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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
[
0
] | 9
|
NA
|
SINGLE_GROUP
| null | 0NONE
| false
| 0ALL
| false
|
Aspirin is a weak acid that crosses the gastric and intestinal mucosa by passive diffusion while in its lipophilic nature.Omeprazole, a proton pump inhibitor, inhibits gastric acid secretion.
We assumed that omeprazole inhibits aspirin absorption, thus reducing its action on platelets.
healthy volunteers, with no known peptic disease or bleeding disorders will be enrolled.
All volunteers will receive 7 days of Aspirin (100mg) alone, followed by 14 days of Aspirin and Omeprazole 20mg twice daily for 3 days and then 20mg once daily.
Blood levels of Aspirin will be determined by High performance liquid chromatography (HPLC), 0, 1, 2, 4, 6, 10, 24 hours after the administration of Aspirin alone on day 7 and Aspirin plus Omeprazole on day 21.
Platelet function tests will be determined by platelet-rich plasma aggregometry in response to Arachidonic acid (500mg/ml), Ristocetin (1.5mg/ml) and Adenosine 5'-diphosphate (20mM) on day 0 as baseline and on day 7 and 21 of the study.
| null |
Aspirin Blood Level Proton Pump Inhiditor Treatment
|
pharmacokinetics aspirin proton pump inhiditor
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: aspirin 100 mg, once daily aspirin 100 mg and omeprazole 20 mg both once daily.
|
intervention 1: aspirin and omeprazole
| 1
|
Ẕerifin | N/A | Israel | 34.84852 | 31.95731
| 0
|
NCT01061034
|
[
2
] | 84
|
RANDOMIZED
|
CROSSOVER
| null | 0NONE
| true
| 0ALL
| false
|
The purpose of this study is to assess the bioequivalence of a new oxycodone formulation (10 mg) relative to the original OxyContin® (OXY) formulation (10 mg) in the fasted state.
|
Oxycodone hydrochloride (oxycodone) is a semi-synthetic opioid analgesic that is effective in the relief of moderate to severe malignant and non-malignant pain.
|
Healthy Volunteers
|
Healthy subjects Opioid
| null | 2
|
arm 1: Reformulated OXY 10 mg x 1 dose arm 2: Original OxyContin® (OXY)10 mg x 1 dose
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Reformulated OXY 10-mg tablet x 1 dose taken without food intervention 2: Original OxyContin® (OXY) 10-mg tablet x 1 dose taken without food
|
intervention 1: Reformulated OXY (oxycodone HCl) intervention 2: Original OxyContin® (OXY) (oxycodone HCl)
| 1
|
Madison | Wisconsin | United States | -89.40123 | 43.07305
| 0
|
NCT01100086
|
[
2
] | 16
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The purpose of this study is to determine the pharmacokinetics (PK) of decitabine administered to patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
| null |
Leukemia
|
Acute myelogenous leukemia myelodysplastic Syndrome cancer
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Intravenous injection; total dose-per-cycle was 135 mg/m\^2 of decitabine.
|
intervention 1: Decitabine (Dacogen)
| 1
|
St Louis | Missouri | United States | -90.19789 | 38.62727
| 0
|
NCT01378416
|
[
3
] | 104
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
This was an extension study consisting of 2 parts. In Part I, all participants received open-label treatment with BIA 2-093 900 mg once daily for 2 weeks. Part II followed a double-blind, parallel-group design in which participants were randomly assigned to treatment with BIA 2-093 300 mg, 900 mg, or 1800 mg once daily. Patients stable in remission continued double-blind therapy until approximately 6 months after the last patient entered Part II.
|
The occurrence of a new manic/depressive episode was considered a treatment failure, and the patient was discontinued from the study. At the end of Part II, 6 months after last patient enrolled and after no longer than approximately 15 months, if patients were still in remission and the investigational product was well-tolerated, patients had the option to enter long-term open-label treatment at the same dosage as used in Part II until a new episode occurred, until marketing was authorized, or until clinical development of BIA 2-093 in the recurrence prevention indication was discontinued. If patients did not enter long-term treatment, an established recurrence prevention medication was prescribed, and BIA 2-093 was tapered off (patients assigned to 1800 mg had the daily dose decreased to 900 mg for 6 days; those assigned to 900 mg or 300 mg received placebo for 6 days).
|
Bipolar I Disorder
|
bipolar I disorder Eslicarbazepine acetate BIA 2-093
| null | 4
|
arm 1: BIA 2-093 1800 mg once daily (Part II followed a double-blind, parallel-group design in which participants were randomly assigned to treatment with BIA 2-093 300 mg, 900 mg, or 1800 mg once daily). Study medication was administered orally, once daily in the evening. arm 2: BIA 2-093 900 mg once daily (Part II followed a double-blind, parallel-group design in which participants were randomly assigned to treatment with BIA 2-093 300 mg, 900 mg, or 1800 mg once daily). Study medication was administered orally, once daily in the evening. arm 3: BIA 2-093 300 mg once daily (Part II followed a double-blind, parallel-group design in which participants were randomly assigned to treatment with BIA 2-093 300 mg, 900 mg, or 1800 mg once daily). Study medication was administered orally, once daily in the evening. arm 4: In Part I, all participants received open-label treatment with BIA 2-093 900 mg once daily for 2 weeks.
|
[
0,
0,
0,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: BIA 2-093 1800 mg taken orally in the evening, for 2 weeks intervention 2: BIA 2-093 900 mg taken orally in the evening, for 2 weeks intervention 3: BIA 2-093 300 mg taken orally in the evening, for 2 weeks. intervention 4: In Part I, patients received one 900 mg BIA 2-093 tablet once daily, taken orally in the evening, for 2 weeks.
|
intervention 1: BIA 2-093 1800 mg once daily [Group 1 (Part II)] intervention 2: BIA 2-093 900 mg once daily [Group 2 (Part II)] intervention 3: BIA 2-093 300 mg once daily [Group 3 (Part II)] intervention 4: BIA 2-093 900 mg (Part I)
| 0
| null | 0
|
NCT01825837
|
[
2
] | 67
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| true
| 0ALL
| false
|
A randomized, double-blind, placebo-controlled and open label active-controlled, 4 period crossover trial to evaluate the effect of eslicarbazepine acetate on cardiac repolarization in healthy adult men and women
|
The purpose of this randomized, double-blind, placebo-controlled and open label active-controlled, 4 period crossover study was to evaluate the effect of therapeutic and supra-therapeutic doses of eslicarbazepine acetate on the placebo corrected time-matched change from baseline using individually corrected QT (QTcI) interval durations in adult healthy volunteers.
|
Epilepsy
| null | 4
|
arm 1: A - BIA 2-093 1200 mg once daily × 5 days B - BIA 2-093 2400 mg once daily × 5 days C - Moxifloxacin 400 mg × 1 dose D - placebo once daily × 5 days arm 2: A - BIA 2-093 1200 mg once daily × 5 days B - BIA 2-093 2400 mg once daily × 5 days C - Moxifloxacin 400 mg × 1 dose D - placebo once daily × 5 days arm 3: A - BIA 2-093 1200 mg once daily × 5 days B - BIA 2-093 2400 mg once daily × 5 days C - Moxifloxacin 400 mg × 1 dose D - placebo once daily × 5 days arm 4: A - BIA 2-093 1200 mg once daily × 5 days B - BIA 2-093 2400 mg once daily × 5 days C - Moxifloxacin 400 mg × 1 dose D - placebo once daily × 5 days
|
[
0,
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: None intervention 2: None intervention 3: None
|
intervention 1: BIA 2-093 intervention 2: Moxifloxacin intervention 3: Placebo
| 1
|
Miramar | Florida | United States | -80.23227 | 25.98731
| 0
|
NCT02283788
|
|
[
2
] | 60
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 1SINGLE
| true
| 0ALL
| false
|
Single center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover design
|
Single center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover design to evaluate and compare the relative bioavailability and therefore the bioequivalence of three doses (400 mg, 600 mg and 800 mg) of eslicarbazepine acetate for two formulations (CTF versus TBM) after a single oral dose administration under fasting conditions
|
Epilepsy
| null | 6
|
arm 1: One Eslicarbazepine acetate (BIA 2-093) 400 mg tablet (To-Be-Marketed Formulation, TBM)
One Eslicarbazepine acetate (BIA 2-093) 400 mg tablet (Clinical Trial Formulation, CTF) arm 2: One Eslicarbazepine acetate (BIA 2-093) 400 mg tablet (Clinical Trial Formulation, CTF) One Eslicarbazepine acetate (BIA 2-093) 400 mg tablet (To-Be-Marketed Formulation, TBM) arm 3: One Eslicarbazepine acetate (BIA 2-093) 600 mg tablet (To-Be-Marketed Formulation, TBM)
One Eslicarbazepine acetate (BIA 2-093) 600 mg tablet (Clinical Trial Formulation, CTF) arm 4: One Eslicarbazepine acetate (BIA 2-093) 600 mg tablet (Clinical Trial Formulation, CTF) One Eslicarbazepine acetate (BIA 2-093) 600 mg tablet (To-Be-Marketed Formulation, TBM) arm 5: One Eslicarbazepine acetate (BIA 2-093) 800 mg tablet (To-Be-Marketed Formulation, TBM)
One Eslicarbazepine acetate (BIA 2-093) 800 mg tablet (Clinical Trial Formulation, CTF) arm 6: One Eslicarbazepine acetate (BIA 2-093) 800 mg tablet (Clinical Trial Formulation, CTF) One Eslicarbazepine acetate (BIA 2-093) 800 mg tablet (To-Be-Marketed Formulation, TBM)
|
[
0,
0,
0,
0,
0,
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: BIA 2-093
| 0
| null | 0
|
NCT02283840
|
|
[
4
] | 551
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this trial is to assess whether 400mg/day of lacosamide is effective in reducing pain caused by distal diabetic neuropathy. Two dose-escalation schemes for lacosamide will be used to further determine the efficacy of the "standard" scheme and to evaluate the efficacy and safety of a more rapid titration scheme. Subjects will be randomly assigned to one of three treatment groups. Subjects in two of the groups will receive lacosamide at a dose of 400mg/day, but different dose-escalation schemes will be used to reach this final dose. The third group of subjects will receive a placebo. Subjects will have a 2 in 3 (66 %) chance of getting lacosamide.
The maximum lacosamide dose in this trial will be 400mg/day. The maximum treatment duration will be 18 weeks, including a two-week Pre-Treatment Phase and a 12 weeks period on a stable dose of lacosamide or placebo.
| null |
Painful Diabetic Neuropathy
|
Painful Diabetic Neuropathy Lacosamide
| null | 3
|
arm 1: Subjects had their dose titrated from 100 mg/day to 400 mg/day at weekly intervals of 100 mg. Subjects in this treatment group reach their target dose of 400 mg/day 3 weeks after Visit 2. All subjects completing the Titration Phase enter a 12-week Maintenance Phase. arm 2: Subjects receive 200 mg/day LCM for the first 3 days, 300 mg/day for the next 4 days, and reach their target dose of 400 mg/day after 1 week. They undergo sham titration for the remaining 3 weeks of the Titration Phase. All subjects completing the Titration Phase enter a 12-week Maintenance Phase. arm 3: Subjects underwent sham titration for the entire Titration Phase. All subjects completing the Titration Phase enter a 12-week Maintenance Phase
|
[
0,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: * Pharmaceutical form: Immediate release film-coated tablets
* Concentration: 50mg/ 100mg
* Route of administration: Oral use intervention 2: * Pharmaceutical form: Immediate release film-coated tablets
* Route of administration: Oral use
|
intervention 1: SPM 929 intervention 2: Placebo
| 1
|
Monheim | N/A | Germany | 10.85834 | 48.84389
| 0
|
NCT00350103
|
[
3
] | 60
|
RANDOMIZED
|
PARALLEL
| 7BASIC_SCIENCE
| 3TRIPLE
| false
| 0ALL
| true
|
To testify the efficacy and safety of traditional Chinese formulae, "Wu-Ling San" and "Yin-Chen Wu-Ling San" for patients with hyperuricemia.
|
The prevalence of hyperuricemia and gout is increasing in Taiwan. It is probably contributed by adapting to Western diet and lifestyle. Previous studies have demonstrated the relationship between hyperuricemia with hypertension, metabolic syndrome, cardiovascular disease and chronic renal disease. While Western medicine shows promising effects in treating hyperuricemia and gout, we are searching for an alternative in traditional Chinese medicine with both safety and efficacy in treating hyperuricemia.
We conducted a randomized double-blinded placebo-controlled clinical trial in adults with hyperuricemia. Sixty patients with serum uric acid level more than 8 mg/dl were enrolled. Patients were then randomized into three arms: Traditional Chinese Medicine formulae: "Wu-Ling San", "Yin-Chen Wu-Ling San" or placebo for 4 weeks. Efficacy and safety were evaluated at Week 2, 4 and 8. Primary endpoint was the serum uric acid\<6 mg/dL at Week 4. Secondary endpoints were the differences between groups in serum uric acid at Week 2 and 8, serum SGPT, SGOT, creatinine, total cholesterol, triglycerides, HDL, LDL, fasting blood glucose, body weight, blood pressures and frequency of gouty attack at Week 4.
|
Hyperuricemia
| null | 3
|
arm 1: Drug : Wu Ling San Extract Granules "Sun-Ten" arm 2: Drug : Yin-Chen-Wu-Ling-San Extract Power "SUN-TEN" arm 3: Drug : 1/10 Wu Ling San
|
[
1,
1,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: assigned to Wu Ling San (n =20) and were instructed to take 4.5 gm 2 times per day of Wu Ling San for a period of 4 weeks. intervention 2: assigned to Yin-Chen Wu Ling San (n =20) and were instructed to take 4.5 gm 2 times per day of Yin-Chen Wu Ling San for a period of 4 weeks. intervention 3: 1/10 Wu Ling San assigned to Placebo (n =20) and were instructed to take 4.5 gm 2 times per day of Placebo for a period of 4 weeks.
|
intervention 1: Wu Ling San intervention 2: Yin-Chen Wu Ling San intervention 3: Placebo
| 0
| null | 0
|
NCT04144088
|
|
[
4
] | 358
|
RANDOMIZED
|
PARALLEL
| 9OTHER
| 0NONE
| false
| 0ALL
| true
|
The purpose of this study is to determine whether patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine have improved survival compared to conventional care treatments. The study will also assess the effect of treatments on response, duration of response, and transformation to acute myeloid leukemia (AML). The study will continue for 12 months following last patient enrolled.
See study AZA PH GL 2003 CL 001 E for information about the extension to this study.
|
Comparison/Control Interventions offered the physician three options:
* Best supportive care (BSC) alone,
* Low-dose cytarabine subcutaneously for 14 days every 28 to 42 days, or
* Standard chemotherapy administered for induction as a continuous intravenous infusion of cytarabine over 7 days plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) on Days 1, 2, and 3; and, for those eligible, 1 or 2 consolidation cycles administered as continuous intravenous infusions of cytarabine for 3 to 7 days with the same anthracycline that was used at induction on Days 1 and 2 (each cycle between 28 to 70 days from the start of the previous cycle).
All three options included best supportive care. Neither the experimental group (azacitidine) nor any of the comparison/control options allowed use of erythropoietin.
Duration of Intervention: Patients will be treated until death, withdrawal, unacceptable toxicity or conclusion of the study.
|
Myelodysplastic Syndromes
| null | 2
|
arm 1: Study Drug plus best supportive care. Treatment with erythropoietin was not permitted arm 2: Physician choice of low dose cytarabine (plus best supportive care), standard chemotherapy (plus best supportive care) or best supportive care (only). Treatment with erythropoietin was not permitted
|
[
0,
1
] | 2
|
[
0,
10
] |
intervention 1: Azacitidine was injected subcutaneously (SC) at an initial dose of 75mg/m\^2/day for 7 days. The 7-day dosing was repeated every 28 days with dose adjustment based on predefined hematology and renal laboratory results. Number of cycles: Azacitidine treatment was to be continued until the end of the study unless treatment was discontinued due to unacceptable toxicity, relapse after complete or partial response, transformation to AML or disease progression. intervention 2: Physician Choice was one of three options:
* Best supportive care (BSC) alone,
* Low-dose cytarabine subcutaneously for 14 days every 28 to 42 days, or
* Standard chemotherapy administered for induction as a continuous intravenous infusion of cytarabine over 7 days plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) on Days 1, 2, and 3; and, for those eligible, 1 or 2 consolidation cycles administered as continuous intravenous infusions of cytarabine for 3 to 7 days with the same anthracycline that was used at induction on Days 1 and 2 (each cycle between 28 to 70 days from the start of the previous cycle).
All three options included best supportive care
|
intervention 1: Azacitidine intervention 2: Physician Choice
| 108
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Indianapolis | Indiana | United States | -86.15804 | 39.76838
St Louis | Missouri | United States | -90.19789 | 38.62727
New York | New York | United States | -74.00597 | 40.71427
Cleveland | Ohio | United States | -81.69541 | 41.4995
Portland | Oregon | United States | -122.67621 | 45.52345
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Liverpool | New South Wales | Australia | 150.92588 | -33.91938
St Leonards | New South Wales | Australia | 151.19836 | -33.82344
Warratah | New South Wales | Australia | N/A | N/A
Hersten | Queensland | Australia | N/A | N/A
Woolloongabba | Queensland | Australia | 153.03655 | -27.48855
Adelaide | South Australia | Australia | 138.59863 | -34.92866
East Melbourne | Victoria | Australia | 144.9879 | -37.81667
Melbourne | Victoria | Australia | 144.96332 | -37.814
Melbourne | Victoria | Australia | 144.96332 | -37.814
Perth | Western Australia | Australia | 115.8614 | -31.95224
Pleven | N/A | Bulgaria | 24.61667 | 43.41667
Plovdiv | N/A | Bulgaria | 24.75 | 42.15
Plovdiv | N/A | Bulgaria | 24.75 | 42.15
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Varna | N/A | Bulgaria | 27.91667 | 43.21667
Varna | N/A | Bulgaria | 27.91667 | 43.21667
Jihlavska | Brno | Czechia | N/A | N/A
Sokolska | Hradec Kralove | Czechia | N/A | N/A
Olomouc | N/A | Czechia | 17.25175 | 49.59552
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Angers | N/A | France | -0.55202 | 47.47156
Clichy | N/A | France | 2.30952 | 48.90018
Lille | N/A | France | 3.05858 | 50.63297
Lyon | N/A | France | 4.84671 | 45.74846
Marseille | N/A | France | 5.38107 | 43.29695
Nantes | N/A | France | -1.55336 | 47.21725
Paris | N/A | France | 2.3488 | 48.85341
Paris | N/A | France | 2.3488 | 48.85341
Rouen | N/A | France | 1.09932 | 49.44313
Toulouse | N/A | France | 1.44367 | 43.60426
Hindenburgdamm | State of Berlin | Germany | N/A | N/A
Bonn | N/A | Germany | 7.09549 | 50.73438
Chemnitz | N/A | Germany | 12.92922 | 50.8357
Dresden | N/A | Germany | 13.73832 | 51.05089
Duisburg | N/A | Germany | 6.76516 | 51.43247
Düsseldorf | N/A | Germany | 6.77616 | 51.22172
Essen | N/A | Germany | 7.01228 | 51.45657
Göttingen | N/A | Germany | 9.93228 | 51.53443
Hamburg | N/A | Germany | 9.99302 | 53.55073
Hamburg | N/A | Germany | 9.99302 | 53.55073
Kiel | N/A | Germany | 10.13489 | 54.32133
Ulm | N/A | Germany | 9.99155 | 48.39841
Haidari | Athens | Greece | N/A | N/A
Heraklio | Crete | Greece | N/A | N/A
Athens | N/A | Greece | 23.72784 | 37.98376
Athens | N/A | Greece | 23.72784 | 37.98376
Ioannina | N/A | Greece | 20.85189 | 39.66486
Pátrai | N/A | Greece | 21.73444 | 38.24444
Budapest | N/A | Hungary | 19.04045 | 47.49835
Pécs | N/A | Hungary | 18.23083 | 46.0725
Szeged | N/A | Hungary | 20.14824 | 46.253
Bologna | N/A | Italy | 11.33875 | 44.49381
Florence | N/A | Italy | 11.24626 | 43.77925
Genova | N/A | Italy | 11.87211 | 45.21604
Milan | N/A | Italy | 12.59836 | 42.78235
Modena | N/A | Italy | 10.92539 | 44.64783
Roma | N/A | Italy | 11.10642 | 44.99364
Roma | N/A | Italy | 11.10642 | 44.99364
Roma | N/A | Italy | 11.10642 | 44.99364
San Giovanni Rotondo | N/A | Italy | 15.7277 | 41.70643
Sassari | N/A | Italy | 8.55552 | 40.72586
Amsterdam | N/A | Netherlands | 4.88969 | 52.37403
Nijmejen | N/A | Netherlands | N/A | N/A
Gdansk | N/A | Poland | 18.64912 | 54.35227
Lodz | N/A | Poland | 19.47395 | 51.77058
Lublin | N/A | Poland | 22.56667 | 51.25
Warsaw | N/A | Poland | 21.01178 | 52.22977
Warsaw | N/A | Poland | 21.01178 | 52.22977
Wroclaw | N/A | Poland | 17.03333 | 51.1
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Barcelona | N/A | Spain | 2.15899 | 41.38879
Barcelona | N/A | Spain | 2.15899 | 41.38879
Barcelona | N/A | Spain | 2.15899 | 41.38879
León | N/A | Spain | -5.57032 | 42.60003
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Palma de Mallorca | N/A | Spain | 2.65024 | 39.56939
Salamanca | N/A | Spain | -5.66388 | 40.96882
Valencia | N/A | Spain | -0.37966 | 39.47391
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Lund | N/A | Sweden | 13.19321 | 55.70584
Malmo | N/A | Sweden | 13.00073 | 55.60587
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Uppsala | N/A | Sweden | 17.63889 | 59.85882
Bournemouth | N/A | United Kingdom | -1.8795 | 50.72048
London | N/A | United Kingdom | -0.12574 | 51.50853
London | N/A | United Kingdom | -0.12574 | 51.50853
Manchester | N/A | United Kingdom | -2.23743 | 53.48095
Norwich | N/A | United Kingdom | 1.29834 | 52.62783
Oxford | N/A | United Kingdom | -1.25596 | 51.75222
Truro | N/A | United Kingdom | -5.05436 | 50.26526
| 1
|
NCT00071799
|
|
[
4
] | 13,619
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
The sponsors of this investigational drug are developing prasugrel (also known as CS-747) as a possible treatment for patients with acute coronary syndrome (heart attack or chest pain) who need, or are expected to need, a percutaneous coronary intervention (PCI; also called a balloon angioplasty). Prasugrel was compared with Clopidogrel to determine which drug is better at reducing deaths, future heart attacks, or stroke.
| null |
Coronary Arteriosclerosis Acute Coronary Syndromes
| null | 2
|
arm 1: Oral loading dose of six 10 mg prasugrel tablets and four placebo tablets matched to clopidogrel, followed by an oral maintenance dose of prasugrel one 10 mg tablet and one placebo tablet matched to clopidogrel once daily arm 2: Oral loading dose of four 75 mg clopidogrel tablets and six placebo tablets matched to prasugrel, followed by an oral maintenance dose of one 75 mg clopidogrel tablet and one placebo tablet matched to prasugrel once daily
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Administered orally intervention 2: Administered orally
|
intervention 1: Prasugrel intervention 2: Clopidogrel
| 1
|
Indianapolis | Indiana | United States | -86.15804 | 39.76838
| 0
|
NCT00097591
|
|
[
4
] | 238
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The purpose of this study is to determine if flexibly-dosed ziprasidone is safe and effective for the treatment of children and adolescents (ages 10-17) with bipolar I disorder (manic or mixed).
| null |
Bipolar Disorder
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Oral ziprasidone capsules of 20 mg, 40 mg, 60 mg, and 80 mg strength administered BID. intervention 2: Oral placebo capsules of 20 mg, 40 mg, 60 mg, and 80 mg strength administered BID.
|
intervention 1: Ziprasidone oral capsules intervention 2: placebo oral capsules
| 50
|
Scottsdale | Arizona | United States | -111.89903 | 33.50921
Orange | California | United States | -117.85311 | 33.78779
San Diego | California | United States | -117.16472 | 32.71571
Denver | Colorado | United States | -104.9847 | 39.73915
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
Tavares | Florida | United States | -81.72563 | 28.80416
Decatur | Georgia | United States | -84.29631 | 33.77483
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Des Plaines | Illinois | United States | -87.8834 | 42.03336
Schaumburg | Illinois | United States | -88.08341 | 42.03336
Terre Haute | Indiana | United States | -87.41391 | 39.4667
Lexington | Kentucky | United States | -84.47772 | 37.98869
Owensboro | Kentucky | United States | -87.11333 | 37.77422
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
Shreveport | Louisiana | United States | -93.75018 | 32.52515
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
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
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
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
Columbus | Ohio | United States | -82.99879 | 39.96118
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
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Charleston | South Carolina | United States | -79.93275 | 32.77632
Arlington | Texas | United States | -97.10807 | 32.73569
DeSoto | Texas | United States | -96.85695 | 32.58986
Fort Worth | Texas | United States | -97.32085 | 32.72541
Lake Jackson | Texas | United States | -95.43439 | 29.03386
Plano | Texas | United States | -96.69889 | 33.01984
San Antonio | Texas | United States | -98.49363 | 29.42412
Kirkland | Washington | United States | -122.20874 | 47.68149
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
| 1
|
NCT00257166
|
|
[
4
] | 421
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
This is a 3-week study to evaluate FEV1 following treatment with drugs in persistent asthma which is also active during allergy seasons in pediatric patients with seasonal aeroallergen sensitivity.
| null |
Asthma
| null | 2
|
arm 1: montelukast arm 2: placebo
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: montelukast 5 mg chewable tablet once daily. Up to 3 weeks of treatment. intervention 2: Placebo. Up to 3 weeks of treatment
|
intervention 1: montelukast sodium intervention 2: Comparator: Placebo
| 0
| null | 1
|
NCT00289874
|
|
[
4
] | 49
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
This study will compare triple and double drug regimens in the treatment of patients with depression, hypomania, or mania.
|
Early studies have shown lithium to produce a high percentage of satisfactory clinical response in patients with bipolar disorders. These studies, however, do not include lithium-refractory subgroups, such as bipolar II disorder patients. When the wide spectrum of bipolar disorders is considered, the lithium response rate decreases significantly. More broadly effective regimens are needed.
