnosed with relapsed follicular non-Hodgkin's lymphoma. Patients without an HLA-matched sibling will receive an autologous HSCT. Patients with an HLA-matched sibling will receive a non-myeloablative allogeneic HSCT.
The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two strategies to improve the outcome for follicular lymphoma patients with chemosensitive disease. All patients will undergo cytoreduction with cyclophosphamide 4 gm/m\^2 and rituximab 375 mg/m\^2 x 2 doses. Rituximab will be given in two doses, approximately 1 week apart, with the cyclophosphamide administered the day after the first dose of rituximab. Patients assigned to the autologous arm will have their hematopoietic stem cells mobilized from this cytoreductive regimen. Patients with an HLA-matched sibling will undergo a non-myeloablative allogeneic HSCT. Pre-transplant conditioning will consist of fludarabine 30 mg/m\^2/day and cyclophosphamide 750 mg/m\^2/day x 3 days with rituximab 375 mg/m\^2/day on Days -13 and -6 pre-HSCT and on Days +1 and +8 post-HSCT. The immunosuppressive regimen will consist of tacrolimus and methotrexate (MTX) to control graft-versus-host and host-versus-graft reactions. Patients without an HLA-matched sibling who have collected an adequate autologous hematopoietic cell graft, defined as at least 2.0 \* 10\^6 CD34+ cells/kg, will receive a preparative regimen of total body irradiation (TBI) 1200 cGy or Carmustine (BCNU) 15 mg/kg. In addition, VP-16 60 mg/kg and cyclophosphamide 100 mg/kg will be given for both autologous preparative regimens. Post-autologous HSCT therapy with rituximab 375 mg/m\^2 weekly x 4 doses will commence between Days 42-75 post-HSCT.
|
Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Follicular Lymphoma
|
Prot_SAP_ICF_000.pdf:
BMT CTN 0202
Autologous vs. Non-Myeloablative Allogeneic
Hematopoietic Stem Cell Transplantation (HSCT)
for Patients with Chemosensitive Follicular Non-
Hodgkin’s Lymphoma Beyond First Complete
Response or First Partial Response
NCT00096460
Autologous vs. Non-Myeloablative Allogeneic Hematopoietic Stem
Cell Transplantation (HSCT) for Patients with Chemosensitive
Follicular Non-Hodgkin’s Lymphoma Beyond First Complete
Response or First Partial Response
BMT CTN PROTOCOL 0202
VERSION 4.0
Study Co-Chairpersons
Ginna Laport, M.D. 1
Robert Negrin, M.D. 1
Protocol Team
Marian Ewell, Sc.D 2
John Klein, Ph.D. 3
David Maloney, M.D., Ph.D 4
Julie Marchick, M.P.H. 2
Auayporn Nadamanee, M.D. 5
Patrick Stiff, M.D. 6
Marcie Tomblyn, M.D.7
Julie Vose, M.D. 8
Sponsored by the National Institutes of Health
National Heart, Lung and Blood Institute
National Cancer Institute
1 Stanford Hospital and Clinics
2 The EMMES Corporation
3 Center for International Blood and Marrow
Transplant Research (CIBMTR), Medical
College of Wisconsin
4 Fred Hutchinson Cancer Research Center
5 City of Hope National Medical Center
6 Loyola University Health System
7 University of Minnesota
8 University of Nebraska Medical Center
BMT CLINICAL TRIALS NETWORK
Follicular Lymphoma Protocol - 0202
Version 4.0 dated January 17, 2006
Core Study Participants:
Non-Core Study Participants:
Case Western Reserve Consortia
Oregon Health & Science University
University Hospitals of Cleveland
Washington University
City of Hope National Medical Center
Dana Farber/Partners Cancer Center
Duke University Medical Center-Adult
Stanford Hospital and Clinics
UCSD/SCRIPPS School of Medicine
University of Florida College of Medicine (Shands)
University of Michigan Medical Center
University of Minnesota
University of Nebraska Medical Center
University of Pennsylvania Cancer Center
University of Texas, MD Anderson Cancer Center
Baylor University Medical Center
Blood and Marrow Transplant Group of Georgia
Emory University
Hackensack University Medical Center
H. Lee Moffitt Cancer Center
Indiana BMT at Beech Grove
Kansas City Blood & Marrow Transplant Center
Karmanos Cancer Institute, BMT
Loyola University Medical Center
Medical College of Wisconsin
Providence Portland Medical Center
Temple University
University of Maryland
University of Pittsburgh
University of Wisconsin
Vanderbilt University Medical Center
Virginia Commonwealth University Medical Center
BMT CLINICAL TRIALS NETWORK
Follicular Lymphoma Protocol - 0202
Version 4.0 dated January 17, 2006
i
PROTOCOL SYNOPSIS - BMT CTN PROTOCOL #0202
Autologous vs. Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT) for Patients with Chemosensitive Follicular Non-Hodgkin’s Lymphoma Beyond
First Complete Response or First Partial Response
Study Co-Chairpersons:
Ginna Laport, M.D. and Robert Negrin, M.D.
Accrual Objective:
A minimum of 80 patients with recurrent follicular non-Hodgkin’s
lymphoma (REAL classification follicle center lymphoma, follicular
grades I and II or patients with histologically confirmed WHO
classification follicular lymphoma grades 1, 2, 3a or 3b) and an HLA-
matched sibling will be entered on the protocol. It is expected during
the same period that an additional 187-320 patients without an HLA-
matched sibling will be entered on the protocol.
Study Design:
This study is designed as a Phase II/III, multi-center trial, comparing
two transplant strategies to determine whether non-myeloablative
allogeneic HSCT will improve long-term progression-free survival
compared to autologous HSCT. Recipients will be biologically
assigned to the appropriate treatment arm depending on the availability
of an HLA-matched sibling.
Accrual Period:
The estimated accrual period is three years.
Primary Objective:
The primary objective is to compare progression-free survival (PFS) at
three years between the two treatment arms.
Secondary Objectives:
Secondary objectives for the comparison of non-myeloablative
allogeneic HSCT vs. autologous HSCT are three-year overall survival,
time to progression, time to complete response (CR) and partial
response (PR), time to off-study therapy, incidence of infections, and
incidence of NCI Common Terminology Criteria Adverse Events
(CTCAE) Version 3.0 Grade ≥ 3 toxicities.
Secondary objectives for the non-myeloablative allogeneic HSCT
recipients include incidence and severity of acute and chronic GVHD,
and incidence of primary and secondary graft failure.
The efficacy of cyclophosphamide plus rituximab in vivo purging will
also be evaluated as well as the prediction of disease relapse by
measurement of t(14;18) by quantitative polymerase chain reaction
(PCR).
Quality of life as measured by the SF-36 and the FACT-BMT will be
described in both patient populations.
Eligibility Criteria:
Eligible patients are ≤ 75 years of age with Karnofsky performance
score ≥ 70% who have histologically confirmed recurrent follicular
lymphoma (REAL classification follicle center follicular grades I and
II or patients with histologically confirmed WHO classification
follicular lymphoma grades 1, 2, 3a or 3b). Patients must have
received ≤ 3 prior treatment regimens. Monoclonal antibody therapy
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and local radiation will not be counted as prior therapies. Patients
must demonstrate chemosensitive disease by achieving reduction in
lymph node axial diameter to < 3 cm or > 50% reduction in estimated
lymph node volume AND ≤ 20% BM involvement after their most
recent salvage therapy. Patients do not have to express t(14;18).
Treatment Description:
Within 4 weeks of enrollment and after HLA typing and evaluation of
potential sibling donors is complete, all patients will receive
cyclophosphamide 4 gm/m2 on Day 2 concomitantly with rituximab
375 mg/m2 on Days 1 and 8. G-CSF 10 mcg/kg/day (autologous
patients) or 5 mcg/kg/day (allogeneic patients) SQ or IV will be given
starting 2 days after the initiation of cyclophosphamide. Patients
assigned to the autologous HSCT arm will undergo leukapheresis upon
blood count recovery. After the mobilization process is complete,
autologous patients will then receive either fractionated total body
irradiation (FTBI) 1200 cGy or BCNU 15 mg/kg. VP-16 60 mg/kg
and cyclophosphamide 100 mg/kg will also be given followed by
autologous HSCT. Patients must have an adequate autograft defined
as ≥ 2.0 x 106 CD34+ cells/kg. Rituximab 375 mg/m2 x 4 weekly
doses, to begin on approximately Day +42, will be given as
maintenance therapy. Patients with an HLA-matched sibling will
receive a non-myeloablative conditioning regimen of fludarabine
30 mg/m2/day and cyclophosphamide 750 mg/m2/day from Day -6 to -
4 followed by infusion of G-CSF mobilized donor hematopoietic stem
cells. Rituximab 375 mg/m2 will be administered on Day -13, -6, +1
and +8. GVHD prophylaxis will consist of tacrolimus (IV or PO) until
Day +90 followed by a taper and methotrexate 5 mg/m2 IV on Day +1,
+3, and +6 post-HSCT. All patients will undergo PCR analysis for
t(14:18) from the peripheral blood after blood count recovery from the
cyclophosphamide/rituximab cytoreductive/mobilization regimen and
on Day +28, +84, +180 and yearly post-HSCT if positive at any time
from diagnosis to initial study evaluation.
Quality of Life:
The FACT-BMT and MOS SF-36 instruments will be used to describe
the health-related quality of life (HQL) of patients. A secondary
analysis will compare the HQL between the two treatment arms. The
self-report questionnaire will be performed prior to cytoreductive/
mobilization therapy and at two years post-HSCT for English and
Spanish speaking patients only.
Study Duration:
Patients will be followed for at least three years post-HSCT.
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TREATMENT SCHEMA
* Only required for patients who had a positive PCR at any point prior to study entry or at the
baseline screen on study.
Eligible patients following salvage chemotherapy:
Yes
No
Quantitative PCR t(14;18)
Cyclophosphamide 4 gm/m2
Rituximab 375 mg/m2 x 2 doses
G-CSF 5 mcg/kg
Quantitative PCR
t(14;18)* at blood count
Non-myeloablative conditioning
Fludarabine 30 mg/m2 (Days -6 to -4)
Cyclophosphamide 750 mg/m2 (Days -6 to -4)
Rituximab 375 mg/m2 (Days -13, -6, +1, +8)
Infusion of G-CSF mobilized allogeneic
hematopoietic stem cells
Quantitative t(14;18) PCR after
blood count recovery,
Days +28, +84, +180 and yearly
until 3 years post-transplant if
positive at any time from diagnosis
to initial study evaluation*
Quantitative PCR t(14;18)
Cyclophosphamide 4 gm/m2
Rituximab 375 mg/m2 x 2 doses
G-CSF 10 mcg/kg
Collection of HSCs ≥ 2x106 CD34+ cells/kg
Autologous Conditioning
FTBI 1200 cGy (Days –8 to –5) or
BCNU 15 mg/kg (Day –6), then
followed by VP-16 60 mg/kg (Day –4)
Cyclophosphamide 100 mg/kg (Day –2)
Infusion of G-CSF mobilized autologous
hematopoietic stem cells
Quantitative t(14;18) PCR after blood count recovery,
Days +28, +84, +180 and yearly until 3 years post-
transplant if positive at any time from diagnosis to
initial study evaluation*
Quantitative PCR t(14;18) at blood count recovery and
PCR on each leukaphereis product*
Rituximab maintenance 375 mg/m2
Days +42, +49, +56 and +63 post-HSCT
Availability of an HLA-matched sibling donor?
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TABLE OF CONTENTS
1.
BACKGROUND AND RATIONALE ............................................................................ 1-1
1.1.
Background ......................................................................................................................... 1-1
1.2.
Autologous Hematopoietic Stem Cell Transplantation ................................................ 1-1
1.3.
Minimal Residual Disease ................................................................................................. 1-2
1.4.
In Vivo Purging with Rituximab ...................................................................................... 1-3
1.5.
Relapse Prevention with Rituximab ................................................................................ 1-4
1.6.
Allogeneic Hematopoietic Stem Cell Transplantation for Follicular Lymphoma ... 1-4
1.6.1.
Non-myeloablative Allogeneic Hematopoietic Stem Cell Transplantation ................ 1-5
1.7.
Study Approach and Treatment ...................................................................................... 1-6
2.
STUDY DESIGN ................................................................................................................ 2-1
2.1.
Study Overview .................................................................................................................. 2-1
2.2.
Hypothesis and Specific Objectives ................................................................................. 2-1
2.2.1.
Hypothesis ....................................................................................................................... 2-1
2.2.2.
Study Objectives ............................................................................................................. 2-2
2.3.
Patient Eligibility ................................................................................................................ 2-2
2.3.1.
Initial Patient Inclusion Criteria ..................................................................................... 2-2
2.3.2.
Initial Patient Exclusion Criteria .................................................................................... 2-3
2.4.
Patient Eligibility Criteria for Proceeding to HSCT .................................................... 2-3
2.5.
Patient Eligibility Criteria for Maintenance Therapy for Recipients of Autologous
HSCT ............................................................................................................................... 2-4
2.6.
Allogeneic Hematopoietic Stem Cell Donor Criteria.................................................... 2-4
2.6.1.
Donor Inclusion Criteria ................................................................................................. 2-4
2.6.2.
Donor Exclusion Criteria ................................................................................................ 2-4
2.7.
Study Treatments ............................................................................................................... 2-5
2.7.1.
HLA-Typing of Potential Sibling Donors ..................................................................... 2-5
2.7.2.
Body Weight Formulas ................................................................................................... 2-5
2.7.3.
Cytoreductive Therapy/Mobilization Chemotherapy ................................................... 2-6
2.7.3.1.
Allopurinol....................................................................................................................... 2-6
2.7.3.2.
Cyclophosphamide and rituximab administration/mobilization .................................. 2-6
2.7.4.
High Dose Chemotherapy with Autologous HSCT ...................................................... 2-7
2.7.4.1.
Conditioning regimen - chemotherapy-based regimen ................................................. 2-8
2.7.4.2.
Conditioning regimen - total body irradiation-based regimen ..................................... 2-8
2.7.4.3.
Rituximab maintenance therapy ................................................................................... 2-10
2.7.5.
Non-myeloablative Allogeneic Stem Cell Transplantation for Patients with an HLA-
matched Sibling ............................................................................................................. 2-10
2.7.5.1.
Conditioning regimen ................................................................................................... 2-11
2.7.5.2.
Graft-versus-host disease (GVHD) prophylaxis ......................................................... 2-11
2.7.6.
Collection and Infusion of Allogeneic HSC ................................................................ 2-12
2.7.6.1.
G-CSF administration to donors .................................................................................. 2-12
2.7.6.2.
HSC collection and evaluation ..................................................................................... 2-12
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2.7.6.3.
Allogeneic hematopoietic stem cell infusion .............................................................. 2-13
2.8.
Supportive Care................................................................................................................ 2-13
2.8.1.
Post-autologous HSCT.................................................................................................. 2-13
2.8.1.1.
Prophylaxis against infections ...................................................................................... 2-13
2.8.1.2.
Blood products .............................................................................................................. 2-14
2.8.1.3.
Post-HSCT immunization schedule ............................................................................. 2-14
2.8.2.
Post Non-myeloablative Allogeneic HSCT ................................................................. 2-14
2.8.2.1.
Prophylaxis against infections ...................................................................................... 2-14
2.8.2.2.
Blood products .............................................................................................................. 2-15
2.8.2.3.
Post-HSCT growth factors ............................................................................................ 2-15
2.8.2.4.
Post-HSCT immunization schedule ............................................................................. 2-15
2.8.2.5.
Post-HSCT donor cellular infusions (DCI) ................................................................. 2-15
2.9.
PCR Monitoring for t(14;18) .......................................................................................... 2-15
2.10. Participant Risks .............................................................................................................. 2-15
2.11. Therapy Toxicities............................................................................................................ 2-16
2.11.1.
Total Body Irradiation (TBI) ........................................................................................ 2-16
2.11.2.
Cyclophosphamide ........................................................................................................ 2-16
2.11.3.
Carmustine (BCNU) ..................................................................................................... 2-16
2.11.4.
VP-16 (Etoposide) ......................................................................................................... 2-16
2.11.5.
Rituximab ...................................................................................................................... 2-16
2.11.6.
Fludarabine .................................................................................................................... 2-17
2.11.7.
Methotrexate .................................................................................................................. 2-17
2.11.8.
Tacrolimus ..................................................................................................................... 2-17
2.11.9.
G-CSF (filgrastim) ........................................................................................................ 2-17
3.
STUDY ENDPOINTS........................................................................................................ 3-1
3.1.
Definition of Disease Status .............................................................................................. 3-1
3.2.
Primary Endpoint to be Compared Between Autologous HSCT Recipients and Non-
myeloablative Allogeneic HSCT Recipients .............................................................. 3-2
3.2.1.
Three Year Progression-Free Survival........................................................................... 3-2
3.3.
Secondary Endpoint to be Compared Between Autologous HSCT Recipients and
Non-myeloablative Allogeneic HSCT Recipients ..................................................... 3-2
3.3.1.
Three Year Overall Survival........................................................................................... 3-2
3.3.2.
Time to Progression ........................................................................................................ 3-2
3.3.3.
Time to CR and PR ......................................................................................................... 3-3
3.3.4.
Time to Off-study Therapy ............................................................................................. 3-3
3.3.5.
Incidence of Infections .................................................................................................... 3-3
3.3.6.
Incidence of CTCAE Version 3.0 Grade ≥ 3 toxicities ................................................ 3-3
3.3.7.
Treatment Related Mortality .......................................................................................... 3-3
3.4.
Endpoints That Only Apply to Non-myeloablative Allogeneic Recipients ............... 3-3
3.4.1.
Incidence of Primary and Secondary Graft Failure....................................................... 3-3
3.4.2.
Incidence and Severity of Graft-versus-Host Disease (GVHD) .................................. 3-4
3.5.
Other Endpoints ................................................................................................................. 3-4
3.5.1.
Efficacy of Rituximab and Cyclophosphamide in Vivo Purging ................................. 3-4
3.5.2.
Prognostic Value of t(14;18) by PCR in Predicting Relapse ....................................... 3-4
3.5.3.
Quality of Life ................................................................................................................. 3-4
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3.6.
Regimen-related Toxicities Safety Monitoring Endpoints .......................................... 3-4
3.6.1.
Allogeneic HSCT ............................................................................................................ 3-4
3.6.2.
Autologous HSCT ........................................................................................................... 3-5
4.
PATIENT ENROLLMENT AND EVALUATION ...................................................... 4-1
4.1.
Enrollment Procedures...................................................................................................... 4-1
4.1.1.
Screening and Eligibility Procedures ............................................................................. 4-1
4.1.2.
SWOG Patient Registration Procedures ........................................................................ 4-2
4.2.
Study Monitoring ............................................................................................................... 4-2
4.2.1.
Follow-up Schedule ........................................................................................................ 4-2
4.2.2.
Weekly GVHD Monitoring Post Non-myeloablative Allogeneic Transplant ............ 4-4
4.2.3.
Adverse Event Reporting ................................................................................................ 4-4
4.2.4.
Patient Assessments ........................................................................................................ 4-4
4.2.4.1.
Evaluations prior to rituximab and cyclophosphamide ................................................ 4-4
4.2.4.2.
Post initiation of rituximab and cyclophosphamide ...................................................... 4-5
4.2.4.3.
Evaluations prior to the autologous or non-myeloablative allogeneic HSCT ............. 4-5
4.2.4.4.
Post-HSCT evaluations ................................................................................................... 4-6
4.2.4.5.
Prior to initiation of rituximab maintenance therapy in autologous HSCT recipients 4-7
4.2.4.6.
Sampling schedule for quantitative PCR of t(14;18) from peripheral blood sample.. 4-8
4.2.4.7.
Sampling schedule for chimerism analysis of peripheral blood in non-myeloablative
allogeneic transplant recipients ...................................................................................... 4-8
4.2.4.8.
Required observations for HLA-matched sibling donor............................................... 4-8
5.
STATISTICAL CONSIDERATIONS ............................................................................ 5-1
5.1.
Study Overview .................................................................................................................. 5-1
5.1.1.
Primary Endpoint ............................................................................................................ 5-1
5.1.2.
Accrual ............................................................................................................................. 5-1
5.1.3.
Biologic Assignment ....................................................................................................... 5-2
5.1.4.
Intention-to-Treat Principle ............................................................................................ 5-2
5.2.
Statistical Issues Related to Non-randomized Assignment.......................................... 5-2
5.2.1.
Selection of Patients to Screen for the Study ................................................................ 5-2
5.2.2.
Compliance with Biologic Assignment ......................................................................... 5-3
5.2.3.
Effects of Transplant Center ........................................................................................... 5-3
5.2.4.
Effects of Disease Risk Status ........................................................................................ 5-4
5.2.5.
Effects of Baseline Factors ............................................................................................. 5-4
5.3.
Sample Size and Power Calculations .............................................................................. 5-4
5.4.
Interim Analysis and Stopping Guidelines..................................................................... 5-5
5.4.1.
Guidelines for Accrual Monitoring ................................................................................ 5-5
5.4.2.
Guidelines for Efficacy Monitoring ............................................................................... 5-5
5.4.3.
Guidelines for Safety Monitoring .................................................................................. 5-6
5.5.
Analysis Plan ..................................................................................................................... 5-10
5.5.1.
Analysis of the Primary Endpoint ................................................................................ 5-10
5.5.2.
Analysis of Secondary Endpoints ................................................................................ 5-10
5.5.3.
Analyses of Patients on the Non-myeloablative Allogeneic HSCT Treatment Arm 5-14
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LIST OF APPENDICES
APPENDIX A
REFERENCES
APPENDIX B
CONSENT FORMS
APPENDIX C
LABORATORY PROCEDURES
APPENDIX D
HUMAN SUBJECTS
APPENDIX E
STATISTIC FOR TESTING THREE-YEAR
PROGRESSION-FREE SURVIVAL
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CHAPTER 1
1.
BACKGROUND AND RATIONALE
1.1. Background
Although patients with follicular non-Hodgkin’s lymphoma (NHL) typically experience a
relatively indolent course, the disease is rarely curable with conventional chemotherapy. Patients
with follicular NHL are usually treated only when symptoms require palliation or if bulky
disease exists since no survival advantage has been shown as compared to administering
conventional treatment at initial diagnosis. While most patients achieve a remission with initial
chemotherapy, a continuous pattern of relapse occurs resulting in progressively shorter remission
durations. Additionally, the increased response rates conferred by anthracycline-containing
regimens have not translated into improved survival and thus the median survival time of 6 to 10
years has not been significantly impacted over the last decade [1-3].
1.2. Autologous Hematopoietic Stem Cell Transplantation
In light of the discouraging results with conventional chemotherapy, high dose chemotherapy
with autologous HSCT has been explored as an alternative approach in patients with follicular
NHL. Several studies have shown improved disease-free survival (DFS) but one recently
published study has also shown an advantage for overall survival [3-8]. The European Group for
Blood and Marrow Transplantation (EBMT) conducted a randomized trial known as the CUP
Trial in which 140 patients with relapsed follicular NHL were randomized to either
chemotherapy alone, autologous HSCT with a purged autograft using monoclonal antibodies or
autologous HSCT with an unpurged autograft. With a median follow-up of 69 months, the
patients who received an autologous HSCT, purged or unpurged, show a significantly higher
two-year progression-free and overall survival (OS). There was no difference between the two
autologous HSCT arms in these endpoints. Overall survival at four years for the chemotherapy
arm, unpurged autologous HSCT arm and purged autologous HSCT arm was 46%, 71% and
77%. The two-year progression-free survival (PFS) was 26%, 58% and 55% respectively. There
was a significant reduction in hazard rates for both progression-free and overall survival when a
comparison was made between the chemotherapy patients and the combined groups of
autologous HSCT patients.
As with conventional chemotherapy, the outcome for patients who receive autologous HSCT is
related to the number of prior chemotherapy regimens received. Patients transplanted in first
remission benefit more than those receiving a transplant after numerous prior therapies. Two
retrospective studies and one prospective study have shown that patients with follicular
lymphoma undergoing autologous HSCT who had received > 3 prior chemotherapy regimens
showed inferior survival compared to patients treated with < 3 prior regimens [3-6]. Bierman et
al in one of the largest single institution retrospective analyses, reported on 100 patients with
follicular NHL. That study demonstrated a 4-year estimated failure-free survival and overall
survival of 44% and 65%, respectively [4]. Response rates (RR) were high with an 82% overall
RR with 68% achieving a complete remission (CR). Treatment-related mortality was 8%.
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However, despite these encouraging numbers, there was no definite evidence of a plateau in
failure-free survival (See Figure 1). The retrospective study by Cao et al of 49 patients with
follicular NHL showed similar results with a 4-year disease-free survival (DFS) and OS of 44%
and 60%, respectively [5]. The prospective study of 64 follicular NHL patients reported by
Rohatiner et al also concurred with these findings reporting a significant correlation between
survival and the total number of previous regimens with patients who received < 3 regimens
surviving longer compared to patients who received > 3 treatment cycles [6].
Another important factor influencing outcome is the previous sensitivity of the patients to
chemotherapy. A recent EBMT analysis of 467 patients indicated that patients who had
previously responded to chemotherapy have similar OS and PFS whether transplanted in 1st
remission or after chemosensitive recurrence. The OS and PFS were considerably lower in
patients with chemoresistant disease [7] (see Figure 2).
Fig. 1: Failure-free survival after
autologous HSCT according to number of
prior courses of chemotherapy
Fig. 2: EBMT registry data showing OS after
autologous HSCT according to previous
response to chemotherapy
1.3.
Minimal Residual Disease
The characteristic t(14;18) gene translocation characteristic of 70-80% of patients with follicular
NHL leads to overexpression of the bcl-2 gene in the bone marrow even when there is no
histologic evidence of bone marrow involvement [10]. The presence of the bcl-2 rearrangement
in the bone marrow of follicular NHL patients is another important prognostic indicator and there
has been increasing evidence that the presence of the bcl-2 rearrangement may be a useful
surrogate endpoint to monitor treatment efficacy in indolent NHL [10,11]. In the t(14;18)
translocation, the bcl-2 gene is moved from chromosome 18 to the immunoglobulin heavy chain
(IgH) locus on chromosome 14 [12]. The resultant bcl-2 gene product is an inhibitor of
apoptosis and it is believed that bcl-2 overexpression may be an important factor in
lymphomagenesis [13]. Cells bearing this translocation can be detected in the peripheral blood
or bone marrow by the highly sensitive polymerase chain reaction (PCR) technique [14]. Thus
PCR for t(14;18) provides a sensitive, quantitative and convenient measure of minimal residual
disease and there is a clear association between the induction of molecular remission and PFS
[11].
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Freedman et al reported that the presence of minimal residual disease in the reinfused marrow
was the most significant prognostic factor for relapse in the autologous HSCT setting [11]. In
this particular study of 153 patients with follicular NHL, patients with bcl-2 negative bone
marrow after ex vivo purging with monoclonal antibodies had significantly longer relapse-free
survival (RFS) compared to those who still had the detectable bcl-2 rearrangement. The eight-
year freedom from recurrence was 83% compared to 19% for patients who were
PCR+(p=.0001). Continued PCR negativity in follow-up bone marrow samples was also
strongly predictive of continued CR and the 12-year OS from diagnosis was 69%. This data
provided compelling evidence that autologous HSCT may prolong OS in patients with follicular
NHL considering that historically the median OS from diagnosis has been 8 years.
1.4.
In Vivo Purging with Rituximab
Contamination of the hematopoietic stem cell graft by tumor cells is thought to be a major factor
contributing to the high relapse rates seen with autologous HSCT. Reducing the rate of relapse
may be achieved by pre-HSCT purging of the hematopoietic stem cell product followed by post-
HSCT maintenance. Various in vitro methods have been utilized to decrease or eliminate
residual tumor cells from the harvest product. Such techniques have included purging with B-
cell monoclonal antibodies, chemotherapeutic agents such as mafosfamide and CD34+ positive
selection [15-18]. While all of these methods have reduced the level of tumor cell
contamination, most grafts have remained PCR positive and there have been no randomized
trials to date strongly supporting the use of in vitro purging in this setting [8,19]. Additionally,
in vitro purging methods are typically expensive, labor intensive, require reagents that are not
generally available and can be associated with substantial cell losses [20]. For example, the
above mentioned study by Freedman et al required the use of 3 monoclonal antibodies and rabbit
complement to achieve successful marrow purging [11].
One of the most promising strategies to reduce relapse involves in vivo purging with rituximab.
In contrast to in vitro purging methods aimed at removing contaminating tumor cells from the
hematopoietic stem cell harvest, the administration of rituximab in vivo depletes the peripheral
blood of all CD20+ cells preventing contamination of the graft by lymphoma cells [21].
Rituximab is a human/mouse monoclonal antibody recognizing CD20+, an antigen expressed on
all cells of B cell lineage including B cell NHL [22]. Rituximab eradicates B cells by
complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. It can
induce apoptosis in CD20+ cells and may be synergistic with chemotherapy. The B cells in the
peripheral blood of patients treated with rituximab are rapidly and effectively cleared for more
than three months [21]. This strategy has been effectively used in patients with both aggressive
and indolent lymphomas including untreated patients with follicular NHL and a low tumor
burden [24-26].
Rituximab has been successfully incorporated into the hematopoietic stem cell mobilization
regimen by several groups for the purpose of in vivo purging [27-32]. Rituximab purging has not
demonstrated any negative effects with regards to hematopoietic stem cell yield or function with
hematopoietic recovery being comparable following transplantation in purged versus unpurged
patients [27]. Most importantly, the clearance of bcl-2 positive cells in the graft has been
unequivocally documented in B cell NHL patients including grafts from follicular lymphoma
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patients. In a prospective study with 15 patients with mantle cell lymphoma or follicular
lymphoma, Magni et al administered 2 cycles of intensive chemotherapy with 2 doses of
rituximab [31]. Ninety-three percent of the patents who received rituximab had PCR-negative
harvests compared to only 40% of 10 control patients who had received the identical
chemotherapeutic regimen without rituximab. Four other studies that incorporated rituximab
into the mobilization regimen yielded PCR negative harvests ranging from 60%-100% of the
products that were known to be PCR+ prior to collection [28-30, 33]. However, it should be
noted that the largest sample size of these 5 studies consisted of only 13 patients. The optimal
timing and dosing of rituximab administration during mobilization still remains to be clearly
established but current reports have ranged from 1 to 4 doses. The effect of in vivo purging on
clinical outcome is still not clear but should become more evident as the data mature.
1.5. Relapse Prevention with Rituximab
While in vivo purging addresses the problem of tumor contamination in the hematopoietic stem
cell graft, the regrowth of persistent malignant cells in the recipient represents another obstacle
to prolonged survival. Post-transplant or maintenance chemotherapy with rituximab in the
follicular NHL setting is currently the subject of active investigation. Buckstein et al
administered rituximab maintenance therapy to 17 patients with follicular NHL who had also
received rituximab prior to the mobilization regimen. At a median of one year follow-up, all
assessable patients remained in CR and all 7 patients evaluable for molecular monitoring
remained bcl-2 negative at 6 months. In this same study, four of 12 patients who received alpha-
interferon instead of rituximab for maintenance relapsed at a median follow-up of 28 months
[34]. Horwitz et al administered four weekly infusions of rituximab to 28 patients with NHL
beginning 42 days after transplant with further infusions given at 6 months. All patients had
rapid depletion of B cells with no increase in infection or significant adverse events except for an
isolated neutropenia that occurred in 54% of patients. The neutropenic episodes did not result in
significant adverse events and all episodes resolved spontaneously within seven days or
responded to G-CSF administration. At a median follow-up of 30 months, the event-free
survival and OS was 83% and 88% respectively [35]. In other published reports, Magni et al and
Ladetto et al demonstrated the safety and feasibility of incorporating rituximab for the purposes
of in vivo purging and post-HSCT maintenance in patients with B-cell NHL including follicular
NHL [31, 33]. There are other ongoing studies evaluating rituximab maintenance therapy post-
HSCT including a large comprehensive EBMT study that is evaluating both in vivo purging and
maintenance with rituximab in a multi-center study with an accrual goal of 460 patients with
follicular NHL in 2nd or 3rd remission.
1.6. Allogeneic Hematopoietic Stem Cell Transplantation for Follicular Lymphoma
High dose chemoradiotherapy with allogeneic hematopoietic stem cell/bone marrow
transplantation has also been considered for patients with recurrent follicular NHL with the goal
of harnessing a graft-versus-lymphoma effect and to circumvent the tumor cell contamination
associated with autologous hematopoietic stem cell harvests [36-38]. Considerable evidence has
shown that an immune-mediated graft-versus-malignancy effect occurs after allogeneic HSCT
and that it contributes to the achievement of durable remissions in patients with hematologic
malignancies [39-41]. The most direct evidence of the graft-versus-malignancy effect is the re-
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induction of CR by withdrawal of immunosuppression and/or the infusion of donor lymphocytes
in patients who had relapsed after allogeneic HSCT [42, 43]. This treatment strategy has been
widely described among patients with acute and chronic myelogenous leukemia with several
responses seen in lymphoma and myeloma patients [44-46]. Von Besien et al described 4
patients with NHL who relapsed after allogeneic HSCT and then subsequently responded to
withdrawal of immunosuppression [47].
Although no randomized trials have been performed, several studies have reported a lower risk
of relapse compared to autologous HSCT. However, this benefit has been invariably offset by
the treatment-related mortality associated with allogeneic HSCT. In 1997, the Center for
International Blood and Marrow Transplant Research (CIBMTR) reported the results of 113
patients with follicular NHL who underwent allogeneic HSCT with HLA-matched siblings [37].
The three-year probability of DFS and OS was 49% with only a 16% incidence of relapse.
However, treatment-related mortality was 40% with pulmonary complications leading the causes
of non-relapse deaths. A recently updated analysis from the CIBMTR compared the outcomes of
904 patients with follicular NHL who underwent either myeloablative allogeneic HSCT (n=176),
purged autologous HSCT (n=131) or unpurged autologous HSCT (n=597). The risk for relapse
was 54% lower in the allogeneic recipients (p<.001) and 26% lower in recipients of purged
autotransplants (p=.04) than in recipients of unpurged autotransplants. However, in a
multivariate analysis, the risk of treatment-related mortality was 4.4 times higher after allogeneic
than after autologous transplantation (p<.001), which resulted in comparable 5-year probabilities
of overall survival(52% after allogeneic, 62% after purged autologous, 55% after unpurged
autologous)[48]. In a smaller retrospective study from the Netherlands, the results of 18 patients
who underwent autologous HSCT was compared to 10 patients who received an allogeneic
HSCT. The PFS rates after two years were 68% and 22% for the allogeneic and autologous
patients, respectively. Three of the allogeneic patients died from treatment-related mortality as
opposed to none of the autologous patients [36].
1.6.1. Non-myeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Non-myeloablative allogeneic HSCT incorporates a less intensive preparative regimen and relies
solely on the immunotherapeutic effects of the allograft to confer antileukemic activity rather
than the cytoreductive effects of high dose chemotherapy. The therapeutic benefit of allogeneic
HSCT is derived from donor immunocompetent T cells that mediate an important graft-versus-
malignancy effect. Initial attempts to administer an allogeneic hematopoietic stem cell graft
without a conditioning regimen resulted in high rates of graft failure [49]. Therefore, it became
apparent that some degree of immunosuppression is required to achieve engraftment and
sustained mixed chimerism. A mixed chimera patient has hematopoietic cells of donor and
recipient origins for varying lengths of time following allogeneic hematopoietic stem cell
transplantation as opposed to a complete chimeric patient where only cells of donor origin are
detectable. A mixed chimeric state may be adequate to be clinically efficacious in patients with
autoimmune diseases or inborn errors of metabolism. However, full donor chimerism or at least
a high level of donor hematopoiesis may be a prerequisite to eliminate malignant cells and effect
a cure [50, 51].
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Non-myeloablative allogeneic HSCT also induces less immune compromise in the patient as the
duration and depth of neutropenia is reduced and host-derived immunocompetent cells are not
immediately eliminated. Furthermore, the less intense regimen has been shown to allow for
faster recovery of a T cell repertoire that is more complex and robust compared to the T cell
repertoire of patients who received a myeloablative regimen [52, 53]. The transfusion
requirements of recipients of non-myeloablative allogeneic HSCT are also significantly reduced
compared to recipients of myeloablative allogeneic HSCT [54].
Some of the most promising data employing non-myeloablative allogeneic HSCT in follicular
NHL patients was recently reported by the M.D. Anderson Cancer Center [55]. Twenty patients
with indolent NHL received a conditioning regimen of fludarabine and cyclophosphamide +
rituximab. Tacrolimus and methotrexate were given for graft-versus-host disease (GVHD)
prophylaxis. The median age was 51 years old (range 31-68 years old) and all patients had
advanced recurrent disease or were previously treated. The median number of prior
chemotherapy regimens ranged from 1-5 (median, 2). All had received salvage chemotherapy
and had stable or responding disease. Twelve patients were in second or greater complete
remission at the time of transplantation. All patients achieved a CR after transplantation with no
recurrences at a median follow-up of 21 months. All patients achieved engraftment of donor
cells with the median percentage of donor cells at 1 month being 80% (range, 10%-100%). The
actuarial probability of being alive and in remission at 2 years was 84%. The incidence of grade
II-IV acute GVHD was 20% and the cumulative incidence of chronic GVHD was 64%. Only
one patient died from a treatment-related complication.
The EBMT recently described the use of reduced-intensity conditioning for 188 patients with
low-grade lymphoma including 52 patients with follicular and small lymphocytic NHL. The
median age of the low grade NHL patients was 46(range, 27-65). The median number of prior
chemotherapy regimens was 3 (range, 1-5) and 29% had previously received an autologous
HSCT. Forty-four (85%) demonstrated chemosensitive disease at the time of transplant. Most
patients received a fludarabine-based preparative regimen with 10% of patients receiving BEAM
(BCNU, etoposide, cytarabine, melphalan), a more intensive and ablative regimen. Of the low-
grade NHL patients, the 2 year PFS and OS was 54% and 65% respectively with a 21%
progression rate. Treatment-related mortality was 31%, which was considerably higher than the
previously mentioned M.D. Anderson study. The use of a more intensive conditioning regimen
most likely contributed to toxicity [56].
1.7. Study Approach and Treatment
Numerous studies have demonstrated that autologous HSCT has clearly improved the PFS for
patients with follicular lymphoma yet disease relapse remains a major obstacle to eventual cure
of the disease. This issue will be addressed by the addition of maintenance therapy with
rituximab after autologous HSCT while the patient is in a state of minimal residual disease. For
those patients with an HLA-matched sibling, initial results of non-myeloablative allogeneic
HSCT hold promise and will rely primarily on the graft-versus-malignancy effect to generate an
anti-tumor response with the incorporation of rituximab in the conditioning regimen to enhance
tumor control early and allow time for the graft-versus-malignancy effect to establish. Adequate
immunosuppression will be required to prevent both graft rejection and GVHD. In this study
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these two treatment strategies will be compared in an effort to identify an optimal approach to
the treatment of follicular NHL.
Patients with either follicular small cleaved or follicular mixed NHL who have received ≤ 3 prior
regimens and who have demonstrated chemosensitive disease will receive initial cytoreductive
therapy with cyclophosphamide and rituximab with G-CSF support. Patients will be biologically
assigned to a treatment arm. Patients with an HLA-matched sibling will receive a non-
myeloablative allogeneic HSCT using a conditioning regimen of fludarabine, rituximab and
cyclophosphamide and an immunosuppressive regimen combined with tacrolimus and
methotrexate for achieving donor engraftment and prevention of GVHD. Patients without an
available HLA-matched sibling will undergo an autologous HSCT. The preparative regimen will
consist of either total body irradiation or BCNU. VP-16 and cyclophosphamide will be given for
both autologous preparative regimens. Rituximab will be administered to autologous patients
post-HSCT to eradicate minimal residual disease. Quantitative PCR monitoring for the bcl-2
fusion transcript will be performed at baseline, after blood count recovery from mobilization
therapy, and on Days +28, +84, +180 and yearly until three years post-HSCT if positive at any
time since diagnosis until the initial study evaluation. The primary objective will be to compare
3-year progression-free survival between the two groups.
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CHAPTER 2
2.
STUDY DESIGN
2.1. Study Overview
The overall study design is that of biologic assignment based on the availability of an HLA-
matched sibling, to one of two strategies to improve the outcome for follicular lymphoma
patients with chemosensitive disease. All patients will undergo cytoreduction with
cyclophosphamide 4 gm/m2 and rituximab 375 mg/m2 x 2 doses. Rituximab will be given in two
doses, approximately 1 week apart, with the cyclophosphamide administered the day after the
first dose of rituximab. Patients assigned to the autologous arm will have their hematopoietic
stem cells mobilized from this cytoreductive regimen. Patients with an HLA-matched sibling
will undergo a non-myeloablative allogeneic HSCT. Pre-transplant conditioning will consist of
fludarabine 30 mg/m2/day and cyclophosphamide 750 mg/m2/day x 3 days with rituximab 375
mg/m2/day on Days -13 and -6 pre-HSCT and on Days +1 and +8 post-HSCT. The
immunosuppressive regimen will consist of tacrolimus and methotrexate (MTX) to control graft-
versus-host and host-versus-graft reactions. Patients without an HLA-matched sibling who have
collected an adequate autologous hematopoietic cell graft, defined as ≥ 2.0 x 106 CD34+ cells/kg,
will receive a preparative regimen of total body irradiation (TBI) 1200 cGy or BCNU 15 mg/kg.
In addition, VP-16 60 mg/kg and cyclophosphamide 100 mg/kg will be given for both
autologous preparative regimens. Post-autologous HSCT therapy with rituximab 375 mg/m2
weekly x 4 doses will commence between Days 42-75 post-HSCT.
A secondary analysis comparing the outcome of autologous HSCT patients will be made against
contemporary/historical controls who underwent autologous HSCT but did not receive rituximab
maintenance chemotherapy. These patients will be identified from the CIBMTR database.
2.2. Hypothesis and Specific Objectives
2.2.1. Hypothesis
Non-myeloablative allogeneic hematopoietic stem cell transplantation will reduce the rate of
disease progression compared to autologous hematopoietic stem cell transplantation. For
patients with a matched sibling donor, an allogeneic strategy may prove superior to an
autografting strategy since the immunotherapeutic effects of an allograft is a potentially powerful
therapy in eradicating minimal residual disease and conferring a lasting anti-tumor effect.
The addition of maintenance rituximab post-autologous HSCT will improve the PFS of patients
compared to contemporary/historical controls undergoing autologous HSCT without
maintenance rituximab.
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2.2.2. Study Objectives
The primary objective is to compare 3-year progression-free survival between the two transplant
arms. Secondary objectives will compare 3-year survival, time to progression, time to CR and
PR, time to off-study therapy, incidence of infection and incidence of Common Terminology
Criteria for Adverse Events (CTCAE) Version 3.0 Grade ≥ 3 toxicities. The efficacy of
cyclophosphamide plus rituximab in vivo purging will also be evaluated as well as the prediction
of relapse by measurement of t(14;18) by quantitative PCR. Other secondary outcomes in the
allogeneic transplant arm include the incidence and severity of acute and chronic GVHD and
primary and secondary graft failure. Health-related quality of life for English and Spanish
speaking patients of both groups will be described and exploratory comparisons will be made
between the two groups. The relative safety of the two arms will be assessed through the
collection of toxicity data, routine laboratory monitoring and adverse event monitoring.
2.3. Patient Eligibility
Patients must meet specified eligibility criteria to enroll on the study. Additional criteria must
also be met to continue to successive stages of the protocol. All questions regarding eligibility
criteria should be directed to the Protocol Coordinator at 301-251-1161.
2.3.1. Initial Patient Inclusion Criteria
Patients fulfilling the following criteria will be eligible for entry into this study:
1. Patients with histologically confirmed recurrent REAL classification follicle center
lymphoma, follicular grades I and II, OR patients with histologically confirmed WHO
classification follicular lymphoma grades 1, 2, 3a or 3b. For either classification, the
diffuse component or presence of large cleaved cells (if present) cannot be > 50% of high
power field. Patients do not have to express t(14;18) to be eligible.
2. Patients who are ≤ 75 years old at time of first registration.
3. Patients who have received ≤ 3 prior regimens of chemotherapy. Monoclonal antibody
therapy and involved field radiation therapy will not be counted as a prior therapy.
4. Patients who are beyond 1st CR or 1st PR AND who demonstrate chemosensitive disease
are eligible for the study. Chemosensitive disease will be defined as < 20% bone marrow
involvement in the aspirate or core biopsy with follicular lymphoma AND lymph node
size in axial diameter of < 3 cm or a > 50% reduction in estimated lymph node volume to
be measured as product of bi-dimensional measurements. PET scanning will not be used
for staging or response purposes.
5. Patients with adequate organ function as measured by:
a) Cardiac: left ventricular ejection fraction at rest ≥ 45%
b) Hepatic: bilirubin < 2x the upper limit of normal and ALT and AST < 3x the
upper limit of normal
c) Renal: creatinine clearance > 40 mL/min
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d) Pulmonary: DLCO, FEV1, FVC ≥ 50% of predicted (corrected for hemoglobin)
6. If the patient is < 18 years of age and they have reached the age of assent, then they must
have completed the local IRB assent process.
7. Patients who have signed the informed consent.
8. Patients must be able to receive cyclophosphamide and rituximab mobilization
chemotherapy no earlier than 3 weeks from the beginning of the most recent cycle of
salvage chemotherapy and no later than 6 weeks from enrollment.
2.3.2. Initial Patient Exclusion Criteria
Patients with the following will be ineligible for registration onto this study:
1. Karnofsky performance score < 70%.
2. Patients with follicular lymphoma that show histologic evidence of transformation.
3. Patients with uncontrolled hypertension.
4. Patients with uncontrolled bacterial, viral or fungal infection (currently taking medication
and progression without clinical improvement).
5. Patients with prior malignancies except resected basal cell carcinoma or treated cervical
carcinoma in situ. Cancer treated with curative intent > 5 years previous will be reviewed
on a case-by-case basis by a Protocol Chair or Medical Monitor.
6. Female patients who are pregnant (positive β-HCG) or breastfeeding.
7. Patients seropositive for HIV.
8. Fertile men or women unwilling to use contraceptive techniques during treatment.
9. Prior autologous or allogeneic HSCT.
10. Known anaphylactic reaction to rituximab.
2.4. Patient Eligibility Criteria for Proceeding to HSCT
In order to continue on protocol and receive either an autologous or non-myeloablative HSCT,
the following conditions must be achieved:
1. Collection of an autologous or allogeneic graft of ≥ 2.0 x 106 CD34+ cells/kg
2. Blood count recovery defined as ANC > 1000/mm3 and platelets > 100 x 109/L
Patients must be able to proceed to either non-myeloablative allogeneic or autologous HSCT
within six weeks of peripheral blood count recovery following the cytoreductive/mobilization
regimen outlined in Section 2.7.3. Autologous patients will undergo leukapheresis upon blood
count recovery.
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If peripheral blood counts have not recovered within a standard time frame, the patient’s
treatment plan should be discussed with a Protocol Chair or Medical Monitor. A decision
regarding the patient’s future treatment will be made on a case-by-case basis.
2.5. Patient Eligibility Criteria for Maintenance Therapy for Recipients of Autologous
HSCT
In order to be eligible to continue on protocol and receive maintenance therapy with rituximab,
patients must have recovered sufficiently from their autologous transplant. Rituximab will be
given to patients between Day 42 and Day 75 post-HSCT.
Recovery from autografting will be defined as achievement of the following clinical criteria:
1. Liver and renal function tests within the inclusion criteria for initial autograft.
2. Off intravenous antibiotics and off amphotericin B formulations for proven, probable or
possible fungal infections.
3. No active CMV infections or for patients with CMV infection post-autograft, treated with
ganciclovir, valganciclovir or foscarnet per institutional guidelines and CMV antigenemia
negative.
4. Mucositis resolved and off hyperalimentation.
2.6. Allogeneic Hematopoietic Stem Cell Donor Criteria
2.6.1. Donor Inclusion Criteria
1. The donor must be a 6/6 HLA phenotypically matched sibling to the patient. The
minimum level of typing is HLA –A, -B by serologic methodology and HLA DRB1 by
DNA methodology.
2. If the donor is < 18 years of age and they have reached the age of assent, then they must
have completed the local IRB assent process.
3. Donor must consent to G-CSF administration and to leukapheresis for HSC collection.
4. Donor must have adequate veins for leukapheresis or agree to placement of central venous
catheter (femoral, subclavian).
5. Age ≤ 75 years at the time patient is initially registered on study.
2.6.2. Donor Exclusion Criteria
1. Identical twin of patient.
2. Female patients who are pregnant (positive β-HCG) or breastfeeding.
3. Infection with HIV, viral hepatitis (B or C).
4. Known allergy to G-CSF.
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5. Current serious systemic illness.
6. Uncontrolled bacterial, viral or fungal infection (currently taking medication and
progression of clinical symptoms).
7. Donors receiving experimental therapy or investigational agents.
8. Donors with cancer other than treated basal cell or carcinoma in situ of cervix. Cancer
treated with curative intent > 5 years previous will be reviewed on a case-by-case basis by
a Protocol Chair or Medical Monitor.
2.7. Study Treatments
The immediate pre-HSCT evaluation will be carried out according to the operating procedures of
the participating institutions and should be in keeping with the data reporting requirements of
this study. Similarly, special orders and procedures will be those defined by the BMT CTN
Manual of Procedures (MOP). All patients enrolled on this protocol will be hospitalized in
accordance with the procedures for recipients of autologous and non-myeloablative allogeneic
HSCT as defined by the treating institutions. All questions regarding study treatments should be
directed to the Protocol Coordinator at 301-251-1161.
2.7.1. HLA-Typing of Potential Sibling Donors
All potential sibling donors must be HLA-typed. HLA-matched siblings must be evaluated for
suitability for donation until either an HLA-matched sibling donor is identified or all HLA-
matched siblings are excluded as donors. This testing and evaluation must be completed by the
time of study enrollment.
2.7.2. Body Weight Formulas
All chemotherapy, rituximab and tacrolimus (or cyclosporine, if applicable) should be dosed
based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. For patients
who weigh less than 100% of their IBW, dosing should be based on actual body weight (ABW).
For patients who weigh more than 120% of their IBW, dosing should be based on the adjusted
ideal body weight (AIBW).
1. Ideal Body Weight (IBW) Formulas:
Males IBW = 50 kg + 2.3 kg/inch over 5 feet
Females IBW = 45.5 + 2.3 kg/inch over 5 feet
For patients less than 5 feel, subtract 2.3 kg/inch
2. Adjusted Ideal Body Weight (AIBW) Formula:
AIBW = IBW + [(0.25) x (ABW – IBW)]
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2.7.3. Cytoreductive Therapy/Mobilization Chemotherapy
2.7.3.1.
Allopurinol
Patients may receive allopurinol 300 mg/day PO for 10 days starting one day prior to receiving
the cyclophosphamide according to local institutional practice. (Dose adjusted according to
renal function per standard recommendations.)
2.7.3.2.
Cyclophosphamide and rituximab administration/mobilization
Prior to undergoing autologous or non-myeloablative allogeneic HSCT, all patients will receive
cyclophosphamide 4 gm/m2 with rituximab 375 mg/m2 x 2 doses with G-CSF support. See
Table 2.7.3.2 for the treatment schedule. This regimen shall begin no earlier than 3 weeks
from the beginning of the most recent cycle of salvage chemotherapy and no later than 6
weeks post-enrollment. Rituximab may be administered in the office/hospital of the referring
hematologist/oncologist. Cyclophosphamide must be administered at the transplant center.
Table 2.7.3.2: Cytoreductive/Mobilization Treatment Schedule
Day
1
2
3
4
5
6
7
8
Cyclophosphamide 4 g/m2
X
Rituximab 375 mg/m2
X
X
G-CSF 10 mcg/kg or 5 mcg/kg *
X---------------------------
1. Cyclophosphamide: 4 g/m2 IV x 1 dose to be administered over 2 hours on Day 2 of the
schedule. Hydration, if used per institutional guidelines, is to be started pre-
cyclophosphamide and continued until 24 hours after the completion of the
cyclophosphamide infusion. Alternatively, mesna may be used in doses per institutional
guidelines (recommended usage is at least 20% of the cyclophosphamide dose prior to each
dose of cyclophosphamide and repeated 4 hours and 8 hours after each cyclophosphamide
dose).
Cyclophosphamide should be dosed based on ideal body weight (IBW) for patients who
weigh 100-120% of their IBW. For patients who weigh less than 100% of their IBW,
dosing should be based on actual body weight (ABW). For patients who weigh more than
120% of their IBW, dosing should be based on the adjusted ideal body weight (AIBW).
See Section 2.7.2 for body weight formulas.
2. Rituximab: 375 mg/m2 IV x 2 doses total, with the first dose to be administered on Day 1
and the second dose administered on Day 8. Mix rituximab in either 0.9% NS or D5W
according to institutional practice. Rituximab must be infused through an infusion pump
and should not be mixed or diluted with any other solutions or drugs. Doses may be
rounded to nearest vial size (e.g. if dose is ≤ 750 mg, then round to 700 mg; if > 750 mg,
then round to 800 mg). Dosing is based on the body weight formulas in Section 2.7.2.
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Premedication should be administered prior to rituximab per institutional guidelines
(recommended: diphenhydramine 50 mg PO, 30 minutes prior to treatment and
acetaminophen 650 mg PO, 30 minutes prior to treatment).
3. G-CSF*: 10 mcg/kg for the autologous patients administered at once, or fractionated to 5
mcg/kg SQ BID, or 5 mcg/kg for the allogeneic patients SQ or IV to start daily on Day 4 (2
days after cyclophosphamide administration). G-CSF dosing can be rounded based on
patient’s actual body weight (see Section 2.7.2 for body weight formulas) and available G-
CSF vial sizes to best approximate of 10 mcg/kg or 5 mcg/kg (e.g. < 70 kg use 300 mcg
vial, 70 to 90 kg use 480 mcg vial and > 90 kg use 2 x 300 mcg vials).
For the autologous HSCT patients, autologous hematopoietic stem cells will be
collected after the cyclophosphamide + rituximab + G-CSF regimen. G-CSF will
continue until leukapheresis is complete. Leukapheresis will commence per institutional
guidelines and will continue until the target of ≥ 2.0 x 106 CD34+ cells/kg are collected.
Cells will be cryopreserved per institutional guidelines. Patients who collect ≥ 1.0 x 106
CD34+ cell/kg but < 2.0 x 106 CD34+ cells/kg will proceed to high dose chemotherapy.
Patients with < 1.0 x 106 CD34+ cells/kg after three collections will continue to be followed
for relapse, progression and survival. Patients may proceed to transplant off-study at the
discretion of their attending physician and subsequent management of these patients is at
the discretion of their attending physician.
For autologous HSCT patients, G-CSF will continue until leukapheresis is complete. For
the non-myeloablative allogeneic HSCT patients, G-CSF will continue until ANC
> 500/mm3 x 3 days.
2.7.4. High Dose Chemotherapy with Autologous HSCT
Patients without an available HLA-matched sibling will proceed to autologous HSCT. Patients
must proceed to HSCT within six weeks of peripheral blood count recovery following the
cytoreductive regimen outlined in Section 2.7.3. Blood count recovery will be defined as ANC >
1000/mm3 and platelets > 100 x 109/L. Two conditioning regimens are available: a
chemotherapy only regimen or a TBI-based regimen. See Tables 2.7.3.2 and 2.7.4.1,
respectively.
At the commencement of this trial, institutions must specify if they will be uniformly using
the TBI-based or chemotherapy-based regimen. If for some reason in a center that has
specified that the TBI regimen will be used (i.e. previous involved field radiation therapy
precludes patient from TBI), a patient cannot receive TBI, the chemotherapy-based regimen
specified below must be utilized and this must be noted at the time of patient registration.
Patients who are 60 years and older will be assigned to receive the chemotherapy-based
conditioning regimen.
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2.7.4.1.
Conditioning regimen - chemotherapy-based regimen
Table 2.7.4.1: Autologous HSCT - Chemotherapy-Based Regimen
Day
-6
-5
-4
-3
-2
-1
0
+5
BCNU
15 mg/kg
VP-16
60 mg/kg
Cyclophosphamide
100 mg/kg
PBSCT
G-CSF
5 mcg/kg
1. BCNU: 15 mg/kg based on the body weight formulas in Section 2.7.2 (maximum dose not
to exceed 550 mg/m2 based on actual body weight) IV x 1 dose to be administered over 2
hours on Day -6 pre-HSCT.
2. VP-16: 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4. VP-16 dosing
should be based on ideal body weight (IBW) for patients who weigh 100-120% of their
IBW. For patients who weigh less than 100% of their IBW, dosing should be based on
actual body weight (ABW). For patients who weigh more than 120% of their IBW, dosing
should be based on the adjusted ideal body weight (AIBW). See Section 2.7.2 for body
weight formulas. The concentrated etoposide solution (20 mg/mL) is to be drawn up into
syringes and administered via a syringe pump or transferred to an empty non-DEPH bag
for infusion. Administer the etoposide dose via a Y-site connection or an adjacent lumen
running concomitantly with normal saline at 200 mL/hr.
3. Cyclophosphamide: 100 mg/kg IV x 1 dose to be administered over 2 hours on Day -2
pre-HSCT.
Cyclophosphamide should be dosed based on ideal body weight (IBW) for patients who
weigh 100-120% of their IBW. For patients who weigh less than 100% of their IBW,
dosing should be based on actual body weight (ABW). For patients who weigh more than
120% of their IBW, dosing should be based on the adjusted ideal body weight (AIBW).
See Section 2.7.2 for body weight formulas.
4. G-CSF: 5 mcg/kg SQ or IV to start on Day +5 post-HSCT and continue until ANC
> 500/mm3 x 3 days. G-CSF dosing should be based on actual body weight – see Section
2.7.2 for body weight formulas. G-CSF dosing can be rounded based on patient weight and
available G-CSF vial sizes to best approximate 5 mcg/kg (e.g., < 70 kg use 300 mcg vial,
70 to 90 kg use 480 mcg vial and > 90 kg use 2 x 300 mcg vials).
2.7.4.2.
Conditioning regimen - total body irradiation-based regimen
Table 2.7.4.2: Autologous HSCT - TBI-Based Regimen
Day
-8
-7
-6
-5
-4
-3
-2
-1
0
+5
FTBI
FTBI
FTBI
FTBI
VP-16
60
mg/kg
Cyclophosphamide
100 mg/kg
PBSCT
G-CSF
5 mcg/kg
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1. Fractionated Total Body Irradiation: TBI may be administered according to either one
of the following two schedules:
A) Hyperfractionated TBI: TBI is administered at a dose rate of < 20 cGy/minute. Doses
of 120 cGy/fraction are administered at no less than 4-hour intervals three times/day or
2 times/day for a total of 10 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5). The
exact number of treatments per day (one to three) can vary according to institutional
practice but should include a total of 10 treatments over 4 days. Sequential doses are
administered anteriorposterior with standard (5 half value) lung blocks shielding the
lung parenchyma for the final 600 cGy. At the time of the last two TBI fractions, the
blocked areas of anterior and posterior chest walls will be boosted with electrons to a
cumulative chest wall dose of approximately 1200 cGy (300 cGy/fraction x 2 anteriorly
and posteriorly). Alternatively, the TBI treatments may be administered with 50%
transmission lung blocks anteriorly and posteriorly throughout, with the electron chest
wall boosts to 1200 cGy (300 cGy x 2, anteriorly and posteriorly) administered during
the course of the 10 TBI treatments. The energy of the electron beam will be chosen to
deliver 90% of the dose to the chest wall. The dose will be calculated at the central axis
in the midplane. Appropriate dosimetry will be confirmed prior to or during the 1st TBI
treatment and compensators will be allowed to keep the dose inhomogeneity at ≤ 10%.
Corrections for lung inhomogeneity are not required.