Participants in this study will be randomly assigned to receive either lithium plus divalproex or lithium, divalproex, and lamotrigine for 7 months. Symptoms of depression and mania will be assessed with scales and patient questionnaires.
|
Bipolar Disorder
|
Depression
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Lithium monotherapy was initiated at 450 mg once daily and titrated slowly over three weeks to a minimum blood level of 0.5 milliequivalent /L (mEq/L). intervention 2: Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (\< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum dose of 200 mg per day. intervention 3: Divalproex was then initiated at 250 mg twice daily and increased slowly over five weeks to a minimum blood level of 50 μg/mL. intervention 4: Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (\< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum dose of 200 mg per day.
|
intervention 1: Lithium intervention 2: Lamotrigine intervention 3: Divalproex intervention 4: Placebo
| 0
| null | 0
|
NCT00063362
|
[
5
] | 1,077
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
To determine if linezolid is superior to vancomycin in the treatment of complicated skin and soft tissue infections due to MRSA in adult subjects
| null |
Skin/Soft Tissue Infections Methicillin Resistant Staphylococcus Aureus (MRSA)
| null | 0
| null | null | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: linezolid intervention 2: vancomycin
| 126
|
Montgomery | Alabama | United States | -86.29997 | 32.36681
Tucson | Arizona | United States | -110.92648 | 32.22174
Los Angeles | California | United States | -118.24368 | 34.05223
Palm Springs | California | United States | -116.54529 | 33.8303
Rancho Mirage | California | United States | -116.41279 | 33.73974
San Pedro | California | United States | -118.29229 | 33.73585
Santa Fe Springs | California | United States | -118.08535 | 33.94724
Sylmar | California | United States | -118.44925 | 34.30778
Torrance | California | United States | -118.34063 | 33.83585
Torrance | California | United States | -118.34063 | 33.83585
Torrance | California | United States | -118.34063 | 33.83585
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Hartford | Connecticut | United States | -72.68509 | 41.76371
Hartford | Connecticut | United States | -72.68509 | 41.76371
New Haven | Connecticut | United States | -72.92816 | 41.30815
New Haven | Connecticut | United States | -72.92816 | 41.30815
Atlantis | Florida | United States | -80.10088 | 26.5909
Melbourne | Florida | United States | -80.60811 | 28.08363
Miami | Florida | United States | -80.19366 | 25.77427
Pensacola | Florida | United States | -87.21691 | 30.42131
Atlanta | Georgia | United States | -84.38798 | 33.749
Augusta | Georgia | United States | -81.97484 | 33.47097
Blue Ridge | Georgia | United States | -84.32409 | 34.86397
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Chicago | Illinois | United States | -87.65005 | 41.85003
Decatur | Illinois | United States | -88.9548 | 39.84031
Hines | Illinois | United States | -87.8395 | 41.85364
Maywood | Illinois | United States | -87.84312 | 41.8792
North Chicago | Illinois | United States | -87.84118 | 42.32558
Northlake | Illinois | United States | -87.89562 | 41.91725
Springfield | Illinois | United States | -89.64371 | 39.80172
Springfield | Illinois | United States | -89.64371 | 39.80172
Iowa City | Iowa | United States | -91.53017 | 41.66113
Louisville | Kentucky | United States | -85.75941 | 38.25424
Louisville | Kentucky | United States | -85.75941 | 38.25424
Louisville | Kentucky | United States | -85.75941 | 38.25424
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Baltimore | Maryland | United States | -76.61219 | 39.29038
Baltimore | Maryland | United States | -76.61219 | 39.29038
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
West Roxbury | Massachusetts | United States | -71.1495 | 42.27926
East Lansing | Michigan | United States | -84.48387 | 42.73698
Lansing | Michigan | United States | -84.55553 | 42.73253
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Mpls | Minnesota | United States | N/A | N/A
Saint Paul | Minnesota | United States | -93.09327 | 44.94441
Butte | Montana | United States | -112.53474 | 46.00382
Lincoln | Nebraska | United States | -96.66696 | 40.8
Lincoln | Nebraska | United States | -96.66696 | 40.8
Somers Point | New Jersey | United States | -74.5946 | 39.31762
Stony Brook | New York | United States | -73.14094 | 40.92565
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Akron | Ohio | United States | -81.51901 | 41.08144
Akron | Ohio | United States | -81.51901 | 41.08144
Akron | Ohio | United States | -81.51901 | 41.08144
Columbus | Ohio | United States | -82.99879 | 39.96118
Columbus | Ohio | United States | -82.99879 | 39.96118
Toledo | Ohio | United States | -83.55521 | 41.66394
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
West Reading | Pennsylvania | United States | -75.94743 | 40.3337
Ducktown | Tennessee | United States | -84.3827 | 35.03591
Jackson | Tennessee | United States | -88.81395 | 35.61452
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Fort Worth | Texas | United States | -97.32085 | 32.72541
Forth Worth | Texas | United States | N/A | N/A
Houston | Texas | United States | -95.36327 | 29.76328
St. George | Utah | United States | -113.58412 | 37.10415
St. George | Utah | United States | -113.58412 | 37.10415
Tacoma | Washington | United States | -122.44429 | 47.25288
Buenos Aires | Buenos Aires | Argentina | N/A | N/A
Loma Hermosa | Buenos Aires | Argentina | -58.60214 | -34.56867
Buenos Aires | N/A | Argentina | -58.37723 | -34.61315
Córdoba | N/A | Argentina | -64.18853 | -31.40648
Charleroi | N/A | Belgium | 4.44448 | 50.41136
Ghent | N/A | Belgium | 3.71667 | 51.05
Montigny-le-Tilleul | N/A | Belgium | 4.37582 | 50.38056
São José do Rio Preto | São Paulo | Brazil | -49.37944 | -20.81972
São Paulo | São Paulo | Brazil | -46.63611 | -23.5475
Providencia | Santiago Metropolitan | Chile | -70.60454 | -33.43107
Santiago | N/A | Chile | -70.64827 | -33.45694
Barranquilla | Atlántico | Colombia | -74.78132 | 10.96854
Bogota | Cundinamarca | Colombia | N/A | N/A
Floridablanca | Santander Department | Colombia | -73.08644 | 7.06222
Genova | N/A | Italy | 11.87211 | 45.21604
Napoli | N/A | Italy | 14.5195 | 40.87618
Roma | N/A | Italy | 11.10642 | 44.99364
Roma | N/A | Italy | 11.10642 | 44.99364
Udine | N/A | Italy | 13.23715 | 46.0693
Varese | N/A | Italy | 8.82511 | 45.82058
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Kuala Lumpur | N/A | Malaysia | 101.68653 | 3.1412
Guadalajara | Jalisco | Mexico | -103.34749 | 20.67738
Mexico City | Mexico City | Mexico | -99.12766 | 19.42847
Monterrey | Nuevo León | Mexico | -100.31721 | 25.68435
Pragal | Almada | Portugal | -9.16981 | 38.67459
Amadora | N/A | Portugal | -9.23083 | 38.75382
Coimbra | N/A | Portugal | -8.41955 | 40.20564
Lisbon | N/A | Portugal | -9.1498 | 38.72509
Lisbon | N/A | Portugal | -9.1498 | 38.72509
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Smolensk | N/A | Russia | 32.04371 | 54.77944
Singapore | Singapore | Singapore | 103.85007 | 1.28967
Kuilsriver | Western Province | South Africa | N/A | N/A
Johannesburg | N/A | South Africa | 28.04363 | -26.20227
Parow | N/A | South Africa | 18.59992 | -33.89723
Pretoria | N/A | South Africa | 28.18783 | -25.74486
Pretoria | N/A | South Africa | 28.18783 | -25.74486
Córdoba | Cordoba | Spain | -4.77275 | 37.89155
Girona | Gerona | Spain | 2.82493 | 41.98311
Seville | Sevilla | Spain | -5.97317 | 37.38283
Winchester | Hampshire | United Kingdom | -1.3187 | 51.06513
Edinburgh | N/A | United Kingdom | -3.19648 | 55.95206
Leeds | N/A | United Kingdom | -1.54785 | 53.79648
Ciudad Bolívar | Bolívar | Venezuela | -63.54694 | 8.12366
Distrito Capital | Miranda | Venezuela | N/A | N/A
Distrito Capital | Miranda | Venezuela | N/A | N/A
Valencia | Valencia | Venezuela | -68.00044 | 10.16153
Maracaibo | Zulia | Venezuela | -71.61089 | 10.64232
| 0
|
NCT00087490
|
|
[
3
] | 32
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This is a Phase 2 study being conducted at multiple centers in the United States and Germany. Patients having non-small cell lung cancer that has spread to other parts of the body (i.e., metastatic) or is locally advanced (i.e., Stage IIIB with malignant pleural effusion) are eligible to participate. Patients must have disease that has been treated with at least 1 prior treatment for metastatic disease (prior adjuvant treatment for localized disease does not count as prior treatment for metastatic disease). The purpose of the study is to test whether the angiogenesis inhibitor AG-013736 is an effective treatment for advanced non-small cell lung cancer as shown by the number of patients in the study who experience significant and durable tumor shrinkage
| null |
Lung Neoplasms Carcinoma, Non-small Cell Lung
| null | 1
|
arm 1: AG-013736 is a vascular endothelial growth factor \[VEGF\] inhibitor
|
[
0
] | 1
|
[
0
] |
intervention 1: Axitinib (AG-013736) tablet administered orally at a dose of 5 milligrams (mg) twice daily (BID) in cycles of 4 weeks.
|
intervention 1: axitinib
| 11
|
Irvine | California | United States | -117.82311 | 33.66946
Orange | California | United States | -117.85311 | 33.78779
Chicago | Illinois | United States | -87.65005 | 41.85003
Park Ridge | Illinois | United States | -87.84062 | 42.01114
Coon Rapids | Minnesota | United States | -93.28773 | 45.11997
Fridley | Minnesota | United States | -93.26328 | 45.08608
Robbinsdale | Minnesota | United States | -93.33856 | 45.03219
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Nashville | Tennessee | United States | -86.78444 | 36.16589
Madison | Wisconsin | United States | -89.40123 | 43.07305
Gauting | N/A | Germany | 11.37703 | 48.06919
| 0
|
NCT00094094
|
|
[
4
] | 761
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
Study 0015 (NCT00107952) compares the safety and effectiveness of an investigational drug, telavancin, with vancomycin for the treatment of hospital-acquired pneumonia.
| null |
Bacterial Pneumonia
|
Nosocomial pneumonia MRSA
| null | 2
|
arm 1: None arm 2: None
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Telavancin 10 mg/kg/day IV for up to 21 days. intervention 2: Vancomycin 1 Gm IV q 12 hrs for up to 21 days
|
intervention 1: Telavancin intervention 2: Vancomycin
| 1
|
Springfield | Massachusetts | United States | -72.58981 | 42.10148
| 0
|
NCT00107952
|
[
3
] | 357
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
The primary objective of this study is to determine the safe and effective dose range of boceprevir (SCH 503034) in combination with PEG-Intron in adult subjects who have chronic hepatitis C without cirrhosis, and who have failed an adequate course of combination therapy with peginterferon-alfa plus ribavirin. A secondary objective is to explore whether ribavirin provides an additional benefit when combined with PEG-Intron plus boceprevir.
| null |
Chronic Hepatitis C
|
PEG-Intron Ribavirin Protease Inhibitor
| null | 9
|
arm 1: A single dose of PEG is given first, followed 1 week later by PEG + RBV for 12 weeks. If HCV-RNA is undetected, PEG + RBV will continue for another 36 weeks. arm 2: A single dose of PEG is given first, followed 1 week later by PEG + RBV for 12 weeks. If HCV-RNA is detectable, BOC 400 mg TID will be added for 36 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 3: A single dose of PEG is given first, followed 1 week later by PEB + BOC 100 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 4: A single dose of PEG is given first, followed 1 week later by PEG + BOC 200 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 5: A single dose of PEG is given first, followed 1 week later by PEG + BOC 400 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 6: A single dose of PEG is given first, followed 1 week later by PEG + RBV + BOC 400 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 7: A single dose of PEG is given first, followed 1 week later by PEG + BOC 400 for 24 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 8: By first protocol amendment to P03659, this non-randomized arm is added. A single dose of PEG is given first, followed 1 week later by PEG + BOC 800 for 24 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. arm 9: By second protocol amendment to P03659, participants from all arms except Arm 1A will be rolled over into PEG + RBV + BOC 800 for the remainder of the treatment period.
|
[
1,
1,
0,
0,
0,
0,
0,
0,
0
] | 3
|
[
0,
2,
0
] |
intervention 1: 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID intervention 2: 1.5 mcg/kg weekly subcutaneously intervention 3: 200 mg capsules taken twice daily (BID) (total daily dose of 800-1400 mg/day, depending on weight \[weight-based dosing {WBD}\])
|
intervention 1: Boceprevir (BOC) intervention 2: PegIntron (PEG) intervention 3: Ribavirin (RBV)
| 0
| null | 0
|
NCT00160251
|
[
4
] | 240
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| null | 1FEMALE
| null |
To determine the effect and safety of menatetrenone on treatment of postmenopausal osteoporosis comparing with alfacalcidol.
| null |
Postmenopausal Osteoporosis
|
Postmenopausal osteoporosis
| null | 2
|
arm 1: None arm 2: None
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: 15 mg three times a day orally for 12 months intervention 2: 0.25 μg twice a day orally for 12 months
|
intervention 1: menatetranone intervention 2: alfacalcidol
| 5
|
Beijing | N/A | China | 116.39723 | 39.9075
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
| 0
|
NCT00165698
|
[
0
] | 192
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| null |
To compare intravenous magnesium sulfate to oral nifedipine for acute tocolysis of preterm labor
| null |
Obstetric Labor, Premature
| null | 2
|
arm 1: Preterm labor treatment with Magnesium Sulfate. arm 2: Preterm labor treatment with Nifedipine.
|
[
1,
1
] | 2
|
[
0,
0
] |
intervention 1: Preterm labor treatment with Magnesium Sulfate 4 gram bolus followed by 2 gm per hour infusion. 2 Gm bolus as needed and/or rate increase up to 4gm per hour were allowed at the discretion of the treating physician. intervention 2: Preterm labor treatment with Nifedipine 10 mg. sublingually every 20 minutes for three doses, followed by 20 mg. orally every 4 or 6 hours.
|
intervention 1: Magnesium Sulfate intervention 2: Nifedipine
| 1
|
Stanford | California | United States | -122.16608 | 37.42411
| 0
|
NCT00185900
|
|
[
5
] | 84
|
RANDOMIZED
|
PARALLEL
| 1PREVENTION
| 3TRIPLE
| false
| 0ALL
| false
|
Assesses the efficacy of treatment with montelukast 10 mg PO QD x 5 days versus placebo for the treatment of viral-induced upper respiratory infection in healthy adults aged 18-50 years.
|
This is a randomized double-blinded placebo controlled trial to assess the efficacy of treatment with montelukast 10 mg PO QD x 5 days versus placebo for the treatment of viral-induced upper respiratory infection in healthy adults aged 18-50 years. All subjects complete daily assessments of cold symptoms, nasal clearance rates and secretion rates during each day of the study. Phlebotomy is performed once for the determination of cytokine genotyping and allergy skin testing is performed once for the assessment of atopy.
|
Upper Respiratory Infection
|
Cold Upper Respiratory Infection
| null | 2
|
arm 1: Treated for 4 months with montelukast 4 mg per day arm 2: Treated for 4 months with placebo
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Montelukast intervention 2: Placebo
| 1
|
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
| 0
|
NCT00189475
|
[
3
] | 309
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
The purpose of this study is to evaluate the effectiveness and safety of CNTO 148 (golimumab) in patients with severe persistent asthma.
|
This is a multicenter, randomized (the study medication is assigned by chance), double-blind (neither physician nor patient knows the treatment that the patient receives), placebo-controlled (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical study), parallel-group (each group of patients will be treated at the same time), dose-ranging study to evaluate the efficacy and safety of CNTO 148. The study will consists of run-in phase (2 weeks), treatment period (52 weeks) and follow up period (24 weeks). The patients inhaled corticosteroids (ICS) medication will be standardized in the run-in phase and the treatment period contains first 24 weeks of treatment, the patients are required to remain on stable doses of concomitant corticosteroids (CS) medication (steroid stable phase). The steroid stable phase is followed by a 28-week steroid taper phase, during which a reduction of concomitant CS medication will be attempted. After completion of the study treatment, patients are to be followed for an additional 24 weeks. Patients will receive subcutaneous injections of 75, 150, or 300 mg of CNTO 148 or placebo every 4 weeks for 52 weeks followed 50,100, or 200 mg every 4 weeks through week 52. The safety of the patient will be monitored throughout the study.
|
Asthma
|
Asthma Severe Persistent Asthma Subcutaneous injections Immunology disorder Breathlesness
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Type=exact type, unit=mg, number=50, 75, 100, 150, 200 and 300, form=injection, route=subcutaneous. Every 4 weeks partciapnts will receive injections in 4 parallel treatment arms intervention 2: Type=exact type, unit=mg, form=injection, route=subcutaneous. Placebo will be given from from Week 0 through Week 52.
|
intervention 1: CNTO148 intervention 2: Placebo
| 57
|
Los Angeles | California | United States | -118.24368 | 34.05223
San Diego | California | United States | -117.16472 | 32.71571
Stockton | California | United States | -121.29078 | 37.9577
Denver | Colorado | United States | -104.9847 | 39.73915
Hartford | Connecticut | United States | -72.68509 | 41.76371
New Haven | Connecticut | United States | -72.92816 | 41.30815
Chicago | Illinois | United States | -87.65005 | 41.85003
Normal | Illinois | United States | -88.99063 | 40.5142
River Forest | Illinois | United States | -87.81395 | 41.89781
Iowa City | Iowa | United States | -91.53017 | 41.66113
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
North Dartmouth | Massachusetts | United States | -70.97032 | 41.63899
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
St Louis | Missouri | United States | -90.19789 | 38.62727
Cortland | New York | United States | -76.18048 | 42.60118
Elmira | New York | United States | -76.80773 | 42.0898
Charlotte | North Carolina | United States | -80.84313 | 35.22709
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
Lake Oswego | Oregon | United States | -122.67065 | 45.42067
Medford | Oregon | United States | -122.87559 | 42.32652
Portland | Oregon | United States | -122.67621 | 45.52345
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
El Paso | Texas | United States | -106.48693 | 31.75872
Richmond | Virginia | United States | -77.46026 | 37.55376
Bellingham | Washington | United States | -122.48822 | 48.75955
Madison | Wisconsin | United States | -89.40123 | 43.07305
Ghent | N/A | Belgium | 3.71667 | 51.05
Russel | N/A | Bulgaria | N/A | N/A
Sofia | N/A | Bulgaria | 23.32415 | 42.69751
Ostrava | N/A | Czechia | 18.28204 | 49.83465
Poruba | N/A | Czechia | 18.42818 | 49.86247
Ústí nad Labem | N/A | Czechia | 14.03227 | 50.6607
Montpellier | N/A | France | 3.87635 | 43.61093
Pessac | N/A | France | -0.6324 | 44.80565
Tarbes | N/A | France | 0.07139 | 43.23407
Berlin | N/A | Germany | 13.41053 | 52.52437
Großhansdorf | N/A | Germany | 10.28333 | 53.66667
Leipzig | N/A | Germany | 12.37129 | 51.33962
Mainz | N/A | Germany | 8.2791 | 49.98419
Budapest | N/A | Hungary | 19.04045 | 47.49835
Nyíregyháza | N/A | Hungary | 21.71671 | 47.95539
Székesfehérvár | N/A | Hungary | 18.41034 | 47.18995
Szombathely | N/A | Hungary | 16.62155 | 47.23088
Törökbálint | N/A | Hungary | 18.91356 | 47.42931
Leiden | N/A | Netherlands | 4.49306 | 52.15833
Bieńkówka | N/A | Poland | 19.77179 | 49.776
Katowice | N/A | Poland | 19.02754 | 50.25841
Lodz | N/A | Poland | 19.47395 | 51.77058
Torun | N/A | Poland | 18.59814 | 53.01375
Warsaw | N/A | Poland | 21.01178 | 52.22977
Linköping | N/A | Sweden | 15.62157 | 58.41086
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Glasgow | N/A | United Kingdom | -4.25763 | 55.86515
Southampton | N/A | United Kingdom | -1.40428 | 50.90395
| 0
|
NCT00207740
|
[
5
] | 63
|
RANDOMIZED
|
SINGLE_GROUP
| 1PREVENTION
| 2DOUBLE
| false
| 0ALL
| false
|
The aim of this project is to determine if a single dose of oral dexamethasone at the time of discharge from the emergency department (ED) \[after successful treatment\] prevents rebound headache.