B) Fractionated TBI: This regimen calls for doses of 150 cGy/fraction administered at the
same dose rate (< 20 cGy/min) twice daily for a total of 8 doses (1200 cGy) over 4 days
(Day -8, -7, -6 and -5). Doses are separated by a minimum of 5 hours. The dose to the
lungs will reduced to 50% by partial transmission lung blocks used during all TBI
treatments or full thickness (5 HVL) lung blocks during 5 TBI treatments. The chest
wall should then be boosted to a cumulative total dose of 1200 cGy with electrons (300
cGy/fraction x 2 anteriorly and posteriorly). The dose will be calculated at the central
axis in the midplane. Appropriate dosimetry will be confirmed prior to or during the 1st
TBI treatment and compensators will be allowed to keep the dose inhomogeneity at
≤ 10%. Corrections for lung inhomogeneity are not required.
2. VP-16: 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4 pre-HSCT. VP-
16 dosing should be based on the body weight formulas in Section 2.7.2. Infuse through an
IV of normal saline at 250 cc/hr (see previous regimen comment).
3. Cyclophosphamide: 100 mg/kg IV x 1 dose to be administered over 2 hours on Day -2
pre-HSCT.
Cyclophosphamide should be dosed based on ideal body weight (IBW) for patients who
weigh 100-120% of their IBW. For patients who weigh less than 100% of their IBW,
dosing should be based on actual body weight (ABW). For patients who weigh more than
120% of their IBW, dosing should be based on the adjusted ideal body weight (AIBW).
See Section 2.7.2 for body weight formulas.
4. G-CSF: 5 mcg/kg SQ or IV to start on Day +5 post-HSCT and continue until
ANC > 500/mm3 x 3 days. G-CSF dosing can be rounded based on patient’s actual weight
and available G-CSF vial sizes to best approximate 5 mcg/kg (e.g., < 70 kg use 300 µg vial,
70 to 90 kg use 480 µg vial and > 90 kg use 2 x 300 µg vials).
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2.7.4.3.
Rituximab maintenance therapy
Patients must have sufficiently recovered from autologous HSCT as defined in Section 2.5 in
order to receive rituximab maintenance therapy as specified below:
Dose #1: Day +42 post-autologous HSCT
Dose #2: Day +49 post-autologous HSCT
Dose #3: Day +56 post-autologous HSCT
Dose #4: Day +63 post-autologous HSCT
Rituximab should be given on or around Day +42 post-autologous HSCT but can be given up to
Day +75 post-autologous HSCT if patients are not fully recovered by Day +42 post-autologous
HSCT. If the patient has not fully recovered at Day +75 post-HSCT, a Protocol Chair or
Medical Monitor should be contacted regarding future treatment plans. Rituximab will be
administered weekly in doses of 375 mg/m2 IV x 4. Mix rituximab in either 0.9% NS or D5W
according to institutional practice. Rituximab must be infused through an infusion pump and
should not be mixed or diluted with any other solutions or drugs. Premedication should be
administered prior to rituximab per institutional guidelines (recommended: diphenhydramine 50
mg PO, 30 minutes prior to treatment and acetaminophen 650 mg PO, 30 minutes prior to
treatment).
2.7.5. Non-myeloablative Allogeneic Stem Cell Transplantation for Patients with an HLA-
matched Sibling
Within 6 weeks of peripheral blood count recovery following the cytoreductive regimen outlined
in Section 2.7.3, patients with an available 6/6 HLA-matched sibling will proceed to a non-
myeloablative allogeneic HSCT. Blood count recovery will be defined as ANC > 1000/mm3 and
platelets > 100 x 109/L.
Pre-HSCT conditioning and hematopoietic stem cell infusion may be administered on an
outpatient basis. Patients must comply with all scheduled study visits whether receiving their
transplant as in inpatient or an outpatient.
Table 2.7.5: Non-myeloablative Allogeneic HSCT Schedule*
Day
-13
-6
-5
-4
-3
-2
-1
0
1
8
Fludarabine 30 mg/m2
X
X
X
Cyclophosphamide
750 mg/m2
X
X
X
Rituximab 375 mg/m2
X
X
X
X
PBSCT
X
* See Section 2.7.2 for body weight formulas.
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2.7.5.1.
Conditioning regimen
1. Fludarabine: 30 mg/m2 IV x 3 doses total to be administered daily over 30 minutes on
Days -6, -5 and -4 pre-HSCT. Dosing is based on the body weight formulas in Section
2.7.2.
2. Cyclophosphamide: 750 mg/m IV x 3 doses total to be administered daily over 1 hour on
Days -6, -5 and -4 pre-HSCT. Administer cyclophosphamide approximately 4 hours after
start of fludarabine infusion. Dosing is based on the body weight formulas in Section 2.7.2.
3. Rituximab: 375 mg/m2 IV x 4 doses total to be administered on Days -13 and -6 pre-
HSCT and Days +1 and +8 post-HSCT. Mix rituximab in either 0.9% NS or D5W
according to institutional practice. Dosing is based on the body weight formulas in Section
2.7.2. Rituximab must be infused through an infusion pump and should not be mixed or
diluted with any other solutions or drugs.
2.7.5.2.
Graft-versus-host disease (GVHD) prophylaxis
Table 2.7.5.2: GVHD Prophylaxis Schedule
DAY
-2
-1
0
1
2
3
4
5
6
Tacrolimus 0.09 mg/kg PO
or 0.03 mg/kg IV
X
Daily until Day +90, then start taper
Methotrexate 5 mg/m2 IV
X
X
X
1. Tacrolimus: 0.09 mg/kg/day PO, based on body weight formulas in Section 2.7.2, will
start on Day -2 and continue until Day +90 post-HSCT. Tacrolimus (or cyclosporine, if
applicable) will be given orally in a twice-daily divided dose. Tacrolimus dosing should be
based on actual body weight – see Section 2.7.2 for body weight formulas. Doses should
be adjusted to maintain whole blood “trough” levels at 5-15 ng/mL. Tapering of tacrolimus
doses should commence starting at Day +90 post-HSCT to be completely discontinued by
Day +180 post-HSCT unless GVHD Grade III develops. An equivalent dose of IV
tacrolimus may be used as per local institutional preference. Patients with severe
intolerance to tacrolimus may be placed on cyclosporine.
Patients with severe intolerance to tacrolimus may be placed on cyclosporine at a starting
dose of 5 mg/kg bid PO based on actual body weight. An equivalent dose of IV
cyclosporine may be used as per institutional practice. Doses should be adjusted to
maintain whole blood “trough” levels that target 500 ng/mL (upper end of therapeutic
range) during the first month. Dose reductions should only be made if CSA toxicity is
present or whole blood levels exceed 600 ng/mL in the absence of toxicity. Further CSA
determinations should be performed weekly until CSA is stopped unless high levels are
detected (i.e., > 600 ng/mL), or toxicity is suspected, in which case more frequent
monitoring will be performed as clinically indicated. Dose reductions for high levels
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without
toxicity
should
be
conservative
(e.g.,
25%)
to
avoid
inadequate
immunosuppression.
After Day 28, the CSA level is to be kept within 200-400 ng/mL, according to local
institutional practice until the Day +90 taper is initiated.
2. Methotrexate: 5 mg/m2 IVP will be administered on Days +1, +3 and +6 post-HSCT. In
the event of renal/hepatic impairment, dose changes should be made according to the
following guidelines:
Bilirubin mg/dL
% Dose
Creatinine mg/dL
% Dose
< 2.0
100
< 1.5
100
2.1 – 3.0
50
1.5 – 1.7
75
3.1 – 5.0
25
1.8 – 2.0
50
> 50
hold dose
> 2.0
hold dose
2.7.6. Collection and Infusion of Allogeneic HSC
2.7.6.1.
G-CSF administration to donors
All donors will receive G-CSF 16 mcg/kg/day for 5 consecutive days from Day -4 pre-HSCT to
Day 0. G-CSF dosing should be based on actual body weight – see Section 2.7.2 for body
weight formulas. G-CSF will be administered by daily subcutaneous injections. If necessary,
based on volume, the G-CSF can be given in multiple injection sites. These doses will be
administered before 10:00 AM each day. G-CSF dosing can be rounded based on donor weight
and available G-CSF vial sizes to best approximate 16 mcg/kg.
2.7.6.2.
HSC collection and evaluation
Donors will preferably undergo vein-to-vein collections but may receive an appropriate central
venous catheter inserted on or before the day of apheresis. HSCs will be collected on Day -1
pre-HSCT and stored in the refrigerator at 2-8°C overnight. If necessary, a second collection
will be performed the following day and both collections will be infused. Each collection will be
separately evaluated in the laboratory for cellular composition in keeping with the BMT CTN
MOP for graft characterization.
A minimum dose of 2.0 x 106 CD34+ cells/kg will be collected (according to institutional
practices) and given. If ≥ 5.0 x 106 CD34+ cells/kg are collected on Day -1, a second collection
will not be necessary. If < 2.0 x 106 CD34+ cells/kg are collected after 2 aphereses, a 3rd
collection must be performed on Day +1. All cells collected should be infused.
Cryopreservation of donor hematopoietic stem cells may be acceptable, but this must be
discussed in advance with a Protocol Chair or Medical Monitor.
If < 1.0 x 106 CD34+ cells/kg are collected from the donor after three collections, patients may
proceed to transplant off-study at the discretion of their attending physician and subsequent
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management of these patients is at the discretion of their attending physician. However, such
patients will continue to be followed for relapse, progression and survival.
Table 2.7.6.2: Treatment Schedule for Donor
Days
-4
-3
-2
-1
0
1
G-CSF 16 mcg/kg
X
X
X
X
X
HSC Collection
X
X*
X**
HSC Administration
X
X**
* The 2nd HSC collection can be cancelled only if ≥ 5.0 x 106 CD34+ cells/kg are
collected with the 1st apheresis. G-CSF administration is not required on Day
0 if the second collection is cancelled.
** A 3rd collection is required if < 2.0 x 106 CD34+ cells/kg are collected with the
2 previous aphereses.
2.7.6.3.
Allogeneic hematopoietic stem cell infusion
All patients will receive unmodified (other than volume reduction) G-CSF mobilized
hematopoietic stem cells from an HLA-matched sibling on Day 0 of the treatment regimen. The
hematopoietic stem cells will be infused via a central venous catheter using standard blood
infusion tubing.
2.8. Supportive Care
2.8.1. Post-autologous HSCT
All supportive care will be given in keeping with BMT CTN MOP or local institutional
guidelines.
2.8.1.1.
Prophylaxis against infections
All patients will receive prophylaxis against bacterial, fungal and viral infections during the post-
HSCT period according to the BMT CTN MOP or local institutional guidelines. Additional
specifications/requirements for this study are summarized below. Infectious prophylaxis will
include prophylaxis for:
1. Anti-bacterial: In keeping with the BMT CTN MOP or local institutional standards.
2. Pneumocystis carinii: Prophylaxis will start at the time of engraftment or on Day +30
post-autologous transplant according to institutional preference. Prophylaxis should be
continued until at least 6 months following the autologous HSCT.
3. Anti-fungal Therapy: Anti-fungal prophylaxis will be per local institutional practice and
must be uniformly applied to all patients within each respective center.
4. HSV/VZV: Antiviral prophylaxis will be per local institutional practice and must be
uniformly applied to all patients within each respective center.
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5. IVIG: Replacement to be initiated according to institutional practice if IgG levels fall
below 500 mg/dL.
2.8.1.2.
Blood products
Transfusion thresholds for blood product support will be in keeping with BMT CTN MOP and
standard institutional guidelines. All blood products will be irradiated.
2.8.1.3.
Post-HSCT immunization schedule
Immunization may be given in keeping with the BMT CTN MOP (or local institutional practice).
2.8.2. Post Non-myeloablative Allogeneic HSCT
All supportive care will be given in keeping with BMT CTN MOP and local institutional
guidelines.
2.8.2.1.
Prophylaxis against infections
All patients will receive prophylaxis against bacterial, fungal and viral infections during the post-
HSCT period according to the BMT CTN MOP. Additional specifications/requirements for this
study are summarized below.
Infectious prophylaxis will include prophylaxis for:
1. Anti-bacterial: In keeping with the BMT CTN MOP and local institutional standards.
2. Pneumocystis carinii: Prophylaxis will start at the time of engraftment or on Day +30 post
non-myeloablative allogeneic HSCT transplant according to institutional preference.
Prophylaxis should be continued for at least 1 month after the patient is off all
immunosuppressive medications.
3. Anti-fungal Therapy: Anti-fungal prophylaxis will be per local institutional practice and
must be uniformly applied to all patients within each respective center.
4. HSV/VZV: Antiviral prophylaxis will be per local institutional practice and must be
uniformly applied to all patients within each respective center.
5. CMV: Monitoring and preemptive treatment strategy will be in accordance with the BMT
CTN Technical Committee (Infectious Diseases) MOP and local institutional practice.
The duration of monitoring is recommended for at least 100 days post non-myeloblative
allogeneic HSCT and longer if the patient is on immunosuppressive medications.
6. IVIG: Replacement to be initiated according to institutional practice if IgG levels fall
below 500 mg/dL. IgG levels to be drawn at 12 weeks, 6 months and 1 year post-HSCT
(see Table 4.2.1 or 4.2.4.8b).
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2.8.2.2.
Blood products
Transfusion thresholds for blood product support will be in keeping with BMT CTN MOP and
standard institutional guidelines. All blood products will be irradiated. Allogeneic transplant
candidates who are CMV negative will receive CMV negative or filtered blood products from
study entry.
2.8.2.3.
Post-HSCT growth factors
If neutropenia occurs (ANC < 500/mm3) post-HSCT, the decision to use hematopoietic growth
factors will be guided by the institutional practice of the transplant center.
2.8.2.4.
Post-HSCT immunization schedule
Once a patient is off all immunosuppressive therapy or has evidence of T cell function
(approximately one year post-HSCT), immunizations may be given in keeping with the BMT
CTN MOP and local institutional practice.
2.8.2.5.
Post-HSCT donor cellular infusions (DCI)
At the discretion of the investigator, DCI may be given to patients for tumor progression.
Patients receiving DCI will be considered a failure for the primary study endpoint. DCI will not
be given (on protocol) for low donor or dropping donor chimerism.
2.9. PCR Monitoring for t(14;18)
Quantitative PCR analysis for t(14;18) from peripheral blood will be performed on all patients at
the time of registration. Samples will be collected and quantitative PCR will be performed by a
centralized lab according to the following schedule. If patient was known to be t(14;18) negative
prior to registration this test still must be performed once at the time of registration for
documentation purposes. Patient’s may have had a t(14:18) analysis that was positive prior to
study entry (e.g. at diagnosis). Referring centers should be queried regarding prior patient
testing for t(14:18). Patients with any positive test for t(14:18) since the time of diagnosis must
have the subsequent t(14:18) PCR assessment samples collected. See Section 4.2 and Appendix
C for schedule of samples and details on collection, processing, storage and shipment.
2.10. Participant Risks
Recipients of HSCTs incur risks from pre-HSCT conditioning and post-HSCT therapy, which
must be weighed against the risk of the disease for which the HSCT is prescribed. Major risks
following transplantation include: 1) Infection which can be bacterial, viral, parasitic, or fungal.
Often, these infections are life-threatening, particularly when caused by viral or fungal agents,
and are associated with high mortality in the transplant population; 2) GVHD, either acute or
chronic in nature, may occur following allogeneic transplantation. The degree of GVHD varies
from mild cutaneous reactions to extensive widespread and systemic involvement of skin, liver,
and gastrointestinal tract. Probably due to a direct association, the incidence of fatal infection is
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greater in patients developing GVHD; 3) Graft Failure can occur and is associated with a high
risk of mortality; 4) End Organ Damage of all or any of the major organs may occur as a result of
reactions to drugs (e.g., chemotherapy, antibiotics, anti-fungal medications, tacrolimus,
cyclosporine, etc.), and as a result of destructive processes (e.g., infection, GVHD, etc.), and may
have a fatal outcome; 5) Relapse or progression of lymphoma may occur, especially in patients
with advanced disease status at time of treatment; 6) Unknown Toxicities may occur in any
individual patient due to multiple events and cumulative effects which may involve any and all
organs, including the brain. Brain damage can result in severe loss of cognitive or neurologic
function; and 7) Death.
2.11. Therapy Toxicities
All toxicities will be graded using the Common Terminology Criteria for Adverse Events
(CTCAE) Version 3.0. All of the following listed agents are commercially available.
2.11.1. Total Body Irradiation (TBI)
The radiation therapist performs the dosimetry calculations. TBI may cause nausea, vomiting,
diarrhea, mucositis, myelosuppression, alopecia, and painful swelling of the salivary glands for a
few days. Long-term effects include sterility, secondary malignancies and cataract formation.
2.11.2. Cyclophosphamide
Cyclophosphamide is an alkylating agent as well as an immunosuppressant. Toxicities include
nausea, vomiting, myelosupression, hemorrhagic cystitis, alopecia, sterility, mucositis,
cardiomyopathy and jaundice. It is available as an IV and oral formulation.
2.11.3. Carmustine (BCNU)
Carmustine is an alkylating agent. Toxicities from carmustine include myelosuppression,
nausea, vomiting, transient hypotension, dizziness, hyperpigmentation of the skin, hepatotoxicity
and a delayed inflammatory lung response (pneumonitis). It is available as an IV formulation
only.
2.11.4. VP-16 (Etoposide)
VP-16 is a semi-synthetic podophyllotoxin derivative. Toxicities include nausea, vomiting,
myelosuppression, mucositis, hypotension, hand-foot syndrome (dermatitis), and occasionally
fevers, peripheral neurotoxicity and hepatotoxicity. It is available as an IV and oral formulation.
2.11.5. Rituximab
Rituximab is a chimeric human/mouse monoclonal antibody directed against CD20+, an antigen
expressed on all cells of the B cell lineage. It consists of a murine antigen binding region and a
human Fc region. The majority of toxicities occur during infusion such as rigors, fevers,
hypotension, dyspnea, and nausea/vomiting. Non-infusion toxicities include myelosuppression,
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fatigue and tumor pain. It is available as an IV formulation only. Hepatitis B reactivation with
fulminant hepatitis, hepatic failure and death is a risk in patients who have ever been infected
with the hepatitis B virus and/or are carriers of hepatitis B. The risk of hepatitis B reactivation
may continue for several months after rituximab administration.
2.11.6. Fludarabine
Fludarabine is a purine analog. Toxicities include myelosuppression, immunosuppression,
edema, fever, chills, fatigue, rash, mild nausea/vomiting, paresthesias and myalgias. It is
commercially available as an IV formulation only.
2.11.7. Methotrexate
Methotrexate is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant
cells. Toxicities include mucositis, hyperuricemia, elevated liver functions tests, leukopenia,
thrombocytopenia, nausea, vomiting, diarrhea, anorexia, malaise, fevers, chills, rash,
nephrotoxicity and pneumonitis. It is available as an IV and oral formulation.
2.11.8. Tacrolimus
Tacrolimus is a macrolide antibiotic that is a potent immunosuppressant. Toxicities include
hypertension, peripheral edema, headache, hyperkalemia, hypokalemia, hyperglycemia,
hypomagnesemia, nausea, anorexia, vomiting, cramps, nephrotoxicity, elevated liver function
tests, tremors, paresthesias, rash, pruritus, and increased susceptibility to infection. It is available
as an IV and oral formulation.
2.11.9. G-CSF (filgrastim)
Filgrastim is a myeloid growth factor that stimulates the production, maturation and activation of
neutrophils and activates neutrophils to increase their migration and cytotoxicity. Common
toxicities include myalgias and medullary bone pain. The bone pain can be generally controlled
with non-narcotic analgesia. Less common side effects include fluid retention, pericardial
effusion, local inflammation at the injection site and rarely, cutaneous vasculitis. Transient
laboratory abnormalities include mild elevations in uric acid, LDH, alkaline phosphatase, and
leukocytosis. There have been reported cases of spleen swelling resulting in splenic rupture. It
may be administered as an IV formulation or subcutaneously.
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CHAPTER 3
3.
STUDY ENDPOINTS
3.1. Definition of Disease Status
Patients at each data collection period are classified into one of the following states. Until
relapse/progression, all disease classifications are relative to the patient’s pre-HSCT disease
status. Once the patient has relapsed/progressed, these states are relative to the patient’s best
disease state. PET scanning, flow cytometric, cytogenetic and molecular studies will not be
included in response definitions [57].
1. Complete Remission (CR):
Complete disappearance of all detectable clinical and radiographic evidence of
disease and disappearance of all disease-related symptoms if present before therapy.
All lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 cm in
their greatest transverse diameter for nodes > 1.5 cm before therapy). Previously
involved nodes that were 1.1 - 1.5 cm before treatment must have decreased to ≤ 1 cm
after treatment.
The spleen, if considered to be enlarged before therapy on the basis of a CT scan,
must have regressed in size and must not be palpable on physical exam.
If bone marrow was involved by lymphoma before treatment, this infiltrate must be
cleared after treatment.
Continued CR (CCR) will be applied to patients who were transplanted in CR.
Complete Remission Undetermined (CRU) as above but a residual lymph node mass
of > 1.5 cm must have regressed by > 75% in their sum of the products of the greatest
diameters [56] (SPD) and individual nodes that were previously confluent must have
regressed by > 75% in their SPD. Additionally, indeterminate bone marrow also
applies here (increased number or size of aggregates without cytologic or
architectural atypia).
2. Partial Remission (PR):
≥ 50% reduction in SPD of the 6 largest dominant nodes or nodal masses.
No increase in size of other nodes, liver or spleen.
Splenic and hepatic nodules must regress by least 50% in the SPD.
Bone marrow assessment is irrelevant for determination of a PR because it is
assessable and not measurable disease.
No new sites of disease.
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3. Stable Disease (SD):
Less than a PR (see above) but is not progressive disease (see below).
4. Relapsed Disease (RD):
Applies to patients previously classified as CR, CCR or CRU.
Appearance of any new lesion or increase by ≥ 50% in the size of previously involved
sites.
≥ 50% increase in greatest diameter of any previously identified node > 1 cm in its
short axis or in the SPD of more than 1 node.
5. Progressive Disease (PD):
Applies to patients previously classified as PR or SD.
> 50% increase from nadir in the SPD of any previously identified abnormal node for
PRs or SD.
Appearance of new sites of disease.
3.2. Primary Endpoint to be Compared Between Autologous HSCT Recipients and Non-
myeloablative Allogeneic HSCT Recipients
3.2.1. Three Year Progression-Free Survival
The primary endpoint is three-year progression-free survival. Patients are considered a failure
for this endpoint if they die or if they relapse/progress or receive anti-lymphoma therapy. The
time to this event is the time from enrollment on study until death, relapse/progression, receipt of
anti-lymphoma therapy, or last follow up, whichever comes first.
3.3. Secondary Endpoint to be Compared Between Autologous HSCT Recipients and
Non-myeloablative Allogeneic HSCT Recipients
3.3.1. Three Year Overall Survival
The event is death from any cause. The time to this event is the time from study enrollment to
death or last follow up. Surviving patients are censored at the time of last observation.
3.3.2. Time to Progression
The event is relapse/progression. The time to this event is measured from study enrollment.
Deaths without relapse/progression are considered as a competing risk. Surviving patients with
no history of relapse/progression are censored at time of last follow-up.
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3.3.3. Time to CR and PR
The event is achieving CR (or PR and CR). The time to event is measured from the time of
study enrollment to the time to CR (or PR). Patients who die in a state other than CR (PR) are
considered as failing from a competing risk. Patients alive and not in CR (PR) are censored at
the time of last observation.
3.3.4. Time to Off-study Therapy
The event is the initiation of anti-lymphoma therapy other than those defined by the protocol
arms. The time to this event is measured from study enrollment. Patients who die without
initiation of an off-study therapy will be considered as experiencing a competing risk. Patients
who are alive and have not received an off-study therapy are censored at the time of the last
observation.
3.3.5. Incidence of Infections
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for
each patient. The proportion of patients in each treatment arm with these infections will be
compared.
3.3.6. Incidence of CTCAE Version 3.0 Grade ≥ 3 toxicities
See the BMT CTN MOP for the CTCAE grading scales.
3.3.7. Treatment Related Mortality
Treatment related mortality (TRM) is defined as death occurring in a patient from causes other
than relapse or progression.
3.4. Endpoints That Only Apply to Non-myeloablative Allogeneic Recipients
The following endpoints will be used to describe outcomes associated only for the recipients of
the HLA-matched sibling allograft. They will not be compared between the two treatment arms.
3.4.1. Incidence of Primary and Secondary Graft Failure
Donor engraftment is defined as > 5% donor peripheral blood T cell chimerism by Day +56 post-
HSCT. Primary graft failure is defined as a donor peripheral blood T cell chimerism < 5% at
Day 56 post-HSCT. Methodological requirements for chimerism are outlined in the BMT CTN
MOP.
Secondary Graft Failure is defined by documented engraftment followed by loss of graft as
defined by donor peripheral blood T cell chimerism < 5% as demonstrated by a chimerism assay.
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3.4.2. Incidence and Severity of Graft-versus-Host Disease (GVHD)
See the BMT CTN MOP for definitions of acute and chronic GVHD.
3.5. Other Endpoints
3.5.1. Efficacy of Rituximab and Cyclophosphamide in Vivo Purging
In vivo purging will be measured as the proportion of patients whose peripheral blood converts
from positive for t(14;18) by PCR prior to rituximab and cyclophosphamide to negative
following this therapy.
For patients with known t(14;18) undergoing collection of autologous HSC, PCR for t(14;18)
will be conducted on the collected products in addition to peripheral blood samples. Correlation
between peripheral blood and apheresis product results for t(14;18) will also be determined.
3.5.2. Prognostic Value of t(14;18) by PCR in Predicting Relapse
A quantitative PCR for t(14;18) from peripheral blood will be carried out on patients with known
t(14;18). Results of serial post-HSCT samples will be analyzed to determine if there is a
threshold value that can reliably predict relapse.
3.5.3. Quality of Life
Health Related Quality of Life will be described pre-initiation of rituximab and
cyclophosphamide cytoreductive/mobilization therapy for English and Spanish speaking patients
of both groups utilizing the FACT-BMT self report, transplant specific questionnaire and the
generic quality of life tool, the SF-36. The questionnaires will be scored according to standard
procedures. In addition, an exploratory comparison of the quality of life of the two groups will
be made at two years post-autologous or non-myeloablative allogeneic HSCT.
3.6. Regimen-related Toxicities Safety Monitoring Endpoints
3.6.1. Allogeneic HSCT
There are two regimen-related toxicity monitoring plans for the non-myeloablative allogeneic
HSCT arm. The rates of hepatic and renal toxicities will be monitored. Occurrence of these
toxicities will be recorded as events.
1. Hepatic toxicity, defined as Grade 3 or higher toxicity from the CTCAE Version 3.0,
under the adverse event type liver dysfunction/failure.
2. Renal toxicity is defined as serum creatinine > 3.0 mg/dL.
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3.6.2. Autologous HSCT
There are two regimen-related toxicities that will be monitored in the autologous HSCT arm.
1.
Neutropenia is defined as Grade 3 or higher toxicity from the CTCAE Version 3.0
under the adverse event type blood/bone marrow. This toxicity applies to the specific
time period commencing with the first dose of rituximab post-HSCT and ending at one
year post-HSCT.
2.
Pulmonary toxicity/pneumonitis is defined as Grade 3 or higher toxicity from the
CTCAE Version 3.0 under the adverse event type pulmonary/upper respiratory.
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CHAPTER 4
4.
PATIENT ENROLLMENT AND EVALUATION
4.1. Enrollment Procedures
4.1.1. Screening and Eligibility Procedures
Patients will be registered using the Advantage EDCSM (internet data entry systems). Southwest
Oncology Group (SWOG) centers should follow the instructions in Section 4.1.2 prior to
following the instructions below. The following procedures should be followed:
1. Prior to initiation of rituximab and cyclophosphamide cytoreductive/mobilization
therapy, an authorized user at the transplant center completes a screening form with
demographic and eligibility questions. The Eligibility Form includes a question
confirming that the patient signed the informed consent form.
2. If the patient is eligible, a study number is generated.
3. Potential sibling donors must be evaluated for suitability for donation until either an
HLA-matched sibling donor is identified or all HLA-matched siblings are excluded as
donors. The cytoreductive/mobilization therapy must begin no later than 6 weeks from
enrollment. If an HLA-matched sibling is available, the donor and recipient HLA typing
information is completed on the eligibility form. If an HLA-matched sibling is not
available, the Sibling Information Form is required to obtain information pertaining to
ineligibility of all siblings. This includes siblings not typed because of prior knowledge
that they would not be eligible to donate for medical reasons, typed siblings that are not
HLA matches and HLA-matched siblings who can not donate for medical reasons.
Enrollment
occurs
at
the
time
of
biological
assignment
prior
to
the
cytoreductive/mobilization therapy. Consent may be obtained in advance but the
protocol assessments required prior to the cyotreductive/mobilization therapy should not
be scheduled immediately after the consent is signed if the therapy is not imminent
(within 4 weeks). Patients with a donor are then biologically assigned to the non-
myeloablative allogeneic HSCT arm. Patients without an HLA-matched sibling donor
are then biologically assigned to the autologous HSCT + rituximab maintenance therapy
arm. If an HLA-matched sibling is identified but then declines to be a donor, the patient
may proceed to the autologous HSCT. In accordance with the intention-to-treat principle
for the primary analysis of three-year progression-free survival, this patient will be
classified as an allogeneic HSCT patient since this was their original biologic assignment.
4. After recovery from cytoreductive/mobilization therapy, an authorized user at the clinical
center completes the Pre-HSCT Checklist confirming that the patient has recovered and is
eligible to receive either a non-myeloablative allogeneic HSCT or autologous HSCT.
5. If the patient is eligible, the treatment plan is continued and a visit schedule based on the
transplant date is displayed for printing and is referred to as ‘Segment A Follow-up.’
6. For autologous HSCT patients only: After recovery from autologous HSCT, an
authorized user at the transplant center completes the Pre-Rituximab Checklist to confirm
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the patient has recovered and is eligible to begin receiving rituximab maintenance
therapy.