Hypothesis: That single dose oral dexamethasone 8mg reduces the proportion of patients who suffer rebound headache after treatment for migraine in the ED.
|
Migraine headache can be a debilitating condition. A small but significant proportion of sufferers seek treatment in emergency departments \[ED\], accounting for 2-5% of ED visits.Available data suggests that up to 66% of these patients may experience rebound headache after discharge that affects their ability to function normally \[eg work, social, etc\].It appears that inflammation plays a key role in recurrences. A number of small studies suggest that a single dose of corticosteroids at the time of discharge might prevent rebound headache. To date these studies have used intravenous dexamethasone. The aim of this project is to determine if a single dose of oral dexamethasone at the time of discharge from the ED \[after successful treatment\] prevents rebound headache.
Hypothesis: That single dose oral dexamethasone 8mg reduces the proportion of patients who suffer rebound headache after treatment for migraine in the ED.
Aims: The primary aim is to compare the proportion of patients who experience rebound headache within 48 hours after ED treatment of migraine between a group treated with single dose oral dexamethasone 8mg and a group treated with placebo. Secondary aims are to compare headache severity, analgesia/ health service use, adverse events and return to normal functioning between the groups.
Methods:
Study design: Double blind, randomised placebo controlled clinical trial. Setting: Emergency Department, Western Hospital. Participants: Adult patients \[age \>17 years\] with physician-diagnosed migraine treated in the ED.
Inclusion criteria: Consenting adult patients \[age \>17 years\] with physician-diagnosed migraine treated in the ED who are willing and able to be contacted between 48-72 hours after discharge for follow-up.
Sample size: 76 patients. Note: The study was stopped early for operational reasons. 63 patients were analysed.
|
Migraine
|
Migraine Headache Rebound headache
| null | 2
|
arm 1: This group received intravenous phenothiazine treatment for migraine (dosing at physician discretion) plus placebo. Patients and clinicians were blinded. arm 2: This group received intravenous phenothiazine migraine treatment (dosage at physician discretion) plus oral dexamethasone 8mg at time of emergency department discharge. Patients and clinicians were blinded.
|
[
2,
0
] | 2
|
[
0,
0
] |
intervention 1: Single dose oral dexamethasone 8mg at time of ED discharge intervention 2: Single dose oral placebo at ED discharge
|
intervention 1: Dexamethasone intervention 2: placebo
| 1
|
Melbourne | Victoria | Australia | 144.96332 | -37.814
| 0
|
NCT00216736
|
[
4
] | 329
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the efficacy and safety of alogliptin, once daily (QD), in adults with type 2 diabetes.
|
There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% are type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected.
Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes.
The aim of the current study is to evaluate the efficacy of alogliptin in subjects with type 2 diabetes mellitus who are inadequately controlled and who have failed treatment with diet and exercise. Individuals who participate in this study will be required to commit to a screening visit and up to 14 additional visits at the study center. Study participation is anticipated to be about 34 weeks (or 8.5 months).
|
Diabetes Mellitus
|
Glucose Metabolism Disorder Dysmetabolic Syndrome Type II Diabetes; Diabetes Mellitus Lipoatrophic Dyslipidemia Drug Therapy
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: Alogliptin 12.5 mg, tablets, orally, once daily for up to 26 weeks. intervention 2: Alogliptin 25 mg, tablets, orally, once daily for up to 26 weeks. intervention 3: Alogliptin placebo-matching tablets, orally, once daily for up to 26 weeks.
|
intervention 1: Alogliptin intervention 2: Alogliptin intervention 3: Placebo
| 67
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Peoria | Arizona | United States | -112.23738 | 33.5806
Phoenix | Arizona | United States | -112.07404 | 33.44838
Anaheim | California | United States | -117.9145 | 33.83529
Artesia | California | United States | -118.08312 | 33.86585
Fresno | California | United States | -119.77237 | 36.74773
Lafayette | California | United States | -122.11802 | 37.88576
Northridge | California | United States | -118.53675 | 34.22834
Orange | California | United States | -117.85311 | 33.78779
San Diego | California | United States | -117.16472 | 32.71571
Walnut Creek | California | United States | -122.06496 | 37.90631
Colorado Springs | Colorado | United States | -104.82136 | 38.83388
Denver | Colorado | United States | -104.9847 | 39.73915
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Cocoa Beach | Florida | United States | -80.60922 | 28.32055
Kissimmee | Florida | United States | -81.41667 | 28.30468
Longwood | Florida | United States | -81.3384 | 28.70305
Ocala | Florida | United States | -82.14009 | 29.1872
Ocoee | Florida | United States | -81.54396 | 28.56917
Saint Cloud | Florida | United States | -81.28118 | 28.2489
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Idaho Falls | Idaho | United States | -112.03414 | 43.46658
Avon | Indiana | United States | -86.39972 | 39.76282
Elkhart | Indiana | United States | -85.97667 | 41.68199
Evansville | Indiana | United States | -87.55585 | 37.97476
Baltimore | Maryland | United States | -76.61219 | 39.29038
Sudbury | Massachusetts | United States | -71.41617 | 42.38343
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Berlin | New Jersey | United States | -74.92905 | 39.79123
Burlington | North Carolina | United States | -79.4378 | 36.09569
Morehead City | North Carolina | United States | -76.72604 | 34.72294
Pinehurst | North Carolina | United States | -79.46948 | 35.19543
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Lansdale | Pennsylvania | United States | -75.28379 | 40.2415
West Grove | Pennsylvania | United States | -75.82744 | 39.82205
Charleston | South Carolina | United States | -79.93275 | 32.77632
Columbia | South Carolina | United States | -81.03481 | 34.00071
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Bristol | Tennessee | United States | -82.18874 | 36.59511
Cookeville | Tennessee | United States | -85.50164 | 36.16284
Milan | Tennessee | United States | -88.75895 | 35.91979
Corpus Christi | Texas | United States | -97.39638 | 27.80058
Dallas | Texas | United States | -96.80667 | 32.78306
San Antonio | Texas | United States | -98.49363 | 29.42412
Temple | Texas | United States | -97.34278 | 31.09823
Texarkana | Texas | United States | -94.04769 | 33.42513
Burlington | Vermont | United States | -73.21207 | 44.47588
Multiple Cities | N/A | Argentina | N/A | N/A
Multiple Cities | N/A | Australia | N/A | N/A
Multiple Cities | N/A | Brazil | N/A | N/A
Multiple Cities | N/A | Chile | N/A | N/A
Multiple Cities | N/A | Czechia | N/A | N/A
Multiple Cities | N/A | Dominican Republic | N/A | N/A
Multiple Cities | N/A | Germany | N/A | N/A
Multiple Cities | N/A | Guatemala | N/A | N/A
Multiple Cities | N/A | Hungary | N/A | N/A
Multiple Cities | N/A | India | N/A | N/A
Multiple Cities | N/A | Mexico | N/A | N/A
Multiple Cities | N/A | Netherlands | N/A | N/A
Multiple Cities | N/A | New Zealand | N/A | N/A
Multiple Cities | N/A | Peru | N/A | N/A
Multiple Cities | N/A | Poland | N/A | N/A
Multiple Cities | N/A | South Africa | N/A | N/A
Multiple Cities | N/A | United Kingdom | N/A | N/A
| 0
|
NCT00286455
|
[
5
] | 16
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 4QUADRUPLE
| true
| 0ALL
| false
|
This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated patients with schizophrenia or schizoaffective disorder. The advantage of the crossover design is that each subject will act as their own control and fewer subjects will be required than a between-group design.
|
Specific Aims:
This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated patients with schizophrenia or schizoaffective disorder. The advantage of the crossover design is that each subject will act as their own control and fewer subjects will be required.
Study Procedures:
We have designed this trial to examine effects upon weight, lipids, glucose metabolism, positive symptoms, negative symptoms, and depressive symptoms. This project, examining the usefulness of combination therapy, may offer a possible intervention for patients who are obese and treated with olanzapine, but otherwise experiencing a good clinical response. Many patients, despite the medical problems that may occur, are reluctant to switch their antipsychotic agent.
Location:
This study will be performed at the Freedom Trail Clinic of the Erich Lindemann Mental Health Center by faculty of the Schizophrenia Program of the Massachusetts General Hospital and staff of the Freedom Trail Clinic.
Subjects:
Subjects will include 20 stable outpatients with schizophrenia or schizoaffective disorder treated with olanzapine for at least one year. Prior to enrollment, we will determine that the clinician has optimized the dose of the antipsychotic and maintained the medication at a stable dose for at least 1 month. Patients will be excluded for significant medical illness, substance abuse, or inability to provide informed consent.
Safety Assessments:
Medication Trial:
Patients will have a baseline assessment performed and then randomized to placebo or aripiprazole 15 mg/day for 4 weeks. After the initial 4 weeks of medication patients will be reassessed, have a 2-week washout period and then crossover to the other treatment for another 4 weeks. The olanzapine dose will be unchanged during the trial. Patients will be given a two-week supply of medication at baseline and week 2 and then again at weeks 6 and 8.
Screening Visit The diagnosis of schizophrenia or schizoaffective disorder will be confirmed by a research psychiatrist using DSM IV criteria. A physical examination will be performed and medical history, vital signs, weight, height, waist/hip circumference, skin-fold measurements, 12-lead EKG and demographic information will be obtained. Laboratory measures will include olanzapine blood levels, fasting glucose, insulin, basic chemistry profiles, liver enzymes, CBC, lipid profile, leptin, LDL- particle size, PAI-1, C-reactive protein, sICAM, vWF and a DNA sample will be drawn at screening for future analysis of the 5-HT-2C and H1 receptor genes.
Baseline Assessment:
The following scales will be completed at baseline and will comprise the treatment efficacy battery: Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms (SANS), Clinical Global Impressions scale (CGI), Hamilton Depression Rating Scale (HAM-D), Global Assessment Scale (GAS), Fatigue Scale Inventory (FSI) Trauma History Questionnaire (THQ) and the Quality of Life Scale (QOL). A single rater will perform all assessments. If it is necessary to use a second rater, inter-rater reliability will be established before the addition of the second rater and will be repeated every three months by use of videotaped interviews. The treatment efficacy battery will be repeated at week 4, 6 and 10 except for the THQ, which will only be administered at the beginning of the study.
Safety and Monitoring Assessments:
Blood pressure, heart rate, temperature, weight, waist/hip circumference will be performed at each visit (baseline, weeks 2, 4, 6, 8 and 10). Side effects will be monitored at baseline and weeks 2, 4, 6, 8, and 10 using the Systematic Assessment for Treatment Emergent Events (SAFTEE). Body fat composition will be measured by skin-fold calipers at baseline, week 4, 6 and 10. EPS will be evaluated at baseline and weeks 2, 4, 6, 8 and 10 using the Simpson-Angus Scale, Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS).
Measure of Energy Expenditure and Dietary Assessment:
Patients will be asked to wear an accelerometer for four consecutive days to obtain an objective measure of physical activity. During the same four days the patients will maintain a four-day food record of all food and beverages consumed. This will provide a means of assessing energy intake verses energy output. Patients will also complete the Modifiable Activity Questionnaire (MAQ). Energy expenditure and dietary intake will be assessed at baseline, weeks 4, 6 and 10.
Randomization:
The double-blind, placebo-controlled, crossover study will consist of two random order 4-week treatment arms (aripiprazole 15 mg or placebo) separated by a 2-week adjuvant treatment washout. Following baseline, subjects will be randomized, double-blind, to either aripiprazole or placebo for 4 weeks. After the initial 4 weeks of medication patients will be reassessed, have a 2-week washout period and then crossover to the other treatment for another 4 weeks.
Subject Recruitment:
Potential subjects will be identified by their clinicians at the Freedom Trail Clinic. Patients will give their physician verbal permission to be contacted for research purposes. A member of the research team will meet with the subject and explain the study protocol, including a review of risks and potential benefits. A copy of the study consent form will be provided to the patient at this time. Patients who express interest after this first meeting will be evaluated for competency to provide informed consent by a physician who is not a member of the research team. Patients who are judged to be competent will then be asked to meet with the principal investigator who will review the study protocol and consent form with the patient and obtain informed consent. The human rights officer of the North Suffolk Mental Health Association will be asked to participate in this meeting unless the patient declines. Family and residential staff will also be invited to participate if the patient agrees.
Potential Risks:
Aripiprazole did not produce any serious adverse effects in animal and human safety studies. No consistent abnormality of vital signs, laboratory, EKG or EEG has emerged. In clinical trials, no side effects occurred at rates greater than 2x placebo. Nausea, vomiting, anxiety, headache, dyspepsia, somnolence, orthostatic hypotension, tachycardia, insomnia, akathisia, EPS, and weight gain may be potential side effects.
Benefits:
It is not known if aripiprazole added to olanzapine will help a subject's mood, motivation, hallucinations, and unusual experiences. Other patients may benefit if this study finds that aripiprazole added to olanzapine is useful for treating symptoms of schizophrenia.
Data Management and Statistical Analysis:
Data management and statistical analysis will be provided by Dr. David Schoenfeld from the Massachusetts General Hospital, Biostatistics Center.
Protection of Human Subjects:
Principal members of our research team have all completed certification for protection of human subjects in clinical trials. The clinical protocol will be submitted for approval by the institutional review boards of the Massachusetts Department of Mental Health. Potential subjects will be referred by their clinicians. Clinicians will be asked to sign a statement that verifies that the patient is interested in participating, understands that participation is voluntary, and understands that declining participation will not affect treatment at the facility. A member of the research team will meet with the patient and explain the study protocol, including a review of risks and potential benefits. A copy of the study consent form will be provided to the patient at that time to share with family members or residential staff. Patients who continue to express interest after this first meeting will be evaluated by a physician who is not a member of the research team for capacity to provide informed consent. Patients who are judged to be competent will then be asked to meet with the principal investigator or co-investigator who will review the study protocol and consent form with the patient and obtain informed consent.
|
Schizophrenia
|
Schizophrenia Diabetes Obesity Olanzapine Insulin Resistance
| null | 2
|
arm 1: aripiprazole 15mg/day arm 2: matched placebo for aripiprazole 15mg/day
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Aripiprazole intervention 2: placebo
| 1
|
Boston | Massachusetts | United States | -71.05977 | 42.35843
| 0
|
NCT00351936
|
[
4
] | 27
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
Primary Objective:
1\. To determine the effectiveness of donepezil as compared to placebo for the management of opiate-induced sedation/drowsiness in patients with stable cancer pain
Secondary Objectives:
1. To assess the side-effects in both groups of 1 week treatment of 5 mg donepezil and placebo
2. To assess the effects of donepezil on fatigue (FACIT-Fatigue), and other symptoms (Anderson Symptom Assessment Scale)
3. To assess the effects of donepezil on cognition (Symbol Digit Modalities Test)
4. To assess the effects of donepezil on constipation (number of bowel movements)
|
Donepezil is currently used in the treatment of certain types of mental disorders, including Alzheimer's disease. Recent research studies have shown that donepezil helps to improve drowsiness in cancer patients receiving opioid medication.
Before treatment starts, you will be asked to answer some questions regarding your cancer diagnosis, the medication you are taking, and the symptoms you are having (i.e. pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep problem, constipation, and well-being) and a test for your cognitive status (matching specific numbers with given geometric figures) will be performed. It will take about 30 minutes to complete the evaluation. Women who are at risk of being pregnant must have a negative urine pregnancy test.
If you are qualified to enter the study you will be randomly assigned (as in the toss of a coin) to one of two groups. Participants in one group will receive donepezil for one week. Participants in the other group will receive a placebo (a tablet that does not contain any medication but looks just like the donepezil pill). You will have an equal chance (50/50) of being placed in either group. Neither you nor any the medical staff or researchers on this study will know if you are receiving the study drug or the placebo.
You will take 1 tablet of donepezil/placebo a day for 7 days. The research nurse will contact you by phone (in person if you are in the hospital) daily to ask questions about side effects and other symptoms.
On Day 8, you will need to come to the palliative care clinic for an evaluation. If you can not come to clinic on day 8, evaluation will be performed through telephone. Evaluation of sedation/drowsiness, pain, constipation, fatigue, side effects, effectiveness of the treatment, and a test of nervous system and cognitive status will be performed. If you develop intolerable side effects while on this study, the medication will be stopped and you will be removed from the study.
After evaluation on Day 8, all participants will be offered the chance to receive 1 tablet of donepezil every day for 7 days. The research nurse will follow up with you by phone (in person if you are in the hospital) 3 or 4 days after you received donepezil (open label) to ask questions about side effects and other symptoms.
On Day 15, you will need to come to the palliative care clinic for an evaluation. Evaluation of sedation/drowsiness, pain, constipation, fatigue, side effects, effectiveness of the treatment, and a test of nervous system and cognitive status will be performed. You will be given an option to continue on an additional 8 weeks. During these 8 weeks, the follow up will be conducted by your primary physician.
This is an investigational study. Donepezil has been approved by FDA and is a commercially available drug. Its use in this study is investigational. It can continue to be prescribed by your primary physician after that time if needed. A total of 100 patients will take part in this study. All will be enrolled at M. D. Anderson.
|
Advanced Cancer
|
Advanced Cancer Cancer Pain Donepezil Sedation Placebo
| null | 2
|
arm 1: Oral Donepezil 5 mg daily x 7 days arm 2: Placebo tablet daily x 7 days
|
[
1,
2
] | 2
|
[
0,
0
] |
intervention 1: 5 mg once a day by mouth for 7 day cycle. After evaluation on Day 8, all participants will be offered donepezil every day for 7 days. intervention 2: Placebo tablet once a day by mouth for one 7 day cycle. After evaluation on day 8, all participants offered donepezil every day for 7 days.
|
intervention 1: Donepezil intervention 2: Placebo
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00352664
|
[
3,
4
] | 107
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The purpose of this study is to evaluate whether bepotastine besilate ophthalmic solution is effective in the treatment of acute allergic conjunctivitis
| null |
Conjunctivitis, Allergic
| null | 3
|
arm 1: Bepotastine Besilate Ophthalmic Solution 1.5% arm 2: sterile ophthalmic solution arm 3: sterile ophthalmic solution 1.0%
|
[
0,
2,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: sterile ophthalmic solution intervention 2: sterile ophthalmic solution intervention 3: sterile ophthalmic solution
|
intervention 1: Bepreve intervention 2: Placebo intervention 3: Bepotastine Besilate
| 1
|
Irvine | California | United States | -117.82311 | 33.66946
| 0
|
NCT00424398
|
|
[
4
] | 429
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
This study is designed to assess the effectiveness of mometasone furoate nasal spray (MFNS) once daily compared with placebo in subjects with seasonal allergic rhinitis (SAR) in reducing the total symptom score.
| null |
Seasonal Allergic Rhinitis
| null | 2
|
arm 1: 200 mcg daily arm 2: Two sprays in each nostril in the morning
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Two sprays (50 mcg/spray) in each nostril (200 mcg daily) in the morning intervention 2: Two sprays in each nostril in the morning
|
intervention 1: Mometasone furoate nasal spray intervention 2: Placebo
| 0
| null | 0
|
NCT00468312
|
|
[
5
] | 310
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The purpose of this study is to evaluate how well mometasone furoate nasal spray (MFNS) works to relieve SAR symptoms compared to Placebo when symptoms are induced in a chamber setting. Evaluation will be based on subjects self-assessed nose symptoms. Other areas the study will evaluate are: 1) changes in eye symptoms (ocular symptom severity score) after dosing 2) how long MFNS works in relieving the nose (nasal) and eye (ocular) symptoms after 7 daily doses, 3) measurements of nose (nasal) blockage (obstruction), and 4) measurements of the subject's opinion of the study drugs by asking different questions. This study is could last up to 53 days for some subjects.
| null |
Seasonal Allergic Rhinitis
| null | 2
|
arm 1: MFNS 200 mcg total dose (2 sprays each nostril) arm 2: Placebo (2 sprays each nostril)
|
[
0,
2
] | 2
|
[
0,
10
] |
intervention 1: Mometasone Furoate Nasal Spray: 2 sprays (50 mcg) each nostril (total 200 mcg) intervention 2: Placebo: 2 sprays in each nostril
|
intervention 1: Mometasone Furoate Nasal Spray intervention 2: Placebo
| 0
| null | 0
|
NCT00491504
|
|
[
5
] | 21
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to collect data on patients with severe uveitis that have required re-implantation of the sustained-release fluocinolone drug delivery device due to depletion of study drug in their previous implanted device.
|
Purpose: To collect medical information on a sustained release drug delivery system that delivers the corticosteroid, fluocinolone acetonide, directly into the vitreous cavity of the eye. This system has the potential to maintain therapeutic drug levels in the eye while reducing systemic exposure to the drug to negligible levels. RetisertTM is the trade name for the intravitreal fluocinolone acetonide implant.