4.1.2. SWOG Patient Registration Procedures
Patients from Southwest Oncology Group (SWOG) Member, CCOP and approved affiliate
institutions must be registered through the SWOG Data Operations Center in Seattle using the
SWOG Web Registration System. Affiliate institutions not approved to register patients directly
with the Data Operations Center must register through their member institution. The Data
Operations Center will request information from the SWOG Registration Form. The institution
must have these documents completed entirely prior to registering the patient in the SWOG Web
Registration System. In addition, the Data Operations Center will collect stratification
information, will request the date that the informed consent and HIPAA authorization were
obtained, and will obtain the date of IRB approval for each entry.
4.2. Study Monitoring
4.2.1. Follow-up Schedule
The Follow-up Schedule for scheduled study visits is outlined in Table 4.2.1. A detailed
description of each of the forms and the procedures required for forms completion and
submission can be found in the Data Management Handbook and User’s Guide. The follow-up
period for Segment A is 3 years.
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Table 4.2.1: Follow-up Schedule - Segment A
Study Visit
Target Day
(+ 7 Days Prior to Day 100 Post-HSCT)
(+ 28 Days After Day 100 Post-HSCT)
1 week1, 2, 3
7 days
2 week1, 2, 3
14 days
3 week1, 2, 3
21 days
4 week2, 3
28 days
5 week1
35 days
6 week1
42 days
7 week1
49 days
8 week4
56 days
9 week1
63 days
10 week1
70 days
11 week1
77 days
12 week4, 5
84 days
13 week1
91 days
14 week1
98 days
6 month4, 5
180 days
12 month4, 5
365 days
18 month
540 days
24 month4
730 days
30 month
900 days
36 month4
1,095 days
1GVHD assessments for non-myeloablative allogeneic HSCT arm only
2Chemistry panel required twice per week
3Refer to Section 4.2.4.4 for frequency of follow-up for CBC
4Chemistry panel required at this time point
5IgG level required at this time point
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are
detailed in the Data Management Handbook and User’s Guide. Forms that are not entered into
the web-based data entry system within the specified time will be considered delinquent. A
missing form will continue to be requested either until the form is entered into the web based
data entry system and integrated into the DCC's master database, or until an exception is granted
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and entered into the Missing Form Exception File, as detailed in the Data Management
Handbook.
Reporting Patient Deaths: Recipient Death Information must be entered into the web-based
data entry system within 24 hours of knowledge of the patient’s death. If the cause of death is
unknown at that time, it need not be recorded at that time. However, once the cause of death is
determined, the form must be updated in the web based data entry system.
CIBMTR Data Reporting: All transplant centers will be required to pre-register patients with
the CIBMTR for all transplant patients whether or not they enroll in a BMT CTN Protocol. In
addition, the transplant center must complete the CIBMTR TED Day 100 Report Form
(including the Core, Graft and Disease Inserts) and CIBMTR TED Follow-up Form (including
the Core and Disease Inserts) yearly for all patients enrolled in BMT CTN protocols. CIBMTR
forms will be submitted directly to the CIBMTR at the times specified on the Form Submission
Schedule.
4.2.2. Weekly GVHD Monitoring Post Non-myeloablative Allogeneic Transplant
GVHD should be monitored in accordance with BMT CTN guidelines as specified in the MOP.
Patients should be assessed weekly until Day 100 post-HSCT for GVHD. After Day 100,
patients will be assessed at each study visit for the presence of GVHD.
4.2.3. Adverse Event Reporting
Unexpected, grade 3-5 Adverse Events (AE) will be reported through an expedited AE reporting
system. Unexpected, grade 4-5 AEs must be reported within 24 hours of knowledge of the
event. Unexpected, grade 3 AEs must be reported within three business days of knowledge of
the event. Expected adverse events will be reported using NCI’s Common Terminology Criteria
For Adverse Events Version 3.0 at regular intervals as defined on the Form Submission
Schedule.
4.2.4. Patient Assessments
Tables 4.2.4.8a and 4.2.4.8b summarize patient clinical assessments over the course of the study.
All assessments prior to and after the transplant are considered standard of care.
4.2.4.1.
Evaluations prior to rituximab and cyclophosphamide
The following observations should be determined within the 4 weeks prior to initiating rituximab
and cyclophosphamide mobilization chemotherapy. Observation 3 must be determined ≤ 2
weeks before initiation of therapy. Observation 9c must be done after enrollment.
1. History, physical examination, height and weight.
2. Karnofsky performance score.
3. CBC with differential and platelet count, creatinine clearance, creatinine, bilirubin,
alkaline phosphatase, ALT, AST, LDH, sodium, magnesium, potassium, chloride, and
CO2.
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4. CMV titer, hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab),
herpes simplex titre, syphilis, HIV and HTLV1 antibody).
5. EKG.
6. Left ventricular ejection fraction.
7. DLCO, FEV1, and FVC.
8. HLA typing of heparinized peripheral blood sample to determine availability of HLA-
matched sibling. HLA –A, -B typing can be done by serologic or DNA methods. HLA
DRB1 typing must be done by DNA methodology.
9. Baseline Disease Evaluation:
a) CT scans of neck, chest, abdomen and pelvis. Neck CT only required if previous site
of disease.
b) Bone marrow biopsy and aspirates to pathology and aspirate to cytogenetics. Flow
cytometry not required. Bone marrow core should be ≥ 2 cm total for unilateral or
bilateral samples.
c) 10 mL peripheral blood for quantitative PCR analysis of t(14;18).
10) Quality of life assessment.
11) ABO Rh blood typing.
4.2.4.2.
Post initiation of rituximab and cyclophosphamide
Toxicity assessment upon blood count recovery post rituximab and cyclophosphamide
mobilization chemotherapy and ≤ 2 weeks prior to administration of the HSCT conditioning
therapy.
4.2.4.3.
Evaluations prior to the autologous or non-myeloablative allogeneic HSCT
The following observations will be done ≤ 2 weeks prior to initiation of the HSCT conditioning
therapy.
1. History, physical examination, height and weight.
2. Karnofsky performance score.
3. CBC with differential, platelet count, creatinine, bilirubin, LDH, alkaline phosphatase,
AST, ALT, sodium, magnesium, potassium, chloride, and CO2.
4. Creatinine clearance if
clinically
significant nephrotoxicity
experienced
with
cyclophosphamide and rituximab.
5. Left ventricular ejection fraction if clinically indicated.
6. DLCO, FEV1 and FVC if clinically indicated.
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7. Baseline Disease Evaluation:
a) Bone marrow biopsy and aspirate to pathology and aspirate to cytogenetics only if
bone marrow was involved with lymphoma at any time prior to the rituximab/
cyclophosphamide therapy. Flow cytometry is not required. Bone marrow core
should be ≥ 2 cm total for unilateral or bilateral samples.
b) CT of neck, chest, abdomen and pelvis. Neck CT only required if previous site of
disease.
c) In patients with known t(14;18), 10 mL peripheral blood samples will be drawn for
t(14;18) analysis by PCR. These samples will be processed and stored locally for
later shipment to the BMT CTN Repository for batch analysis.
d) For autologous HSCT patients with known t(14;18), all leukapheresis products will
be tested for t(14;18) analysis by PCR. These samples will be processed and stored
locally for later shipment to the BMT CTN Repository for batch analysis.
8. Heparinized peripheral blood samples from all patients on the non-myeloablative
allogeneic HSCT arm for chimerism assays.
9. Flow cytometry analysis of autologous or allogeneic graft per the Graft Characterization
section of the BMT CTN MOP.
10. One vial (10 cc) of nucleated cells from patient’s peripheral blood for future testing (see
the table on pages C-4/5 for processing/shipping instructions).
11. Review consent document for non-myeloablative allogeneic or autologous HSCT with
patient.
4.2.4.4.
Post-HSCT evaluations
1. CBC at least twice a week from Day 0 until ANC > 500 for 2 days after nadir reached.
Thereafter CBC twice per week until Day 28 (or 4 weeks), then at 8 weeks, 12 weeks, 6
months, one year and then yearly until three years post-HSCT.
2. Comprehensive chemistry panel defined as creatinine, LDH, bilirubin, alkaline
phosphatase, AST, ALT, magnesium, sodium, potassium, chloride, CO2 twice a week
until Day 28 (or four weeks) and then at 8 weeks, 12 weeks, 6 months, one year and then
yearly until three years post-HSCT.
3. Toxicity assessments at 4, 8, 12 weeks, 6 months, one year and every six months until
three years post-HSCT.
4. Disease restaging at 12 weeks, 6 months, and 1 year and annually until three years post-
HSCT.
a. Bone marrow biopsy and aspirate to pathology and aspirate to cytogenetics. Flow
cytometry is not required. Bone marrow core should be ≥ 2 cm total for unilateral or
bilateral samples.
b. CT of neck, chest, abdomen and pelvis. Neck CT only required if previous site of
disease.
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c. In patients with known t(14;18), 10 mL peripheral blood samples will be drawn for
t(14;18) analysis by PCR. These samples will be processed and stored locally for
later shipment to the BMT CTN Repository for batch analysis.
5. Measurement of IgG levels at 12 weeks, 6 months and 1 year post-HSCT.
6. Quality of life assessment at 2 years post-HSCT.
In addition, patients receiving a non-myeloablative HSCT are required to have a history and
physical exam to assess GVHD weekly until Day 100 post-HSCT, then at 6 months, one year
and then yearly until three years post-HSCT. GVHD evaluation and grading to be in keeping
with BMT CTN MOP.
4.2.4.5.
Prior to initiation of rituximab maintenance therapy in autologous HSCT recipients
The following observations will be done ≤ 2 weeks prior to initiation of rituximab maintenance
therapy. This assessment can coincide with the 4 week post-autologous HSCT assessment. If
progressive disease is found during this assessment, the patient will be off-study but continued to
be followed for survival. Subsequent therapy is at the discretion of their attending physician.
1. History, physical examination, height and weight.
2. Karnofsky performance score.
3. CBC with differential, platelet count, creatinine, LDH, bilirubin, alkaline phosphatase,
AST, ALT, sodium, magnesium, potassium, chloride, and CO2.
4. Disease Evaluation:
a. Bone marrow biopsy and aspirate to pathology and aspirate to cytogenetics. Flow
cytometry is not required. Bone marrow core should be ≥ 2 cm total for unilateral or
bilateral samples.
b. CT of neck, chest, abdomen and pelvis. Neck CT only required if previous site of
disease.
c. In patients with known t(14;18), a peripheral blood sample will be drawn for t(14;18)
analysis by PCR. The Day +28 sample can be utilized for this particular time point.
These samples will be processed and stored locally for later shipment to BMT CTN
Repository for batch analysis.
5. Review consent document for rituximab maintenance therapy with patient.
6. HepB SAb, HepB SAg, HepB Core Ab.
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4.2.4.6.
Sampling schedule for quantitative PCR of t(14;18) from peripheral blood sample
1. At study entry.
2. For patients with positive PCR at any time since diagnosis. These samples will be
processed and shipped quarterly to the BMT CTN Repository for batch analysis.
a. After blood count recovery from cyclophosphamide and rituximab cytoreductive/
mobilization therapy.
b. Analysis of each leukapheresis product from autologous HSCT patients.
c. Post-HSCT:
Day +28 post-HSCT
Day +84 post-HSCT
6 months post-HSCT
12 months post-HSCT
Annually until 3 years post-HSCT
4.2.4.7.
Sampling schedule for chimerism analysis of peripheral blood in non-myeloablative
allogeneic transplant recipients
1.
Pre non-myeloablative allogeneic HSCT
2.
Day +28 post non-myeloablative allogeneic HSCT
3.
Day +56 post non-myeloablative allogeneic HSCT
4.
Day +84 post non-myeloablative allogeneic HSCT
5.
6 months post non-myeloablative allogeneic HSCT
6.
12 months post non-myeloablative allogeneic HSCT
4.2.4.8. Required observations for HLA-matched sibling donor
Routine allogeneic donor work-up will be in keeping with FACT guidelines, BMT CTN MOP
and institution standard practice of care. Work-up to include the following:
1. History, physical examination, height and weight.
2. HLA typing of heparinized peripheral blood sample.
3. Laboratory tests:
a. CBC with differential and platelet count, creatinine, bilirubin, LDH, alkaline
phosphatase, AST, ALT, magnesium, sodium, potassium, chloride, CO2, hepatitis
panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), CMV, syphilis,
herpes simplex, HIV and HTLV I serologies and ABO Rh blood typing.
b. If donor has antibodies against red cell antigens of the recipient, the titers will be
determined.
c. CBC will be checked prior to and after each leukapheresis collection, thereafter if
clinically indicated.
4. Heparinized peripheral blood samples (10 mL) for chimerism assays.
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5. One vial (10 cc) of nucleated cells from donor’s peripheral blood for future testing,
collected prior to mobilization (see the table on pages C-4/5 for processing/shipping
instructions).
6. Five vials, each containing 2-5 x 106 nucleated cells from the allograft stem cells (to be
obtained for the central repository per the Graft Characterization section of the BMT
CTN MOP).
7. Left ventricular ejection fraction if clinically indicated.
8. DLCO, FEV1 and FVC if clinically indicated.
9. Evaluation of toxicities experienced post initation of G-CSF.
Donors must be contacted by phone approximately 30 days post initiation of G-CSF for a
toxicity evaluation.
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Table 4.2.4.8a: Baseline, Pre-HSCT, Donor Evaluations
Required Studies/Testing
Prior to Rituximab
and Cyclophos-
phamide
4 Weeks Post 1st
Rituximab Dose
(Pre-HSCT)
Pre-
HSCT1
Pre-Rituximab
Maintenance Therapy
for Autologous HSCT
Recipients7, 16
Donor
History, Physical Examination, Height and
Weight
X
X
X
X
Karnofsky Performance Score
X
X
X
CBC with differential, Platelet Count,
Creatinine, Bilirubin, Alkaline Phosphatase,
AST, ALT, LDH, Sodium, Magnesium,
Potassium, Chloride and CO2
X1
X
X
X 2, 3
ABO Rh Typing
X
X
Creatinine Clearance
X1
X9
CMV Titer, Hepatitis Panel (A,B,C) Herpes
Simplex, Syphilis
X
X
HIV/HTLV1 Antibody
X
X
EKG
X
LV Ejection Fraction
X
X10
X10
DLCO/FEV1/FVC
X
X10
X10
Toxicity Assessment
X
X17
CT Neck, Chest, Abdomen and Pelvis
X11
X11
X11
Bone Marrow Aspirate and Biopsy8
X
X18
X
Peripheral Blood for t(14;18) PCR
X12
X13, 14
X15, 16
Peripheral Blood for HLA Typing
X
X
Blood Samples for Chimerism Assays
X4
X
Nucleated Cells
X6
X5, 6
Flow Cytometry Analysis of Graft
X
Health Quality of Life
X
Consent Review
X
X
X
1 To be performed within 2 weeks of starting conditioning therapy.
2 Including ABO Rh blood typing.
3 CBC will be checked prior to and after leukapheresis collection.
If donor has antibodies against red cell antigens of the recipient,
the titers will be determined.
4 For the allogeneic HSCT arm only.
5 Five vials each containing 2-5 x 106 nucleated cells from
allogeneic donor HSC cryopreserved for central repository.
6 One vial (10 cc) of nucleated cells from peripheral blood for
future testing (see the table on pages C-4/5 for
processing/shipping instructions).
7 This assessment can be coincident with the 4 week post-HSCT
assessment (see Table 4.2.4.8b).
8 Bone marrow aspirate and biopsy samples to pathology, aspirate
for cytogenetic analysis.
9 Creatinine clearance must be done only if clinically significant
nephrotoxicity experienced with cyclophosphamide and rituximab.
10 If clinically indicated.
11 Neck CT only required if previous site of disease.
12 Even if the patient was known to be t(14;18) negative prior to
registration, the test must still be performed at the time of
registration for documentation purposes. This assessment is to
be done after enrollment.
13 Only in patients with known t(14;18) at any time since diagnosis.
14 Additional samples for analysis of each leukapheresis product
from autologous HSCT patients only.
15 The Day +28 post-HSCT sample can be utilized for this time
point.
16 To be performed within 2 weeks of starting rituximab
maintenance therapy.
17 On Days 5 and 30 (via telephone) post initiation of G-CSF..
18 Only if bone marrow was involved with lymphoma at time prior
to the rituximab/cyclophosphamide.
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Table 4.2.4.8b: Post-HSCT Evaluations
Study Assessments/
Testing
Weeks Post-HSCT
Months Post-HSCT
1
2
3
46
5
6
7
8
9
10
11
12
13
14
6
12
18
24
30
36
GVHD Assessments1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBC2
See Section 4.2.4.4 for
details.
X
X
X
X
X
X
Chemistry Panel
2 x per week4
X
X
X
X
X
X
Chimerism5
X
X
X
X
X
Bone Marrow Aspirate and
Biopsy3, 8
X
X
X
X
X
CT Neck, Chest, Abdomen
and Pelvis3, 7
X
X
X
X
X
Peripheral Blood for t(14;18)
PCR9
X
X
X
X
X
X
IgG Levels
X
X
X
Toxicity
X
X
X
X
X
X
X
X
X
Health Quality of Life
X
1 For allogeneic HSCT arm only.
2 Will be reported on case report form only on Day 28 to document engraftment for allogeneic HSCT arm only.
3 Or at time of progression/relapse.
4 Will not be reported on the case report form.
5 Chimerism performed on CD3+ cells from peripheral blood.
6 For the autologous HSCT arm: may coincide with the assessments required prior to initiation of rituximab maintenance therapy.
7 Neck CT only required if previous site of disease.
8 Bone marrow aspirate and biopsy samples to pathology. Bone marrow aspirate to cytogenetics.
9 For patients with possible t(14;18) at any time from diagnosis to study entry.
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CHAPTER 5
5.
STATISTICAL CONSIDERATIONS
5.1. Study Overview
The overall study design is a comparison of two treatment arms determined by biologic
assignment, based on the availability of an HLA-matched sibling, in patients diagnosed with
relapsed follicular non-Hodgkin’s lymphoma. Patients without an HLA-matched sibling will
receive an autologous HSCT. Patients with an HLA-matched sibling will receive a non-
myeloablative allogeneic HSCT.
5.1.1. Primary Endpoint
The primary endpoint for the study is three-year progression-free survival. If any therapy not
specified in the protocol, such as DCI, is given to prevent relapse/progression or to induce a
response, the patient will be considered to have experienced an event for the primary endpoint.
Patients who are lost to follow-up prior to three years will be censored at the time of the last
observation, and the progression-free survival proportion will be estimated using the Kaplan-
Meier method, where time-to-event is measured from enrollment to the minimum of the date of
death, relapse/progression, last-follow-up or the three-year time point.
The statistic for testing for differences in three-year progression-free survival between treatment
arms is described in Appendix E. Basically, the statistic is a standardized weighted sum over
strata formed by the clinical centers of differences in the Kaplan-Meier estimate of survival at
the three-year time-point. If follow-up were complete (no censoring), the test statistic reduces to
a Cochran Mantel Haenszel test of binomial proportions of progression-free survivors at the
three- year time-point.
5.1.2. Accrual
Accrual will remain open until at a minimum, 80 patients are assigned to the allogeneic arm. It
is estimated that three years of accrual will be necessary to enroll the targeted sample size.
Assuming that patients with HLA-matched sibling donors comprise 20-30% of eligible patients,
approximately 187-320 patients will likely be accrued to the autologous arm during the time it
takes to accrue the targeted number of patients on the allogeneic arm.
To adjust for differences in clinical care practices at participating institutions, the primary
analysis of three-year progression-free survival will be stratified by transplant center. At least
two individuals are required to estimate variability within a stratum so, at a minimum, each
center must enroll two patients in each treatment arm. This requirement imposes some
constraints on the selection of participating transplant centers.
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In selecting transplant centers for participation, preference will be given to centers that perform
both autologous and allogeneic transplants, and that anticipate enrollment of at least 12 patients.
However, a pair of centers that collectively meet these criteria may be invited to participate (e.g.
SWOG autologous program with its partner allogeneic program), one of the centers serving as
the “center of record” for the purposes of monitoring and analyzing accrual or other study data.
5.1.3. Biologic Assignment
To prevent bias in determining whether donors are eligible or not for donation, and resultant bias
in the biological assignment, all available siblings will be HLA-typed and all HLA-matched
siblings will be assessed for donation whenever feasible. If a sibling is deemed unsuitable to be
a donor, the reasoning will be reviewed with a Protocol Chair or the Medical Monitor. Patients
with an HLA-matched sibling who is a suitable donor are biologically assigned to the allogeneic
arm of the study. Patients without a suitable HLA-matched sibling donor are assigned to the
autologous arm. The protocol requires that all potential donors be typed and evaluated prior to
the initiation of cytoreductive/mobilization therapy, and within four weeks of enrollment.
5.1.4. Intention-to-Treat Principle
In accordance with the intention-to-treat principle for the primary analysis of three-year
progression-free survival, patients will be classified according to their original biological
assignment, regardless of the therapy actually received. Some secondary and tertiary analyses
such as the assessment of Health Quality of Life or GVHD will be conducted on an as-treated
rather than intention-to-treat basis.
5.2. Statistical Issues Related to Non-randomized Assignment
It is not feasible to randomly assign patients to autologous HSCT versus non-myeloablative
allogeneic HSCT. A randomized study would entail enrolling only patients potentially eligible
for the allogeneic transplant. Since patients with HLA-matched sibling donors comprise only
20-30% of the patient population, restricting enrollment to such patients would make it
impossible to meet the accrual goals for the study in a timely fashion.
There are many possible sources of heterogeneity in a multi-center clinical trial. In a large
randomized trial, chance ensures balance of both known and unknown risk factors across
treatment arms. A non-randomized study is vulnerable to differential assignment of higher risk
patients to one or the other treatment arm. Potential sources of heterogeneity include differences
in: (1) selection of patients to screen for the study; (2) degree of compliance with biological
allocation; (3) in clinical care practices at participating institutions; (4) baseline disease risk
status: and, (5) in baseline factors such as recipient age and performance status. The data
analytic plan to address each of these is discussed briefly.
5.2.1. Selection of Patients to Screen for the Study
Each transplant center is required to register consecutive transplant recipients with the Center for
International Blood and Marrow Transplant Research (CIBMTR). Data are collected on all
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transplanted patients, regardless of whether they are enrolled in a BMT CTN trial. These data
will be used to determine if the proportion of allograft recipients, the demographic composition,
the performance status and the disease risk of patients entered in the study are representative of
the population of transplant patients treated at a center who were potentially eligible for entry in
the study. Disease risk will be assessed using CIBMTR data on disease, disease stage and
duration, age and performance status. Comparison of registered and enrolled patients will be
performed separately within each treatment arm every four months.
5.2.2. Compliance with Biologic Assignment
The procedure for the biological assignment of patients is described in detail in Section 5.1
above. Centers will complete a BMT CTN Sibling Information Form that will capture
information on whether each of the patient’s siblings were typed and, if not, the reason why.
This form will also capture information for HLA-matched siblings not identified as a suitable
donor, and the reason(s) they are not donating. The DCC will query the transplant center for
additional information as needed to validate the biological assignment, and to ensure that the
patient is correctly classified in the final intention-to-treat analysis.
If an HLA-matched sibling is determined unsuitable by the center to be a donor, the reasoning
will be reviewed with a Protocol Chair or the Medical Monitor. It is anticipated that the rates of
donor refusal for the allograft transplant will be roughly comparable across institutions. Centers
with rates of refusal significantly higher than the average will be reviewed by the DCC regarding
their procedures for approaching and enrolling patients. As participation at the center level is by
choice, it is expected that problems with violating the biologic assignment process will be
limited.
Accrual of patients to the allogeneic arm will be monitored. Any center enrolling eight patients
on the autologous arm without enrolling a patient on the allogeneic arm will be reviewed by the
DCC to ensure protocol compliance. This will include a review of patients transplanted for
follicular lymphoma off-study using data from the CIBMTR registration process described
above. Corrective educational measures will be instituted for centers selectively enrolling
patients or failing to follow the biologic assignment design of the protocol.
5.2.3. Effects of Transplant Center
To adjust for differences in clinical care practices at participating institutions, the primary
analysis of three-year progression-free survival will be stratified by transplant center. At least
two individuals are required to estimate variability within a stratum so, at a minimum, each
center must enroll two patients in each treatment arm. Since a transplant center that fails to meet
this goal will comprise a stratum that cannot contribute to the final test statistic, centers will
continue enrollment until this requirement is met.
If patients with HLA-matched sibling donors comprise 25% of the patient population, centers
that accrue at least 12 patients are likely to enroll at least two allograft patients by chance
(probability > 80%). As noted previously, in selecting transplant centers for participation,
preference will be given to centers that perform both autologous and allogeneic transplants, and
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that anticipate enrollment of at least 12 patients. If necessary, centers doing only autologous
transplants will be allowed to partner with a transplant center that performs allogeneic
transplants to facilitate meeting this requirement and to broaden the range of centers able to
participate.
5.2.4. Effects of Disease Risk Status
A post-hoc analysis will be performed assessing the comparability of patients allocated to each
treatment arm with respect to disease risk status, as measured by number of prior regimens (0 or
1 versus 2 or more), and time from diagnosis to transplant. Number of prior regimens will be
compared using a chi-squared test, and time from diagnosis to transplant will be compared using
a Wilcoxon test. If statistically significant (p<0.10) differences in the treatment arms are found
in either of these disease risk prognostic factors, a secondary analysis of the primary endpoint
will be performed adjusting for these covariates in a Cox proportional hazards model.
5.2.5. Effects of Baseline Factors
A post-hoc analysis will be performed assessing the comparability of patients allocated to each
treatment arm with respect to baseline Karnofsky performance score and age. Performance
status will be compared using a chi-square test; and age will be compared using a Wilcoxon test.
If statistically significant (p <0.10) differences in the treatment arms are found with respect to
either of these baseline prognostic factors, a secondary analysis of the primary endpoint will be
performed adjusting for these covariates in a Cox proportional hazards model.
Other baseline factors such as donor age and gender were considered, and rejected, as candidates
for post-hoc adjustment. Donor age is highly correlated with recipient age when HLA-identical
siblings are serving as donors. The range of ages in the study population is not anticipated to be
wide enough to lead to imbalances in the treatment arms. Recipient-donor gender mismatch is
not anticipated to be a strong predictor of outcome in the allograft transplant setting, and thus
does not warrant adjustment.
5.3. Sample Size and Power Calculations
The study sample size is specified in terms of the targeted number of patients with an HLA-
matched sibling donor. Accrual will remain open until at minimum, 80 patients are assigned to
the non-myeloablative allogeneic HSCT arm. During the accrual period, enrollment will be open
to all eligible patients, including those without HLA-matched sibling donors. The exact
composition of the study population will depend on the series of eligible patients presenting at
each clinic. During the accrual period we anticipate enrollment of 80 patients on the non-
myeloablative allogeneic HSCT arm and 187-320 patients on the autologous HSCT arm.
Three-year progression-free survival after autologous HSCT is estimated to be 45% using data
from the CIBMTR. A sample size of 80 non-myeloablative allogeneic HSCT recipients and 187
autologous HSCT recipients is sufficient to achieve > 85% power to detect a 20% difference
between a three-year progression-free survival of 45% after autologous HSCT and three-year
progression-free survival of 65% after non-myeloablative allogeneic HSCT, with a two-sided
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level .05 test of proportions. Note that the final analysis will use a modified Mantel Haenszel
test statistic stratified by clinical center, but the binomial test of proportions serves as a useful
approximation and provides conservative estimates of power.
Table 5.3 shows the power under a variety of scenarios. The number of autologous HSCT
patients is computed assuming that the number of patients with eligible HLA-matched sibling
donors ranges from 20 to 30% of the total patient population.
Table 5.3: Power Under a Variety of Scenarios
Non-myeloablative Allogeneic
HSCT Arm
Autologous HSCT Arm
Power
N
3-Year PFS
N
3-Year PFS
70
.65
163
.45
.81
70
.65
210
.45
.83
70
.65
280
.45
.86
80
.65
187
.45
.86
80
.65
240
.45
.88
80
.65
320
.45
.90
90
.625
210
.45
.80
90
.625
270
.45
.83
90
.625
360
.45
.85
5.4. Interim Analysis and Stopping Guidelines
5.4.1. Guidelines for Accrual Monitoring
Each transplant center is required to enroll at least two patients in each treatment arm. If this
requirement is not met after the first eight patients are enrolled, the DCC will contact the center,
and will evaluate screening and referral practices. The investigation will not halt enrollment,
which will continue until the goal of a minimum of two patients per arm is reached. During the
final analysis, centers which do not have at least one death per treatment arm will be paired with
the nearest geographically located center which fulfills the requirement to form a single strata.
In a simulation study, the proportion of subjects with HLA-matched sibling donors was assumed
to be one-quarter of presenting eligible individuals. Once the target of 80 subjects with HLA-
matched donors was reached, enrollment was continued only at those centers that had not yet
enrolled 2 subjects per treatment group (the minimum required to compute the test statistic).
This resulted in a slight excess in total enrollment. On average 81 subjects were allocated to the
allograft arm, and 243 to the autograft arm.
5.4.2. Guidelines for Efficacy Monitoring
There are no planned interim analyses for efficacy in this study, because the anticipated accrual
period is three years, and the primary endpoint is three-year progression-free survival. However,
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if accrual is much slower than anticipated, the Data and Safety Monitoring Board will be
consulted, and consideration will be given to interim analyses for efficacy in the fourth or fifth
year, using either group sequential methods or stochastic curtailment to conserve type I error.
5.4.3. Guidelines for Safety Monitoring
There are several statistical guidelines employed in this study. These guidelines are designed to
assist an independent Data and Safety Monitoring Board (DSMB) in overseeing the study. The
DSMB may also request interim analyses and develop other criteria for determining when to
intervene in the enrollment or treatment of patients in the study.
The stopping guidelines monitor the incidence of transplant-related mortality and selected
regimen-related toxicities. Transplant-related mortality (TRM) is defined as death in the absence
of disease progression. TRM will be monitored separately in the autologous HSCT and non-
myeloablative allogeneic HSCT arms. Tacrolimus or cyclosporine associated renal and hepatic
toxicity will be monitored in the non-myeloablative allogeneic HSCT arm. Monitoring for
TRM, renal and hepatic toxicity will commence with enrollment and will continue for six
months post-HSCT.
The null hypotheses for sequential monitoring are that the true rate of TRM is less than 15% in
the allogeneic arm and less than 8% in the autologous arm, and that the true incidence of each of
the specified toxicities is less than 10%. If any of the observed incidence rates are substantially
in excess of these targets, the null hypothesis will be rejected and the NHLBI will be notified.
These guidelines are provided as an “early warning” system. Suspension of enrollment is not
automatic, but at the discretion of the NHLBI upon recommendation of the DSMB, which will
have the opportunity to request and review additional analyses.
Transplant-related Mortality (TRM)
The rate of TRM up to six months post-HSCT will be monitored separately in each treatment
arm. Monitoring will be performed monthly until enrollment to that treatment arm is closed.
Each month, the null hypothesis that six month TRM is less than or equal to a threshold value
will be tested against the alternative that it is greater than a threshold value. In the allogeneic
arm, the threshold value will be 15%; in the autologous arm, the threshold value will be 8%. An
extension of the Sequential Probability Ratio Test (SPRT) will be used. A description of this
sequential testing procedure is provided below.
The SPRT can be represented graphically. At each monthly interim analysis, the total time on
study is plotted against the total number of observed deaths. The continuation region of the
SPRT is defined by two parallel lines. Only the lower boundary will be used for monitoring each
treatment arm to protect against poor 180-day TRM. If the graph falls below the lower
boundary, the SPRT rejects the null hypothesis, and concludes that there are more deaths than
predicted by the observed time on study. Otherwise, the SPRT continues until enrollment to the
treatment arm reaches the target goal.
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This procedure assumes an exponential distribution for the time until failure until six months
post-HSCT, but censors follow-up time after six months. Only deaths without relapse or
progression that occur on or before the patient has been followed for six months post-HSCT are
counted. Total time on study is computed as time from enrollment to death, or to six months
post-HSCT, whichever comes first, summed for all individuals on study.
The usual measures of performance of an SPRT are the error probabilities and of rejecting
H0 when = 0 and of accepting H1 when = 1, respectively, and the expected sample size
E(N|i). The tests to be used in this protocol were developed from a SPRT contrasting 15%
versus 30% six-month TRM, in the non-myeloablative allogeneic HSCT arm, and 8% versus
14% in the autologous HSCT arm. The slope and intercept of the lower boundary are 2.00 and -
6.48, respectively, for the non-myeloablative allogeneic HSCT arm, and 4.33 and –17.69,
respectively, for the autologous HSCT arm.
The actual operating characteristics of the truncated tests, shown in Table 5.4.1a, were
determined in a simulation study that assumed uniform accrual of either 80 non-myeloablative
allogeneic HSCT recipients or 240 autologous HSCT recipients over a three year time period,
and exponential time to failure after enrollment.
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Table 5.4.1a: Operating Characteristics of Sequential Testing Procedure
Transplant-related Mortality
from a Simulation Study with 100,000 Replications
Operating Characteristics for Allogeneic Arm N = 80
True 6 Month Post-HSCT
Mortality
15%
20%
25%
30%
Probability Reject Null
0.04
0.24
0.60
0.88
Mean Month Stopped
36.1
32.7
26.1
19.1
Mean # Deaths in 6 Mo.
11
13
13
11
Mean # Patients Enrolled
78
71
57
43
Operating Characteristics for Autologous Arm N = 240
True 6 Month Post-HSCT
Mortality
8%
10%
12%
14%
Probability Reject Null
0.05
0.24
0.57
0.84
Mean Month Stopped
36.0
32.8
26.9
20.5
Mean # Deaths in 6 Mo.
18
20
19
17
Mean # Patients Enrolled
234
214
177
136
In the non-myeloablative allogeneic HSCT arm, the procedure rejects the null hypothesis in
favor of the alternative 4% of the time when the true six-month TRM is 15%, and 88% of the
time when the true rate is 30%. This corresponds to a type I error rate of = 0.04 and a type II
error rate of = 0.12. When the true six-month TRM is 30%, on average, the Data and Safety
Monitoring Board will be consulted 19.1 months after opening, when 11 deaths have been
observed in 43 patients.
In the autologous HSCT arm, the procedure rejects the null hypothesis in favor of the alternative
5% of the time when the true six-month TRM is 8%, and 84% of the time when the true rate is
14%. This corresponds to a type I error rate of = 0.05 and a type II error rate of = 0.16.
When the true six-month TRM is 14%, on average, the Data and Safety Monitoring Board will
be consulted 20.5 months after opening, when 17 deaths have been observed in 136 patients.
Regimen-related Toxicities
The protocol specifies that the following toxicities are safety endpoints:
1) Grade ≥ 3 hepatic toxicity in the non-myeloablative allogeneic HSCT arm
2) Renal toxicity of serum creatinine > 3.0 mg/dL in the non-myeloablative allogeneic
HSCT arm
3) Grade ≥ 3 neutropenia in the autologous HSCT arm after rituximab maintenance therapy
4) Grade ≥ 3 pulmonary toxicity/pneumonitis in the autologous HSCT arm
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Hepatic and renal toxicities are considered sufficiently life-threatening to warrant use of
statistical stopping guidelines to monitor these toxicities monthly. If cumulative incidence rates
exceed the target threshold of 10%, the NHLBI will be notified and may require immediate
DSMB review that could result in termination of enrollment to the non-myeloablative allogeneic
HSCT arm.
Neutropenia and pneumonitis can often be successfully managed through early intervention, and
statistical stopping guidelines will not be used to monitor these toxicities monthly. Instead, the
cumulative incidence of these toxicities will be reported, along with other accumulated safety
and efficacy data, to the DSMB at regularly scheduled meetings.
The stopping guidelines for hepatic and renal toxicity were derived from an SPRT contrasting
10% versus 15% cumulative incidence rates, cumulated at six months post-HSCT. The slope
and intercepts of the lower boundary are 3.74 and –12.97, respectively, for the non-
myeloablative allogeneic HSCT arm. Refer to the description of the stopping guideline for TRM
in Section 5.4.2 for a discussion of the statistical methodology used. The parameters of the
SPRT were adjusted so that the probability of stopping would be approximately < 1%, 10% and
> 85% at cumulative incidence of 5%, 10% and 20%, respectively.
The usual measures of performance of an SPRT are the error probabilities and of rejecting
H0 when = 0 and of accepting H1 when = 1, respectively, and the expected sample size
E(N|i). The actual operating characteristics of the truncated tests, shown in Table 5.4.1b, were
determined in a simulation study that assumed uniform accrual of either 80 non-myeloablative
allogeneic HSCT recipients or 240 autograft recipients over a three year time period, and
exponential time to failure after enrollment.
Table 5.4.1b: Operating Characteristics of Sequential Testing Procedure
Regimen-related Toxicities > 10%
from a Simulation Study with 100,000 Replications
Operating Characteristics for Non-myeloablative Allogeneic HSCT Arm N = 80
True 6 Month Post-HSCT
Incidence
5%
10%
15%
20%
Probability Reject Null
0.00
0.08
0.45
0.84
Mean Month Stopped
35.7
30.0
22.0
Mean # Events in 6 Mo.
3.8
7.3
9.1
8.6
Mean # Patients Enrolled
79.9
77.4
65.7
48.8
In the non-myeloablative allogeneic HSCT arm, the procedure rejects the null hypothesis in
favor of the alternative 8% of the time when the true six-month incidence is 10%, and 84% of the
time when the true rate is 20%. This corresponds to a type I error rate of = 0.08 and a type II
error rate of = 0.16. When the true six-month incidence is 20%, on average, the Data and
Safety Monitoring Board will be consulted 22.0 months after opening, when 8.6 events have
been observed in 48.8 patients.
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5.5. Analysis Plan
All analyses are based on an intent-to-treat. In such an analysis, patients are in the non-
myeloablative allogeneic HSCT arm if they have a suitable HLA-matched sibling donor whether
or not the non-myeloablative allogeneic HSCT occurs.
5.5.1. Analysis of the Primary Endpoint
The primary outcome of the trial is lymphoma progression-free survival at three years post-
HSCT. The primary null hypothesis of the study is that there is no difference in three-year
progression-free survival between the autologous and non-myeloablative allogeneic HSCT arms.
The alternative hypothesis is that progression-free survival differs between autologous and non-
myeloablative allogeneic HSCT strategies. The primary outcome will be assessed in a final
analysis to be performed after the last enrolled patient has been followed for three years post
enrollment.
In the final analysis, the endpoint of 3-year progression-free survival will be estimated using the
Kaplan-Meier product limit estimator, and compared between treatment arms using the modified
Mantel-Haenszel test statistic stratified by clinical center. The test statistic is described in
Appendix E. Additional secondary analyses utilizing this approach will: a) incorporate
progression-free survival beyond the three-year time-point, and b) test for the effect of follicular
lymphoma grade at entry on progression-free survival. Estimates of the differences between
progression-free survival functions and confidence bands for these differences will be performed
using the procedure of Zhang and Klein [58]. In the event that there are no significant
differences between the arms, a post-hoc power analysis will be performed.
In a secondary analysis, outcomes in the autologous transplant arm at 1, 2, and 3 years post-
HSCT will be compared to an external cohort registered with the CIBMTR. In a subset of
autologous transplant patients registered with the CIBMTR who met the basic eligibility criteria
for the study (age 18-70, chemosensitive disease, no more than 3 prior regimens, adequate graft
and performance status), overall survival, disease-free survival, and relapse-free survival were
.87, .64, and .32 at one year post-autologous HSCT, and .70, .45, and .48 at three years post-
autologous HSCT, respectively. Using patient-level data from this trial and from the CIBMTR
registry, the survival curves will be compared using the procedures of Zhang and Klein.
5.5.2. Analysis of Secondary Endpoints
A number of secondary outcomes will be examined to compare the patient’s disease status over
time between treatment arms.
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Overall Survival:
The event is death from any cause. Patients alive at the time of the last observation are censored
at the time of the last observation. In the primary analysis in all enrolled patients, time-to-event
will be measured from enrollment. In a secondary analysis including only patients who received
their HSCT, time-to-event will be measured from the date of HSCT. Overall survival will be
compared between treatment arms using a log-rank test, and the survival curves will be estimated
using the Kaplan Meier Estimator.
Time to Progression:
The event is relapse/progression. Death without relapse/progression is considered a competing
risk. Patients alive with no history of relapse/progression are censored at the time of the last
observation. In the primary analysis in all enrolled patients, time-to-event will be measured from
enrollment. In a secondary analysis including only patients who received their HSCT, time-to-
event will be measured from date of HSCT. Time to progression will be compared between
treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.
Time to CR and CR+PR:
The event is CR (CR or PR). The time to event is the time to CR (CR or PR). Patients who die
in a state other than CR (CR or PR) are considered as failing from a competing risk. Patients
alive and not in CR (CR or PR) at the time of last observation are censored at the time of last
observation. In the primary analysis in all enrolled patients, time-to-event will be measured from
enrollment. In a secondary analysis including only patients who received their HSCT, time-to-
event will be measured from the date of HSCT. Time to CR (CR or PR) will be compared
between treatment arms using a log-rank test, and the cumulative incidence curves will be
estimated.
Time to Off-study Therapy:
The event is the initiation of any anti-lymphoma therapy other than that defined by the protocol
treatment arms. Patients who die without initiation of an off-study therapy will be considered as
experiencing a competing risk. Patients who do not receive an off-study therapy but are alive at
the end of the study will be censored at the time of last observation. In the primary analysis in
all enrolled patients, time-to-event will be measured from enrollment. In a secondary analysis
including only patients who received their HSCT, time-to-event will be measured from date of
HSCT. Time to off-study therapy will be compared between treatment arms using a log-rank
test, and the cumulative incidence curves will be estimated.
Health Quality of Life:
Overview
The goal of the Health Quality of Life (HQL) component of this trial is to describe the HQL of
study participants. In addition, as possible, with the available sample size differences in quality
of life among recipients of the two treatment strategies in this protocol will be examined. All
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patients registered to the clinical trial are potentially eligible for the study, and consent for
participation will be obtained as part of consent for the clinical trial. Patients who cannot
communicate in English or Spanish, cannot complete HQL questionnaires due to cognitive,
linguistic or emotional difficulties, will be excluded from the study. We anticipate that 90% of
registered patients will be eligible, and that compliance will be roughly 80% among surviving
patients, based on experiences with The Unrelated Donor Marrow Transplantation Trial
(formerly the T Cell Depletion Trial) and other studies of HQL conducted for the NHLBI in bone
marrow transplant recipients.
Instruments, Administration and Scoring Methods
In order to minimize response burden and increase the chance of complete response, the
selection of instruments has been limited to the FACT-BMT [58] and the SF-36 [60, 61]. The
FACT-BMT is comprised of a general core questionnaire, the FACT-G, evaluates the Quality of
Life (QOL) of patients receiving treatment for cancer, and a specific module, BMT Concerns,
that addresses disease and treatment-related questions specific to bone marrow transplant. The
MOS SF-36 is a general assessment of health quality of life that has been widely applied in a
variety of outcome studies and is being used in this trial as a generic measure of QOL.
HQL will be assessed through a self-administered questionnaire distributed to patients at clinic
visits. The assessments will be conducted at baseline prior to the cytoreductive/mobilization
therapy and at two years post-HSCT. The protocol permits administration within a two-week
window before the target date for the first interview, and within a +/- two-week window centered
on the target date for the subsequent yearly interviews. The HQL instruments will be scored
according to standard methods for these tools. Specifically, the FACT-BMT will be scored using
software provided in the FACIT Manual Version 4 [59], and the MOS SF-36 will be scored
using software provided in the SF-36 Health Survey Manual and Interpretation Guide [60] and
the SF-36 Physical and Mental Health Summary Scales: A User’s Manual [61].
Analysis and Interpretation of Results
While descriptive analyses will consider all HQL outcomes, following the lead of David Cella in
the analysis of ECOG Study 5592 [62], the primary HQL endpoint for hypothesis testing will be
the Trial Outcome Index (TOI). The FACT-BMT TOI is derived by adding the scores on the
Physical Well-Being and Functional Well-Being subscales of the FACT-BMT, to the BMT
symptoms module score. At two years post-HSCT, it is anticipated that the TOI, which contains
relevant questions about physical functioning and BMT symptoms, will be most sensitive to long
term differences in HQL attributable to differences in treatment strategy.
The initial analysis of the questionnaire data will focus on describing and reporting the HQL of
study participants, through tables, graphs, and summary statistics characterizing the HQL scores
over time in each treatment arm. Differences in QOL between the autologous HSCT and non-
myeloablative allogeneic HSCT arms will be assessed in several ways. First, the marginal QOL
scores given that the patient is alive will be compared at the specific time points described above
using simple T-tests. Second, the Integrated Quality Adjusted Survival [63] will be compared.
This latter approach aggregates QOL over the entire period of observation, and accounts for
potential differences in survival rates. If an examination of patterns of missing data indicates
that there is substantial informative censoring due to causes other than death, techniques for joint
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modeling of survival and longitudinal data developed by Schluchter [64], and extended by
Ibrahim et. al [67], will be considered.
Statistical Power and Sample Size Considerations
The trial is not designed to be powered for a primary endpoint of detecting differences in QOL
between the two treatment strategies. The HQL analysis in the study will be primarily
descriptive. We can, however, estimate the power of the study to detect differences between the
groups based on expected survival and prior HQL studies. The TCD Trial observed a baseline
mean FACT-BMT TOI score of 67.2, with a standard deviation of 13.8 units, and a mean SF-36
Physical Component Score of 41.6, with a standard deviation of 10.2 units. These data are
consistent with published norms for the FACT-BMT in HSCT recipients, and the SF-36 in
cancer patients, respectively [59, 60, 61].
To illustrate the statistical power available, consider a comparison of the FACT-TOI at the two-
year time point between the autologous HSCT and non-myeloablative allogeneic HSCT patients.
Assuming 80 non-myeloablative allogeneic HSCT patients and 240 autologous HSCT patients,
90% of whom will be eligible for HQL study, a 80% survival rate at two years, and an 80%
response rate, approximately 46 allograft patients and 138 autologous HSCT patients will
complete the second year interview. The estimated sample size is sufficient to detect, with
statistical power of 80%, a difference in the FACT-TOI score of 6.6 units, and a difference in the
SF-36 PCS score of 4.9 units, using a two-sided level .05 T-test.
Incidence of Toxicities Grade ≥ 3 According to the CTCAE Version 3.0
For both arms, toxicities that occur over the course of time will be tabulated.
Grade ≥ 3 toxicities will be tabulated for each patient at set intervals over the course of the study.
The proportion of patients developing toxicity will be compared between treatment arms.
Infections
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for
each patient according to criteria in the BMT CTN Manual of Procedures. Infections will be
classified by organism, site and severity. Infection burden will be compared between treatment
arms.
Efficacy of Rituximab and Cyclophosphamide for In Vivo Purging
In vivo purging will be estimated by the proportion of patients whose peripheral blood converts
from positive for the t(14;18) by PCR prior to cytoreductive/mobilization therapy to negative
following this therapy. For patients in the autologous HSCT arm, the correlation between
t(14;18) results for peripheral blood samples and for collected autologous HSC will also be
estimated.
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Prognostic Value of t(14;18) by PCR in Predicting Relapse
A quantitative PCR assay for t(14;18) will be done on peripheral blood in patients with known
t(14;18). Results of serial post-HSCT samples will be analyzed to determine if there is a
threshold value that can reliably predict relapse, using statistical methods for classification and
regression trees. This analysis will be performed after the trial and the information will not be
available to direct clinical care of patients.
5.5.3. Analyses of Patients on the Non-myeloablative Allogeneic HSCT Treatment Arm
Several outcomes in this study are specific to the non-myeloablative allogeneic HSCT arm.
Between treatment arm comparisons will not be performed, but descriptive statistics will be
computed.
Primary and Secondary Graft Failure
Engraftment is defined as having ≥ 5% donor T cells in the peripheral blood (donor T cell
chimerism) chimerism. Median time to engraftment will be estimated from the cumulative
incidence of engraftment, treating death as a competing risk. Time to engraftment will be
measured from the date of receipt of the non-myeloablative allogeneic HSCT.
The rate of Primary Graft Failure will be estimated as the number of patients to engraft by Day
56 post-non-myeloablative allogeneic HSCT, divided by the total number of patients receiving a
non-myeloablative allogeneic HSCT.
The rate of Secondary Graft Failure will be estimated as the number of patients who engraft (at
any time prior to one year after receipt of the non-myeloablative allogeneic HSCT), and
subsequently lose chimerism (< 5%) in the first year post-engraftment, divided by the total
number of patients who engraft in the first year after receipt of the non-myeloablative allogeneic
HSCT.
Incidence and Severity of Graft-Versus-Host Disease
GVHD will be graded according to criteria in the BMT CTN MOP. The cumulative incidence
curves for acute and chronic GVHD will be estimated treating death as a competing risk.
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APPENDIX A
REFERENCES
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APPENDIX A
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13. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol
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CD20 with monoclonal antibodies. Blood 1998;91:1644-1652.
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25. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20
monoclonal antibody therapy for relapsed indolent lymphoma half of patients respond to
four-dose treatment program. J Clin Oncol 1998;16:2825-2833.
26. Colombat P, Salles G, Brousse N et al. Rituximab as single first-line therapy for patients
with follicular lymphoma with a low tumor burden: clinical and molecular evaluation.
Blood 2001;97:101-106.
27. Buckstein R, Imrie K, Spaner D, et al. Stem cell function and engraftment is not affected
by ‘in vivo purging’ with rituximab for autologous stem cell treatment for patients with
low-grade non-Hodgkin’s lymphoma. Semin Oncol 1999;5 (suppl 14):115-122.
28. Salles G, Moullett I, Charlot C, et al. In vivo purging with rituximab before autologous
peripheral blood progenitor cells transplantation in lymphoma patients. Blood 1999;94
(suppl 1): 141a
29. Haioun C, Delfau-Larue MH, Beaujean F et al. Efficiency of in vivo purging with
rituximab followed by high-dose therapy with autologous peripheral blood stem cell
transplantation in B-cell non-Hodgkin’s lymphomas. A single institution study. Blood
2006;96 (Suppl 1):384a
30. Goldberg SL, Pecora AL, Jennis AA et al. Rituximab permits in vivo purging and
collection of tumor-free stem cells prior to autologous transplantation for B-cello non-
Hodgkin’s lymphoma. Blood 1999;94 (suppl 1):141a
31. Magni M, Di Nicola M, Devizzi L et al. Successful in vivo purging of CD34 containing
peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of
both chemotherapy and rituximab infusion. Blood 2000;96:864-869.
32. Voso MT, Pantel G, Weiss M, et al. In vivo depletion of B cells using a combination of
high-dose cytosine arabinoside/mitoxantrone and rituximab for autografting in patients
with non-Hodgkin’s lymphoma. Br J Haematol 2000;109:729-35
33. Ladetto M, Zallio F, Ricca I, et al. Concurrent administration of high-dose chemotherapy
and rituximab is a feasible and effective chemo/immunotherapy for patients with high-
risk non-Hodgkin’s lymphoma. Leukemia 2001;15:1941-1949
34. Buckstein R, Imrie K, Spaner D et al. Consolidative immunotherapy with rituxan in
autologous stem cell transplantation in follicular lymphoma is associated with molecular
remissions. Proc Am Soc Clin Oncol 2000;19:26a
35. Horwitz SM, Negrin RS, Blume KG,et al. Rituximab as adjuvant to high-dose therapy
and autologous hematopoietic cell transplantation for aggressive non-Hodgkin
lymphoma. Blood 2004; 103:777-783
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36. Verdonck LF, Dekker AW, Lokhort HM, et al. Allogeneic versus autologous bone
marrow transplantation for refractory and recurrent low-grade non-Hodgkin’s lymphoma.
Blood 1997;90:4201-4205.
37. van Besien K, Sobocinski KA, Rowlings PA, et al. Allogeneic bone marrow
transplantation for low grade lymphoma. Blood 1998:92:1832-1836.
38. van Besien KW, Khouri IF, Giralt SA. Allogeneic bone marrow transplantation for
refractory and recurrent low grade lymphomas: the case for aggressive treatment. J Clin
Oncol 1995;13:1096-1102.
39. Gale RP, Champlin RE. How does bone marrow transplantation cure leukemia? Lancet
1984;2:28-30.
40. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone
marrow transplantation. Blood 1990;75:555-562.
41. Sullivan KM, Storb R, Buckner CD et al. Graft-versus-host disease as adoptive
immunotherapy in patients with advanced hematologic neoplasms. N Engl J Med
1989;320:828-834.
42. Kolb JH, Schattenberg A, Goldman JM et al. Graft-vs-leukemia effect of donor
lymphocyte infusions in marrow grafted patients. Blood 1985;86:2041-2050.
43. Collins R, Rogers Z, Bennett M, et al. Hematologic relapse of chronic myelogenous
leukemia following allogeneic bone marrow transplantation: apparent graft-vs-leukemia
effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant
1992;10:391-395.
44. Collins RH, Shpillberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients
with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol
1997;15:433-444.
45. Luznik L and Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies
in relapse after allogeneic blood or marrow transplantation.
Cancer Control 2002;9:123-37.
46. Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor lymphocyte infusions for
relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors
for response and long-term outcome. J Clin Oncol 2000;18:3031-3037
47. van Besien KW, de Lima M, Moore DF et al. Management of lymphoma recurrence
after allogeneic transplantation: the relevance of graft-vs-lymphoma effect. Bone
Marrow Transplant 1997;19:977-982.
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48. Van Besien KW, Loberiza FR, Bajorunaite R, et al. Comparison of autologous and
allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003;
102:3521-3529
49. Porter D, Connors J, Van Deerlin V, et al. Graft-versus-tumor induction with donor
leukocyte infusions as primary therapy for patients with malignancies. J Clin Oncol
1999;17:1234-1243.
50. Spitzer TR, McAfee S, Sackstein R, et al. Intentional induction of mixed chimerism and
achievement of anti-tumor responses after nonmyeloablative conditioning therapy and
HLA-matched donor bone marrow transplantation for refractory hematologic
malignancies. Biol Blood Marrow Transplant 2000;6:309-20.
51. Sharabi Y, Abraham VS, Sykes M, et al. Mixed allogeneic chimeras prepared by a non-
myeloablative regimen: requirement for chimerism to maintain tolerance. Bone Marrow
Transplant 1992;9;191-197.
52. Friedman TM, Varadi G, Hopely DD, et al. Nonmyeloablative conditioning allows for
more rapid T-cell repertoire reconstitution following allogeneic matched unrelated bone
marrow transplantation compared to myeloablative approaches. Biol Blood Marrow
Transplant 2001;7:656-664.
53. Chao NJ, Liu CX, Rooney B, et al. Nonmyeloablative regimen preserves "niches"
allowing for peripheral expansion of donor T-cells. Biol Blood Marrow Transplant
2002;8:249-56.
54. Weissinger F, Sandmaier BM, Maloney DG, et al. Decreased transfusion requirements
for patients receiving nonmyeloablative compared with conventional peripheral blood
stem cell transplant from HLA-identical siblings. Blood 2001;98:3584-3588.
55. Khouri I, Saliba RM, Giralt SA et al. Nonablative allogeneic hematopoietic
transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of
toxicity, acute graft-vs-host disease, and treatment-related mortality. Blood
2001;98:3595-3599.
56. Robinson SP, Goldstone AH, Mackinnon S et al. Chemoresistant or aggressive
lymphoma predicts for poor outcome following reduced-intensity allogeneic progenitor
cell transplantation: an analysis from the Lymphoma Working Party of the European
Group for Blood and Bone Marrow Transplantation. Blood 2002;100:4310-4316.
57. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to
standardize response criteria for non-Hodgkin’s lymphoma. J Clin Oncol 1999;17:1244-
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58. Zhang M, and Klein J. Confidence bands for the difference of two survival curves under
proportional hazards model. Lifetime Data Analysis 72243-254, 2001.
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59. Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT)
Measurement Systems, Version 4. Center on Outcomes, Research and Education (Core).
Evanston: Northwestern Healthcare and Northwestern University, 1997.
60. Ware JE, Snow K, Kosinski M, Gandek B. SF-36 Health Survey, Manual and
Interpretation Guide. The Health Institute, 1993.
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User’s Manual. The Health Institute, 1994.
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63. Billingham. Simultaneous Analysis of Quality of Life and Survival. Stat Med 11: 25-48,
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64. Schluchter MD. Methods for the analysis of informatively censored longitudinal data.
Stat Med 11: 1861-70, 1992.
65. Ibrahim JG, Chen MH, Sinha D. Bayesian methods for joint modeling of longitudinal
and survival data with application to cancer vaccine studies. Applied Statistics, 2001.
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APPENDIX B
CONSENT FORMS
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PATIENT CONSENT
IRB #
Page 1 of 24
Patient Initials _________
Informed Consent to Participate in Research
Please read this form carefully. If there are words or part of this document that you do not
understand, you should ask the research doctor or staff to explain any information that is not
clear to you before making a decision whether to participate. Your participation is entirely
voluntary. You may choose not to participate and you may withdraw at any time.
The Principal Investigator (the person in charge of this research) or a representative of the
Principal Investigator will also describe this study to you and answer all or your questions.
Please ask questions about anything that you do not understand.
If you are a parent or guardian of a patient younger than 18 years old and have been asked to
read and sign this form, the “you” in this document refers to the patient.
This is a consent form for a research study. This form is to help you decide if you want to
participate in this study.
The consent form describes a study for patients with follicular lymphoma who have entered
remission from treatment with conventional chemotherapy but the lymphoma has now returned.
Follicular lymphoma is not curable with standard chemotherapy. Standard stem cell transplants
have been used to get patients into remission and improve survival, but the disease still returns.
This study will compare two types of transplants. The purpose is to see if one type of transplant
has better results than the other. The study may also find that patients have similar results with
either type of transplant.
The results that are important to the study include:
Blood counts after transplant
Possible occurrence of infection
Graft-versus-host disease (GVHD)
Return of lymphoma
How long you live after transplant
Your quality of life
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This study will give more information to doctors about future treatment choices. In addition:
You will not be paid to be in this study.
You or your insurance company will pay for all medical bills for your treatment.
You will not be charged for research tests.
You will also face the same risks and benefits as any other transplant patient.
Before you decide to join the study, please read the information below. Feel free to ask
questions to understand your rights. It is your choice to take part in this study. You and your
doctor will discuss other treatment options if you decide not to be in this study.
1.
Name of the Subject (“Study Subject”)
2.
Title of Research Study
Autologous versus Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for
Patients with Chemosensitive Follicular Non-Hodgkin’s Lymphoma Beyond First Complete
Response or First Partial Response
3a.
Principal Investigator Contact Information
Insert name, affiliation and contact information.
3b.
Contact Information for Emergencies After Hours or on Weekends or Holidays
Call (xxx) xxx-xxxx, the in-patient Bone Marrow Transplant Unit. Ask to speak to the Charge
Nurse.
4.
Sponsor and Source of Funding or Other Material Support
The research in this study is paid for by the National Institutes of Health (NIH). The Blood and
Marrow Transplant Clinical Trials Network (BMT CTN) will direct the research study.
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5.
Study Purpose
This study will compare the results from two types of blood stem cell transplant along with the drug
rituximab for patients who have follicular lymphoma. The two types of stem cell transplant
(SCT) that are compared in this study are AUTOLOGOUS SCT and NON-MYELOABLATIVE
ALLOGENEIC SCT. Both autologous SCT and non-myeloablative allogeneic SCT have
successfully treated this kind of lymphoma.
6.
Study Plan
Patients who are able to use matched, donated stem cells from a brother or sister will have an
allogeneic non-myeloablative SCT. Patients without a matched brother or sister will have an
autologous SCT.