Hypothesis: The RetisertTM will be a safe and effective method to manage patients with severe uveitis
|
Uveitis
|
uveitis Cystoid Macular Edema (CME) fluocinolone acetonide non-infectious uveitis affecting the posterior segment
| null | 1
|
arm 1: 0.59 mg Fluocinolone Acetonide implant
|
[
0
] | 1
|
[
0
] |
intervention 1: 0.59 mg Fluocinolone Acetonide implant
|
intervention 1: 0.59 mg Fluocinolone Acetonide implant
| 1
|
Durham | North Carolina | United States | -78.89862 | 35.99403
| 0
|
NCT00543296
|
[
5
] | 83
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This is a randomized, open label, parallel group comparison study. Following a 1-week screening period, patients will be randomized to 1 of 2 treatment groups: ezetimibe added to ongoing statin treatment (ezetimibe plus simvastatin, atorvastatin or pravastatin at doses of 10/20, 10/10 or 10/20 mg), or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg, or pravastatin 40 mg). Study drug will be administered once daily in the evening for 8 weeks. Patients will be instructed to follow a National Cholesterol Education Program (NCEP) or similar cholesterol-lowering dietary regimen throughout the study.
| null |
Hypercholesterolemia
| null | 2
|
arm 1: None arm 2: None
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: ezetimibe 10 mg plus ongoing statin (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) once daily for 8 weeks intervention 2: simvastatin 40 mg or atorvastatin 20 mg or pravastatin 40 mg once daily for 8 weeks
|
intervention 1: Ezetimibe + Statin (simvastatin, atorvastatin, or pravastatin) intervention 2: Double Statin (simvastatin, atorvastatin, or pravastatin)
| 0
| null | 0
|
NCT00652327
|
|
[
4
] | 19
|
RANDOMIZED
|
PARALLEL
| 4SUPPORTIVE_CARE
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to assess the maintenance of effect after long-term treatment of Sativex® in subjects with neuropathic pain.
|
A five week randomised-withdrawal phase (Part B) for a subset of subjects who took part in a 38 week, multicentre, open label (Part A) follow-on study to evaluate, the maintenance of effect of, the development of tolerance through exposure to, and safety of, Sativex® in the treatment of subjects with neuropathic pain. Subjects returned to the centre for an end of treatment visit at week 38 of Part A (Visit 5, Day 266), followed by Visits 5b (week 39), 5c (week 43) and an end of study visit took place 28 days after Visit 5c or withdrawal from the study.
|
Pain Peripheral Neuropathy
|
Pain Peripheral Neuropathy
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Maximum permitted dose was eight actuations in any three hour period and 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours intervention 2: containing peppermint oil, 0.05% (v/v), quinoline yellow, 0.005% (w/v), sunset yellow, 0.0025% (w/v), in ethanol:propylene glycol (50:50) excipient
|
intervention 1: Sativex® intervention 2: Placebo
| 1
|
Solihull | West Midlands | United Kingdom | -1.78094 | 52.41426
| 0
|
NCT00713817
|
[
2
] | 88
|
RANDOMIZED
|
CROSSOVER
| null | 0NONE
| true
| 0ALL
| false
|
To assess the bioequivalence of reformulated OXY tablets (40 mg) relative to the original OxyContin® (OXY) formulation (40 mg) in the fed state.
|
Oxycodone hydrochloride (oxycodone) is a semi-synthetic opioid analgesic that is effective in the relief of moderate to severe malignant and non-malignant pain.
|
Healthy Volunteers
|
Healthy subjects Opioid
| null | 2
|
arm 1: Reformulated OXY 40 mg x 1 dose arm 2: Original OxyContin® (OXY) 40 mg x 1 dose
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Reformulated OXY 40-mg tablet x 1 dose taken with food intervention 2: Original OxyContin® (OXY) 40-mg tablet x 1 dose taken with food
|
intervention 1: Reformulated OXY (oxycodone HCl) intervention 2: Original OxyContin® (OXY) (oxycodone HCl)
| 1
|
Austin | Texas | United States | -97.74306 | 30.26715
| 0
|
NCT01100320
|
[
2
] | 92
|
RANDOMIZED
|
CROSSOVER
| null | 0NONE
| true
| 0ALL
| false
|
The purpose of this study is to assess the bioequivalence of a new oxycodone formulation (40 mg) relative to the original OxyContin® (OXY) formulation (40 mg) in the fasted state.
|
Oxycodone hydrochloride (oxycodone) is a semi-synthetic opioid analgesic that is effective in the relief of moderate to severe malignant and non-malignant pain.
|
Healthy
|
Healthy subjects Opioid Healthy volunteers
| null | 2
|
arm 1: Reformulated OXY 40 mg x 1 dose arm 2: Original OxyContin® (OXY) 40 mg x 1 dose
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: Reformulated OXY 40-mg tablet x 1 dose taken without food intervention 2: Original OxyContin® (OXY) 40-mg tablet x 1 dose taken without food
|
intervention 1: Reformulated OXY (oxycodone HCl) intervention 2: Original OxyContin® (OXY) (oxycodone HCl)
| 1
|
Evansville | Indiana | United States | -87.55585 | 37.97476
| 0
|
NCT01101165
|
[
2
] | 48
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| true
| 1FEMALE
| false
|
The purpose of this study is to examine and compare the uptake of Yasmin (oral contraceptive containing drospirenone and ethinylestradiol) with or without levomefolate calcium (Metafolin, a registered vitamin supplement) in the body and to examine and compare the uptake of levomefolate calcium with or without Yasmin in the body, in healthy volunteers not using hormonal contraception.
| null |
Contraception
| null | 3
|
arm 1: single oral administration of 1 film-coated SHT470FA tablet (Yasmin with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) arm 2: single oral administration of 1 film-coated SHT04532A tablet (with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium \[MTHF-Ca\]) arm 3: single oral administration of 1 coated tablet SHT04532C, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium \[MTHF-Ca\])
|
[
0,
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: single oral administration of 1 coated tablet SH T470FA (Yasmin, film-coated tablets with ethinylestradiol (EE) as free steroid), containing 0.030 mg EE + 3 mg drospirenone (DRSP) intervention 2: single oral administration of 1 coated tablet SH T04532A (film-coated tablet with ethinylestradiol (EE) as clathtrate), containing 0.030 mg EE + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin intervention 3: single oral administration of 1 coated tablet SH T04532C, containing 0.451 mg Metafolin
|
intervention 1: EE 0.03 mg/DRSP 3 mg (Yasmin, BAY86-5131) intervention 2: EE 0.03mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE30/DRSP/L-5-MTHF Ca) intervention 3: L-5-MTHF Ca 0.451 mg (Metafolin)
| 1
|
Hamburg | City state of Hamburg | Germany | 9.99302 | 53.55073
| 0
|
NCT01253174
|
|
[
3
] | 45
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The purpose of this study was to evaluate the safety of 2 dosage regimens of Intravenous (IV) iron Ferric Carboxymaltose (FCM) in comparison to placebo in patients with Restless Legs Syndrome (RLS)
| null |
Restless Legs Syndrome (RLS)
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Ferric Carboxymaltose (FCM) intervention 2: Placebo
| 0
| null | 0
|
NCT01382901
|
|
[
3
] | 26
|
NON_RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
Study to determine the pharmacokinetics (PK) of pramipexole (PPX) after administration of a single dose orally (p.o.) in pediatric patients with the diagnosis of RLS
| null |
Restless Legs Syndrome
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: None intervention 2: None intervention 3: None
|
intervention 1: MIRAPEX® - low intervention 2: MIRAPEX® - medium intervention 3: MIRAPEX® - high
| 0
| null | 0
|
NCT02231918
|
|
[
2
] | 18
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| true
| 0ALL
| false
|
Single-centre, open-label, randomised, gender-balanced, 3-way crossover, 3-period, 3-sequence study in 18 healthy male and female subjects.
|
Single-centre, open-label, randomised, gender-balanced, 3-way crossover, 3-period, 3-sequence study in 18 healthy male and female subjects. The study consisted of 3 periods separated by a washout of 7 days or more between doses. Subjects received a single oral 800 mg dose of eslicarbazepine acetate following a standard meal in one period, and following at least 10 hours of fasting in two periods.
|
Epilepsy
| null | 3
|
arm 1: Tablets 800 mg. Administration:Oral. arm 2: Tablets 800 mg. Administration:Oral. arm 3: Tablets 2 x 400 mg. Administration:Oral.
|
[
0,
0,
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: BIA 2-093
| 0
| null | 0
|
NCT02288312
|
|
[
4
] | 84
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| true
|
The purpose of this study is to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of teduglutide compared with placebo in subjects with parenteral nutrition (PN)-dependent short bowel syndrome (SBS).
|
Teduglutide is an analog of glucagon-like peptide 2 (GLP-2), a naturally occurring hormone that regulates the growth, proliferation, and maintenance of cells lining the gastrointestinal tract. Teduglutide has been shown in animal studies and previous human clinical trials to increase the size and number of these cells, thereby increasing the absorptive surface area of the intestines.
The multicenter, double-blind, international Phase III trial will randomly assign approximately 80 patients to receive daily subcutaneous injections of 0.05 milligrams or 0.10 milligrams of teduglutide per kilogram of body weight, or a placebo. Dosing will continue for a period of six months. The primary endpoint in the study is a reduction in the use of intravenous feeding, which is often required to sustain life in patients with SBS.
|
Short Bowel Syndrome
|
Short Bowel Syndrome Parenteral Nutrition SBS
| null | 3
|
arm 1: Placebo injectable subcutaneously daily into the thigh or abdomen arm 2: teduglutide 0.05 mg/kg/d arm 3: teduglutide 0.1 mg/kg/d
|
[
2,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: placebo injectable subcutaneously daily into thigh or abdomen intervention 2: Teduglutide 0.05 mg/kg/d daily injectable subcutaneously into the thigh or abdomen intervention 3: Teduglutide 0.1 /g/kg/d daily injection subcutaneously into thigh or abdomen
|
intervention 1: Placebo intervention 2: Teduglutide 0.05 mg/kg/d intervention 3: Teduglutide 0.1 mg/kg/d
| 32
|
Scottsdale | Arizona | United States | -111.89903 | 33.50921
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Kansas City | Kansas | United States | -94.62746 | 39.11417
Omaha | Nebraska | United States | -95.94043 | 41.25626
Albany | New York | United States | -73.75623 | 42.65258
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Cleveland | Ohio | United States | -81.69541 | 41.4995
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Providence | Rhode Island | United States | -71.41283 | 41.82399
Charleston | South Carolina | United States | -79.93275 | 32.77632
Brussels | N/A | Belgium | 4.34878 | 50.85045
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Copenhagen | N/A | Denmark | 12.56553 | 55.67594
Lille | N/A | France | 3.05858 | 50.63297
Lyon | N/A | France | 4.84671 | 45.74846
Lyon | N/A | France | 4.84671 | 45.74846
Paris | N/A | France | 2.3488 | 48.85341
Berlin | N/A | Germany | 13.41053 | 52.52437
Berlin | N/A | Germany | 13.41053 | 52.52437
Frankfurt | N/A | Germany | 10.53333 | 49.68333
Amsterdam | N/A | Netherlands | 4.88969 | 52.37403
Olsztyn | N/A | Poland | 20.49416 | 53.77995
Warsaw | N/A | Poland | 21.01178 | 52.22977
Salford | Greater Manchester | United Kingdom | -2.29042 | 53.48771
Harrow | N/A | United Kingdom | -0.33208 | 51.57835
| 0
|
NCT00081458
|
[
2
] | 74
|
RANDOMIZED
|
SEQUENTIAL
| 0TREATMENT
| 2DOUBLE
| true
| 0ALL
| null |
The primary objective of this study is to assess the safety and tolerability of romosozumab following single dose subcutaneous (SC) or intravenous (IV) administration in healthy men and postmenopausal women.
| null |
Osteopenia
|
Amgen First in Human Postmenopausal Phase 1
| null | 2
|
arm 1: Participants were randomized to receive a single dose of matching placebo administered by subcutaneous or intravenous injection. arm 2: Participants were randomized to receive a single dose of romosozumab administered by subcutaneous or intravenous injection. The starting dose was 0.1 mg/kg, with sequential escalation up to 10 mg/kg.
|
[
2,
0
] | 2
|
[
0,
0
] |
intervention 1: Administered subcutaneously or intravenously intervention 2: Administered subcutaneously or intravenously
|
intervention 1: Romosozumab intervention 2: Placebo
| 0
| null | 0
|
NCT01059435
|
[
4
] | 1,668
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
This was a multi-center, randomized, double-blind, parallel group study with 12 weeks of treatment of acne vulgaris. Efficacy and safety evaluations were performed at Screening (safety only), Baseline and Weeks 1, 2, 4, 8 and 12. All Investigator's Global Assessment evaluators and lesion counters must be trained and approved by Galderma. The evaluator of a participant should remain the same during the study.
The primary objective was to demonstrate the superiority in efficacy and assess safety of adapalene/benzoyl peroxide topical gel (adapalene/benzoyl peroxide gel) versus adapalene topical gel, 0.1% (adapalene monad); benzoyl peroxide topical gel, 2.5% (benzoyl peroxide monad) and topical gel vehicle (gel vehicle) in the treatment of acne vulgaris for up to 12 weeks.
| null |
Acne Vulgaris
|
Acne vulgaris Adapalene Benzoyl Peroxide
| null | 4
|
arm 1: Participants were treated with adapalene 0.1 % \[weight by weight (W/W)\]/benzoyl peroxide 2.5 % (W/W) gel topically daily in the evening for 12 Weeks. arm 2: Participants were treated with 0.1% of adapalene gel topically daily in the evening for 12 Weeks. arm 3: Participants were treated with 2.5% of benzoyl peroxide gel topically daily in the evening for 12 Weeks. arm 4: Participants were treated with gel vehicle topically daily in the evening for 12 Weeks.
|
[
0,
0,
0,
2
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Adapalene 0.1 % \[weight by weight (W/W)\]/benzoyl peroxide 2.5 % (W/W) gel topically daily in the evening for 12 Weeks. intervention 2: 0.1% of adapalene gel topically daily in the evening for 12 Weeks. intervention 3: 2.5% of benzoyl peroxide gel topically daily in the evening for 12 Weeks. intervention 4: Participants were treated with gel vehicle topically daily in the evening for 12 Weeks.
|
intervention 1: Adapalene/Benzoyl Peroxide intervention 2: Adapalene Gel, 0.1% intervention 3: Benzoyl Peroxide Gel 2.5% intervention 4: Gel Vehicle
| 1
|
San Antonio | Texas | United States | -98.49363 | 29.42412
| 0
|
NCT00422240
|
[
5
] | 100
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| null | false
| 0ALL
| false
|
An 18 months randomised double-blind study with two parallel arms with start dose of inhaled SERETIDE 50/100mcg BD or FLIXOTIDE 100mcg BD, Phase I is 6 months where the patient will be up-titrated until well controlled is achieved, After 6 months the treatment continues without changes during 9 months = PhaseII. The aim is to investigate and evaluate the assumption that the combination therapy with SERETIDE controls mild persistent asthma better than inhaled corticosteroids(FLIXOTIDE) alone.
| null |
Asthma
|
asthma exacerbation persistent bronchial hyperresponsiveness mild GINAII
| null | 2
|
arm 1: Eligible participants received a starting dose of 50/100 mcg Seretide (combination of Sal/FP) via Diskus inhaler, twice daily. During the first 6 months, when the asthma was unstable/uncontrolled, dose was increased in a stepwise fashion to 50/250 mcg and 50/500 mcg (if still unstable). After the initial 6 months, the treatment was fixed without further changes. The total treatment period was 18 months. arm 2: Eligible participants received a starting dose of 100 mcg Flixotide (FP only) via Diskus inhaler, twice daily. During the first 6 months, when the asthma was unstable/uncontrolled, dose was increased in a stepwise fashion to 250 mcg and 500 mcg (if still unstable). After the initial 6 months, the treatment was fixed without further changes. The total treatment period was 18 months.
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Seretide intervention 2: Flixotide
|
intervention 1: Seretide intervention 2: Flixotide
| 1
|
Luleå | N/A | Sweden | 22.15465 | 65.58415
| 0
|
NCT00455923
|
[
3
] | 20
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Current therapies for adults with recurrent or refractory mixed gliomas provide very limited benefit to the patient. The anti-cancer properties of Antineoplaston therapy suggest that it may prove beneficial in the treatment of adults with recurrent or refractory mixed gliomas.
PURPOSE: This study is being performed to determine the effects (good and bad) that Antineoplaston therapy has on adults with recurrent or refractory mixed gliomas.
|
OBJECTIVES:
* To determine the efficacy of Antineoplaston therapy in adults with recurrent or refractory mixed gliomas as measured by an objective response to therapy (complete response, partial response or stable disease).
* To determine the safety and tolerance of Antineoplaston therapy in adults with recurrent or refractory mixed gliomas.
OVERVIEW: This is a single arm, open-label study in which adults with recurrent or refractory mixed gliomas receive gradually escalating doses of intravenous Antineoplaston therapy (Atengenal + Astugenal) until the maximum tolerated dose is reached. Treatment continues for at least 12 months in the absence of disease progression or unacceptable toxicity. After 12 months, patients with a complete or partial response or with stable disease may continue treatment.
To determine objective response, tumor size is measured utilizing MRI scans, which are performed every 8 weeks for the first two years, every 3 months for the third and fourth years, every 6 months for the 5th and sixth years, and annually thereafter.
PROJECTED ACCRUAL: A total of 20-40 patients will be accrued to this study
|
Mixed Gliomas
|
recurrent adult mixed glioma refractoy adult mixed glioma
| null | 1
|
arm 1: Antineoplaston therapy (Atengenal + Astugenal) by IV infusion every four hours for at least 12 months. Study subjects receive increasing dosages of Atengenal and Astugenal until the maximum tolerated dose is reached.
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: Adults with a recurrent or refractory mixed glioma will receive Antineoplaston therapy (Atengenal + Astugenal). intervention 2: Adults with a recurrent or refractory mixed glioma will receive Antineoplaston therapy (Atengenal + Astugenal).
|
intervention 1: Atengenal intervention 2: Astugenal
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00003473
|
[
3
] | 48
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The goal of this clinical research study is to learn if giving CAMPATH-1H with rituximab can shrink or slow the growth of the disease in patients with chronic lymphoid disorders that have either not responded or whose disease has returned after treatment with standard therapies.
|
Objectives:
1. To determine the efficacy and response rates of Campath-1H when given as a continuous intravenous infusion followed by subcutaneous injection plus rituximab in the treatment of chronic lymphoid disorders that are refractory to conventional therapy, have relapsed, or have no established frontline therapy.
2. To assess the safety of the combination of Campath-1H when given as a continuous intravenous infusion followed by subcutaneous injection plus rituximab in chronic lymphoid disorders that express both CD52 and CD20 cell surface antigens.
3. To measure levels of soluble (s) CD20 and sCD52 as well as levels of Campath-1H, rituximab and antibody complexes of rituximab/CD20 and Campath-1H/CD52 in patients with chronic lymphoid disorders treated with Campath-1H plus rituximab.
|
Chronic Lymphocytic Leukemia
|
Chronic Lymphocytic Leukemia CD-52 and CD-20 Positive Refractory Relapsed
| null | 1
|
arm 1: Campath 15 mg/day continuous intravenous (IV) infusion x 6 days, then twice a week for 3 weeks as 30 mg injection under skin to complete 4 week treatment course.
Rituximab 375 mg/m\^2 IV infusion day 1, then 500 mg/m\^2 on days 8, 15 + 22.
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: 15 mg/day Continuous infusion by vein (IV) for 6 days then given twice a week for remaining three weeks as 30 mg injection under skin to complete one treatment course of 4 weeks. intervention 2: 375 mg/m\^2 IV infusion on day 1, then 500 mg/m\^2 on days 8, 15, and 22.
|
intervention 1: Campath-1H intervention 2: Rituximab
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00071396
|
[
3
] | 89
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 1SINGLE
| false
| 0ALL
| true
|
This study will evaluate the lung's immune response to mycobacterium tuberculosis (Mtb) infection and will modulate that response with interferon-gamma.
|
BACKGROUND:
Mtb infects one-third of the world's population and ranks seventh in terms of global morbidity and mortality. Patients with bilateral pulmonary tuberculosis (TB), cavitary disease, and persistently positive sputum smears pose a special risk for treatment failure and/or relapse.
DESIGN NARRATIVE:
Cavitary pulmonary TB will be studied and interferon-gamma will be used as the intervention. The outcome of this study will be the changes in mycobacteriology, chest radiography, and bronchoalveolar lavage (BAL) cells.
The primary outcome will be sputum conversion, which will be measured at Weeks 4 and 8.
The key secondary outcomes of this study will include a chest computerized tomography (CT) scan and BAL to measure the flow of cytometry and cytokine levels. Both outcomes will be measured at baseline and at Month 4.
|
Tuberculosis AIDS-related Complex
| null | 3
|
arm 1: Isoniazid, Rifampin, Pyrazinamide Anti-Tuberculous Therapy arm 2: Aerosol Interferon-Gamma plus Isoniazid, Rifampin, and Pyrazinamide arm 3: Subcutaneous Interferon-Gamma plus Isoniazid, Rifampin, and Pyrazinamide
|
[
2,
0,
0
] | 3
|
[
0,
0,
10
] |
intervention 1: Participants will receive aerosol interferon-gamma. intervention 2: Patients will receive subcutaneous interferon-gamma intervention 3: None
|
intervention 1: Aerosol Interferon-Gamma intervention 2: Subcutaneous interferon-gamma intervention 3: Placebo
| 2
|
New York | New York | United States | -74.00597 | 40.71427
Cape Town | N/A | South Africa | 18.42322 | -33.92584
| 0
|
NCT00201123
|
|
[
5
] | 41
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| true
| 1FEMALE
| true
|
Remifentanil is a ultra short-acting synthetic opioid. It is rapidly metabolized by non-specific blood and tissue esterases. We wanted to investigate the efficacy and safety of remifentanil used as analgesia during labour. Intravenous patient controlled analgesia (ivpca) were used to administer remifentanil. Doses used were 0,15-1,05 mikrogr/kg, with a lock-out time of 2 minutes. 41 women were included in the study. Blood-pressure, heartrate, SaO2, respiration rate and sedation were recorded every 15.minute. Fetal heart rate was recorded for the whole periode of treatment (CTG, STAN). Vaginal contraction pain were assessed by the parturients every 15.minute using a Visual Analogue Scale (VAS). Midwives also recorded their impression of the parturients pain. The parturients level of sedation were recorded by anesthesiologist and midwife every 15.minute. Apgar scores were registered at 1, 5 and 10 min after delivery. Umbilical cord blood analysis regarding blood gases and concentration of remifentanil were performed. After delivery, both mother and midwife evaluated efficacy and safety; Global satisfaction score, if the remifentanil doses were sufficient, nausea, vomiting, level of sedation and dizziness.
|
Primary and secondary outcome measures presented under "results"
|
Labour Pain Satisfaction Adverse Effects
|
Remifentanil, parenteral opioids, obstetric analgesia, IVPCA
| null | 1
|
arm 1: Bolus dose steps of 0.15 microgr/kg, with a 2-min lock-out time
|
[
1
] | 1
|
[
0
] |
intervention 1: Intravenous patient controlled analgesia (ivpca) during labour
|
intervention 1: Remifentanil
| 1
|
Kristiansand | Vest-Agder | Norway | 7.9956 | 58.14671
| 0
|
NCT00202722
|
[
3
] | 49
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| false
| 0ALL
| false
|
The investigator wish therefore to continue these studies on theophylline principally by conducting a small clinical pilot study on 20-30 COPD patients in a randomised, double-blind, placebo-controlled, parallel-group study.
|
The global burden of COPD - a common and debilitating chronic inflammatory disease that is characterised by the progressive development of airflow limitation (shortness of breath - SOB) and is poorly reversible with currently available drugs -is increasing. Cigarette smoking is strongly linked with the ongoing inflammation; inflammation that can continue even when the patient has stopped smoking. The severity of airflow limitation (SOB) is correlated with the degree of pulmonary (lung) inflammation.
Histone deacetylases (HDACs)are important molecules in suppressing this pulmonary inflammation. We have recently shown that patients with COPD have a reduction in total HDAC which correlates with the severity of their lung disease.
Corticosteroids (anti-inflammatory treatment) act, at least in part, by recruitment of these HDACs to the site of active inflammatory gene transcription (which reduces the production of inflammatory molecules) and are widely used in COPD in patients with severe disease. Unfortunately, in COPD, inhaled corticosteroids seem to have little effect on the underlying inflammation (though in a selective group of patients with COPD they do reduce the number of infections a patient may have by a small amount).
Theophylline has been used in the treatment of asthma and COPD for over 70 years, but its use has recently declined. Data so far obtained in primary cells (cells from patients used in the laboratory) from COPD patients suggests that low dose theophylline (\~5mg/l) should be effective in restoring steroid sensitivity in patients with COPD (and hence reduce inflammation thus improving SOB).
|
COPD
|
COPD
| null | 2
|
arm 1: Inhaled Theophylline placebo capsule, then placebo, then active Theophylline arm 2: Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline
|
[
2,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: 500 u intervention 2: None intervention 3: Theophylline placebo capcule
|
intervention 1: Fluticasone Propionate intervention 2: placebo intervention 3: Theophylline
| 1
|
Windsor | Berks | United Kingdom | -0.6 | 51.48333
| 0
|
NCT00241631
|
[
4
] | 493
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The purpose of this study is to evaluate the efficacy and safety of alogliptin, once daily (QD), combined with pioglitazone in adults with type 2 diabetes mellitus
|
There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% are type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected.
Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes.
The aim of the current study is to evaluate the efficacy of alogliptin in combination with pioglitazone in subjects who are inadequately controlled on a thiazolidinedione (pioglitazone or rosiglitazone) alone or in combination with metformin or a sulfonylurea. Individuals who participate in this study will be required to commit to a screening visit and up to 14 additional visits at the study center. Study participation is anticipated to be about 34 weeks (or 8.5 months).
|
Diabetes Mellitus
|
Glucose Metabolism Disorder Dysmetabolic Syndrome Type II Diabetes Diabetes Mellitus Lipoatrophic Dyslipidemia Drug Therapy
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
1,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks intervention 2: Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks intervention 3: Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks
|
intervention 1: Alogliptin and pioglitazone intervention 2: Alogliptin and pioglitazone intervention 3: Pioglitazone
| 77
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Phoenix | Arizona | United States | -112.07404 | 33.44838
Anaheim | California | United States | -117.9145 | 33.83529
Artesia | California | United States | -118.08312 | 33.86585
Fresno | California | United States | -119.77237 | 36.74773
Mission Viejo | California | United States | -117.672 | 33.60002
Northridge | California | United States | -118.53675 | 34.22834
Orange | California | United States | -117.85311 | 33.78779
San Diego | California | United States | -117.16472 | 32.71571
Walnut Creek | California | United States | -122.06496 | 37.90631
Colorado Springs | Colorado | United States | -104.82136 | 38.83388
Denver | Colorado | United States | -104.9847 | 39.73915
Norwalk | Connecticut | United States | -73.4079 | 41.1176
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Clearwater | Florida | United States | -82.8001 | 27.96585
Cocoa Beach | Florida | United States | -80.60922 | 28.32055
Hollywood | Florida | United States | -80.14949 | 26.0112
Kissimmee | Florida | United States | -81.41667 | 28.30468
Longwood | Florida | United States | -81.3384 | 28.70305
New Port Richey | Florida | United States | -82.71927 | 28.24418
Ocala | Florida | United States | -82.14009 | 29.1872
Ocoee | Florida | United States | -81.54396 | 28.56917
Saint Cloud | Florida | United States | -81.28118 | 28.2489
Tampa | Florida | United States | -82.45843 | 27.94752
Lawrenceville | Georgia | United States | -83.98796 | 33.95621
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Idaho Falls | Idaho | United States | -112.03414 | 43.46658
Chicago | Illinois | United States | -87.65005 | 41.85003
Avon | Indiana | United States | -86.39972 | 39.76282
Elkhart | Indiana | United States | -85.97667 | 41.68199
Evansville | Indiana | United States | -87.55585 | 37.97476
Lafayette | Indiana | United States | -86.87529 | 40.4167
Erlanger | Kentucky | United States | -84.60078 | 39.01673
Baltimore | Maryland | United States | -76.61219 | 39.29038
Sudbury | Massachusetts | United States | -71.41617 | 42.38343
Chesterfield | Missouri | United States | -90.57707 | 38.66311
St Louis | Missouri | United States | -90.19789 | 38.62727
Omaha | Nebraska | United States | -95.94043 | 41.25626
Berlin | New Jersey | United States | -74.92905 | 39.79123
Burlington | North Carolina | United States | -79.4378 | 36.09569
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Hickory | North Carolina | United States | -81.3412 | 35.73319
Morehead City | North Carolina | United States | -76.72604 | 34.72294
Pinehurst | North Carolina | United States | -79.46948 | 35.19543
Wilmington | North Carolina | United States | -77.94604 | 34.23556
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Dayton | Ohio | United States | -84.19161 | 39.75895
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Medford | Oregon | United States | -122.87559 | 42.32652
Lansdale | Pennsylvania | United States | -75.28379 | 40.2415
West Grove | Pennsylvania | United States | -75.82744 | 39.82205
Charleston | South Carolina | United States | -79.93275 | 32.77632
Columbia | South Carolina | United States | -81.03481 | 34.00071
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Bristol | Tennessee | United States | -82.18874 | 36.59511
Cookeville | Tennessee | United States | -85.50164 | 36.16284
Milan | Tennessee | United States | -88.75895 | 35.91979
Corpus Christi | Texas | United States | -97.39638 | 27.80058
Dallas | Texas | United States | -96.80667 | 32.78306
San Antonio | Texas | United States | -98.49363 | 29.42412
Temple | Texas | United States | -97.34278 | 31.09823
Texarkana | Texas | United States | -94.04769 | 33.42513
Burlington | Vermont | United States | -73.21207 | 44.47588
Multiple Cities | N/A | Argentina | N/A | N/A
Multiple Cities | N/A | Australia | N/A | N/A
Multiple Cities | N/A | Brazil | N/A | N/A
Multiple Cities | N/A | Czechia | N/A | N/A
Multiple Cities | N/A | Germany | N/A | N/A
Multiple Cities | N/A | Guatemala | N/A | N/A
Multiple Cities | N/A | Hungary | N/A | N/A
Multiple Cities | N/A | India | N/A | N/A
Multiple Cities | N/A | Mexico | N/A | N/A
Multiple Cities | N/A | Netherlands | N/A | N/A
Multiple Cities | N/A | New Zealand | N/A | N/A
Multiple Cities | N/A | Peru | N/A | N/A
Multiple Cities | N/A | South Africa | N/A | N/A
| 0
|
NCT00286494
|
[
4
] | 1,308
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 1FEMALE
| true
|
The purpose of this study is to determine whether the misoprostol vaginal insert (50 mcg and 100 mcg) can safely and effectively speed time to vaginal delivery compared to Cervidil (R) in women who need to have cervical ripneing and induction of labor.
|
Induction of labor is required in approximately 20% of pregnant women. Although contractions can be brought on by oxytocin ("pitocin"), some women need help in softening the cervix, or mouth of the womb (uterus), before oxytocin can be started. Prostaglandins have been shown to ripen, or soften, the cervix; at present, the only prostaglandin approved for marketing by FDA for this purpose is dinoprostone. Dinoprostone can be delivered in several ways; one method is to use a polymer vaginal insert that slowly releases the dinoprostone directly to the cervical tissues. This product is called Cervidil (R) and has been marketed for more than 10 years in the United States. Misoprostol is another form of prostaglandin that is approved for protecting the stomach and intestinal lining for patients taking NSAIDs. Misoprostol has also been used by many obstetricians for cervical ripening and inducing contractions, but, it is not approved by FDA for this purpose.
The same company that makes the Cervidil polymer insert has made an insert that will slowly release misoprostol. This study will determine whether this investigational insert containing misoprostol will decrease time to vaginal delivery compared to Cervidil. Two different doses of misoprostol will be tested (50 micrograms and 100 micrograms); each vaginal insert will gradually release a small, controlled amount of misoprostol over up to 24 hours.
Comparator: The Cervidil (R) vaginal insert containing dinoprostone will be the comparator in this study.
|
Cervical Ripening Labor, Induced
|
Cervical ripening Induction of labor Dinoprostone vaginal insert Cervidil Misoprostol vaginal insert Modified Bishop's Score PGE2 PGE1 Uterine Hyperstimulation Cesarean section
| null | 3
|
arm 1: Misoprostol vaginal insert 100 mcg over 24h arm 2: Misoprostol vaginal insert 50 mcg over 24h arm 3: Cervidil 10 mg over 24h
|
[
0,
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Hydrogel polymer intravaginal insert with retrieval system. One insert is to remain in the posterior fornix of the vagina until removed for one of the following conditions: onset of active labor; maternal/fetal complication, e.g. non-reassuring fetal heart rate. Record if the insert falls out prior to meeting one of the first two criteria. In no case is the insert to remain in place longer than 24h. intervention 2: Hydrogel polymer intravaginal insert with retrieval system. One insert is to remain in the posterior fornix of the vagina until removed for one of the following conditions: onset of active labor; maternal/fetal complication, e.g. non-reassuring fetal heart rate. Record if the insert falls out prior to meeting one of the first two criteria. In no case is the insert to remain in place longer than 24h. intervention 3: Hydrogel polymer intravaginal insert with retrieval system. One insert is to remain in the posterior fornix of the vagina until removed for one of the following conditions: onset of active labor; maternal/fetal complication, e.g. non-reassuring fetal heart rate. Record if the insert falls out prior to meeting one of the first two criteria. In no case is the insert to remain in place longer than 24h.
|
intervention 1: Misoprostol vaginal insert 100 mcg intervention 2: Misoprostol vaginal insert 50 mcg intervention 3: Dinoprostone vaginal insert (Cervidil)
| 52
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Mesa | Arizona | United States | -111.82264 | 33.42227
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Tucson | Arizona | United States | -110.92648 | 32.22174
Long Beach | California | United States | -118.18923 | 33.76696
Orange | California | United States | -117.85311 | 33.78779
San Jose | California | United States | -121.89496 | 37.33939
Newark | Delaware | United States | -75.74966 | 39.68372
St. Petersburg | Florida | United States | -82.67927 | 27.77086
Tampa | Florida | United States | -82.45843 | 27.94752
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Alpharetta | Georgia | United States | -84.29409 | 34.07538
Flint | Michigan | United States | -83.68746 | 43.01253
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Lincoln | Nebraska | United States | -96.66696 | 40.8
Morristown | New Jersey | United States | -74.48154 | 40.79677
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Johnson City | New York | United States | -75.95881 | 42.11563
Mineola | New York | United States | -73.64068 | 40.74927
New York | New York | United States | -74.00597 | 40.71427
New York | New York | United States | -74.00597 | 40.71427
The Bronx | New York | United States | -73.86641 | 40.84985
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Columbus | Ohio | United States | -82.99879 | 39.96118
Dayton | Ohio | United States | -84.19161 | 39.75895
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Portland | Oregon | United States | -122.67621 | 45.52345
Abington | Pennsylvania | United States | -75.11795 | 40.12067
Allentown | Pennsylvania | United States | -75.49018 | 40.60843
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Wynnewood | Pennsylvania | United States | -75.27074 | 40.00289
Greenville | South Carolina | United States | -82.39401 | 34.85262
North Charleston | South Carolina | United States | -79.97481 | 32.85462
Chattanooga | Tennessee | United States | -85.30968 | 35.04563
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Memphis | Tennessee | United States | -90.04898 | 35.14953
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
Temple | Texas | United States | -97.34278 | 31.09823
Ogden | Utah | United States | -111.97383 | 41.223
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Salt Lake City | Utah | United States | -111.89105 | 40.76078
West Jordan | Utah | United States | -111.9391 | 40.60967
West Valley City | Utah | United States | -112.00105 | 40.69161
Bellevue | Washington | United States | -122.20068 | 47.61038
Weston | Wisconsin | United States | -89.54762 | 44.8908
St. John's | Newfoundland and Labrador | Canada | -52.70931 | 47.56494
Halifax | Nova Scotia | Canada | -63.57688 | 44.64269
Saskatoon | Saskatchewan | Canada | -106.66892 | 52.13238
| 0
|
NCT00308711
|
[
3
] | 333
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The objective of the study is to test the efficacy, safety and tolerability of several doses of BI 1356 BS (1, 5, or 10 mg taken once daily) compared to placebo given for 12 weeks together with metformin in patients with type 2 diabetes mellitus who are not at goal with their HbA1c levels. In addition, there will be an unblinded treatment arm with glimepiride as add-on therapy to metformin for comparison. The influence of several factors (gender, age, weight, race, etc.) on the bioavailability and efficacy of BI 1356 BS will also be tested in this study.
| null |
Diabetes Mellitus, Type 2
| null | 5
|
arm 1: Patients receive Linagliptin low dose tablets once daily arm 2: Patients receive Linagliptin medium dose tablets once daily arm 3: Patients receive Linagliptin high dose tablets once daily arm 4: Patients receive tablets identical to those containing Linagliptin low, medium and high dose arm 5: Patients receive Glimepiride tablets once daily
|
[
0,
0,
0,
2,
1
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: Linagliptin medium dose tablet once daily intervention 2: Linagliptin high dose tablet once daily intervention 3: Linagliptin low dose tablet once daily intervention 4: Placebo tablets once daily intervention 5: Glimepiride tablets once daily
|
intervention 1: Linagliptin intervention 2: Linagliptin intervention 3: Linagliptin intervention 4: Placebo intervention 5: Glimepiride
| 48
|
Joué Les Tours | N/A | France | N/A | N/A
Joué Les Tours | N/A | France | N/A | N/A
Joué-lès-Tours | N/A | France | 0.66513 | 47.34907
Joué-lès-Tours | N/A | France | 0.66513 | 47.34907
Paris | N/A | France | 2.3488 | 48.85341
Aschaffenburg | N/A | Germany | 9.15214 | 49.97704
Bosenheim | N/A | Germany | 7.91382 | 49.84472
Dresden | N/A | Germany | 13.73832 | 51.05089
Düsseldorf | N/A | Germany | 6.77616 | 51.22172
Heidelberg | N/A | Germany | 8.69079 | 49.40768
Immenstadt im Allgäu | N/A | Germany | 10.21394 | 47.55996
Mainz | N/A | Germany | 8.2791 | 49.98419
Neuwied | N/A | Germany | 7.47057 | 50.4336
Offenbach A. M. | N/A | Germany | N/A | N/A
Saarbrücken | N/A | Germany | 7.00982 | 49.23262
Saint Ingbert/Oberwürzbach | N/A | Germany | N/A | N/A
Sinsheim | N/A | Germany | 8.87867 | 49.2529
Sulzbach-Rosenberg | N/A | Germany | 11.74598 | 49.50126
Wangen | N/A | Germany | 9.83247 | 47.6895
Würzburg | N/A | Germany | 9.95121 | 49.79391
Banská Bystrica | N/A | Slovakia | 19.15349 | 48.73946
Bratislava | N/A | Slovakia | 17.10674 | 48.14816
Bratislava | N/A | Slovakia | 17.10674 | 48.14816
Nové Mesto nad Váhom | N/A | Slovakia | 17.8309 | 48.75763
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Malmo | N/A | Sweden | 13.00073 | 55.60587
Uddevalla | N/A | Sweden | 11.9424 | 58.34784
Uppsala | N/A | Sweden | 17.63889 | 59.85882
Dnyepropetrovsk | N/A | Ukraine | N/A | N/A
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Ashford | N/A | United Kingdom | 0.87376 | 51.14648
Baillieston, Glasgow | N/A | United Kingdom | N/A | N/A
Bath | N/A | United Kingdom | -2.36172 | 51.3751
Birmingham | N/A | United Kingdom | -1.89983 | 52.48142
Camberley | N/A | United Kingdom | -0.74261 | 51.33705
Chorley | N/A | United Kingdom | -2.61667 | 53.65
Dundee | N/A | United Kingdom | -2.97489 | 56.46913
Exeter | N/A | United Kingdom | -3.52751 | 50.7236
Gillingham | N/A | United Kingdom | 0.54863 | 51.38914
Glasgow | N/A | United Kingdom | -4.25763 | 55.86515
Guildford | N/A | United Kingdom | -0.57427 | 51.23536
Liverpool | N/A | United Kingdom | -2.97794 | 53.41058
London | N/A | United Kingdom | -0.12574 | 51.50853
Manchester | N/A | United Kingdom | -2.23743 | 53.48095
Newcastle upon Tyne | N/A | United Kingdom | -1.61396 | 54.97328
Reading | N/A | United Kingdom | -0.97113 | 51.45625
| 0
|
NCT00309608
|
|
[
4
] | 255
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
This study compares the efficacy and safety of intravenous (IV) iron (VIT45) versus oral iron (ferrous sulfate) administered to subjects who suffer from anemia and are diagnosed with non-dialysis dependent chronic kidney disease (NDD-CKD).
|
This study compares the efficacy and safety of intravenous (IV) iron (VIT45) versus oral iron (ferrous sulfate) administered to subjects who suffer from anemia and are diagnosed with non-dialysis dependent chronic kidney disease (NDD-CKD).
|
Anemia
|
Anemia Chronic Kidney Disease Iron
| null | 2
|
arm 1: A maximum dose of 1,000 mg of FCM over 15 minutes on day 0, and a maximum dose of 500 mg of FCM over 15 minutes on days 17 and 31 based on Ferritin and TSAT values. arm 2: 325 mg/TID x 8 weeks
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: 325 mg/TID x 8 weeks intervention 2: A maximum dose of 1,000 mg of FCM over 15 minutes on day 0, and a maximum dose of 500 mg of FCM over 15 minutes on days 17 and 31 based on Ferritin and TSAT values.
|
intervention 1: Ferrous Sulfate tablets intervention 2: Ferric Carboxymaltose (FCM)
| 1
|
Norristown | Pennsylvania | United States | -75.3399 | 40.1215
| 0
|
NCT00317239
|
[
3
] | 43
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study is to examine the safety and efficacy of OPC-6535 (tetomilast) and to determine its optimal dose by once-daily oral administration at 0, 12.5, 25, or 50 mg for 8 weeks in combination with a fixed oral dose of 5-aminosalicylic acid (5-ASA) in patients with active ulcerative colitis.
| null |
Colitis, Ulcerative
|
OPC-6535 ulcerative colitis
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: None
|
intervention 1: OPC-6535(Tetomilast)
| 8
|
Chubu Region | N/A | Japan | N/A | N/A
Chugoku Region | N/A | Japan | N/A | N/A
Hokkaido Region | N/A | Japan | N/A | N/A
Kanto Region | N/A | Japan | N/A | N/A
Kinki Region | N/A | Japan | N/A | N/A
Kyushu Region | N/A | Japan | N/A | N/A
Shikoku Region | N/A | Japan | N/A | N/A
Touhoku Region | N/A | Japan | N/A | N/A
| 0
|
NCT00317356
|
[
3
] | 29
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
The purpose of this study to examine the safety and efficacy of OPC-6535 and determine its optimal dose by once-daily oral administration at 0, 25, or 50 mg for 8 weeks in combination with a fixed oral dose of 5-aminosalicylic acid (5-ASA) or in combination with a fixed oral dose of 5-ASA and enteral nutrition in patients with active Crohn's disease.
| null |
Crohn Disease
|
OPC-6535 Crohn's disease
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: None
|
intervention 1: OPC-6535(Tetomilast)
| 8
|
Chubu Region | N/A | Japan | N/A | N/A
Chugoku Region | N/A | Japan | N/A | N/A
Hokkaido Region | N/A | Japan | N/A | N/A
Kanto Region | N/A | Japan | N/A | N/A
Kinki Region | N/A | Japan | N/A | N/A
Kyushu Region | N/A | Japan | N/A | N/A
Shikoku Region | N/A | Japan | N/A | N/A
Touhoku Region | N/A | Japan | N/A | N/A
| 0
|
NCT00317369
|
[
3
] | 302
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The objective of the current study is to investigate the efficacy, safety and tolerability of several doses of BI 1356 BS (0.5, 2.5 and 5 mg daily) compared to placebo over 12 weeks of treatment in patients with Type 2 diabetes and insufficient glycemic control. In addition, there will be an open-label treatment arm with metformin for sensitivity measurement with this patient population. Population pharmacokinetics of BI 1356 BS will also be assessed in this study.
| null |
Diabetes Mellitus, Type 2
| null | 5
|
arm 1: Placebo tablets matching BI 1356 arm 2: BI 1356 dose 1 once daily arm 3: BI 1356 dose 2 once daily arm 4: BI 1356 dose 3 once daily arm 5: Metformin
|
[
2,
0,
0,
0,
1
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: Placebo matching BI 1356 intervention 2: BI 1356 dose 3 once daily intervention 3: BI 1356 dose 2 once daily intervention 4: BI 1356 dose 1 once daily intervention 5: Metformin
|
intervention 1: Placebo intervention 2: BI 1356 dose 3 once daily intervention 3: BI 1356 dose 2 once daily intervention 4: BI 1356 dose 1 once daily intervention 5: Metformin
| 71
|
Chula Vista | California | United States | -117.0842 | 32.64005
La Jolla | California | United States | -117.2742 | 32.84727
Walnut Creek | California | United States | -122.06496 | 37.90631
Denver | Colorado | United States | -104.9847 | 39.73915
Hollywood | Florida | United States | -80.14949 | 26.0112
Jacksonville | Florida | United States | -81.65565 | 30.33218
Miami | Florida | United States | -80.19366 | 25.77427
Miami | Florida | United States | -80.19366 | 25.77427
Orlando | Florida | United States | -81.37924 | 28.53834
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Topeka | Kansas | United States | -95.67804 | 39.04833
Wichita | Kansas | United States | -97.33754 | 37.69224
Baltimore | Maryland | United States | -76.61219 | 39.29038
Springfield | Massachusetts | United States | -72.58981 | 42.10148
Chesterfield | Missouri | United States | -90.57707 | 38.66311
Butte | Montana | United States | -112.53474 | 46.00382
Omaha | Nebraska | United States | -95.94043 | 41.25626
Albany | New York | United States | -73.75623 | 42.65258
Endwell | New York | United States | -76.02103 | 42.11285
New Hyde Park | New York | United States | -73.68791 | 40.7351
Columbus | Ohio | United States | -82.99879 | 39.96118
Mentor | Ohio | United States | -81.33955 | 41.66616
Medford | Oregon | United States | -122.87559 | 42.32652
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Columbia | South Carolina | United States | -81.03481 | 34.00071
Greer | South Carolina | United States | -82.22706 | 34.93873
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
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
Tyler | Texas | United States | -95.30106 | 32.35126
Salem | Virginia | United States | -80.05476 | 37.29347
Federal Way | Washington | United States | -122.31262 | 47.32232
Renton | Washington | United States | -122.21707 | 47.48288
Miranda | New South Wales | Australia | 151.10005 | -34.03857
Box Hill | Victoria | Australia | 145.12545 | -37.81887
Dandenong | Victoria | Australia | 145.2 | -37.98333
East Ringwood | Victoria | Australia | N/A | N/A
Fremantle | Western Australia | Australia | 115.74557 | -32.05632
Nedlands | Western Australia | Australia | 115.8073 | -31.98184
Calgary | Alberta | Canada | -114.08529 | 51.05011
Calgary | Alberta | Canada | -114.08529 | 51.05011
Red Deer | Alberta | Canada | -113.802 | 52.26682
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Vancouver | British Columbia | Canada | -123.11934 | 49.24966
Winnipeg | Manitoba | Canada | -97.14704 | 49.8844
Hamilton | Ontario | Canada | -79.84963 | 43.25011
Oakville | Ontario | Canada | -79.68292 | 43.45011
Ottawa | Ontario | Canada | -75.69812 | 45.41117
Sarnia | Ontario | Canada | -82.40407 | 42.97866
Thornhill | Ontario | Canada | -79.4163 | 43.80011
Toronto | Ontario | Canada | -79.39864 | 43.70643
Montague | Prince Edward Island | Canada | -62.64866 | 46.16681
Sainte-Foy | Quebec | Canada | -71.29217 | 46.78139
Saskatoon | Saskatchewan | Canada | -106.66892 | 52.13238
Olomouc | N/A | Czechia | 17.25175 | 49.59552
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Prague | N/A | Czechia | 14.42076 | 50.08804
Sternberk | N/A | Czechia | 17.29889 | 49.73044
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Moscow | N/A | Russia | 37.61556 | 55.75222
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Saint Petersburg | N/A | Russia | 30.31413 | 59.93863
Kharkiv | N/A | Ukraine | 36.25475 | 49.98177
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Kiev | N/A | Ukraine | 30.5238 | 50.45466
Lviv | N/A | Ukraine | 24.02324 | 49.83826
Vinnitsa | N/A | Ukraine | 37.71861 | 49.84639
| 0
|
NCT00328172
|
|
[
4
] | 190
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
A clinical study to determine the safety and efficacy of sitagliptin in patients with Type 2 Diabetes Mellitus who have inadequate glycemic (blood sugar) control on metformin therapy.