An autologous SCT uses your own stem cells for the transplant:
Before transplant, your stem cells are collected in a process called leukapheresis, then frozen
(or cryopreserved).
You will have high doses of chemotherapy, with or without radiation, to kill the lymphoma
cells in your body.
The high amounts of chemotherapy and radiation also damage your bone marrow and
immune system.
Your blood stem cells will be given back to you to undo the effects of the chemotherapy.
An allogeneic SCT uses blood stem cells from a brother or sister donor for the transplant. The type
of allogeneic transplant used in this study is called a non-myeloablative allogeneic stem cell
transplant .
Non-myeloablative allogeneic SCTs use lower amounts of chemotherapy and radiation than
what is used in standard allogeneic transplants.
After the chemotherapy, the stem cells from your donor will be given to you.
Your immune system will be replaced by the donor’s immune system.
A non-myeloablative allogeneic SCT depends on the donor’s immune system to destroy the
lymphoma cells in your body.
Rituximab Therapy
Whether you receive the autologous or non-myeloablative allogeneic SCT, you also will receive
several doses of a drug called rituximab. Rituximab is a drug that is not considered
chemotherapy but is called a monoclonal antibody. This drug works by attacking only the B
cells in your body. B cells are a type of white blood cell in your blood, bone marrow and lymph
nodes that normally help fight infection. However, in patients with follicular lymphoma, it is the
B cells that become malignant (cancerous) and become lymphoma cells. Rituximab is already
commonly used either alone or together with chemotherapy for patients with follicular
lymphoma and other types of lymphoma.
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Patient Initials _________
7.
Procedures and Tests that are Being Done as Part of you Care
If you agree to participate in this study, your transplant process will include many steps to:
Evaluate your health.
Determine if you have a matched brother or sister donor.
Prepare your body for a stem cell transplant.
Receive your stem cell transplant.
Help your body recover after transplant.
Measure your health and well-being over three years after your transplant.
If you have a matched brother or sister donor, in order for them to participate they will also have
a health evaluation and if able to donate their cells collected for transplant and sign a consent for
the study.
The treatment will start with cytoreduction. Cytoreduction is a process to kill as many lymphoma
cells as possible in your body before transplant. All study participants will have cytoreduction
before either type of stem cell transplant (autologous or allogeneic non-myeloablative). This
process uses chemotherapy and rituximab to lower the number of lymphoma cells and another
drug, filgrastim (G-CSF) to rebuild your white blood cells:
Rituximab (also called Rituxan) – to lower the number of lymphoma cells,
Cyclophosphamide – also to lower the number of lymphoma cells, and
Filgrastim (G-CSF) – to increase production of healthy white blood cells.
Table 1: Cytoreduction Schedule
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8
Rituximab
Cyclophosphamide
Filgrastim
If you will be receiving the autologous SCT, you will undergo a procedure called leukapheresis
about 12-13 days after receiving the cyclophosphamide. This collects stem cells from your
bloodstream as your blood counts recover from the treatment mentioned above. The stem cells
are then frozen and stored (cryopreserved). The procedure is explained in more detail at the end
of this form.
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A)
Non-myeloablative stem cell transplant
If you have a genetically (HLA) matched brother or sister, you will have a non-myeloablative
allogeneic SCT. Your brother or sister must be willing and able to donate blood stem cells for your
transplant.
Once your body recovers in about 4 to 6 weeks from the cytoreduction treatment, you will start
the conditioning regimen also known as the preparative regimen. This is done to prepare your
body for transplant.
Your doctor will use a combination of two drugs and rituximab given through your veins:
Rituximab – to lower the number of lymphoma cells, and
Cyclophosphamide – also to lower the number of lymphoma cells and lower the chance of
donor stem cell rejection, and
Fludarabine – to lower the chance of donor stem cell rejection.
The purpose of this treatment is to weaken your immune system and lower the chance that your
body will reject the donated stem cells.
You will receive two more drugs during this process to lower the chance of rejecting the donor cells
and to lower the chance of developing serious graft-versus-host disease:
Tacrolimus
Methotrexate
Tacrolimus can be taken as a pill or by injection into your vein. Your doctor will decide how you
will take it. You will need to take the tacrolimus for at least 6 months. You may need to take it
longer if you develop graft-versus-host disease. Methotrexate will be given through your vein for 3
doses on the first, third and sixth day after your transplant.
Graft-versus-host disease (GVHD) is a condition where the donated stem cells attack your skin,
liver, intestines and other organs. There is about a 50-60% chance that GVHD will happen after a
non-myeloablative allogeneic SCT, but in most cases it is a mild form of GVHD. GVHD can be
both helpful and harmful. Mild GVHD may protect against the return of your lymphoma, by
attacking the cancer cells. There is approximately a 10-15% chance that serious GVHD may cause
organ damage or even death in some cases.
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Table 2: Conditioning Schedule for Non-myeloablative SCT
Days BEFORE Transplant
-13
-6
-5
-4
-3
-2
-1
0
Fludarabine
Cyclophosphamide
Rituximab
Tacrolimus
daily
Transplant
You will have your transplant on “Day Zero (0).”
Days AFTER Transplant
1
2
3
4
5
6
7
8
Rituximab
Tacrolimus *
Methotrexate
* Tacrolimus will be given daily for at least 6 months or longer if GVHD occurs
B)
Autologous stem cell transplant
If you have an autologous stem cell transplant, you will have your own cells collected before the
transplant.
Once your body recovers, about 4 to 6 weeks after the cytoreduction treatment, you will start the
conditioning regimen which is also be called the preparative regimen. The conditioning
regimen will be chemotherapy based and may include total body irradiation. Whether you
receive irradiation in addition to chemotherapy will be determined by your physician and by
what preparative regimen is routinely used at your particular hospital/institution. This depends
on the doctors at your transplant center. Conditioning is done to prepare your body for
transplant. All of the drugs listed below will be given through your veins except the filgrastim,
which will be given subcutaneously (injection just under the skin). You will start daily
subcutaneous injections of filgrastim starting 5 days after your transplant day to help your white
blood cells recover faster.
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Your doctor will use:
Cyclophosphamide – to lower the number of lymphoma cells
Rituximab – also to lower the number of lymphoma cells
Carmustine or Fractionated Total Body Irradiation – to lower the number of lymphoma
cells
VP-16 – to lower the number of lymphoma cells
Filgrastim (G-CSF) – to help your bone marrow make white blood cells after
chemotherapy
Only one of the tables below will apply to you. It depends on if you receive total body irradiation
plus chemotherapy, or chemotherapy alone. You will have your transplant on “Day Zero (0).”
Table 3: Preparative Schedule Using Chemotherapy and Total Body Irradiation
Day
-8
-7
-6
-5
-4
-3
-2
-1
0
Radiation
Radiation
Radiation
Radiation
VP-16
Cyclopho-
sphamide
Transplant
Table 4: Preparative Schedule Using Chemotherapy Only
Day
-6
-5
-4
-3
-2
-1
0
Carmustine
VP-16
Cyclopho-
sphamide
Transplant
Your rituximab maintenance therapy will start about six weeks after your transplant. You will
receive 4 weekly doses of rituximab through your veins. The rituximab therapy is to remove any
lymphoma cells that may have survived the high dose chemotherapy.
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8.
What are risks of this research study?
Details of all potential side effects, including those that occur rarely, are discussed in the
Appendix.
You will face risks from the transplant itself, and from treatments given before and after the
transplant. Your doctor thinks these risks are less than the risk from your cancer. Your heart,
lungs, liver, bladder, kidneys, brain or other organs may be damaged by the chemotherapy or
irradiation, or by other drugs given to you after the transplant. Your risk of infection is also
increased when undergoing a stem cell transplant. This is due to the chemotherapy that weakens
your immune system. Potential infection can be caused by either a bacteria, virus or a fungal
organism. Your doctors will monitor you closely for any sign of infection, especially fevers.
During the cytoreductive phase, the most common complications are fever, chills and shortness
of breath during infusion of rituximab, nausea from the cyclophosphamide, and bone pain from
the filgrastim. Patients will be at risk for infections and may need transfusions during the 7-14
days when the blood counts are low following this treatment. Those patients who will have
stem cells collected may experience temporary numbness or tingling of the fingertips or around
the mouth during the blood stem cell collection procedure.
Autologous transplant patients commonly experience some nausea when receiving the
chemotherapy or irradiation. Infusion of the stem cells may be accompanied by an unusual taste
for a few hours, transient nausea, and occasionally shortness of breath. Nausea, diarrhea and
sore throat usually occur about a week after transplantation and lasts for several days. The blood
counts are very low for about 2 weeks after transplantation, and during this time, the patient is at
high risk for infection and bleeding. Most patients require transfusions of red blood cells and
platelets during this time. While the risk of early death following autologous transplant is low,
death could occur. The patient may also fail transplant treatment due to relapse of lymphoma.
Allogeneic transplant patients may experience any of the side effects from chemotherapy, drug
therapy or cell therapy as listed in the appendix. The patient's blood counts are expected to be
low for about 1 week after transplant and this increases the risk of serious and even life-
threatening infection. Transfusions of blood and/or platelets and/or intravenous antibiotics may
be necessary. There is a possibility that the donor cells will not "take", in other words, not
engraft. The period of low blood counts could then be longer but the patient's own marrow
function and cell count recovery would be expected to recover. If engraftment occurs, there is
about a 50% chance that graft versus host disease (GVHD) will occur. GVHD occurs when the
donor’s immune system attacks the patient's organs. The most common organs affected are: 1.)
the skin which would result in rash, peeling, and/or deeper injury, 2.) the gut which would cause
diarrhea, cramping and possible blood loss, and 3.) the liver which would cause inflammation
and/or dysfunction or failure. Medications, including tacrolimus and methotrexate will be given
to reduce the risk of acute GVHD. However, if GVHD occurs, additional therapy would be
required to treat it. The GVHD might be stopped or it could progress and result in life-
threatening medical problems, including late chronic GVHD or possibly death. It is possible that
the patient could experience injury to any organ or system as a result of required medications,
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transfusions, transplant, and/or other therapies. While the risk of early death following non-
myeloablative transplant is low, death could occur. The patient may also fail transplant
treatment due to relapse of lymphoma.
9.
What other choices are there if I do not take part in this study?
Participation in this study is entirely voluntary. You are free to refuse to be in the study, and
your refusal will not affect current or future health care you receive at this institution. You and
your doctor will discuss any other treatment options available to you including:
Treatment with other drugs or combination of drugs.
A standard autologous stem cell transplant.
A standard or non-myeloablative allogeneic stem cell transplant.
No therapy directed against your lymphoma at this time, with care to help you feel more
comfortable.
10.
Are there benefits to taking part in this research study?
You may receive no direct benefits from this study. You may or may not benefit from the
scheduled medical assessments required for this study, and extra support from personnel working
for this study.
You may be helping other patients get better treatment in the future.
11.
What will be done with my blood and tissue samples?
Research Blood Samples
Genetic material is any sample of tissue, blood, fluid, etc. obtained from you during the study.
With your permission, 10 mL of your blood will be collected prior to the transplant and stored to be
used solely for research purposes. The samples will be stored for future studies that will look at
responses to treatment based on factors not yet known. These factors may relate to characteristics
of your follicular NHL or to how your body tolerated the study treatments. Usually these blood
samples can be drawn from you at the time of routine blood collections. Your confidentiality will
be maintained because no identifying markers (name, etc.) will remain with the sample.
All BMT CTN research samples will be paired with the respective donor or recipient sample and
given unique bar code designations that cannot be linked back to the donor or the recipient. All
research samples will become property of the NHLBI after conclusion of the BMT CTN Protocol
#0202 study. An NHLBI Biologic Specimen Repository Utilization Committee will advise
NHLBI on requests for samples to perform research with these anonymous samples. If an
Investigator’s request for these samples is approved by the committee, the NHLBI may provide a
panel of the specimens requested using unique code numbers. Laboratory test results, clinical
information, etc., associated with the coded samples are provided to the Investigator only after
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completion of the main protocol. Samples sent to researchers cannot be linked with any
remaining sample at the repository.
If you agree to allow your blood to be kept for research, you are free to change your mind at any
time. We ask that you contact {Principal Investigator} in writing and let him know you are
withdrawing your permission for your blood to be used for research. His mailing address is on the
first page of this form.
You are free not to take part in this additional future research. There will be absolutely no
change in your care as a result of your refusal to give these additional samples. Please
indicate your choice(s) below:
I agree to have 10 mL of blood collected for future research.
No, I do not agree to have10 mL of blood collected for future research.
__________________________________
________________________
Signature
Date
12.
What if not enough cells are collected to use for transplant?
Your doctor will decide if it is safe to proceed to the planned transplant procedure, depending on
how many stem cells are actually collected. The risk of being transplanted with a low number of
stem cells is that your blood counts may return to normal levels very slowly or they may stay low
permanently. If this occurs, you may need many blood and/or platelet transfusions and/or your risk
of infection may increase. If you do not proceed to transplant, your doctor can offer other
alternatives such as chemotherapy and/or radiation if he/she feels this is appropriate.
13.
What are the costs?
You and/or your insurance company will pay all medical expenses relating to, or arising from
stem cell transplantation. Research tests will not be charged to you.
For questions about your costs, financial responsibilities, and/or medical insurance coverage for
your transplant and this study, please contact /Center/ Financial Counselor at /Number/.
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14.
Will I be paid to take part in this research study?
No.
15.
What will happen if I am sick or hurt because of this study?
If you are injured or become ill while taking part in this study, medical care will be provided at
this center. No funds have been set aside to pay you if you are injured. You or your insurance
company will be charged for ongoing medical care and/or hospitalization.
Contact your doctor or one of the people listed at the start of this form if you are concerned about
a research-related injury.
16.
Can I change my mind about taking part in this research study?
You may decide to quit this study at any time, for any reason, without notice. However, if you
quit after you have had some or all of the treatment but before your transplant, then your blood
counts may not return and you could die.
If you decide to quit, we ask that you tell [the Principal Investigator] in writing (his/her address
is on the front page of this form). If you do take back your consent, there will be no penalty and
you will not lose anything you are entitled to and will continue to receive medical care.
If you have any questions about your rights as a study subject, you may phone the Institutional
Review Board (IRB) office at /number/.
17.
Can my information still be collected and used if I leave the research study?
If you quit the study, we ask that you let us continue using all information that was already
collected. We also ask that you let your doctor continue to tell us about your progress until 5 years
after your transplant. You may say no at any time.
18.
Can the Principal Investigator remove me from this research study?
You can be taken off the study (with or without your consent) for any of these reasons:
Staying in the study would be harmful to you.
You need treatment not allowed in this study.
You do not follow directions.
The study is cancelled.
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19.
How will my information be kept private?
The centers and doctors in charge of this study will keep your personal information as private as
possible. They will do their best to see that it is shared only when required by state or federal law or
the terms of this consent. It is impossible to promise total privacy.
In addition to following state and federal law, the organizations listed below may read or copy your
records to make sure the study information is correct. Your research and medical records will have
your name on them. They will include things such as your medical history, results of your blood
tests and exams, as well as reports about your treatment and office visits. We will do all we can to
keep your medical records private. Your name will not be used in any report of study results.
In order to understand the results of the study, people from the /Center Name/ and the Blood
Marrow Transplant Clinical Trials Network (BMT CTN) Data Coordinating Center (DCC) will
need to see medical records with your name on them. These people include:
Doctors in the study,
Transplant center committees,
People (who are not doctors) who check the safety and progress of studies,
Members of the Institutional Review Board (this committee safe-guards the rights of
persons taking part in research), and
People from the government (the National Institutes of Health and the Food and Drug
Administration) might also need to see medical records with your name on them.
Your research and medical records may be shown to these organizations:
/Institution/
The National Institutes of Health (NIH)
Office of Human Research Protection (OHRP)
The Food and Drug Administration (FDA)
Institutional Review Board (IRB)
Data and Safety Monitoring Board (DSMB), not part of /Institution/
Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Data Coordinating
Center (DCC)
Southwest Oncology Group (SWOG)
Information related to or resulting from your stem cell transplant will be reported to the Center
for International Blood and Marrow Transplant Research (CIBMTR). The CIBMTR is a
voluntary organization of basic and clinical scientists working together in an effort to gather
information on results of stem cell and marrow transplants. This information is used to guide
clinical decisions and identify ways to improve transplant outcomes. Scientific data or medical
information (not identifiable with you) that could be useful to others may be presented at
meetings and/or published in medical journals.
For questions about access to your medical records, please contact /name / at/number/.
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20.
How long do you keep my information?
Study records will be kept indefinitely by the transplant center for re-analysis and follow-up.
If you have questions about the keeping of your research records or access to your files, please
call /name/at /number/.
21.
How will the researcher(s) benefit from your being in this study?
The researchers have no money invested in this study. But, in general, presenting research results
helps the career of a scientist. Therefore, the Principal Investigator may benefit if the results of this
study are presented at scientific meetings or in the scientific press. In addition, the Principal
Investigator is being paid a small amount to cover the cost of performing the study at their Center.
22.
HIPAA1 authorization to use and disclose individual health information for
research purposes
a. Purpose: As a research participant, I authorize the Principal Investigator and the researcher’s
staff to use and disclose my individual health information for the purpose of conducting the
research study entitled Autologous vs. Non-Myeloablative Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT) for Patients With Chemosensitive Follicular Non-Hodgkin’s Lymphoma
Beyond First Complete Response or First Partial Response.
b. Individual Health Information to be Used or Disclosed: My individual health information
that may be used or disclosed to conduct this research includes: demographic information
(e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with
prior treatment), physical examination findings, and laboratory test results obtained at the
time of work up and after transplantation (e.g., CT scan, blood tests, biopsy results).
c. Parties Who May Disclose My Individual Health Information: The researcher and the
researcher’s staff may obtain my individual health information from:
(list hospitals, clinics or providers from which health care information can be requested)
____________________________________________________________________________________
______________________________________________________________________
______________________________________________________________________
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health
information
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d. Parties Who May Receive or Use My Individual Health Information: The individual
health information disclosed by parties listed in item c and information disclosed by me
during the course of the research may be received and used by the following parties:
Principal Investigator and the researcher’s staff
Dr. Ginna Laport and Dr. Robert Negrin, Study Chairpersons, and staff/laboratories at
Stanford Hospitals and Clinics
Staff/laboratories identified in the protocol for the evaluation of other laboratory
samples; e.g., TBD for quantitative PCR testing.
National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute
(NCI), both of the National Institutes of Health (NIH), study sponsors
Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data
coordinating center
Southwest Oncology Group (SWOG), clinical trials cooperative group
U.S. government agencies that are responsible for overseeing research such as the
Food and Drug Administration (FDA) and the Office of Human Research Protections
(OHRP)
U.S. government agencies that are responsible for overseeing public health concerns
such as the Centers for Disease Control (CDC) and federal, state and local health
departments.
e. Right to Refuse to Sign this Authorization: I do not have to sign this Authorization. If I
decide not to sign the Authorization, I will not be allowed to participate in this study or
receive any research-related treatment that is provided through the study. However, my
decision not to sign this authorization will not affect any other treatment, payment, or
enrollment in health plans or eligibility for benefits.
f. Right to Revoke: I can change my mind and withdraw this authorization at any time by
sending a written notice to the Principal Investigator to inform the researcher of my
decision. If I withdraw this authorization, the researcher may only use and disclose the
protected health information already collected for this research study. No further health
information about me will be collected by or disclosed to the researcher for this study.
g. Potential for Re-disclosure: My individual health information disclosed under this
authorization may be subject to re-disclosure outside the research study and no longer
protected. Examples include potential disclosures for law enforcement purposes,
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities
and public health measures.
h. This authorization does not have an expiration date.
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23.
Further Information
If you have further questions concerning this study at any time, you are free to ask your physician
whose contact information is available on the cover page of this consent form.
If you have questions regarding your rights as a research participant, you may also contact a
representative of the IRB at (XXX) XXX-XXXX.
Dr./Ms./Mr. ___________________________ has explained the above matters to you and you
understand that explanation. She/he has offered to answer your questions concerning the
procedures involved in this study. You understand the purpose of this treatment as well as the
potential benefits and risks that are involved. You have decided to volunteer after reading and
understanding all the information on this form. You hereby give your informed and free consent
to be a participant in this research investigation. Upon signing this form you will receive a copy.
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24.
Signatures
As a representative of this study, I have explained to the participant the purpose, the procedures,
the possible benefits, and the risks of this research study; the alternatives to being in the study;
and how privacy will be protected:
Signature of person obtaining consent
Date
Consenting Adults
The purpose of this study, procedures to be followed, risks and benefits have been explained to me.
I have been allowed to ask the questions I have, and my questions have been answered to my
satisfaction. I have been told whom to contact if I have additional questions. I have read this
consent form and agree to be in this study, with the understanding that I may withdraw at any time.
I have been told that I will receive a signed copy of this consent form.
Adult Consenting for Self. By signing this form, you voluntarily agree to participate in this study.
By signing this form, you are not waiving any of your legal rights.
Signature of Adult Consenting for Self
Date
Parent/Adult Legally Representing the Subject. By signing this form, you voluntarily give your
permission for the person named below to participate in this study. You are not waiving any legal
rights for yourself or the person you are legally representing. After your signature, please print your
name and your relationship to the subject.
Signature of Parent/Legal Representative
Date
Print Name of Legal Representative
Relationship to
Participant
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Participants Who Cannot Consent But Can Read and/or Understand about the Study
Although legally you cannot “consent” to be in this study, we need to know if you want to take
part. If you decide to take part in this study, and your parent or the person legally responsible for
you gives permission, you both need to sign. Signing below means that you agree to take part
(assent). The signature of your parent/legal representative above means that he or she gives
permission (consent) for you to take part.
Assent Signature of Participant
Date
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APPENDIX TO PARTICIPANT CONSENT
RISKS AND TOXICITIES RELATED TO A STEM CELL TRANSPLANT
There are certain risks related to a blood stem cell transplant. There are risks from the
medications and irradiation (if given) therapy you will receive as part of the conditioning for the
transplant and risks related to the transplant itself. Most of these risks and side effects are listed
below, but they will vary from person to person.
Risks Related to the Transplant Conditioning Regimen
SECTION A
FOR ALL PATIENTS (AUTOLOGOUS AND ALLOGENEIC PATIENTS):
Rituximab (Rituxan): This medication is used to reduce cancer cells. Common side effects
associated with rituximab include a reaction such as fevers chills or shortness of breath during the
actual infusion of the drug. This typically can happen with your very first infusion of this drug.
Your doctor or nurse may need to temporarily slow down or stop the drug infusion until your
symptoms lessen. A much less common side effect can be a severe allergic reaction called
anaphylaxis, which could cause severe shortness of breath, low blood pressure or tightness in your
throat. Rituximab can also temporarily cause a low white blood cell count and/or weaken your
immune system for up to several months after your last dose of rituximab, which may increase your
risk of infection during that time period. In people who have ever been infected with hepatitis B
virus, there is a risk that the virus can flare up during treatment with drugs that affect your immune
system, such as Rituxan. This could lead to liver failure or even death. The risk of hepatitis B virus
flaring up may continue for several months after you stop taking Rituxan. If you become jaundiced
(yellowing of the skin and eyes) or develop viral hepatitis while taking Rituxan or after stopping
treatment, you should tell your study doctor immediately. Your study doctor will discuss this risk
with you and explain what testing is recommended to check for hepatitis.
Cyclophosphamide (Cytoxan): This is a common medication used to treat cancer. This
medication kills cancer cells by stopping them from growing. Cyclophosphamide may cause you
to have diarrhea (loose stools), nausea (feeling sick to your stomach), vomiting (throwing up),
short-term hair loss, short-term bladder problems, and, at times, bleeding from the bladder (blood
in your urine). A few patients may have bladder damage and bleeding for a longer time. You
will be given large amounts of a sterile solution through your central line to protect your bladder.
The central line is placed just prior to receiving the cyclophosphamide (within a few days of the
first dose). A bladder catheter (thin plastic tube) may be inserted into your bladder, if your
physician thinks that it can help you. Cyclophosphamide slows the making of new blood cells.
This causes a risk of infection and/or severe bleeding until the transplanted donor cells begin to
work in you. You will get blood transfusions as needed. Cyclophosphamide also lowers your
immune (defense) system and as a result you may have more infections. In a small number of
patients, cyclophosphamide can damage the heart muscle causing the heart not to pump as well
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(heart failure). If this occurs you may have shortness of breath and have fluids build-up in your
body. Cyclophosphamide can damage the male (testes) or female (ovaries) sex glands. In men,
the number of sperm may be reduced but you would still be able to have intercourse. Women
who are still menstruating may have irregular periods or may no longer have any periods.
Whether you are a man or woman, this medication will likely greatly decrease your chances of
being able to have a child.
Filgrastim (also called G-CSF for Granulocyte Colony Stimulating Factor) : Less than ½
teaspoon (2 mL) filgrastim will be injected under your skin each day and this could cause some
minor pain at the injection site. Most people experience varying levels of pain in their bones
when treated with this drug which usually feels like muscle aches, bone pain and/or headaches.
The pain is usually relieved with acetaminophen (Tylenol). Aspirin or aspirin-containing
drugs must not be taken during filgrastim administration and during leukapheresis without
physician approval. A less common side effect is a skin rash. These symptoms go away within a
few days after stopping the drug. Other rare potential side effects include signs of allergy such
as a rapid heart rate, dizziness, shortness of breath, itching or rash. Temporary changes in
laboratory values that monitor liver and bone changes can also occur as well as a temporary
increase in your white blood cell count. These return to normal after stopping the drug.
Rarely, people receiving filgrastim have experienced swelling of their spleen and on occasion,
internal bleeding from rupture of the spleen. Rupture of the spleen can present as general fatigue
and weakness, flank or abdominal pain or loss of consciousness from low blood pressure.
Rupture of the spleen can be very serious and is potentially life threatening. Management of this
problem could require blood transfusions or surgery. There is less than a 1% chance of this
occurring. If you have any unusual symptoms, you should report them immediately.
Risks and Procedures Related to the Transplant Procedure
The following risks are not specifically related to any one drug or the transplanted donor cells, but
they are risks that are a part of the transplant procedure. The following applies to ALL patients.
Venipuncture: Although you may require a central venous catheter to donate cells, there may
be an occasional need to have an intravenous catheter placed in your arm(s) or you may need to
have blood withdrawn from the veins of your arm(s). Drawing blood from the arm may be
associated with bleeding into the skin and may very rarely result in an infection.
Central Venous Catheter: A central venous catheter is a flexible sterile tube that can be placed
into a large vein either under the collar bone or in your groin area so that blood can be
withdrawn. This tube is placed under local anesthesia and will be placed just prior to receiving
the cyclophosphamide/rituximab that is given during the cytoreduction process. Complications
include blood clots and infection. Clotting may necessitate removal of the catheter or treatment
of the clot by injecting a medicine that dissolves blood clots. If you develop an infection, you
will require treatment with antibiotics. If the catheter is placed under the collarbone, other
uncommon side effects may include swelling of the face and arm and/or lung collapse. If the
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lung collapses, it may be necessary to place a tube between the ribs to allow the lung to re-
expand.
Bleeding: Platelets help your blood to clot. Your platelets will be low until the new bone
marrow grows and, as a result, bleeding may occur. This can be minor bleeding, such as
nosebleeds or bruising, but more serious, life-threatening bleeding in the lungs, brain and other
organs can occur if the platelet count remains low. Usually, there is success in preventing major
bleeding problems with transfusions of platelets. However, some patients may not respond well
to transfused platelets and may be at serious risk for bleeding.
Veno-Occlusive Disease (VOD): This can occur as a result of high dose chemotherapy,
radiation therapy, or both. Veno-occlusive causes severe damage to the liver. Symptoms include
jaundice (yellowing of the skin and eyes), weight gain, and extra fluid build-up in the abdominal
cavity and other parts of the body. It can often be managed successfully, and completely resolve
but can potentially cause death.
Mouth Sores and Diarrhea: The chemotherapy and radiation cause irritation in the lining of the
mouth and intestines. This can result in painful mouth sores and diarrhea and you may need
medication to help control the pain. If your mouth sores are severe you may not be able to eat
normally until the sores are healed. Mouth sores get better when the white blood count starts to
rise.
Capillary Leak Syndrome: This may occur as a result of chemotherapy and radiation therapy.
The blood vessels may become ‘leaky’ and fluid enters the abdominal cavity, lungs, and other
tissues. You may gain water weight and not go to the bathroom as often as you normally do.
Capillary leak syndrome can be difficult to manage if extra fluid enters the lungs and causes
difficulty breathing. You may die if there is continued fluid collection in the lungs.
Unexpected Organ Damage and Other Side Effects: Although your major organs function
well, it is possible you may experience unexpected, life-threatening heart, lung, kidney, or liver
damage as a result of the transplant. Occasionally, the high doses of chemotherapy and radiation
cause severe lung damage that cannot always be treated. If this happens, you may need to use
oxygen or even a respirator. The lung damage can be life threatening. Rarely, multi-organ
failure (such as lung and kidney failure) may occur, which is often fatal.
Late Effects: You may experience side effects that occur several months to many years after
your transplant. You may experience poor function of the thyroid gland, requiring you to take
thyroid medication. As a result of radiation, cataracts may occur earlier in life compared to a
person who had not had a transplant. If you develop cataracts they may require treatment. It is
rare, but your kidneys could be affected, causing anemia or high blood pressure. There is also a
risk you may develop a second cancer including leukemia as a result of the chemotherapy,
radiation and/or your lymphoma. If secondary cancers occur they generally do not occur until 10
to 15 years after the transplant but can occur sometimes within five years after transplant. The
long-term effects upon heart, lung, and brain are unknown.
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Fluid Build-up: You will receive intravenous fluids during the transplant process and you may
have difficulty eliminating this fluid. Furosemide is a drug that is often given to help eliminate
this excess fluid. This drug may cause hearing loss and loss of body chemicals such as
potassium and sodium.
Risk to the Unborn
The treatment that you are undertaking has not been proven to be safe at any stage of pregnancy.
Therefore, if you are pregnant or nursing, you are not eligible for this study. Women who have
the potential of becoming pregnant must use some form of effective birth control.