| null |
Type 2 Diabetes Mellitus (T2DM)
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Patients will receive blinded sitagliptin 100 mg q.d. and open-label metformin ≥ 1500 mg/day for up to 30 weeks. Sitagliptin 100 mg q.d. and metformin ≥ 1500 mg/day will be administered as oral tablets. intervention 2: Patients will receive placebo to match sitagliptin 100 mg q.d. and open-label metformin ≥ 1500 mg/day for up to 30 weeks. Sitagliptin 100 mg q.d. and metformin ≥ 1500 mg/day will be administered as oral tablets.
|
intervention 1: sitagliptin 100 mg q.d./metformin ≥ 1500 mg/day intervention 2: comparator: placebo to match sitagliptin 100 mg q.d./metformin ≥ 1500 mg/day
| 0
| null | 0
|
NCT00337610
|
|
[
4
] | 178
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
This is a sixteen-week follow-on and 28 week single-blind extension study for patients who participated in study NK-104-304.
|
This is a sixteen-week, double-blind, active controlled, follow-on and 28 week single blind extension study for patients who participated in NK-104-304.
|
Hypercholesterolemia Dyslipidemia Coronary Heart Disease
|
hypercholesterolemia dyslipidemia CHD pitavastatin simvastatin 2 or more risk factors for coronary heart disease combined dyslipidemia
| null | 2
|
arm 1: Pitavastatin 4 mg once daily arm 2: Simvastatin 40 mg or 80 mg once daily
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: pitavastatin intervention 2: simvastatin
| 28
|
Copenhagen Nv | N/A | Denmark | N/A | N/A
Frederiksberg | N/A | Denmark | 12.53463 | 55.67938
Hellerup | N/A | Denmark | 12.57093 | 55.73204
Vejle | N/A | Denmark | 9.5357 | 55.70927
Breda | N/A | Netherlands | 4.77596 | 51.58656
Eindhoven | N/A | Netherlands | 5.47778 | 51.44083
Groningen | N/A | Netherlands | 6.56667 | 53.21917
Leiden | N/A | Netherlands | 4.49306 | 52.15833
Nijmegen | N/A | Netherlands | 5.85278 | 51.8425
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Velp | N/A | Netherlands | 5.97361 | 51.995
Zoetermeer | N/A | Netherlands | 4.49306 | 52.0575
San Juan | Alicante | Spain | -1.16667 | 39.53333
Córdoba | N/A | Spain | -4.77275 | 37.89155
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Madrid | N/A | Spain | -3.70256 | 40.4165
Santiago de Compostela | N/A | Spain | -8.54569 | 42.88052
Angelhom | N/A | Sweden | N/A | N/A
Gothenburg | N/A | Sweden | 11.96679 | 57.70716
Helsingborg | N/A | Sweden | 12.69437 | 56.04673
Karineholm | N/A | Sweden | N/A | N/A
Ludvika | N/A | Sweden | 15.18776 | 60.14959
Sandviken | N/A | Sweden | 16.76667 | 60.61667
Sandviken | N/A | Sweden | 16.76667 | 60.61667
Södertälje | N/A | Sweden | 17.62525 | 59.19554
Stockholm | N/A | Sweden | 18.06871 | 59.32938
Varberg | N/A | Sweden | 12.25078 | 57.10557
| 0
|
NCT00344175
|
[
3
] | 10
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The objectives in this study are to evaluate: (1) efficacy of buprenorphine transdermal system (BTDS, Butrans™) on postoperative pain following total knee replacement surgery; (2) the impact of BTDS on functional rehabilitative measures after total knee replacement surgery; and 3) the safety of BTDS after total knee replacement surgery. The double-blind treatment period is for 28 days during which time supplemental analgesic medication will be provided to all subjects in addition to study drug.
Purdue Pharma L.P. terminated the trial early due to administrative reasons not related to efficacy or safety. The focus of this study became safety evaluations.
|
Buprenorphine is a synthetic opioid analgesic with over 25 years of international clinical experience indicating it to be safe and effective in a variety of therapeutic situations for the relief of moderate to severe pain.
|
Postoperative Pain
|
Postoperative pain opioid transdermal TKA (total knee arthroplasty)
| null | 4
|
arm 1: Buprenorphine transdermal patch 10 mcg/h applied for 7-day wear arm 2: Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear arm 3: Buprenorphine transdermal patch 30 mcg/h applied for 7-day wear arm 4: Placebo patches were similar to BTDS 10 and 20.
|
[
0,
0,
0,
2
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: Buprenorphine transdermal patch 10 mcg/h applied for 7-day wear. intervention 2: Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear. intervention 3: Buprenorphine transdermal patches 10 mcg/h and 20 mcg/h (total of 30 mcg/h) applied for 7-day wear. intervention 4: Placebo to match BTDS transdermal 10 and 20 patches applied for 7-day wear.
|
intervention 1: Buprenorphine transdermal patch intervention 2: Buprenorphine transdermal patch intervention 3: Buprenorphine transdermal patch intervention 4: Placebo BTDS
| 5
|
Phoenix | Arizona | United States | -112.07404 | 33.44838
San Clemente | California | United States | -117.61199 | 33.42697
Orlando | Florida | United States | -81.37924 | 28.53834
Baltimore | Maryland | United States | -76.61219 | 39.29038
Sewickley | Pennsylvania | United States | -80.1845 | 40.53646
| 0
|
NCT00403234
|
[
4
] | 91
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The study estimates the efficacy and safety of MK0476 and aminophylline intravenous administration in adult participants with acute asthma.
| null |
Asthma
| null | 3
|
arm 1: Montelukast 7 mg IV administration arm 2: Montelukast 14 mg IV administration arm 3: Aminophylline 250 mg IV drip administration
|
[
0,
0,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Montelukast 7 mg single injection (IV bolus administration) over 2-3 minutes intervention 2: Montelukast 14 mg single injection (IV bolus administration) over 5 minutes intervention 3: Aminophylline 250 mg IV drip infusion over 60 minutes
|
intervention 1: montelukast sodium intervention 2: montelukast sodium intervention 3: aminophylline hydrate
| 0
| null | 0
|
NCT00442338
|
|
[
2
] | 23
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
Eligible male and female subjects with renal impairment (aged 18-78 years) and healthy control subjects (aged 35 to 78 years) will be enrolled in the study. Subjects with renal impairment will be enrolled and entered into three groups based on their renal function: Mild Impairment, Moderate Impairment, and Severe Impairment(not requiring dialysis). Control subjects will have normal renal function.
The screening visits will occur within 14 days prior to plerixafor administration on study day one. Subjects will be monitored for 10 hours following administration of the study drug. In addition, subjects will return to the clinic at 24 and 48 hours after plerixafor administration for blood samples and safety assessments.
|
This is a phase I, open label, multi-center study in which up to eighteen subjects with renal impairment and six healthy control subjects with normal renal function will receive a single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection.
Eligible male and female subjects with renal impairment (aged 18-78 years) and healthy control subjects (aged in the upper age range of the renal impairment subjects) will be enrolled in the study. Subjects with renal impairment will be enrolled and stratified into three cohorts using their Screening 24 hour urine collection to measured creatinine clearance (CLcr) values (an estimate of Glomerular Filtration Rate): Mild Impairment (CLcr = 51-80 ml/min), Moderate Impairment (CLcr = 31-50 ml/min), and Severe Impairment (CLcr \<31 ml/min, not requiring dialysis). Control subjects will have normal renal function (CLcr \>90 ml/min), as determined by a Screening 24 hour urine collection.
The screening visits will occur within 14 days prior to plerixafor administration on study day one. Subjects will be monitored for 10 hours following administration of the study drug. In addition, subjects will return to the clinic at 24 and 48 hours after plerixafor administration for blood samples and safety assessments.
This study was previously posted by AnorMED, Inc. In November 2006, AnorMED, Inc. was acquired by Genzyme Corporation. Genzyme Corporation is the sponsor of the trial.
|
Renal Impairment
|
AMD3100
| null | 4
|
arm 1: Participants with normal renal function (creatinine clearance (CLcr) \> 90 ml/min) who serve as the study control. Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. arm 2: Participants have mild renal impairment (creatinine clearance (CLcr) = 51 to 80 mL/min). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. arm 3: Participants have moderate renal impairment (creatinine clearance (CLcr) = 31 to 50 mL/min). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. arm 4: Participants have severe renal impairment (creatinine clearance (CLcr) \< 31 mL/min, not requiring dialysis). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection.
|
[
1,
0,
0,
0
] | 1
|
[
0
] |
intervention 1: Single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection
|
intervention 1: plerixafor
| 3
|
Santa Ana | California | United States | -117.86783 | 33.74557
Saint Paul | Minnesota | United States | -93.09327 | 44.94441
Omaha | Nebraska | United States | -95.94043 | 41.25626
| 0
|
NCT00445302
|
[
3
] | 21
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 2MALE
| false
|
Idebenone is a synthetic analogue of coenzyme Q10 and is a powerful antioxidant and essential constituent of the process of energy production on the cellular level. It can protect mitochondria from oxidative damage and boost their impaired function. It is thought that this mechanism will slow decline in heart function that is part of the disease process of Duchenne Muscular Dystrophy (DMD). It is possible that patients may benefit in terms of muscle strength and respiratory function. This pilot trial is designed to investigate this.
| null |
Duchenne Muscular Dystrophy (DMD)
|
Duchenne Muscular Dystrophy DMD Duchenne
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: idebenone 450 mg/day (150 mg three times a day) intervention 2: None
|
intervention 1: idebenone intervention 2: placebo
| 1
|
Leuven | N/A | Belgium | 4.70093 | 50.87959
| 0
|
NCT00654784
|
[
4
] | 120
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 2MALE
| false
|
Efficacy and safety of a triptorelin 6-month formulation in patients with advanced prostate cancer. It was assumed that during the study treatment \>90% of the patients would achieve and maintain castrate levels of serum testosterone.
|
Efficacy of triptorelin treatment on gonadotropin (LH) stimulation from hypophysis, as well as on the PSA (prostate specific antigen) levels and safety laboratory parameters. The triptorelin pharmacokinetics and testosterone pharmacodynamics were assessed in a subset of 15 patients.
|
Prostatic Neoplasm
|
triptorelin, 6-month formulation, advanced prostate cancer
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: Triptorelin embonate 22.5 mg 6 month formulation to be injected every 24 weeks
|
intervention 1: triptorelin embonate (INN)
| 1
|
Lyttelton Manor | Centurion | South Africa | N/A | N/A
| 0
|
NCT00751790
|
[
2
] | 18
|
RANDOMIZED
|
CROSSOVER
| 7BASIC_SCIENCE
| 0NONE
| true
| 0ALL
| false
|
This is an open label randomized single dose two-way crossover study to compare the bioavailability of a single oral dose of quinine sulfate 648 mg(2 x 324 mg) when mixed with 120 ml of chocolate pudding relative to the same dose given as two intact capsules.
|
Prior studies have shown that intact quinine sulfate capsules can be taken without regard for food. This is an open label randomized single dose two-way crossover study to compare the bioavailability of a single oral dose of quinine sulfate 648mg(2 x 324 mg capsules) when opened and mixed with 120 ml of chocolate pudding relative to the same dose given as two intact capsules. Eighteen healthy adult subjects will be enrolled. Following a fast of at least 10 hours subjects will be randomized to receive either 648 mg of quinine sulfate as the intact capsules or opened mixed in 120ml of chocolate pudding. Following a washout period of at least 7 days all subjects will be given the alternate dose under similar conditions. Following each dose, blood samples will be collected at times sufficient to determine the difference in bioavailability (if any) between the two methods of drug administration. In addition patients will be monitored for any adverse events including Electrocardiogram (EKG) changes (at baseline and 4 hours after each dose).
|
Healthy
|
Healthy Bioequivalence Pharmacokinetics
| null | 2
|
arm 1: Single dose intact capsules 2 x 324 mg arm 2: Single dose contents of two capsules (2 x 324 mg) opened and mixed in 120 mL of chocolate pudding
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: 2 x 324 mg capsules (648 mg) intervention 2: 2 x 324 mg capsules (648 mg)
|
intervention 1: quinine sulfate intervention 2: quinine sulfate
| 1
|
Saint Laurent, Montreal | Quebec | Canada | N/A | N/A
| 0
|
NCT00806078
|
[
2
] | 220
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| true
| 0ALL
| null |
This study will evaluate:
1. the bioequivalence of simvastatin and simvastatin acid following dose of simvastatin (ZOCOR™) given together with one tablet of MK0524A or as a component of the triple combination tablet MK0524B.
2. the bioequivalence of laropiprant and ER niacin when administered as the triple combination tablet MK0524B or as the double combination tablet MK0524A given together with simvastatin.
| null |
Dyslipidemia
| null | 2
|
arm 1: Period 1: 1 tablet of MK0524B (ER niacin 900 mg/ laropiprant 20 mg/ simvastatin 20 mg).
Period 2: 1 tablet of simvastatin 20 mg (Zocor™) and 1 tablet of MK0524A (ER niacin 1000 mg/ laropiprant 20 mg) as separate tablets. arm 2: Period 1: 1 tablet of simvastatin 20 mg (Zocor™) and 1 tablet of MK0524A (ER niacin 1000 mg/ laropiprant 20 mg) as separate tablets.
Period 2: 1 tablet of MK0524B (ER niacin 900 mg/ laropiprant 20 mg/ simvastatin 20 mg).
|
[
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: Single dose of MK0524B (ER niacin 900 mg/ laropiprant 20 mg/ simvastatin 20 mg) in one of two treatment periods. intervention 2: Single dose of MK0524A (ER niacin 1000 mg/ laropiprant 20 mg) in one of two treatment periods. intervention 3: Single dose simvastatin (Zocor™) 20 mg in one of two treatment periods.
|
intervention 1: MK0524B (ER niacin (+) laropiprant (+) simvastatin) intervention 2: MK0524A (ER niacin + laropiprant) intervention 3: Simvastatin
| 0
| null | 0
|
NCT00943124
|
|
[
4
] | 81
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This study evaluated the safety and efficacy of peginterferon alfa-2a monotherapy in participants with Chronic Hepatitis C (CHC) who have End-Stage Renal Disease (ESRD) and were undergoing hemodialysis.
| null |
Hepatitis C, Chronic
| null | 2
|
arm 1: Chronic Hepatitis C participants with end-stage renal disease undergoing hemodialysis will receive Peginterferon alfa-2a 135 mcg subcutaneously (SC) once weekly up to Week 48. arm 2: Chronic Hepatitis C participants with end-stage renal disease undergoing hemodialysis will receive Peginterferon alfa-2a 90 mcg SC once weekly up to Week 48.
|
[
0,
0
] | 1
|
[
0
] |
intervention 1: Chronic Hepatitis C participants with end-stage renal disease undergoing hemodialysis will receive Peginterferon alfa-2a either 135 or 90 mcg SC once weekly up to Week 48.
|
intervention 1: Peginterferon alfa-2a
| 22
|
Graz | N/A | Austria | 15.45 | 47.06667
Vienna | N/A | Austria | 16.37208 | 48.20849
Brasília | N/A | Brazil | -47.92972 | -15.77972
Porto Alegre | N/A | Brazil | -51.23019 | -30.03283
Sao Jose Rio Preto | N/A | Brazil | N/A | N/A
São Luís | N/A | Brazil | -44.30278 | -2.52972
São Paulo | N/A | Brazil | -46.63611 | -23.5475
Créteil | N/A | France | 2.46569 | 48.79266
Le Kremlin-Bicêtre | N/A | France | 2.36073 | 48.81471
Marseille | N/A | France | 5.38107 | 43.29695
Paris | N/A | France | 2.3488 | 48.85341
Strasbourg | N/A | France | 7.74553 | 48.58392
Toulouse | N/A | France | 1.44367 | 43.60426
Athens | N/A | Greece | 23.72784 | 37.98376
Nikaia | N/A | Greece | 23.65 | 37.96667
Medan | N/A | Indonesia | 98.66667 | 3.58333
Cagliari | N/A | Italy | 9.11917 | 39.23054
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
Izmir | N/A | Turkey (Türkiye) | 27.13838 | 38.41273
Abu Dhabi | N/A | United Arab Emirates | 54.39696 | 24.45118
| 0
|
NCT02806505
|
|
[
4
] | 288
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
The objective of the study was to assess the maintenance effect on scalp psoriasis of Clobex® Shampoo 0.05% when used twice weekly.
|
Psoriasis was a chronic disease that was affecting skin, the scalp and joints. Scalp psoriasis was very common and was having an important impact on people's life.
Primary objective of scalp psoriasis treatments was to gain initial and rapid control of the disease process with a minimum of side-effects and improve patient quality of life.
Still, one of the unmet needs of scalp psoriasis therapies was the maintenance of a long-term remission. For corticosteroids in particular, one of the drawbacks was the disease recurrences after cessation of the treatment.
Therefore, the establishment of a modified corticosteroid dosing regimen that would allow remission with minimal side-effects was suitable.
The purpose of this study was to assess how long a patient successfully maintained in a good condition after use of Clobex® shampoo only twice a week.
|
Scalp Psoriasis
|
maintenance scalp psoriasis Galderma
| null | 3
|
arm 1: In initial open-label phase, participants were applied Clobex® shampoo (Clobetasol Propionate) 0.05 percent (%) weight by weight (W/W) topically to the scalp once daily (twice a week) for 4 weeks (weekly dose was not more than 50 grams \[50 Milliliter\]). arm 2: In maintenance double-blind phase, participants presented with a good efficacy (Global severity score \[GSS\] less than or equal to \[\<=\] 2) in initial phase were randomized to apply Clobetasol Propionate shampoo 0.05 % weight by weight (W/W) twice weekly up to 6 months (wherein weekly dose were not exceeded beyond 50 grams \[50 milliliter\]). In case of relapse (that is \[i.e.\], GSS greater than \[\>\] 2) participants were re-entered to 4-week daily treatment with Clobetasol Propionate shampoo 0.05%. After this 4-week period of daily treatment, if GSS \<= 2, participants were re-entering the maintenance regimen (twice a week). arm 3: In maintenance double-blind phase, participants presented with a good efficacy (Global severity score \[GSS\] \<= 2) in initial phase were randomized to apply Clobex® vehicle shampoo twice weekly up to 6 months (wherein weekly dose was not more than 50 grams \[50 milliliter\]). In case of relapse (i.e., GSS \[greater than\] \> 2) participants were re-entered to 4-week daily treatment with Clobetasol Propionate Shampoo 0.05 % (W/W). After this 4-week period of daily treatment, if GSS \<= 2, participants were re-entering the maintenance regimen (twice a week).
|
[
0,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: Clobex® Shampoo 0.05 % (W/W) topically to scalp for 4 weeks. intervention 2: Clobex® Vehicle Shampoo 0.05 % (W/W) topically to scalp up to 6 months. intervention 3: Clobex® Shampoo 0.05% (W/W) topically to scalp up to 6 months.
|
intervention 1: Clobex® Shampoo intervention 2: Clobex® Vehicle Shampoo intervention 3: Clobex® Shampoo
| 1
|
Québec | N/A | Canada | -71.21454 | 46.81228
| 0
|
NCT00400725
|
[
4
] | 26
|
RANDOMIZED
|
CROSSOVER
| 1PREVENTION
| 2DOUBLE
| false
| 0ALL
| true
|
The study objective was to determine the safety and efficacy of C1INH-nf for the prevention of acute HAE attacks.
|
Subjects were given diary cards and instructed to document all HAE attacks on a daily basis. Subjects evaluated their symptoms over the previous 24 hours, noting the severity and duration of swelling at each of 5 locations (abdominal, genitourinary, facial, respiratory \[including laryngeal\], and/or extremity).
The study design also allowed for administration of open-label C1INH-nf (1,000 U of C1INH-nf administered IV \[repeated after 60 minutes, if necessary\] for treatment of laryngeal angioedema or if deemed necessary by the investigator; 1,000 U of C1INH-nf administered IV \[single dose\] prior to emergency surgical procedures).
A total of 26 subjects were enrolled in the study. One subject received open-label C1INH-nf but withdrew prior to randomization. Another subject was randomized but withdrew prior to receiving study drug. Twenty-four (24) subjects were randomized and treated with blinded study drug. In total, 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 subjects were exposed to C1INH-nf and 23 subjects were exposed to placebo.
|
Hereditary Angioedema
|
Hereditary angioedema HAE C1 esterase inhibitor (human) C1INH-nf
| null | 2
|
arm 1: 1,000 Units (U) of C1INH-nf administered intravenously (IV) every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks. arm 2: Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks.
|
[
0,
0
] | 2
|
[
2,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: C1 esterase inhibitor [human] (C1INH-nf) intervention 2: Placebo (saline)
| 16
|
Scottsdale | Arizona | United States | -111.89903 | 33.50921
San Diego | California | United States | -117.16472 | 32.71571
Walnut Creek | California | United States | -122.06496 | 37.90631
Suwanee | Georgia | United States | -84.0713 | 34.05149
Honolulu | Hawaii | United States | -157.85833 | 21.30694
Evansville | Indiana | United States | -87.55585 | 37.97476
Lake Charles | Louisiana | United States | -93.2044 | 30.21309
Wheaton | Maryland | United States | -77.05526 | 39.03983
Libby | Montana | United States | -115.556 | 48.38829
New York | New York | United States | -74.00597 | 40.71427
Columbus | Ohio | United States | -82.99879 | 39.96118
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Lake Oswego | Oregon | United States | -122.67065 | 45.42067
Dallas | Texas | United States | -96.80667 | 32.78306
Woodville | Texas | United States | -94.41548 | 30.7752
Parkersburg | West Virginia | United States | -81.56151 | 39.26674
| 0
|
NCT01005888
|
[
3
] | 336
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
IBIS-2 is a study using SB-480848 versus placebo in subjects with angiographically documented coronary heart disease. Endpoints include coronary imaging, endothelial function, biomarkers, safety and tolerability.
|
Integrated Biomarker and Imaging Study -2 (IBIS-2): An International, Multicenter, Randomized, Placebo-controlled, Parallel-group, 1 Year Treatment, Integrated Biomarkers and Imaging Study in Subjects with Angiographically Documented Coronary Heart Disease (CHD) to Examine the Effects of the Novel Lipoprotein-associated Phospholipase A2 (Lp-PLA2) inhibitor SB-480848 on Intermediate Cardiovascular Endpoints, Patient Safety and Tolerability.
|
Atherosclerosis
|
Coronary artery disease Lipoprotein-associated Phospholipase A2 palpography hs-CRP endothelial function intravascular ultrasound
| null | 4
|
arm 1: Enrolled subjects (subjects with ACS and evidence of myocardial necrosis) will receive 160mg of SB-480848 once daily with food for 52 weeks arm 2: Enrolled subjects (subjects with ACS and evidence of myocardial necrosis) will receive SB-480848 matching placebo once daily with food for 52 weeks arm 3: Enrolled subjects (non-ACS subjects and those ACS subjects without evidence of myocardial necrosis) will receive 160mg of SB-480848 once daily with food for 52 weeks arm 4: Enrolled subjects (non-ACS subjects and those ACS subjects without evidence of myocardial necrosis) will receive SB-480848 matching placebo once daily with food for 52 weeks
|
[
0,
2,
0,
2
] | 2
|
[
0,
0
] |
intervention 1: SB-480848 is available as enteric-coated, free-base micronized tablet intervention 2: Placebo is available as enteric-coated, free-base micronized tablet
|
intervention 1: SB-480848 intervention 2: SB-480848 matching placebo
| 26
|
Vienna | N/A | Austria | 16.37208 | 48.20849
Aalst | N/A | Belgium | 4.0355 | 50.93604
Antwerp | N/A | Belgium | 4.40026 | 51.22047
Liège | N/A | Belgium | 5.56749 | 50.63373
Prague | N/A | Czechia | 14.42076 | 50.08804
Aarhus N | N/A | Denmark | 10.17317 | 56.20367
Besançon | N/A | France | 6.01815 | 47.24878
Brest | N/A | France | -4.48628 | 48.39029
Heidelberg | Baden-Wurttemberg | Germany | 8.69079 | 49.40768
Ulm | Baden-Wurttemberg | Germany | 9.99155 | 48.39841
Munich | Bavaria | Germany | 11.57549 | 48.13743
Bad Nauheim | Hesse | Germany | 8.73859 | 50.36463
Essen | North Rhine-Westphalia | Germany | 7.01228 | 51.45657
Bad Segeberg | Schleswig-Holstein | Germany | 10.30745 | 53.93775
Hamburg | N/A | Germany | 9.99302 | 53.55073
Eindhoven | N/A | Netherlands | 5.47778 | 51.44083
Enschede | N/A | Netherlands | 6.89583 | 52.21833
Leeuwarden | N/A | Netherlands | 5.80859 | 53.20139
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Bergen | N/A | Norway | 5.32415 | 60.39299
Katowice | N/A | Poland | 19.02754 | 50.25841
Krakow | N/A | Poland | 19.93658 | 50.06143
Marid | N/A | Spain | N/A | N/A
Santander | N/A | Spain | -3.80444 | 43.46472
Lucerne | N/A | Switzerland | 8.30635 | 47.05048
| 0
|
NCT00268996
|
[
3
] | 399
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The purpose of this study is to compare the efficacy and safety of a weekly regimen of two FDA approved drugs in combination versus one FDA approved drug in subjects with advanced non-small cell lung cancer who have received one previous chemotherapy excluding TAXOTERE or HYCAMTIN.
| null |
Lung Cancer, Non-Small Cell Non-Small-Cell Lung Cancer
|
HYCAMTIN TAXOTERE non-small cell lung cancer NSCLC docetaxel topotecan Stage IIIB/IV Advanced
| null | 0
| null | null | 2
|
[
0,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: Topotecan/Docetaxel combination intervention 2: Docetaxel
| 85
|
Huntsville | Alabama | United States | -86.58594 | 34.7304
Mobile | Alabama | United States | -88.04305 | 30.69436
Tucson | Arizona | United States | -110.92648 | 32.22174
Little Rock | Arkansas | United States | -92.28959 | 34.74648
Fresno | California | United States | -119.77237 | 36.74773
Los Angeles | California | United States | -118.24368 | 34.05223
Poway | California | United States | -117.03586 | 32.96282
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
Boca Raton | Florida | United States | -80.0831 | 26.35869
Boca Raton | Florida | United States | -80.0831 | 26.35869
Lakeland | Florida | United States | -81.9498 | 28.03947
Miami Shores | Florida | United States | -80.19283 | 25.86315
Orange Park | Florida | United States | -81.70648 | 30.16607
Orlando | Florida | United States | -81.37924 | 28.53834
Stuart | Florida | United States | -80.25283 | 27.19755
Columbus | Georgia | United States | -84.98771 | 32.46098
Decatur | Illinois | United States | -88.9548 | 39.84031
Elk Grove Village | Illinois | United States | -87.97035 | 42.00392
Skokie | Illinois | United States | -87.73339 | 42.03336
Urbana | Illinois | United States | -88.20727 | 40.11059
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Bowling Green | Kentucky | United States | -86.4436 | 36.99032
Louisville | Kentucky | United States | -85.75941 | 38.25424
Louisville | Kentucky | United States | -85.75941 | 38.25424
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
Lafayette | Louisiana | United States | -92.01984 | 30.22409
Lake Charles | Louisiana | United States | -93.2044 | 30.21309
Frederick | Maryland | United States | -77.41054 | 39.41427
Boston | Massachusetts | United States | -71.05977 | 42.35843
Grosse Pointe Woods | Michigan | United States | -82.90686 | 42.44365
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Robbinsdale | Minnesota | United States | -93.33856 | 45.03219
Springfield | Missouri | United States | -93.29824 | 37.21533
St Louis | Missouri | United States | -90.19789 | 38.62727
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Reno | Nevada | United States | -119.8138 | 39.52963
Hackensack | New Jersey | United States | -74.04347 | 40.88593
Buffalo | New York | United States | -78.87837 | 42.88645
East Syracuse | New York | United States | -76.07853 | 43.06534
Manhasset | New York | United States | -73.69957 | 40.79788
New Hyde Park | New York | United States | -73.68791 | 40.7351
Nyack | New York | United States | -73.91791 | 41.09065
Rochester | New York | United States | -77.61556 | 43.15478
The Bronx | New York | United States | -73.86641 | 40.84985
Fayetteville | North Carolina | United States | -78.87836 | 35.05266
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Canton | Ohio | United States | -81.37845 | 40.79895
Dunmore | Pennsylvania | United States | -75.63241 | 41.4198
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Columbia | South Carolina | United States | -81.03481 | 34.00071
Hilton Head Island | South Carolina | United States | -80.73816 | 32.19382
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Nashville | Tennessee | United States | -86.78444 | 36.16589
Irving | Texas | United States | -96.94889 | 32.81402
Tyler | Texas | United States | -95.30106 | 32.35126
Abingdon | Virginia | United States | -81.97735 | 36.70983
Norfolk | Virginia | United States | -76.28522 | 36.84681
Norfolk | Virginia | United States | -76.28522 | 36.84681
Spokane | Washington | United States | -117.42908 | 47.65966
Tacoma | Washington | United States | -122.44429 | 47.25288
Milwaukee | Wisconsin | United States | -87.90647 | 43.0389
Sheboygan | Wisconsin | United States | -87.71453 | 43.75083
Casper | Wyoming | United States | -106.31308 | 42.86663
Calgary | Alberta | Canada | -114.08529 | 51.05011
Moncton | New Brunswick | Canada | -64.7965 | 46.09454
Kingston | Ontario | Canada | -76.48098 | 44.22976
Kitchener | Ontario | Canada | -80.5112 | 43.42537
London | Ontario | Canada | -81.23304 | 42.98339
Ottawa | Ontario | Canada | -75.69812 | 45.41117
St. Catharines | Ontario | Canada | -79.24267 | 43.17126
Toronto | Ontario | Canada | -79.39864 | 43.70643
Toronto | Ontario | Canada | -79.39864 | 43.70643
Weston | Ontario | Canada | -79.51513 | 43.70359
Greenfield Park | Quebec | Canada | -73.46223 | 45.48649
Lévis | Quebec | Canada | -71.17793 | 46.80326
Sainte-Foy | Quebec | Canada | -71.29217 | 46.78139
Kielce | N/A | Poland | 20.62752 | 50.87033
Krakow | N/A | Poland | 19.93658 | 50.06143
Olsztyn | N/A | Poland | 20.49416 | 53.77995
Poznan | N/A | Poland | 16.92993 | 52.40692
Szczecin Zdunowo 20 | N/A | Poland | N/A | N/A
| 0
|
NCT00065182
|
[
4
] | 2,333
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The objective of this study is to determine the effectiveness of PEG-Intron 1.5 ug/kg/wk plus REBETOL (ribavirin) 800-1400 mg/day in adults with chronic hepatitis C with moderate to severe liver fibrosis or cirrhosis who failed to respond to previous treatment with an alpha interferon in combination with ribavirin. Patients who do not respond to PEG-Intron plus REBETOL (ribavirin) will be enrolled in a long-term maintenance study to evaluate the effectiveness of PEG-Intron monotherapy versus no treatment for the prevention of disease progression (Protocols P02569 and P02570).
| null |
Hepatitis Hepatitis C, Chronic Fibrosis Liver Cirrhosis
| null | 1
|
arm 1: None
|
[
0
] | 2
|
[
2,
0
] |
intervention 1: PegIntron (peginterferon alfa-2b) administered at a dose of 1.5 mcg/kg subcutaneously (SC) once a week (QW) for up to 48 weeks intervention 2: REBETOL (ribavirin) administered on a weight basis: 800-1400 mg/day orally (PO) for up to 48 weeks
|
intervention 1: PegIntron (peginterferon alfa-2b; SCH 54031) intervention 2: REBETOL (ribavirin; SCH 18908)
| 0
| null | 1
|
NCT00039871
|
|
[
5
] | 569
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
This single arm study will evaluate the efficacy and safety of PEGASYS (180 micrograms sc weekly) plus ribavirin (1000-1200mg po daily) in treatment-naive Latino patients versus non-Latino Caucasian patients with chronic hepatitis C- genotype 1. The anticipated time on study treatment is 3-12 months and the target sample size is 500+ patients.
| null |
Hepatitis C, Chronic
| null | 2
|
arm 1: Participants received peginterferon alfa-2a 180 microgram (mcg)/0.5 mL by subcutaneous injection once a week in combination with ribavirin 1000 or 1200 mg per day, which was taken orally in split doses for 48 weeks. Participants with \<75 kg (165 lbs) of body weight received 1000 mg/day (400 mg in the morning and 600 mg in the evening). Participants with \>=75 kg (165 lbs) of body weight received 1200 mg/day (600 mg in the morning and 600 mg in the evening). arm 2: Participants received peginterferon alfa-2a 180 mcg/0.5 mL by subcutaneous injection once a week in combination with ribavirin 1000 or 1200 mg per day which was taken orally in split doses. Participants with \<75 kg (165 lbs) of body weight received 1000 mg/day. Participants with \>=75 kg (165 lbs) of body weight received 1200 mg/day for 48 weeks.
|
[
0,
0
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: 1000-1200mg po daily for 48 weeks intervention 2: 180 micrograms sc/week for 48 weeks intervention 3: 1000-1200mg po daily for 48 weeks intervention 4: 180 micrograms sc/week for 48 weeks
|
intervention 1: Ribavirin intervention 2: Peginterferon alfa-2a intervention 3: Ribavirin intervention 4: Peginterferon alfa-2a
| 60
|
Scottsdale | Arizona | United States | -111.89903 | 33.50921
Tucson | Arizona | United States | -110.92648 | 32.22174
Anaheim | California | United States | -117.9145 | 33.83529
Fountain Valley | California | United States | -117.95367 | 33.70918
Fresno | California | United States | -119.77237 | 36.74773
Lancaster | California | United States | -118.13674 | 34.69804
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
Redlands | California | United States | -117.18254 | 34.05557
Sacramento | California | United States | -121.4944 | 38.58157
San Bernardino | California | United States | -117.28977 | 34.10834
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Francisco | California | United States | -122.41942 | 37.77493
San Luis Obispo | California | United States | -120.65962 | 35.28275
Ventura | California | United States | -119.29317 | 34.27834
Pueblo | Colorado | United States | -104.60914 | 38.25445
Boca Raton | Florida | United States | -80.0831 | 26.35869
Bradenton | Florida | United States | -82.57482 | 27.49893
Miami | Florida | United States | -80.19366 | 25.77427
North Miami Beach | Florida | United States | -80.16255 | 25.93315
Plantation | Florida | United States | -80.23184 | 26.13421
Austell | Georgia | United States | -84.63438 | 33.81261
Chicago | Illinois | United States | -87.65005 | 41.85003
Chicago | Illinois | United States | -87.65005 | 41.85003
Gurnee | Illinois | United States | -87.90202 | 42.3703
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
New Orleans | Louisiana | United States | -90.07507 | 29.95465
Baltimore | Maryland | United States | -76.61219 | 39.29038
Framingham | Massachusetts | United States | -71.41617 | 42.27926
Worcester | Massachusetts | United States | -71.80229 | 42.26259
St Louis | Missouri | United States | -90.19789 | 38.62727
Vineland | New Jersey | United States | -75.02573 | 39.48623
Bayside | New York | United States | -73.77708 | 40.76844
New York | New York | United States | -74.00597 | 40.71427
Rochester | New York | United States | -77.61556 | 43.15478
Chapel Hill | North Carolina | United States | -79.05584 | 35.9132
Fayetteville | North Carolina | United States | -78.87836 | 35.05266
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
Fort Sam Houston | Texas | United States | -98.4417 | 29.45303
Fort Worth | Texas | United States | -97.32085 | 32.72541
Galveston | Texas | United States | -94.7977 | 29.30135
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Fairfax | Virginia | United States | -77.30637 | 38.84622
Seattle | Washington | United States | -122.33207 | 47.60621
Tacoma | Washington | United States | -122.44429 | 47.25288
Ponce | N/A | Puerto Rico | -66.62398 | 18.01031
Santurce | N/A | Puerto Rico | -67.14018 | 18.19523
| 1
|
NCT00107653
|
|
[
4
] | 331
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 1FEMALE
| false
|
This study will be investigating the efficacy and safety administration of multiple doses of intravenous (IV) acetaminophen (IVAPAP) in the 48 hour period following Gynecologic Surgery.
|
The research hypothesis is that IV Acetaminophen will provide greater reduction in pain intensity and greater pain relief for moderate and severe pain as compared to placebo in the 48 hours following surgery.
|
Postoperative Pain Hysterectomy
|
Pain Gynecologic IV Acetaminophen Postoperative Analgesic
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Intravenous acetaminophen 1 g/100 mL intervention 2: IV Placebo 100 mL solution dosed at same frequency as IV Acetaminophen every 6 hours (q6h)
|
intervention 1: IV Acetaminophen intervention 2: IV Placebo 100 mL solution
| 27
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Sheffield | Alabama | United States | -87.69864 | 34.76509
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Arcadia | California | United States | -118.03534 | 34.13973
Glendale | California | United States | -118.25508 | 34.14251
Pasadena | California | United States | -118.14452 | 34.14778
San Clemente | California | United States | -117.61199 | 33.42697
Boynton Beach | Florida | United States | -80.06643 | 26.52535
Ft. Pierce | Florida | United States | -80.32561 | 27.44671
Holly Hill | Florida | United States | -81.03756 | 29.24359
Inverness | Florida | United States | -82.33037 | 28.83582
Miami | Florida | United States | -80.19366 | 25.77427
Vero Beach | Florida | United States | -80.39727 | 27.63864
Royal Oak | Michigan | United States | -83.14465 | 42.48948
Camden | New Jersey | United States | -75.11962 | 39.92595
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Albany | New York | United States | -73.75623 | 42.65258
New York | New York | United States | -74.00597 | 40.71427
Stony Brook | New York | United States | -73.14094 | 40.92565
The Bronx | New York | United States | -73.86641 | 40.84985
Columbus | Ohio | United States | -82.99879 | 39.96118
Altoona | Pennsylvania | United States | -78.39474 | 40.51868
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
| 1
|
NCT00399568
|
[
3
] | 40
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Current therapies for a brain stem glioma provide very limited benefit to the patient. The anti-cancer properties of Antineoplaston therapy suggest that it may prove beneficial in the treatment of brain stem gliomas.
PURPOSE: This study is being performed to determine the effects (good and bad) that Antineoplaston therapy has on children (\> 6 months of age) and adults with newly-diagnosed or recurrent brain stem gliomas.
|
OBJECTIVES:
* To determine the efficacy of Antineoplaston therapy in patients with a brain stem glioma, as measured by an objective response to therapy (complete response, partial response or stable disease).
* To determine the safety and tolerance of Antineoplaston therapy in patients with a brain stem glioma.
OVERVIEW: This is a single arm, open-label study in which patients receive gradually escalating doses of intravenous Antineoplaston therapy (Atengenal + Astugenal) until the maximum tolerated dose is reached. Treatment continues for at least 12 months in the absence of disease progression or unacceptable toxicity. After 12 months, patients with a complete or partial response or with stable disease may continue treatment.
To determine objective response, tumor size in measured utilizing MRI scans, which are performed every 8 weeks for the first 2 years, every 3 months for the 3rd and 4th years, every 6 months for the 5th and 6th years, and annually thereafter.
PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study.
|
Brain Stem Gliomas
|
recurrent adult brain stem glioma untreated adult brain stem glioma untreated childhood brain stem glioma recurrent childhood brain stem glioma
| null | 1
|
arm 1: Antineoplaston therapy (Atengenal + Astugenal) by IV infusion every four hours for at least 12 months. Study subjects receive increasing dosages of Atengenal and Astugenal until the maximum tolerated dosage is reached.
|
[
0
] | 1
|
[
0
] |
intervention 1: Patients with a brain stem glioma will receive Antineoplaston therapy (Atengenal + Astugenal)
|
intervention 1: Antineoplaston therapy (Atengenal + Astugenal)
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00003459
|
[
3
] | 13
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
RATIONALE: Current therapies for adult recurrent/progressive oligodendrogliomas provide very limited benefit to the patient. The anti-cancer properties of Antineoplaston therapy suggest that it may prove beneficial in the treatment of childhood brain tumors.
PURPOSE: This study is being performed to determine the effects (good and bad) that Antineoplaston therapy has on adult recurrent/progressive oligodendrogliomas.
|
OVERVIEW: This is a single arm, open-label study in which adults with recurrent/progressive oligodendrogliomas receive gradually escalating doses of intravenous Antineoplaston therapy (Atengenal + Astugenal) until the maximum tolerated dose is reached. Treatment continues for at least 12 months in the absence of disease progression or unacceptable toxicity.
OBJECTIVES:
* To determine the efficacy of Antineoplaston therapy in adults with recurrent/progressive oligodendrogliomas, as measured by an objective response to therapy (complete response, partial response or stable disease).
* To determine the safety and tolerance of Antineoplaston therapy in adults with recurrent/progressive oligodendrogliomas.
* To determine objective response, tumor size is measured utilizing MRI scans, which are performed every 8 weeks for the first two years, every 3 months for the third and fourth years, every 6 months for the 5th and sixth years, and annually thereafter.
PROJECTED ACCRUAL: A total of 20-40 patients will be accrued to this study.
|
Oligodendroglioma, Adult
|
Recurrent/progressive adult oligodendroglioma Recurrent/progressive adult anaplastic oligodendroglioma
| null | 1
|
arm 1: Antineoplaston therapy (Atengenal + Astugenal) by IV infusion every four hours for at least 12 months. Study subjects receive increasing dosages of Atengenal and Astugenal until the maximum tolerated dose is reached.
|
[
0
] | 1
|
[
0
] |
intervention 1: Adults with a recurrent/progressive Oligodendroglioma will receive Antineoplaston therapy (Atengenal + Astugenal).
|
intervention 1: Antineoplaston therapy (Atengenal + Astugenal)
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00003472
|
[
4
] | 600
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| true
|
The study is designed as a Phase III, randomized, double-blind, multicenter, prospective, comparative study of fluconazole versus voriconazole for the prevention of fungal infections in allogeneic transplant recipients. Recipients will be stratified by center and donor type (sibling vs. unrelated) and will be randomized to either the fluconazole or voriconazole arm in a 1:1 ratio.
|
BACKGROUND:
Allogeneic blood and marrow transplant patients are highly susceptible to invasive fungal infection prior to engraftment, due to neutropenia and mucosal injury. After engraftment, an impairment of cell mediated immunity from graft-versus-host disease (GVHD) and the use of aggressive immunosuppressive therapies, such as corticosteroids, leave patients vulnerable to invasive fungal infections. Recipients of alternate donor transplants are especially susceptible due to slow reconstitution of cell mediated immunity.
Fluconazole prophylaxis in prospective randomized trials of both autologous and allogeneic transplant recipients has been demonstrated to reduce invasive fungal infections due to yeasts prior to engraftment. A prolonged course of fluconazole given during the first 75 days (to cover the early post-engraftment period of risk) is highly effective in the prevention of early and later yeast infections. This has translated into a survival benefit. A recent analysis of long-term outcomes of these individuals demonstrated a continuing benefit beyond the course of prophylaxis with a further benefit in survival. In another study of various factors associated with survival after matched unrelated donor transplants, fluconazole prophylaxis was an independent predictor for overall survival in a multivariate analysis. Fluconazole prophylaxis has been found to be effective and safe with few substantive drug interactions and has been widely adopted by transplant clinicians.
DESIGN NARRATIVE:
This is a randomized, double-blind, multicenter, prospective, comparative study of fluconazole versus voriconazole for the prevention of fungal infections in allogeneic hematopoietic transplant recipients and cord blood recipients in children under the age of 12. Prior to the start of the pre-transplant conditioning regimen, participants will give written informed consent and be screened for eligibility. Participants who meet all entry criteria will be assigned randomly to voriconazole or fluconazole within 72 hours of Day 0. Participants will begin the study drug on Day 0 (after completion of the conditioning regimen). Day 0 is defined as the day infusion of the stem cell product is completed. The study drug will be continued until Day 100 following transplant or until one or more criteria for early withdrawal are met. Continuation of the study drug beyond Day 100 is permitted for participants who meet specific criteria. The development of any fungal infection during prophylaxis will be classified according to the definitions listed in the protocol.
|
Lymphoma Infection Leukemia
|
Myelodysplastic and Myeloproliferative Diseases
|
Prot_SAP_ICF_000.pdf:
BMT CTN 0101
A Randomized Double-blind Trial of Fluconazole vs.
Voriconazole for the Prevention of Invasive Fungal
Infection in Allogeneic Blood and Marrow
Transplant Patients
NCT00075803
A Randomized Double-blind Trial of Fluconazole vs. Voriconazole
for the Prevention of Invasive Fungal Infections in Allogeneic
Blood and Marrow Transplant Patients
BMT CTN PROTOCOL 0101
VERSION 7.0
Study Chairpersons
John Wingard, M.D.1
Thomas Walsh, M.D.2
Protocol Team
Shelly Carter, Sc.D.3
Brent Logan, Ph.D.6
Dennis Confer, M.D.4
Kieren Marr, M.D.7
Iris Gersten, M.S.3
Trudy Small, M.D.8
Joanne Kurtzberg, M.D.5
Sponsored by the National Institutes of Health
National Heart, Lung and Blood Institute
National Cancer Institute
1 University of Florida, Shands Hospital
2 National Cancer Institute
3 The EMMES Corporation
4 National Marrow Donor Program
5 Duke University Medical Center
6 Center for International Blood and
Marrow Transplant Research, Medical
College of Wisconsin
7 Fred Hutchinson Cancer Research Center
8 Memorial Sloan-Kettering Cancer Center
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
CORE STUDY PARTICIPANTS
Case Western Reserve University Consortium
Oregon Health & Science University
St. Louis Children’s Hospital
University Hospitals of Cleveland
Washington University
City of Hope National Medical Center
Dana Farber/Partners Cancer Center
Duke University Medical Center
Fred Hutchinson Cancer Research Center
Johns Hopkins University
Memorial Sloan-Kettering Cancer Center
Pediatric Blood and Marrow Transplant Consortium
Cardinal Glennon Children’s Hospital-St. Louis University
Children’s Mercy Hospital, University of Missouri
Children’s Memorial Hospital, Chicago
Children’s National Medical Center, Washington, DC
Hackensack University Medical Center
Texas Transplant Institute
Stanford Hospital and Clinics
UCSD/SCRIPPS School of Medicine
University of Florida College of Medicine
University of Michigan Medical Center
University of Minnesota
University of Nebraska Medical Center
University of Pennsylvania Hospital
University of Texas, MD Anderson Cancer Research Center
NON-CORE STUDY PARTICIPANTS
H. Lee Moffitt Cancer Center
Indiana University Medical Center
Kansas City Cancer Centers, Central BMT
Karmanos Cancer Institute
Hackensack University Medical Center
Roswell Park Cancer Institute
Texas Transplant Institute
University of Alabama at Birmingham
Virginia Commonwealth University/MCV Hospitals
Wake Forest University Baptist Medical Center
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
i
PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 0101
A Randomized Double-blind Trial of Fluconazole versus Voriconazole for the Prevention
of Invasive Fungal Infections in Allogeneic Blood and Marrow Transplant Recipients
Co-Principal Investigators:
John R. Wingard, M.D., Thomas Walsh, M.D.