Sterility and Future Childbearing Potential for Men and Women
Chemotherapy and/or irradiation may cause lasting effects on the reproductive potential of both
men and women treated in this manner. It should be emphasized that your cancer
treatment/therapy may cause your menstrual periods to become irregular or cease altogether.
However, this DOES NOT MEAN THAT YOU CANNOT BECOME PREGNANT, and you
must use birth control.
Risks Related to the Infusion of Bone Marrow or Peripheral Blood Stem Cells
The stem cell infusion is given similar to a blood transfusion. The infusion of stem cells usually
has few side effects. Rarely the infusion may cause a headache, chest pain or trouble breathing,
a slight fever, or blood in the urine. You will be given pre-medications just prior to the infusion
to decrease the risk of a reaction. For the autologous patients, some patients react to the
preservative called DMSO, which is used in the freezing process of your stem cells. Common,
less serious reactions for patients of an autologous or allogeneic SCT include mild wheezing,
mild shortness of breath, back or chest pain or lightheadedness. In rare instances, a severe
allergic reaction can occur called anaphylaxis, which could cause a drop in blood pressure or
extreme difficulty in breathing. You will be monitored very closely.
SECTION B
For AUTOLOGOUS STEM CELL TRANSPLANT PATIENTS:
VP-16 (etoposide): This is a common medication used to treat cancer. This medication kills
cancer cells by stopping them from growing. VP-16 may cause you to have diarrhea (loose
stools), nausea (feeling sick to your stomach), vomiting (throwing up), short-term hair loss and
skin peeling, especially in the areas of your hands, feet and underarms. VP-16 slows the making
of new blood cells. This causes a risk of infection and/or severe bleeding until the transplanted
donor cells begin to work in you. You will get blood transfusions as needed. VP-16 also lowers
your immune (defense) system and as a result you may have more infections. VP-16 can
damage the male (testes) or female (ovaries) sex glands. In men, the number of sperm may be
reduced but you would still be able to have intercourse. Women who are still menstruating may
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have irregular periods or may no longer have any periods. Whether you are a man or woman,
this medication will likely greatly decrease your chances of being able to have a child.
Total Body Irradiation (applicable to certain patients receiving the autologous SCT): Total
body irradiation may cause you to have diarrhea (loose stools), nausea (feeling sick to your
stomach), vomiting (throwing up), mouth sores, and painful swelling of the saliva glands for a
few days. You may also experience short-term hair loss. Total body irradiation kills both sick
and normal marrow, leading to a lack of red blood cells, white blood cells, and platelets. The
short-term loss of these blood cells could cause you to become anemic, develop an infection,
and/or bleeding. This will continue until the transplanted donor cells begin to work in you. You
will get blood transfusions as needed. There is a risk that cataracts (cloudiness) may develop in
your eyes. This may mean partial loss of vision, and you may need contact lenses or surgery to
remove the cataracts. The total body irradiation dose used will probably result in sterility (not
being able to have children) as noted in the cyclophosphamide paragraph on the previous page.
It is not known whether the use of total body irradiation will cause more side effects or problems
with your health in the future.
Carmustine (also called BCNU) and Etoposide (also called VP-16) (applicable to certain
patients receiving the autologous SCT): Side effects from these drugs include nausea (feeling
sick to your stomach), vomiting (throwing up), low blood counts, skin rash, diarrhea (loose stools),
mouth sores, fevers, and fatigue. Rarely, liver and/or kidney damage can occur. Because of your
weakened immune system, a less common side effect is an infection that can be caused either by a
bacteria, virus or fungus for which you will be immediately treated with antibiotics. A delayed but
less common side effect of the BCNU that can occur about 1-2 months after transplant is
pneumonitis or inflammation of your lungs. This can present as a persistent cough, shortness of
breath, fevers, persistent fatigue, chest discomfort when taking a deep breath or a sudden decrease in
stamina. This would be treated with prednisone. Lung injury from BCNU usually gets better with
treatment but some patients have permanent lung damage and some patients die from this side
effect.
Leukapheresis: During this procedure, your central venous catheter will be connected to the
leukapheresis machine. This machine draws blood out of part of your catheter continuously and
filters the stem cells out of your blood stream. The rest of your blood is then returned to your
body via another part of your line. Your blood will be thinned with an anticoagulant during the
collection procedure to keep your blood from clotting (clogging and thickening) in the tubing
and in the machine. This anticoagulant sometimes causes low calcium levels in your blood,
which you would feel as temporary numbness or tingling of the fingertips or around the mouth.
Should you experience any numbness, you must tell the nurse operating the machine so that oral
or intravenous calcium can be given to you. If not corrected, this complication could progress to
severe muscle cramps. Other possible unpleasant effects of the collection procedure include
lightheadedness, nausea or more rarely, fainting due to temporary lowering of the blood pressure,
as well as becoming chilled during the procedure. This procedure takes about 3-4 hours per
daily session. Depending on the number of stem cells in your blood, it usually takes 1-3 daily
sessions to collect enough stem cells.
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SECTION C
For ALLOGENEIC STEM CELL TRANSPLANT PATIENTS:
Fludarabine (applicable to patients receiving the allogeneic SCT): This medication is used in
stem cell transplants to reduce the risk of rejecting the donor’s transplanted cells. Likely side
effects you may experience are low white blood cell count with increased risk of infection, low
platelet count with increased risk of bleeding, and anemia (low red blood cell count) with
tiredness or low energy.
Risk Related Specifically to the ALLOGENEIC Transplant Procedure:
Graft-versus-Host Disease (GVHD)
After the graft begins to function, there is a further risk of a reaction of the graft against your
tissues. This reaction is called GVHD and may cause a skin rash, or abnormalities of the liver,
or stomach. GVHD may cause nausea (feeling sick to your stomach), vomiting (throwing up),
lack of appetite, stomach cramps, diarrhea (loose stools), and bleeding of the gut. Chronic
GVHD may occur later after transplantation and may involve problems with the eyes, mouth,
lips, throat and liver. Early (acute) or late (chronic) GVHD may become severe enough to result
in death. GVHD is treated with drugs that weaken the immune system, and therefore make you
more susceptible to infections.
Risks Related to the Medications Used to Help Prevent Graft-versus-Host Disease (GVHD)
NOTE: These drugs also decrease the risk of rejection of the donor cells.
Tacrolimus: This medication is used to try to prevent GVHD. The immediate side effects you
may experience include nausea (feeling sick to your stomach) or vomiting (throwing up) when
the medications are given orally. Other side effects you may experience include high blood
pressure (hypertension), shaking of the hands (tremor), increased hair growth and possibly an
effect on mental function. If you experience these effects they generally go away when the dose
of the medication is decreased. A few patients have had a seizure while taking these
medications. You may experience a change of liver or kidney function, in which case the
medication dose will be reduced or possibly even withheld. Occasionally, the kidney damage
caused may require the use of an artificial kidney machine (hemodialysis).
Some patients given tacrolimus develop diabetes and must take insulin while taking tacrolimus.
Methotrexate: This is also a medication used to try to prevent GVHD. Methotrexate causes
damage to cells, and therefore can affect many different tissues of your body. It may cause or
can worsen the mouth sores or inflammation of the mouth which you may have already
developed from the procedures and medications used to prepare you for the transplant. It may
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also cause nausea (feeling sick to your stomach) and vomiting (throwing up). Methotrexate may
slow down the recovery of blood cells after transplantation. Methotrexate can cause kidney
damage. If your kidney is already damaged for other reasons, it can worsen kidney function. If
kidney damage does occur, the methotrexate dose may be reduced or the mediation may not be
given at all.
Tacrolimus, Methotrexate, and Steroids: These medications interfere with the body’s defense
system (the immune system). This may cause you to have more infections (especially viral
infections and pneumonia) for several months after transplant.
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Informed Consent to Participate in Research
Please read this form carefully. If there are words or part of this document that you do not
understand, you should ask the research doctor or staff to explain any information that is not
clear to you before making a decision whether to participate. Your participation is entirely
voluntary. You may choose not to participate.
The Principal Investigator (the person in charge of this research) or a representative of the
Principal Investigator will also describe this study to you and answer all or your questions.
Please ask questions about anything that you do not understand.
This is a consent form for a research study. This clinical trial is a research study to determine
better treatment for patients with follicular lymphoma.
We invite you to join this study because:
Your brother or sister has follicular lymphoma
Your blood stem cells are a match for your brother or sister
Your brother’s or sister’s disease may be treated by a blood stem cell transplant, and
Your brother or sister want to join the follicular lymphoma research study
It is very important for you to know your choices before you decide to join a research study.
Your brother or sister who has low grade follicular lymphoma may be helped by a blood stem
cell transplant (SCT). Stem cells are cells found in the bone marrow and blood stream that
rebuild your blood, bone marrow and the immune system.
This study uses two sources of blood stem cells for transplant: autologous and allogeneic.
An autologous transplant uses blood stem cells collected from the patient.
An allogeneic transplant uses blood stem cells collected from a brother or sister who
are a tissue match with the patient.
Doctors currently use both sources of blood stem cells for transplants. The doctors do not know
which type of transplant, autologous or allogeneic, is the better treatment for patients with
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follicular lymphoma. Information from this study will help doctors understand the best treatment
choices for follicular lymphoma.
We determined that you are a tissue-match to your brother or sister by testing your blood. We
tested to see if your antigens matched your brother or sister’s antigens. Since all of these
antigens matched, your brother or sister is a tissue-match with you. Therefore, your brother or
sister has been assigned to receive an allogeneic stem cell transplant.
This consent describes the collection of stem cells from your blood to transplant into your
brother or sister. The donation process for stem cells is not experimental. The treatment for
your brother or sister is part of a research clinical trial.
This consent form outlines the process, potential risks and benefits of donating your stem cells
for transplantation into your brother or sister.
1.
Name of the Donor
2.
Title of the Research Study
Autologous vs. Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT) For Patients With Chemosensitive Follicular Non-Hodgkin’s Lymphoma Beyond First
Complete Response or First Partial Response
3a.
Principal Investigator Contact Information
Insert name, affiliation, and contact information.
3b.
Contact Information for Emergencies After Hours or on Weekends or Holidays
Call (xxx) xxx - xxxx, the in-patient Bone Marrow Transplant Unit. Ask to speak to the Charge
Nurse.
4.
Sponsor and Source of Funding and Other Material Support
The research in this study is paid for by the National Institutes of Health (NIH). The Blood and
Marrow Transplant Clinical Trials Network (BMT CTN) will direct the research study.
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5.
Study Purpose
You are being invited to participate in this research study because current therapy does not help
everyone with follicular lymphoma.
The goal of this clinical research study is to determine whether autologous or allogeneic stem
cell transplantation is the better therapy for patients with low grade follicular lymphoma who
require a transplant to treat their disease.
You are being asked to donate blood stem cells to your brother or sister because you are a tissue
match with them. Donating blood stem cells is not experimental.
6.
What will be done if you take part in this research study?
You will undergo a brief medical evaluation and a series of blood tests to prepare for the possible
stem cell donation. The following tests and procedures will be done:
Medical history, physical examination
Blood tests
Urine tests
If you are a woman able to have children, a blood test to check for pregnancy will be
done. If you are pregnant, you cannot take part in this study.
Other tests, such as a chest x-ray or electrocardiogram (ECG or EKG, a picture of the
electrical action of the heart) will be done if your physician feels it is necessary.
If your medical evaluation shows any problems or concerns, you will be told about them. This
will be kept private and not shared with your brother or sister unless you agree.
Procedures:
Only a small quantity of stem cells is normally present in the blood. A drug called filgrastim,
also called G-CSF (granulocyte-colony stimulating factor), can increase the number of these
stem cells in the blood. This drug allows enough stem cells to be collected from you for
transplantation into your brother or sister.
If the medical exam and blood tests confirm that you are a suitable donor, you will receive
injections of filgrastim into the skin (like an insulin injection) once a day for 5 days to help the
release of your stem cells into your blood. You must come to the donor center or clinic each day
for the filgrastim injections unless these can be arranged at home.
On the fourth and fifth day of filgrastim injections (and possibly the sixth day) you will go to the
donor center to have stem cells collected by a machine called a blood cell separator. The
procedure of collecting stem cells is called apheresis. Each apheresis procedure takes about 4 to
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6 hours. The procedure of collecting stem cells involves removing blood from a vein in one arm,
passing the blood through the machine where stem cells are collected, and the rest of your blood
cells and plasma (the liquid portion of your blood) are returned to you through a vein in your
other arm. This procedure will involve placing a needle in each of your arms, collecting the cells
over approximately four to six hours during which time you will be required to lie relatively still.
If the veins in your arms are not large enough for the needles, you will need to have a temporary
central venous catheter placed to collect your stem cells. A central venous catheter is a sterile
flexible tube that will be placed into a large vein under local anesthesia. Your physician will
explain this procedure to you in more detail and you will be required to sign a separate consent
form for this procedure.
Sometimes, not enough stem cells are obtained with two aphereses. If this occurs, you will need
to undergo a third apheresis procedure to try to collect enough stem cells.
This process will not remove all of your blood and bone marrow of stem cells. Healthy people
have enough stem cells after the collection (aphereses) to make a normal amount of blood cells
and the body will replace the lost stem cells with new ones.
You will be weighed and have blood tests (1-2 teaspoons) including a complete blood count
before each collection. We repeat the complete blood count after each apheresis procedure.
The following table summarizes the schedule and procedures you undergo when donating stem
cells.
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DONATION SCHEDULE
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Filgrastim
(16 mcg/kg/SQ)
injection
You may need
to do another
day
More blood
tests done
You may need
to do another
day
(Apheresis)
Blood stem
cell collection
You may need
to do another
day
Blood cells
counted
You may need
to do another
day
7.
How long will I be in the study?
You will be in the study for up to a few months from the time you sign the consent until
approximately one month after stem cell collection. The actual process of taking filgrastim and
then collecting your stem cells though takes less than a week. You will be contacted by phone
approximately 30 days after initiation of G-CSF. You will be asked to answer questions about
your health since your stem cells were collected.
Your doctor may decide to take your brother or sister off this study if their condition becomes
worse, side effects of their treatment are severe or life threatening, or the treatment is no longer
in their best interest. If your brother or sister leaves the study there will be no need for you to
donate stem cells.
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Your doctor may also decide to take you off this study if the filgrastim or if the leukapheresis
procedure causes severe, unmanageable or life threatening side effects to you.
You may stop participating at any time. However, if you decide to leave the study, we
encourage you to talk to the study doctor first. Leaving the study early may affect your brother
or sister’s treatment.
8.
Will you provide blood samples for research?
Research Blood Samples
Genetic material is any sample of tissue, blood, fluid, etc. obtained from you during the study.
With your permission, 3-5 teaspoons from your stem cell collection and 3-5 teaspoons of your
blood (taken from your vein) will be collected prior to the recipient’s transplant and stored to be
used solely for research purposes. The samples will be stored for future studies that will look at
responses to treatment based on factors not yet known. Your confidentiality will be maintained
because no identifying markers (name, etc.) will remain with the sample.
All BMT CTN research samples will be paired with the respective donor or recipient sample and
given unique bar code designations that cannot be linked back to the donor or the recipient. All
research samples will become property of the NHLBI after conclusion of the BMT CTN Protocol
#0202 study. An NHLBI Biologic Specimen Repository Utilization Committee will advise
NHLBI on requests for samples to perform research with these anonymous samples. If an
Investigator’s request for these samples is approved by the committee, the NHLBI may provide a
panel of the specimens requested using unique code numbers. Laboratory test results, clinical
information, etc., associated with the coded samples are provided to the Investigator only after
completion of the main protocol. Samples sent to researchers cannot be linked with any
remaining sample at the repository.
If you agree to allow your stem cells and blood to be kept for research, you are free to change your
mind at any time. We ask that you contact [Principal Investigator] in writing and let him know you
are withdrawing your permission for your stem cells and blood to be used for research. His mailing
address is on the first page of this form.
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You are free not to take part in this additional future research. There will be absolutely no
change in your care as a result of your refusal to give these additional samples. Refusal to
participate does not affect your brother or sister’s care. Please indicate your choice(s) below:
I agree to have blood and stem cells collected prior to the recipient’s transplant for future
research.
No, I do not agree to have blood and stem cells collected prior to the recipient’s transplant for
future research.
____________________________________
_____________________________
Signature
Date
9.
What will happen if not enough stem cells are collected from me?
The doctor will decide if it is safe to proceed to the planned transplant procedure, depending on how
many stem cells are actually collected. The risk of being transplanted with a low number of stem
cells is that your sibling’s blood counts will return to normal levels very slowly or they may stay
low permanently. If this occurs, he/she may need many blood and/or platelet transfusions and/or
the risk of infection may increase. If he/she does not proceed to transplant, the doctor can offer
other alternatives such as chemotherapy and/or radiation if he/she feels this is necessary.
10.
What are the possible discomforts and risks?
There may be side effects from taking filgrastim and donating stem cells. The filgrastim and
leukapheresis may cause some, all or none of the side effects listed below. You should discuss
these with your doctor. In addition, there is always the chance of new, unexpected or previously
unknown side effects. Other drugs will be given to make side effects less serious and less
uncomfortable. Many side effects go away shortly after the filgrastim and leukapheresis is
stopped.
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Risks and side effects include:
Filgrastim (G-CSF): Less than ½ teaspoon (2 mL) filgrastim will be injected under your skin
each day and this could cause some minor pain at the injection site. Most people experience
varying levels of pain in their bones when treated with this drug which usually feels like muscle
aches, bone pain and/or headaches. The pain is usually relieved with acetaminophen (Tylenol).
Aspirin or aspirin-containing drugs must not be taken during figrastim administration and during
leukapheresis without physician approval. A less common side effect is a skin rash. These
symptoms go away within a few days after stopping the drug. Other rare possible side effects
include signs of allergy such as a rapid heart rate, dizziness, shortness of breath, itching or rash.
Temporary changes in laboratory values that monitor liver and bone changes can also occur as
well as a temporary increase in your white blood cell count. These return to normal after
stopping the drug.
Rarely, normal donors receiving figrastim have experienced swelling of their spleen and on
occasion, internal bleeding from rupture of the spleen. Rupture of the spleen can present as
general fatigue and weakness, flank or abdominal pain or loss of consciousness from low blood
pressure. Rupture of the spleen can be very serious and is potentially life threatening.
Management of this problem could require blood transfusions or surgery. There is less than a
1% chance of this occurring. Other, unpredictable side effects may, occur which have not been
reported. If you have any unusual symptoms, you should report them immediately.
Possible interactions of figrastim with other drugs have not been fully evaluated; therefore, it is
important that you report all drugs, both prescription and non-prescription to your physician.
Long-term (beyond one year) safety data on filgrastim administered to normal, healthy people is
limited but so far has not identified any late problems for donors.
Leukapheresis; A needle will be placed in each arm. Pain and bruising could occur in both
arms, but severe bleeding in the arm is rare. Your blood will be thinned with an anticoagulant
during the collection procedure to keep your blood from clotting (clogging and thickening) in the
tubing and in the machine. This anticoagulant sometimes causes low calcium levels in your
blood, which you would feel as temporary numbness or tingling of the fingertips or around the
mouth. Should you experience any numbness, you must tell the nurse operating the machine so
that oral or intravenous calcium can be given to you. If not corrected, this complication could
lead to severe muscle cramps. Other possible unpleasant effects of the collection procedure
include lightheadedness, nausea or more rarely, fainting due to temporary lowering of the blood
pressure, as well as becoming chilled during the procedure.
You will lose some blood cells called platelets with the stem cells. These cells help stop
bleeding. If your platelet count falls enough to place you in danger of bleeding, (less than
30,000 mL) any further collections will be delayed until your platelet count increases.
Central Venous Catheter; If your arm veins are inadequate (too small) to allow leukapheresis,
you will need a central venous catheter to donate cells. A central venous catheter is a flexible
sterile tube that can be placed into a large vein either under the collar bone or in your groin area
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so that blood can be withdrawn. This tube is placed under local anesthesia. Complications
include blood clots and infection. Clotting may require removal of the catheter or treatment of
the clot by injecting a medicine that dissolves blood clots. If you develop an infection, you will
require treatment with antibiotics. If the catheter is placed under the collarbone, other
uncommon side effects may include swelling of the face and arm and/or lung collapse. If the
lung collapses, it may be necessary to place a tube between the ribs to allow the lung to re-
expand.
Venipuncture; Although you may require a central venous catheter to donate cells, there may be
an occasional need to have an intravenous catheter placed in your arm(s) or you may need to
have blood withdrawn from the veins of your arm(s). Drawing blood from the arm may be
associated with bleeding into the skin and may very rarely result in an infection.
Risks to the Unborn: Since the filgrastim used in this study can affect an unborn baby, you
should not become pregnant or father a baby while on filgrastim.
11a.
What are the possible benefits to you for taking part in this study?
If you agree to take part in this study, there is no direct medical benefit to you.
11b.
What are the possible benefits to others?
The possible benefit to your brother or sister may be improvement in the control of their
lymphoma and possibly prolonged survival. We hope the information learned from this study will
benefit other patients with lymphoma in the future.
12.
If you choose to take part in this study, will it cost you anything?
There is no financial benefit to you by participating in this treatment protocol. Usually, the
insurance policy of the stem cell recipient will cover the cost of the donor evaluation and stem
cell collection. The transplant coordinator will help you identify insurance coverage before you
incur charges for your evaluation and donation. If you have concerns or questions regarding
coverage or potential charges, you should contact (contact person’s name) at (xxx) xxx- xxxx to
review the situation.
13.
Will you receive compensation for taking part in this research study?
No.
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14.
What if you are injured because of the study?
You agree to take the risks listed above. If you experience an injury that is directly caused by this
study, only the professional medical care you receive at the [participating clinical facility] will be
provided without charge. Hospital expenses will be paid by you or your insurance provider. No
other compensation is offered. By signing this form, you have not waived any of your legal rights.
15.
What other options or treatments are available if you do not want to be in this study?
Participation in this study is entirely voluntary. You are free to refuse to be in the study and your
refusal will not influence current or future health care you receive at this institution.
Instead of being in this study, your brother or sister may have these options:
Treatment with other drugs or combination of drugs.
A standard autologous stem cell transplant.
A traditional allogeneic or non-myeloablative stem cell transplant.
No therapy at this time, with care to help them feel more comfortable.
Your brother or sister may receive these treatments at this or other centers even if you or they
choose not to take part in this study.
16a.
How can you withdraw from this research study?
If you agree to be in this study, you are free to change your mind. At any time you may withdraw
your consent to be in this study. If you do withdraw your consent, there will be no penalty and you
will not lose any benefits to which you are otherwise entitled. If you decide to withdraw, we ask
that you notify [Principal Investigator] in writing; his/her mailing address is on the first page of this
form.
You must be aware, however, that a decision not to participate once treatment of your brother or
sister begins, could have serious harmful consequences for the health of your brother/sister. Not
donating stem cells after your brother or sister has received their pre-transplant chemotherapy
and/or irradiation may result in his or her death.
If you have any questions regarding your rights as a donor, you may phone the Institutional Review
Board (IRB) office at (xxx) xxx-xxxx.
16b.
If you withdraw, can information about you still be used and/or collected?
If you withdraw from the study, we will ask your permission to continue using all information
about you that has already been collected as part of the study prior to your withdrawal.
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16c.
Can the Principal Investigator withdraw you from this research study?
Your participation can be withdrawn (with or without your consent) for any of the following
reasons:
You do not qualify to be in the study because you do not meet the study requirements.
You need a medical treatment not allowed in this study.
The investigator decides that continuing in the study would be harmful to you.
The study treatments have a bad effect on you.
You become pregnant
Other protocol-specific reasons; for example, if the dose of treatment and/or drugs you have
been given has been found to be unsafe.
The study is cancelled by the National Institutes of Health (NIH) for other administrative
reasons.
17.
How will your privacy and the confidentiality of your research records be protected?
Study records that identify you will be kept confidential as required by law. You will not be
identified by name in the study records. Your records will be assigned a unique code number. The
key to the code will be kept in a locked file in the Data Coordinating Center. Authorized persons
from [Clinical Center Name], the hospital or clinic (if any) involved in this research, and the
Institutional Review Board have the legal right to review your research records and will protect the
confidentiality of them to the extent permitted by law. This research study is sponsored and
conducted under the authority of the National Institute of Health; therefore, the sponsor and the
sponsor’s agent also have the legal right to review your research records. Otherwise, your research
records will not be released without your consent unless required by law or a court order.
If the results of this research are published or presented at scientific meetings, your identity will not
be disclosed.
18.
Expiration Date for Retention of Records
The study results will be retained in your research record for at least six years or until after the study
is completed, whichever is longer. At that time either the research information not already in your
medical record will be destroyed or your name and other identifying information will be removed
from such study results. Research information in your medical record will be kept indefinitely.
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19.
How will the researcher(s) benefit from your being in this study?
In general, presenting research results helps the career of a scientist. Therefore, the Principal
Investigator may benefit if the results of this study are presented at scientific meetings or in
scientific journals. In addition, the sponsor is paying the Principal Investigator to conduct this
study.
20.
HIPAA1 authorization to use and disclose individual health information for
research purposes
a. Purpose: As a research participant, I authorize the Principal Investigator and the researcher’s
staff to use and disclose my individual health information for the purpose of conducting the
research study entitled Autologous vs. Non-Myeloablative Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT) for Patients With Chemosensitive Follicular Non-Hodgkin’s Lymphoma
Beyond First Complete Response or First Partial Response.
b. Individual Health Information to be Used or Disclosed: My individual health information
that may be used or disclosed to conduct this research includes: demographic information
(e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with
prior treatment), physical examination findings, and laboratory test results obtained at the
time of work up and after transplantation (e.g., CT scan, blood tests, biopsy results).
c. Parties Who May Disclose My Individual Health Information: The researcher and the
researcher’s staff may obtain my individual health information from:
(list hospitals, clinics or providers from which health care information can be requested)
____________________________________________________________________________________
______________________________________________________________________
______________________________________________________________________
d. Parties Who May Receive or Use My Individual Health Information: The individual
health information disclosed by parties listed in item c and information disclosed by me
during the course of the research may be received and used by the following parties:
Principal Investigator and the researcher’s staff
Dr. Ginna Laport and Dr. Robert Negrin, Study Chairpersons, and staff/laboratories at
Stanford Hospitals and Clinics
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health
information
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Staff/laboratories identified in the protocol for the evaluation of other laboratory
samples; e.g., TBD for quantitative PCR testing.
National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute
(NCI), both of the National Institutes of Health (NIH), study sponsors
Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data
coordinating center
Southwest Oncology Group (SWOG), clinical trials cooperative group
U.S. government agencies that are responsible for overseeing research such as the
Food and Drug Administration (FDA) and the Office of Human Research Protections
(OHRP)
U.S. government agencies that are responsible for overseeing public health concerns
such as the Centers for Disease Control (CDC) and federal, state and local health
departments.
e. Right to Refuse to Sign this Authorization: I do not have to sign this Authorization. If I
decide not to sign the Authorization, I will not be allowed to participate in this study or
receive any research-related treatment that is provided through the study. However, my
decision not to sign this authorization will not affect any other treatment, payment, or
enrollment in health plans or eligibility for benefits.
f. Right to Revoke: I can change my mind and withdraw this Authorization at any time by
sending a written notice to the Principal Investigator to inform the researcher of my
decision. If I withdraw this Authorization, the researcher may only use and disclose the
protected health information already collected for this research study. No further health
information about me will be collected by or disclosed to the researcher for this study.
g. Potential for Re-disclosure: My individual health information disclosed under this
Authorization may be subject to re-disclosure outside the research study and no longer
protected. Examples include potential disclosures for law enforcement purposes,
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities
and public health measures.
h. This Authorization does not have an expiration date.
21.
Further Information
If you have further questions concerning this project at any time, you are free to ask them of
Dr._______________, who will be available to answer them. His/her telephone number is located
on the first page of this consent.
If you have further questions about your disease you are also free to contact The Cancer Information
Service of the National Cancer Institute (NCI) using their toll-free number 1-800-422-6237.
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Version 4.0 dated January 17, 2006
DONOR CONSENT
IRB #
Page 14 of 15
Donor Initials _________
22.
Signatures
As a representative of this study, I have explained to the donor the purpose, the procedures, the
possible benefits, and the risks of this research study; the alternatives to being in the study; and
how privacy will be protected:
______
Signature of person obtaining consent
Date
Consenting Adults
The purpose of this study, procedures to be followed, risks and benefits have been explained to me.
I have been allowed to ask the questions I have, and my questions have been answered to my
satisfaction. I have been told whom to contact if I have additional questions. I have read this
consent form and agree to be in this study, with the understanding that I may withdraw at any time.
I have been told that I will receive a signed copy of this consent form.
Adult Consenting for Self. By signing this form, you voluntarily agree to participate in this study.
By signing this form, you are not waiving any of your legal rights.
Signature of Adult Consenting for Self
Date
Parent/Adult Legally Representing the Subject. By signing this form, you voluntarily give your
permission for the person named below to participate in this study. You are not waiving any legal
rights for yourself or the person you are legally representing. After your signature, please print your
name and your relationship to the subject.
Signature of Parent/Legal Representative
Date
Print Name of Legal Representative
Relationship to Participant
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DONOR CONSENT
IRB #
Page 15 of 15
Donor Initials _________
23.
Participants Who Cannot Consent But Can Read and/or Understand about the
Study
Although legally you cannot “consent” to be in this study, we need to know if you want to take part.
If you decide to take part in this study, and your parent or the person legally responsible for you
gives permission, you both need to sign. Your signing below means that you agree to take part
(assent). The signature of your parent/legal representative above means that he or she gives
permission (consent) for you to take part.
Assent Signature of Donor
Date
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Follicular Lymphoma Protocol - 0202
Version 4.0 dated January 17, 2006
APPENDIX C
LABORATORY PROCEDURES
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C-1
APPENDIX C
LABORATORY PROCEDURES
1. HLA TYPING
HLA testing and evaluation must be completed within four weeks of study enrollment and prior
to the initiation of the cytoreductive/mobilization therapy. The cytoreductive/mobilization
therapy must begin no later than four weeks from enrollment.
HLA typing of heparinized peripheral blood can be done by either serologic or DNA methods for
HLA-A, -B. DNA methods must be utilized for DRB1.
The specimens for HLA typing will be:
a) Donor - 5 mL peripheral blood sample(s) from sibling member, and
b) Patient - 5 mL peripheral blood sample from the recipient.
2. CHIMERISM - Non-myeloablative Allogeneic HSCT Patients and Donor
A heparinized peripheral blood sample from patient and donor is required for chimerism studies
2 weeks pre-allogeneic HSCT to subsequently determine the host or donor origin of ANC
recovery. All pre-HSCT samples will be stored for future evaluation of post-HSCT chimerism.
A 10 mL heparinized peripheral blood sample must also be obtained from the patient at weeks 4,
8, and 12, then at 6 and 12 months post-allogeneic HSCT.
3. PATHOLOGY/CYTOGENETICS STUDIES
Unilateral bone marrow biopsies aspirates are required for pathology analysis and bone marrow
aspirates are required for cytogenetic analysis prior to the cytoreductive/mobilization therapy.
Other bone marrow assessments as summarized in the schedule of evaluations (Chapter 4) do not
require the inclusion of bone marrow pathology/cytogenetics unless the original diagnostic
marrow or the baseline marrow documented abnormal pathology/cytogenetics.
Pathology and cytogenetic studies will be conducted per institutional guidelines.
4. FLOW CYTOMETRY
According to the BMT CTN Graft Evaluation MOP, the hematopoietic stem cell content of the
product (graft) should be determined using CD45-FITC and CD34-PE staining to identify stem
cells within the WBC component of the product.
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C-2
Allogeneic donor products will also be analyzed to determine the B, T and NK cell content using
CD3, CD4, CD8, CD19 and CD56 expression as detected by flow cytometry. Autologous grafts
require CD34 enumeration at a minimum.
Flow cytometry will be done in keeping with the BMT CTN MOP and local institutional
practice, and will be performed prior to infusion of the graft.
5. IMMUNOGLOBULIN MONITORING
IgG levels will be monitored in non-myeloablative allogeneic and autologous HSCT patients.
IgG levels should be determined at 12 weeks, 6 months and 1 year post-HSCT. Testing will be
done in keeping with the BMT CTN MOP and local institutional practice.
6. POLYMERASE CHAIN REACTION (PCR)
Peripheral blood (10 mL) will be collected for determination of the presence of t(14;18) by PCR.
The initial evaluation (i.e., baseline sample) will be shipped directly to the BMT CTN Reference
Laboratory, The Methodist Hospital (TMH), and results will be obtained real-time directly from
TMH to the appropriate Transplant Center. The baseline sample will be labeled with labels
provided by the NHLBI Repository. Baseline samples will be collected using two, 6.0 mL
lavender top EDTA vacutainers (BD #367863) with 5 mL of peripheral blood in each vacutainer.
Baseline samples will be shipped cool, using frozen gel packs, via Federal Express priority
overnight Monday through Friday prior to the initiation of the cytoreductive/mobilization
therapy. The BMT CTN DCC will provide all shipping costs for these samples.
It is the responsibility of the CRA, or designated individual, at the Transplant Center to inform
TMH of an upcoming shipment via fax or email. The communication should contain the date of
shipment, the patient(s) transplant center-specific identifier and Federal Express tracking
number. The Protocol Coordinator at EMMES should be copied on e-mail communications
and/or receive a copy of the faxed documents via fax at 301-251-1355.
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All other PCR t(14;18) assessments (i.e., all post-baseline samples) as summarized in the
schedule of evaluation (Chapter 4) are not required to be obtained unless patient had a positive
test at any time from initial diagnosis. Other PCR samples will be collected using two 6.0 mL
lavender top vacutainers (5.0 mL of peripheral blood in each vacutainer) with an ACD additive
(BD #364816), processed by ficoll to obtain a white blood cell pellet and shipped quarterly to the
NHLBI Repository, SeraCare BioServices, in compliance with the shipping procedures specified
in the BMT CTN MOP.
Misti Dowell
NHLBI Repository
SeraCare BioServices
217 Perry Parkway
Gaithersburg, MD 20877
Phone:
(301) 208-8100; Fax: (301) 208-8829
7.
RESEARCH SPECIMENS
BMT CTN research samples will be paired with the respective donor or recipient sample and
given unique bar code designations that cannot be linked back to the donor or the recipient. All
research samples will become property of the NHLBI after conclusion of the BMT CTN Protocol
#0202 study. An NHLBI Biologic Specimen Repository Utilization Committee will advise
NHLBI on requests for samples to perform research with these anonymous samples. If an
Investigator’s request for these samples is approved by the committee, the NHLBI may provide a
panel of the specimens requested using unique code numbers. Laboratory test results, clinical
information, etc., associated with the coded samples are provided to the Investigator only after
completion of the main protocol. Samples sent to researchers cannot be linked with any
remaining sample at the repository.
For Donors:
Five vials, each containing 2-5 x 106 nucleated cells (~1ml per cryovial) from the donor stem
cells must be obtained prior to the allogeneic transplant. Transplant Centers should follow
controlled-rate freezing SOPs for cryopreserving research samples as for product storage.
Samples will be shipped annually to the NHLBI Repository in compliance with the shipping
procedures specified in the BMT CTN MOP.
In addition, peripheral blood (10 mL nucleated cell sample) will be collected prior to
mobilization and shipped quarterly to the Repository in compliance with the shipping procedures
specified in the BMT CTN MOP.
For Patients:
Peripheral blood (10mL nucleated cell sample) will be collected for future testing prior to the
non-myeloablative allogeneic or autologous transplant and shipped quarterly to the Repository in
compliance with the shipping procedures specified in the BMT CTN MOP.
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SCHEDULE OF LABORATORY EVALUATION
Type of Sample
Type of Storage
Dates Samples Obtained
Shipping Specifications
Test
Location
HLA Typing
5 mL peripheral blood
or according to
institutional practice
Store according
to institutional
practice
Prior to cytoreductive/mobilization therapy.
N/A
Transplant
Center
Chimerism
10 mL heparinized
peripheral blood or
according to
institutional practice
Store according
to institutional
practice
2 weeks prior to the initiation of allogeneic
HSCT conditioning therapy for patient and
donor. Weeks 4, 8 and 12, 6 months and one
year post-allogeneic transplant for patient.
N/A
Transplant
Center
Pathology/
Cytogenetic
Studies
Volume of bone
marrow biopsy and
aspirate determined
according to
institutional practice
Store according
to institutional
practice
Prior to cytoreductive/mobilization therapy.
Bone marrow biopsies and aspirates must be
done prior to the transplant, prior to initiation
of rituximab maintenance therapy (if
applicable) and at 12 weeks, 6 months, and
yearly until 3 years post-HSCT only if
previously documented bone marrow
involvement prior to cytoreductive/
mobilization therapy or at time of clinical
suspicion for progression.
N/A
Transplant
Center
Flow Cytometry
Volume of graft
determined according
to institutional practice
Store according
to institutional
practice
Prior to infusion of autologous or allogeneic
stem cell product.
N/A
Transplant
Center
IgG Levels
Volume of blood
determined according
to institutional practice
Store according
to institutional
practice
12 weeks, 6 months and 1 year post-HSCT.
N/A
Transplant
Center
Donor Research
Specimen
Nucleated Cells
From Allograft
5 vials each containing
2 - 5 x 106 nucleated
cells from allograft
(~1 mL for each vial)
Follow
controlled-rate
freezing SOPs for
cryopreservation
of samples as for
product storage at
-150°
Prior to allogeneic transplant at time of
donation.
Liquid nitrogen shipment
yearly to Repository in
compliance with shipping
procedures specified in
the BMT CTN MOP
TBD
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C-5
Type of Sample
Type of Storage
Dates Samples Obtained
Shipping Specifications
Test
Location
Donor Research
Specimen
Nucleated Cells
from Peripheral
Blood
10 mL peripheral blood
Obtain white
blood cell pellet
(by ficoll) and
freeze in cryovial
at -150°
Prior to donor mobilization.
Frozen shipment
quarterly to Repository in
compliance with shipping
procedures specified in
the BMT CTN MOP
TBD
Patient
Research
Specimen
Nucleated Cells
from Peripheral
Blood
10 mL peripheral blood
Obtain white
blood cell pellet
(by ficoll) and
freeze in cryovial
at -150°
≤ 2 weeks prior to initiation of HSCT
conditioning non-myeloablative allogeneic or
autologous transplant.
Frozen shipment
quarterly to Repository in
compliance with shipping
procedures specified in
the BMT CTN MOP
TBD
PCR for
Presence of
t(14;18)
10 mL peripheral blood
(5 mL in each
vacutainer)
For baseline
sample: 2 x 6 mL
lavender top
EDTA
vacutainers.
For all other
samples: obtain
white blood cell
pellet (by ficoll)
and freeze in
cryovial at -150°.
Any positive test from the time of diagnosis
then required prior to transplant and post-
HSCT maintenance therapy (if applicable); 4
and 12 weeks, 6 months, 12 months and
annually until 3 years post-HSCT. For
autologous patients who were positive at
study entry or prior: Each time leukapheresis
product obtained.
Baseline sample shipped
real-time on frozen gel
packs, via Federal
Express priority
overnight to Baylor
College of Medicine, The
Methodist Hospital. All
other samples frozen
shipment quarterly to
NHLBI Repository in
compliance with shipping
procedures specified in
the BMT CTN MOP.
Baseline
sample:
The
Methodist
Hospital;
Post-
baseline
samples:
TBD
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Version 4.0 dated January 17, 2006
APPENDIX D
HUMAN SUBJECTS
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D-1
APPENDIX D
HUMAN SUBJECTS
1.
Subject Consent
A conference will be held with the patient, donor and family to discuss this study and alternative
treatments available for the treatment of the underlying disease. The Principal Investigator or
another designated physician will conduct the conference. All potential risks associated with the
use of rituximab, cyclophosphamide, TBI, and immunosuppressive drugs should be discussed as
objectively as possible. It should be explained that patients offered this protocol have advanced
FL with life expectancy of no more than several years with conventional treatments.
Furthermore, it should be explained that the patient would be likely to benefit in terms of disease
control and prolongation of survival from an autologous transplant alone, but would likely
relapse from the disease. In addition, the risk of conventional allogeneic transplant for FL
should be described.
The consent document should be reviewed with the patient and family prior to proceeding to
either non-myeloablative or autologous HSCT and rituximab maintenance therapy (for
autologous HSCT patients).
The procedure for collecting hematopoietic stem cells and toxicities of G-CSF will be explained
to the donor. The donor should be counseled as to the risks of treatment with G-CSF and be
informed that leukapheresis at several time points may be necessary.
Informed consent from the donor and patient will be obtained using a form approved the
Institutional Review Board of the institution enrolling the patient.
2.
Confidentiality
Confidentiality will be maintained by individual names being masked and assigned a patient
identifier code. The code relaying the patient’s identity with the ID code will be kept separately
at the center. The ID code will be transmitted to the BMT CTN Data Coordinating Center upon
enrollment.
3.
Participation of Women and Minorities and Other Populations
Women and ethnic minorities and other populations will be included in this study. Accrual of
women and minorities at each center will be monitored to determine whether their rates of
enrollment are reflective of the distribution of potentially eligible women and minorities
expected from data reported to the CIBMTR and from published data on incidence of FL in these
groups. Centers will be notified if their rates differ significantly from those expected and asked
to develop appropriate recruitment strategies.
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Version 4.0 dated January 17, 2006
APPENDIX E
THE STATISTIC FOR TESTING THREE-YEAR
PROGRESSION-FREE SURVIVAL
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Version 4.0 dated January 17, 2006
E-1
APPENDIX E
THE STATISTIC FOR TESTING THREE-YEAR
PROGRESSION-FREE SURVIVAL
The test statistic for this protocol is motivated by two requirements:
1) The test statistic must consider only long-term differences in PFS.
Differences in engraftment, graft-versus-host disease, and infectious complications may
cause crossing hazards of mortality early in the study, and it is not desirable for these
early survival differences to affect the final study outcome.
2) The test statistic must be robust and maintain its size and power in the face of sparse
strata.
The study is not randomized, clinical center effects are problematic and a stratified test
will be employed. Many clinical centers, each potentially enrolling a small number of
patients, will be required to meet the study’s accrual goals.
The study focuses on a primary endpoint of three-year progression-free survival, as this endpoint
will be unaffected by crossing hazards of mortality early in the study, and reflects the primary
interest in long term cure. Information past the three-year time-point is not considered in the
primary analysis, as it complicates the interpretation and description of the endpoint, e.g. “three
years and longer progression-free survival.”
If the data were not subject to censoring, the ideal test statistic would be the stratified Cochran
Mantel Haenszel test comparing the proportion of subjects who are alive without progression at
three years post-transplant. However, it is more realistic to assume that some individuals will be
censored prior to the three-year time-point. We propose to use a modified stratified CMH test,
where the Kaplan-Meier actuarial estimates of survival replace the binomial proportions of
survivors.
This test statistic is based on the paper “A Partially Grouped Logrank Test” by Sposto, Stablein
and Carter-Campbell, Statistics in Medicine, Vol. 16, 695-704 (1997). The authors argue that in
the setting where early differences in survival are irrelevant to the ultimate outcome, a grouped
log-rank test which groups all information prior to a specified time point (tc) is preferable to a
weighted log-rank test that de-emphasizes early differences in survival but does not ignore them.
The authors derive the mean and variance of the contribution of the grouped data table to the
Mantel-Haenszel version of the logrank statistic, using a hypergeometric argument.
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E-2
Grouped Data Table
Failure
Non-Failure
At Risk
Group 1
x
x
N
1
1
N
Group 0
y
y
N
0
0
N
Total
y
x
z
z
N
N
Sposto et. al. estimate the quantities in the grouped table as follows:
))
(
ˆ
1(
1
1
ct
S
N
x
, and
))
(
ˆ
1(
0
0
ct
S
N
y
, where
1
N and
0
N are the numbers initially at risk, and
)
(
ˆ
1
ct
S
,
)
(
ˆ
0
ct
S
are
the product limit estimates of the survival functions at time ct .
Under the assumption that
)
(
)
(
)
(
0
1
t
S
t
S
t
S
for all
ct
t
, and using the asymptotic normal
approximation to the distribution of the product limit estimate, Sposto et. al. show that the
conditional distribution of xgiven
y
x
z
is normal with mean
N
N
z
z
x
E
1
)
|
(
and
variance
)]
(ˆ
[
)
|
(
0
1
ct
S
V
N
N
z
x
V
, where
)
(ˆ
ct
S
is the product limit estimate in both samples
combined, and
)]
(ˆ
[
ct
S
V
is its asymptotic variance, which in practice, is estimated using
Greenwood’s formula.
Sposto et. al. propose the following product limit based log rank test statistic:
2
)
|
(ˆ
))
|
(
(
c
i
c
i
t
t
i
t
t
i
PL
V
z
x
V
S
z
x
E
x
LR
where
iS and
iV are the usual logrank numerator and denominator contributions for ordered
failure times
c
i
t
t
.
We re-express the test statistic in a simpler form as follows:
2
0
1
0
0
)]
(ˆ
[ˆ
))
(
ˆ
)
(ˆ
(
c
i
c
i
t
t
i
c
t
t
i
c
c
PL
V
t
S
V
N
N
S
t
S
t
S
N
LR
In the primary analysis of the endpoint of three-year progression-free survival, we set
ct = 3
years, and do not collect information past this time point. The square root of the LRPL test
statistic is then summed over clinical strata to obtain a stratified test, and a continuity correction
is introduced. Using notation specific to our application, the test statistic is now written:
strata
Pooled
Allo
Auto
strata
Auto
Pooled
Auto
PL
S
V
N
N
S
S
N
Z
))
3
(
ˆ
(ˆ
2
/
1
)3
(
ˆ
)
3
(
ˆ
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E-3
It should be noted that in the absence of censoring, this test statistic reduces to the Mantel-
Haenszel test for comparing binomial proportions in stratified data.
In the secondary analysis of the endpoint of three-year progression-free survival, we again set
ct = 3 years, but use the original Sposto et. al. test statistic, LRPL , which includes the terms for
the contributions of the log-rank test statistic after the three-year time-point. It is not anticipated
that LRPL will lead to qualitatively different results from ZPL, but the extra information may
improve the power of the test substantively if accrual is much slower than anticipated.
The Mantel-Haenszel formulation of the log rank test maintains its large sample properties in
modest sample sizes, even though it is comprised of sparse strata corresponding to individual
death times. Similarly, the test statistic ZPL has been shown in simulation studies to control type
I error at nominal target levels even in the presence of moderate censoring and sparse strata.
When follow-up is complete (no censoring) the power of test statistic ZPL is that of a stratified
CMH test of binomial proportions. The power calculations given in Chapter 5, Statistical
Considerations, are based on large sample results for the unstratified chi-squared test in the
absence of center-to-center heterogeneity, but have been confirmed by simulations using
stratified test statistic ZPL in the presence of center-to-center heterogeneity.
| 2
|
arm 1: Cyclophosphamide and Rituximab with Filgrastim conditioning and chemotherapy or radiation therapy prior to autologous Hematopoietic Stem Cell Transplant (HSCT). Rituximab maintenance therapy following HSCT. arm 2: Non-myeloablative conditioning regimen followed by allogeneic Hematopoietic Stem Cell Transplant (HSCT). Graft-versus-Host Disease (GVHD) Prophylaxis therapy following HSCT.
|
[
1,
1
] | 8
|
[
0,
0,
4,
0,
3,
3,
0,
0
] |
intervention 1: Prior to undergoing HSCT, all patients will receive Cyclophosphamide 4 gm/m2 with Rituximab 375 mg/m2 x 2 doses and G-CSF support. intervention 2: Autologous HSCT patients will receive 10 mcg/kg/day and allogeneic HSCT patients will receive 5 mcg/kg/day subcutaneous (SQ) or intravenous (IV) starting 2 days after the initiation of Cyclophosphamide. intervention 3: Chemotherapy - BCNU 15 mg/kg IV x 1 dose to be administered over 2 hours on Day -6 pre-HSCT. VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4.
Radiation - administered at a rate of \< 20 cGy/min in one of the following doses; 120 cGy/fraction are administered at no less than 4-hour intervals three times/day or 2 times/day for a total of 10 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5), or doses of 150 cGy/fraction twice daily for a total of 8 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5). VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4 pre-HSCT.
Cyclophosphamide 100 mg/kg IV x 1 dose to be administered over 2 hours on Day -2 pre-HSCT. G-CSF 5 mcg/kg SQ or IV to start on Day +5 post-HSCT and continue until ANC \> 500/mm3 x 3 days. intervention 4: Fludarabine 30 mg/m2 IV x 3 doses total to be administered daily over 30 minutes on Days -6, -5 and -4 pre-HSCT. Cyclophosphamide 750 mg/m IV x 3 doses total to be administered daily over 1 hour on Days -6, -5 and -4 pre-HSCT. Administer cyclophosphamide approximately 4 hours after start of fludarabine infusion. Rituximab 375 mg/m2 IV x 4 doses total to be administered on Days -13 and -6 pre HSCT and Days +1 and +8 post HSCT. intervention 5: Infusion of G-CSF mobilized allogeneic hematopoietic stem cells intervention 6: Infusion of G-CSF mobilized autologous hematopoietic stem cells intervention 7: Patients must have sufficiently recovered from autologous HSCT in order to receive rituximab maintenance therapy as specified below:
Dose #1: Day +42 post-autologous HSCT Dose #2: Day +49 post-autologous HSCT Dose #3: Day +56 post-autologous HSCT Dose #4: Day +63 post-autologous HSCT intervention 8: Tacrolimus 0.09 mg/kg/day PO, based on body weight formulas will start on Day -2 and continue until Day +90 post-HSCT. Tacrolimus (or cyclosporine, if applicable) will be given orally in a twice-daily divided dose. Methotrexate 5 mg/m2 Intravenous Pyelogram (IVP) will be administered on Days +1, +3 and +6 post-HSCT.
|
intervention 1: Cyclophosphamide and Rituximab intervention 2: Filgrastim intervention 3: Chemotherapy or Radiation therapy intervention 4: Non-myeloablative Conditioning regimen intervention 5: Allogeneic transplant intervention 6: Autologous transplant intervention 7: Rituximab maintenance therapy intervention 8: GVHD Prophylaxis
| 30
|
Duarte | California | United States | -117.97729 | 34.13945
La Jolla | California | United States | -117.2742 | 32.84727
La Jolla | California | United States | -117.2742 | 32.84727
Stanford | California | United States | -122.16608 | 37.42411
Gainesville | Florida | United States | -82.32483 | 29.65163
Tampa | Florida | United States | -82.45843 | 27.94752
Atlanta | Georgia | United States | -84.38798 | 33.749
Atlanta | Georgia | United States | -84.38798 | 33.749
Atlanta | Georgia | United States | -84.38798 | 33.749
Beech Grove | Indiana | United States | -86.08998 | 39.72199
Boston | Massachusetts | United States | -71.05977 | 42.35843
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Detroit | Michigan | United States | -83.04575 | 42.33143
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
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
Durham | North Carolina | United States | -78.89862 | 35.99403
Cleveland | Ohio | United States | -81.69541 | 41.4995
Portland | Oregon | United States | -122.67621 | 45.52345
Portland | Oregon | United States | -122.67621 | 45.52345
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
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
Richmond | Virginia | United States | -77.46026 | 37.55376
Madison | Wisconsin | United States | -89.40123 | 43.07305
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
| 0
|
NCT00096460
|
|
[
0
] | 42
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gefitinib before surgery may shrink the tumor so it can be removed.
PURPOSE: This phase II trial is studying how well gefitinib works in treating patients who are undergoing surgery for stage I, stage II, or stage III non-small cell lung cancer.
|
OBJECTIVES:
Primary
* Determine the effects of neoadjuvant gefitinib on downstream signaling pathways, including Src-Stat3, PI3K/Akt, ERK activity, and Bcl-2 family members in patients with resectable stage I-IIIA non-small cell lung cancer.
* Determine the effects of this drug on cell cycle and apoptosis within the primary tumor, by measuring changes in pre- and post-treatment Ki-67, Mcm2, cleaved caspase-3, and ApoTag, in these patients.
Secondary
* Determine the clinical response rate in patients treated with this drug.
* Determine the pathological response rate, defined as \> 95% necrosis or fibrosis in the pathological specimen, in patients treated with this drug.
* Determine the metabolic activity of this drug in these patients.
* Determine the safety, tolerability, and feasibility of this drug, in terms of toxicity and post-treatment resectability, in these patients.
* Correlate plasma and tumor concentrations of this drug with changes in post-treatment molecular markers in these patients.
* Identify a gene profile that predicts response to this drug in these patients.
OUTLINE: This is an open-label, pilot study.
Patients receive oral gefitinib once daily for 4 weeks in the absence of disease progression or unacceptable toxicity.
Within 3 days after completion of gefitinib, patients undergo restaging evaluation. Patients whose disease is still considered resectable proceed to surgery. Patients undergo thoracotomy with lobectomy or pneumonectomy OR sleeve resection. Patients also undergo mediastinal lymph node dissection. After surgical resection, treatment with gefitinib may continue off study at the discretion of the principal investigator.
After completion of study therapy, patients are followed at 30 days, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.
PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study within 12.5 months.
|
Lung Cancer
|
stage II non-small cell lung cancer stage IIIA non-small cell lung cancer stage IA non-small cell lung cancer stage IB non-small cell lung cancer
| null | 1
|
arm 1: The ZD1839 250-mg tablet will be taken once a day, every day about the same time. It can be taken with or without food.
At the time of surgery, investigators will collect tissue from the participant's tumor once it has been removed. This tissue will be used to study the effect of ZD1839 on tumor growth.
|
[
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: ZD1839
| 1
|
Tampa | Florida | United States | -82.45843 | 27.94752
| 0
|
NCT00104728
|
[
3
] | 4
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Drugs used in chemotherapy, such as FR901228, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.
PURPOSE: This phase II trial is studying how well FR901228 works in treating patients with unresectable stage III or stage IV malignant melanoma.
|
OBJECTIVES:
Primary
* Determine the response rate in patients with unresectable stage III or stage IV malignant melanoma treated with FR901228 (depsipeptide).
Secondary
* Determine the progression-free and overall survival of patients treated with this drug.
* Determine the toxicity profile of this drug in these patients.
OUTLINE: This is a multicenter study.
Patients receive FR901228 (depsipeptide) intravenously (IV) over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year.
PROJECTED ACCRUAL: A total of 22-40 patients will be accrued for this study within 18 months.
|
Malignant Melanoma Melanoma
|
stage III melanoma stage IV melanoma Depsipeptide
| null | 1
|
arm 1: Depsipeptide is administered as a 4-hour IV infusion weekly in doses of 13 mg/m\^2 for 3 weeks. Repeat cycle every 28 days until unacceptable toxicity or disease progression.
|
[
0
] | 1
|
[
0
] |
intervention 1: Given IV
|
intervention 1: Depsipeptide
| 0
| null | 0
|
NCT00104884
|
[
3
] | 40
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
The purpose of the trial was to determine whether a 36-ingredient micronutrient supplement (primarily vitamins and minerals) is beneficial for the treatment of bipolar disorder, when studied under randomized and fully blinded conditions and compared to a placebo. The supplement is referred to as MCN36, because it contains 36 nutrients. Based on the preliminary research on this supplement, it is hypothesized that patients who take MCN36 for 8 weeks will experience improved mood stability relative to those who take the placebo. All participants must live EITHER in the vicinity of Calgary, Alberta, Canada, OR in the area of San Diego, California.
|
This RCT (randomized clinical trial) compared MCN36 to placebo in patients randomized to receive one or the other for 8 weeks. Close medical supervision was provided with weekly appointments. At the end of the 8 weeks, all participants were offered the opportunity of entering an 8-week open-label extension.
The efficacy objective of this study was to assess the efficacy of MCN36 compared with placebo in otherwise medication-free adults with bipolar disorder I and II, in improving overall symptomatology at the end of 8 weeks of therapy as assessed under randomized and fully blinded conditions
* as measured by the clinician using the Overall Bipolarity Index (OBI) (primary outcome measure).
* as measured by the clinician using the Clinical Global Impressions for Bipolar Disorder (CGI-BP) for Severity.
* as measured by self-report recorded on the Outcome Questionnaire (OQ).
* in terms of rate of response, with response defined as a reduction of 50% or more in either the depression or the mood elevation component of the OBI.
* in terms of functional states and health-related quality of life as measured by The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36).
The safety-related objective was to assess the safety of MCN36 compared with placebo in terms of
* laboratory analyses
* treatment-emergent adverse events, which will be solicited at each appointment using the Adverse Event Log.
Participants had two appointments for screening and confirming suitability for the trial. Between those two appointments, they provided a blood sample, and met with a research nurse. They also kept a 7-day food record of their food intake prior to the second appointment. If suitability was confirmed at the second visit, they entered the randomized phase.
|
Bipolar Disorder
|
bipolar disorder mood disorders manic depression nutrition
| null | 2
|
arm 1: Placebo comparator, 6 placebo capsules three times a day arm 2: nutritional supplement intervention, 6 nutritional supplement capsules three times a day; the nutritional supplement is a 36-ingredient micronutrient supplement (primarily vitamins and minerals) and is referred to as MCN36, because it contains 36 nutrients.
|
[
2,
0
] | 2
|
[
0,
0
] |
intervention 1: nutritional supplement intervention 2: nutritional supplement
|
intervention 1: MCN36 (nutritional supplement) intervention 2: Placebo
| 2
|
San Diego | California | United States | -117.16472 | 32.71571
Calgary | Alberta | Canada | -114.08529 | 51.05011
| 0
|
NCT00109577
|
[
3
] | 30
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
Cilengitide may stop the growth of glioblastoma multiforme by blocking blood flow to the tumor. Giving cilengitide before and after surgery may be an effective treatment for glioblastoma multiforme. This phase II trial is studying how well cilengitide works in treating patients who are undergoing surgery for recurrent or progressive glioblastoma multiforme.
|
PRIMARY OBJECTIVES:
I. Determine the 6-month progression-free survival rate in operative patients with recurrent or progressive glioblastoma multiforme treated with cilengitide.
SECONDARY OBJECTIVES:
I. Determine the safety and toxicity of this drug in these patients.
OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment groups for the preoperative treatment component.
Preoperative Treatment Group I: Patients receive high-dose cilengitide IV over 1 hour on days -8, -4, and -1.
Preoperative Treatment Group II: Patients receive low-dose cilengitide IV over 1 hour on days -8, -4, and -1.
Resection: All patients undergo tumor resection on day 0.
Postoperative Treatment: Beginning within 2 weeks after surgery, all patients receive high-dose cilengitide IV over 1 hour twice weekly for 4 weeks. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months.
PROJECTED ACCRUAL: A total of 44 patients (22 per preoperative treatment group) will be accrued for this study.
|
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Recurrent Adult Brain Tumor
| null | 2
|
arm 1: Preoperative Treatment: Patients receive high-dose cilengitide IV over 1 hour on days -8, -4, and -1. (High dose 2000mg)
Resection: All patients undergo tumor resection on day 0.
Postoperative Treatment: Beginning within 2 weeks after surgery, all patients receive high-dose cilengitide IV over 1 hour twice weekly for 4 weeks. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. arm 2: Preoperative Treatment: Patients receive low-dose cilengitide IV over 1 hour on days -8, -4, and -1. (500mg)
Resection: All patients undergo tumor resection on day 0.
Postoperative Treatment: Beginning within 2 weeks after surgery, all patients receive high-dose cilengitide IV over 1 hour twice weekly for 4 weeks. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity
|
[
0,
0
] | 4
|
[
0,
3,
10,
10
] |
intervention 1: Given IV intervention 2: Undergo tumor resection intervention 3: Correlative studies intervention 4: Correlative studies
|
intervention 1: cilengitide intervention 2: therapeutic conventional surgery intervention 3: pharmacological study intervention 4: laboratory biomarker analysis
| 1
|
Watertown | Massachusetts | United States | -71.18283 | 42.37093
| 0
|
NCT00112866
|
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