Accrual Objective:
Allogeneic blood or marrow transplant recipients and cord blood
recipients in children under the age of 12 will be targeted for accrual.
Per study arm, approximately 300 recipients (a total of 600 recipients)
will be accrued.
Accrual Period:
The estimated accrual period is three years.
Study Design:
The study is designed as a Phase III, randomized, double-blind,
multicenter, prospective, comparative study of fluconazole versus
voriconazole in the prevention of fungal infections in allogeneic
transplant recipients. Recipients will be stratified by center and donor
type (sibling vs. unrelated) and will be randomized to either the
fluconazole or voriconazole arm in a 1:1 ratio.
Primary Objective:
The primary objective is to compare the fungal-free survival rates
between the two study arms through Day 180.
Secondary Objectives:
The secondary objectives will be to compare the frequency of invasive
fungal infection, time to invasive fungal infection, survival rate,
duration of amphotericin B or caspofungin therapy for possible
invasive fungal infection, time to neutrophil and platelet engraftment,
time to and severity of acute and chronic GVHD, and to perform
exploratory analyses of quantitative aspects of the galactomannan
assay. The relative safety of the two antifungals will also be assessed
through the collection of adverse events and routine laboratory
monitoring.
Eligibility Criteria:
Recipients must be diagnosed with leukemia or myelodysplastic
syndrome (MDS). Lymphoma patients with chemosensitive disease
and a related donor are eligible. Recipients must receive a
myeloablative, 5/6 or 6/6 HLA-matched allogeneic blood or marrow
transplant, be two years of age or older, have adequate physical
function and give signed informed consent prior to enrollment.
Treatment Description:
Recipients will begin the study drug on Day 0 (day infusion of stem
cell product is initiated). The development of any fungal infection
during
prophylaxis
will
be
classified
according
to
revised
EORTC/MSG definitions (see Tables 3.1.1a and 3.1.1b). Study drug
will be continued until Day 100 post-transplant or until invasive
infection occurs, or the recipient develops a Grade III or IV toxicity
attributable to the study drug. For recipients of any type of graft
receiving at least 1.0 mg/kg/day of prednisone (or equivalent steroid
dose) on Day 90-100 or for recipients of T cell depleted grafts,
receiving immunoprophylaxis post-transplant or having CD4+ counts
< 200/L on Day 90-100, study drug will be continued until Day 180.
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
ii
Study Duration:
Recipients will be followed for a minimum of one year post-transplant.
Fluconazole
or
voriconazole
will
be
taken
(depending
on
randomization arm) beginning at Day 0 of transplant for at least 100
days (or longer as specified above).
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
iii
TABLE OF CONTENTS
1.
BACKGROUND AND RATIONALE .............................................................................. 1-1
1.1.
Study Background............................................................................................................... 1-1
1.2.
Human Clinical Pharmacokinetics of Voriconazole ............................................................. 1-3
1.3.
Clinical Efficacy of Voriconazole ....................................................................................... 1-5
1.4.
Rationale for Study ............................................................................................................. 1-7
2.
STUDY DESIGN............................................................................................................... 2-1
2.1.
Study Overview .................................................................................................................. 2-1
2.2.
Hypotheses and Specific Objectives .................................................................................... 2-1
2.2.1.
Primary Hypothesis............................................................................................................. 2-1
2.2.2.
Secondary Hypothesis ......................................................................................................... 2-1
2.2.3.
Study Objectives ................................................................................................................. 2-1
2.3.
Patient Eligibility ................................................................................................................ 2-2
2.3.1.
Eligibility Criteria ............................................................................................................... 2-2
2.3.2.
Exclusion Criteria ............................................................................................................... 2-3
2.4.
Treatment Plan .................................................................................................................... 2-4
2.4.1.
Drug Dosages ..................................................................................................................... 2-4
2.4.2.
Administration Procedures .................................................................................................. 2-5
2.4.3.
Dosage and Formulation Adjustments ................................................................................. 2-7
2.4.4.
Study Drug Supply.............................................................................................................. 2-8
2.4.5.
Pharmaceutical Information ................................................................................................ 2-8
2.4.6.
Early (Premature) Withdrawal of Study Drug .................................................................... 2-11
2.4.6.1.
Patient early withdrawal from study treatment ................................................................... 2-11
2.4.6.2.
Breaking the blind ............................................................................................................. 2-13
2.4.7.
Contraindications, Drug Interaction and Monitoring .......................................................... 2-14
2.4.7.1
Voriconazole and fluconazole ........................................................................................... 2-14
2.4.7.2
Voriconazole drug interactions .......................................................................................... 2-15
2.4.8.
Duration of Study Drug ..................................................................................................... 2-16
2.4.9.
Recommendations for Treatment of Documented Fungal Infections .................................. 2-16
2.4.10.
Guidelines for Empirical Antifungal Therapy with Amphotericin B or Caspofungin Usage for
Patients not “Off Study”.................................................................................................... 2-17
2.4.10.1.
Required tests prior to use of empirical antifungal therapy ............................................. 2-17
2.4.10.2.
Pre-engraftment requirements and amphotericin B/caspofungin dose ............................. 2-17
2.4.10.3.
Post-engraftment requirements and amphotericin B/caspofungin dose ............................ 2-17
2.4.10.4.
Continuation of study drug during empirical antifungal therapy ..................................... 2-18
2.4.11.
Other Antifungal Therapy ................................................................................................. 2-18
2.4.12.
Use of the Galactomannan Assay ...................................................................................... 2-18
2.4.13.
Supportive Care ................................................................................................................ 2-19
2.4.13.1.
Prophylaxis against infections ........................................................................................ 2-19
2.4.13.2.
Identification of opportunistic infections ........................................................................ 2-20
2.4.14.
Diagnosis of GVHD .......................................................................................................... 2-21
2.4.14.1.
Acute GVHD................................................................................................................. 2-21
2.4.14.2.
Chronic GVHD ............................................................................................................. 2-21
2.4.15.
Risks and Toxicities .......................................................................................................... 2-21
2.4.16.
Genetic Variation Study Sampling: Single Nucleotide Polymorphisms from Donor ........... 2-22
BMT CLINICAL TRIALS NETWORK
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Version 7.0 dated March 29, 2006
iv
3.
STUDY ENDPOINTS ....................................................................................................... 3-1
3.1.
Primary Endpoint ................................................................................................................ 3-1
3.2.
Secondary Endpoints........................................................................................................... 3-6
3.3.
Safety Monitoring Endpoints............................................................................................... 3-7
4.
PATIENT ENROLLMENT AND EVALUATION ......................................................... 4-1
4.1.
Enrollment and Randomization ........................................................................................... 4-1
4.1.1
Screening and Enrollment Procedures ................................................................................. 4-1
4.1.2
Randomization .................................................................................................................... 4-1
4.2.
Study Monitoring ................................................................................................................ 4-1
4.2.1.
Follow-up Schedule ............................................................................................................ 4-1
4.2.2.
Assessments........................................................................................................................ 4-4
4.2.3.
Fungal Infection (possible, presumptive, probable or proven) .............................................. 4-7
4.2.4.
Discontinuation of Study Drug ............................................................................................ 4-7
4.2.5.
GVHD Monitoring .............................................................................................................. 4-8
4.2.6.
Serious Adverse Event Reporting ........................................................................................ 4-8
5.
STATISTICAL CONSIDERATIONS.............................................................................. 5-1
5.1.
Study Design ...................................................................................................................... 5-1
5.2.
Sample Size and Power Considerations ............................................................................... 5-1
5.3.
Interim Analysis and Stopping Guidelines ........................................................................... 5-2
5.3.1.
Interim Analysis for Efficacy .............................................................................................. 5-2
5.3.2.
Guidelines for Safety Monitoring ........................................................................................ 5-3
5.4.
Demographic and Baseline Characteristics .......................................................................... 5-5
5.5.
Analysis of Secondary Endpoints ........................................................................................ 5-6
5.6.
Safety Analysis ................................................................................................................... 5-8
LIST OF APPENDICIES
APPENDIX A
REFERENCES
APPENDIX B
CONSENT FORMS
APPENDIX C
LABORATORY PROCEDURES
APPENDIX D
GALACTOMANNAN ASSAY
APPENDIX E
HUMAN SUBJECTS
APPENDIX F
VORICONAZOLE AND FLUCONAZOLE DILUTION AND INFUSION
INSTRUCTIONS
APPENDIX G
DOSING TABLES
APPENDIX H
ORDER FORM FOR DOSE ADJUSTMENT OF STUDY DRUG
APPENDIX I
DERIVATION OF THE SPRT FOR UNCENSORED EXPONENTIAL SURVIVAL
TIMES
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
1-1
CHAPTER 1
1.
BACKGROUND AND RATIONALE
1.1. Study Background
Allogeneic blood and marrow transplant patients are highly susceptible to invasive fungal
infection prior to engraftment due to neutropenia and mucosal injury. After engraftment, an
impairment of cell mediated immunity from GVHD and the use of aggressive
immunosuppressive therapies such as corticosteroids [1] leave patients vulnerable to invasive
fungal infections. Recipients of alternate donor transplants are especially susceptible due to slow
reconstitution of cell mediated immunity.
Fluconazole prophylaxis in prospective randomized trials [2, 3] of both autologous and
allogeneic transplant recipients has been demonstrated to reduce invasive fungal infections due
to yeasts prior to engraftment. A prolonged course of fluconazole given during the first 75 days
(to cover the early post-engraftment period of risk) is highly effective in prevention of early and
later yeast infections [4]. This has translated into a survival benefit. A recent analysis of long-
term outcomes of these individuals demonstrated a continuing benefit beyond the course of
prophylaxis with a further benefit in survival [5]. In another study of various factors associated
with survival after matched unrelated donor transplants, fluconazole prophylaxis was an
independent predictor for overall survival in a multivariate analyses [6]. Fluconazole
prophylaxis has been found to not only be effective but safe with few substantive drug
interactions and has been widely adopted by transplant clinicians.
The recently published guidelines for preventing opportunistic infections among hematopoietic
stem cell transplant recipients, a joint effort of the Centers for Disease Control, the Infectious
Disease Society of America, and the American Society for Blood and Marrow Transplantation
[7], noted that “No regimen has been reported to be clearly effective or superior in preventing
aspergillosis, and therefore no recommendation can be made. Further studies are needed to
determine the optimal strategy for aspergillosis prevention.” At a “State of the Science” Meeting
on Hematopoietic Stem Cell Transplantation held April 1, 2000, jointly sponsored by the
American Society for Blood and Marrow Transplantation and the National Institutes of Health,
the Infectious Complications Working Group deemed the highest priority study would be testing
of new antifungals and development of strategies to control invasive mould infections after BMT
[8].
Voriconazole, a triazole with broad-spectrum antifungal activity [9-18 and reviewed in 19], is
available in both oral and intravenous formulations. Although there are more drug interactions
with voriconazole than fluconazole, it is well tolerated in clinical use [13-15, 18, 20, 21]. As
empirical therapy in febrile neutropenic patients, voriconazole proved to be associated with
fewer breakthrough infections than liposomal amphotericin B (AmBisome) with less toxicity in a
prospective randomized comparison [20]. The availability of an oral formulation of
voriconazole makes it appealing for use long-term and its availability as an intravenous
formulation allows its use in patients with oral mucositis, nausea, vomiting or other
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
1-2
gastrointestinal toxicities frequently seen in BMT recipients which might impair compliance
with an oral agent. Accordingly, prolonged use through 100 days, like fluconazole, may be
associated not only with reduced frequency of invasive fungal infection but also with a survival
benefit and prolonged protection even beyond cessation of drug.
Two studies have evaluated another azole, itraconazole, as long-term antifungal prophylaxis after
allogeneic BMT [22, 23]. Itraconazole has similar broad-spectrum antifungal activity including
activity against aspergillus as voriconazole does. However, itraconazole is less reliably and well
absorbed by mouth (20%) and has substantial interpatient varability in contrast to excellent,
reliable absorbance (96%) of voriconazole. Itraconazole can be difficult to tolerate orally, and a
pilot trial including a pharmacokinetic analysis of itraconazole at Stanford was unable to be
completed. Itraconazole also has substantial negative inotropic effects that have proven to be
deleterious in patients who have received anthracyclines or in those receiving concomitant high
dose cyclophosphamide. This cardiotoxicity of itraconazole has resulted in a warning from the
FDA; it is not shared by voriconazole. In one of the two itraconazole trials by Winston et al.
[22], a reduction in invasive fungal infections was noted (in comparison to fluconazole), but
there were inadequate numbers of aspergillus cases to determine how effective it is as
prophylaxis against aspergillosis. Of concern was an excess of deaths in the itraconazole group
(21 of 71 versus 12 of 67) and an increase in adverse events leading to discontinuation of drug in
the itraconazole group (6 versus 1). The second randomized trial comparing itraconazole and
fluconazole by Marr et al. [23] used a higher dose of itraconazole to ensure therapeutic blood
concentrations. The trial was stopped prematurely after nearly 300 patients were enrolled
(substantially more enrollees than in the Winston study) due to excessive toxicity in the
itraconazole arm. A significant excess of renal and hepatic toxicity was noted in the patients in
the itraconazole arm. The smaller sample size of the Winston study may have missed important
toxicities of itraconazole due to too few patients. Thirty-six percent of patients on itraconazole
stopped the drug due to toxicity. There was no reduction in the frequency of fungal infections in
the itraconazole arm in the Marr trial, although among those who were able to tolerate it in a
posthoc subset analysis, there were fewer infections in patients who could take itraconazole.
Taking both itraconazole HCT trials together, there currently is insufficient data to state
definitively that itraconazole is safe and effective in the allogeneic BMT setting for longterm
prophylaxis.
The risk of invasive aspergillosis after allogeneic BMT ranges between 7% and 24% in various
series [4, 24-32]. In the center with the lowest rate, 7% (seen in patients transplanted between
1990-1992) [4, 5], a larger analysis over time indicated an increase from 5.7 to 11.2% spanning
the earlier report and more recently [31]. A still more recent survey of aspergillosis at that center
found an infection rate of 12% [56]. Most centers find rates of invasive aspergillosis in the range
of 11-15%. Several of the series included both low-risk patients (autologous transplant
recipients) along with high-risk patients (allogeneic transplant recipients). By excluding low-risk
transplant recipients (autologous BMT recipients), including other fungal pathogens in addition
to aspergillus (those organisms not controlled by fluconazole), adding cases of probable
aspergillosis and incorporating the galactomannan assay into the diagnostic criteria, we estimate
the rate of invasive fungal infection in patients receiving fluconazole to be at least 15% and are
using that as the estimate in this trial.
BMT CLINICAL TRIALS NETWORK
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Version 7.0 dated March 29, 2006
1-3
Because of poor sensitivity and specificity of clinical criteria and difficulty in performing
invasive diagnostic procedures in this patient population, more accurate and less invasive
diagnostic assays have been sought. Recently, the double-sandwich ELISA assay for
galactomannan has been found to be highly sensitive and specific [33-35]; it performs well in the
BMT recipient patient population [29, 33]. Maertens et al identified 12 episodes of proven
invasive aspergillosis in 99 consecutive allogeneic stem cell transplant recipients plus 3 episodes
of probable invasive aspergillosis. Using a sandwich ELISA technique, serum samples were
assayed for the presence of galactomannan twice weekly. Two or more consecutive sera tested
positive in all episodes documented by clinical and microbiologic criteria. Galactomannan was
detected prior to any clinical signs of invasive aspergillosis in 5 of the 12 patients and preceded
fever or other symptoms in 9 of the 12. In 93% of culture positive episodes, galactomannan was
detected before isolation of aspergillosis. Galactomannan was detected prior to the presence of
radiographic abnormalities in 91%. Using classical criteria for initiation of empirical antifungal
therapy, the assay was positive a median of 6 days prior to standard criteria for empirical therapy
in 87% of cases. Autopsies of patients suspected of having invasive fungal infection but with
negative galactomannan assays demonstrated no histologic evidence of invasive aspergillus. In a
retrospective survey using banked serum from patients found to have proven invasive
aspergillosis when compared with controls, Marr showed that the galactomannan assay has a
high degree of sensitivity and specificity [29]. As with the Maertens study, Marr found the
presence of galactomannan in the serum prior to the diagnosis in two-thirds of patients using
classical diagnostic criteria.
Incorporation of the galactomannan assay along with the classical criteria will improve accuracy
and may increase the number of cases documented (by upgrading possible cases not proven by
classical criteria to proven or probable cases with the galactomannan assay) in the context of a
clinical trial. The assays will be performed at a certified contract laboratory or a certified
hospital laboratory associated with the transplant center (see Appendix C). The data will be
analyzed in grading aspergillosis cases as either possible, presumptive, probable or proven in
accordance with revised EORTC/MSG consensus case definitions (see Section 3.1).
1.2. Human Clinical Pharmacokinetics of Voriconazole
Voriconazole has been administered to over 3000 healthy volunteers or patients with fungal
infections in single or multiple dosing regimens, by oral and intravenous routes.
In order to improve its solubility, voriconazole is formulated with sulphobutylether-cyclodextrin
(SBECD) for intravenous administration. Volunteer studies show that the cyclodextrin is
completely renally cleared at a rate consistent with creatinine clearance. Multiple dosing
indicates that there is no accumulation of SBECD and the mean elimination half-life after 10
days dosing is 1.6 hours.
Voriconazole is widely distributed throughout body fluids and the volume of distribution is about
2 L/kg. Following oral administration of voriconazole, absorption is rapid with a mean time to
maximum plasma concentration of 1 to 2 hours post dose. Single and multiple dose
administration of voriconazole in the presence of a high-fat meal delays absorption. Multiple
dosing in the presence of food reduces systemic exposure by 32% compared to the fasted state.
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
1-4
As a precaution, it is recommended that voriconazole should not be taken within one hour of
eating.
Voriconazole in adults has non-linear pharmacokinetics with regard to dose [57, 58]. For
example, a two-fold increase in single oral dose resulted in a three to four fold increase in the
AUC0-last (the area under the concentration time curve from time 0 to the last observed
concentration above the limit of detection). For the intravenous formulation, the single dose
pharmacokinetics are linear up to 4 mg/kg, thereafter they become non-linear with similar
increase in the AUC seen with a doubling of dose. For oral multiple dosing, comparison across
cohorts suggests that for a 1.5 fold increase in dose there is a three to four fold increase in the
AUC (the area under the concentration time curve from time 0 to the end of the dosing interval).
There is wide inter-patient variability in the pharmacokinetics of voriconazole with the
coefficient of variation of 126% for AUC for a 3 mg/kg Q12H oral dose and 76% for
intravenous 3 mg/kg Q12H dosing. Multiple dosing at intravenous doses of 3 mg/kg Q12H and
oral doses of 200 mg Q12H results in a mean accumulation of approximately three fold and a
maximum accumulation of five fold which is not predictable from the single dose data. For both
intravenous and oral administration at single and multiple doses, voriconazole has a mean
terminal phase half-life of about six hours. Steady state, for both intravenous and oral dosing, is
achieved within six days. Use of a loading dose (6 mg/kg) results in steady state being achieved
by 24 hours of dosing.
The pharmacokinetic data from phase II studies showed that voriconazole exhibits a high degree
of inter-patient variability. In the 175 patients analyzed, the average AUC, maximum plasma
concentration and time to maximum plasma concentration were consistent with healthy volunteer
data at equivalent doses. The average bioavailability was high, 96% of subjects had observed
plasma voriconazole concentrations within the range 1-10 mcg/mL.
Salivary levels of voriconazole are approximately 65% of plasma levels (range 51 to 79%). This
is consistent with a plasma protein binding of about 58%. Comparison of the oral and
intravenous systemic exposure following single doses and at steady state after multiple dosing
indicates that the bioavailability of the oral dose lies within the range of 58 to 90%.
Plasma pharmacokinetics of intravenous voriconazole in immunocompromised children aged 2–
11 were assessed and compared with those of healthy adults. In contrast to adults where
nonlinear kinetics were observed, in children, the elimination of voriconazole was linear after
doses of 3 and 4 mg/kg [60]. Comparison of observed and simulated pediatric and adult
pharmacokinetic data indicated that plasma concentrations and area under the concentration-time
curve of 3 and 4 mg/kg in children were lower than the corresponding dosages in adults.
Nevertheless, the peak plasma concentrations in pediatrics still substantially exceed the reported
mean inhibitory concentrations (MICs) for most species of Candida, aspergillus and other
filamentous fungi. Doses of 4 mg/kg in children appear to achieve AUCs that approximate the
AUCs in adults dosed at 3 mg/kg.
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1.3. Clinical Efficacy of Voriconazole
The clinical efficacy, safety and tolerance of voriconazole have been tested in three Phase II
studies in Europe; oropharyngeal candidiasis in HIV positive patients [36], acute aspergillosis in
immunocompromised patients [37] and chronic fungal infections in non-neutropenic patients. In
addition, preliminary efficacy data are available in pediatric patients who received voriconazole
compassionately.
In a seven day double-blind, dose ranging study in 165 HIV positive patients with oropharyngeal
candidiasis (dose levels 50 mg QD, 200 mg QD or 200 mg Q12H), clinical efficacy (cured +
improved) in the intention to treat (ITT) analysis was 80% at 50 mg QD, 100% at 200 mg QD
and 89% at 200 mg Q12H. Mycological efficacy (reduction in colony counts < 11
colonies/culture) in the ITT analysis increased with dose from 33% at 50 mg QD to 74% at 200
mg Q12H. The drug was generally well tolerated and the only drug-related adverse event of any
significance was transient visual disturbance. The visual events had resolved fully in all patients
at follow-up.
Based upon the plasma pharmacokinetic profile of voriconazole, there may be a dose-response
relationship between higher dosages and improved antifungal efficacy. The geometric-mean
inhibitory concentrations (GMIC) of voriconazole vs. aspergillus spp. range from 0.19 to 0.58
ug/mL. Although the GMIC cannot be as closely correlated with clinical efficacy as MIC can
for an antibiotic, it is generally considered desirable for plasma concentrations of an antifungal
agent to cover the GMIC. Plots of Cmin data showed that a dosage of 4 mg/kg IV BID resulted
in trough plasma levels of voriconazole > 0.5 g/mL in 6 of 7 subjects. However, a dosage of
3 mg/kg IV BID resulted in trough levels of voriconazole > 0.5 g/mL in only 4 of 14 subjects.
A second open, non-comparative study was conducted using 200 mg PO Q12H of voriconazole
for up to 24 weeks in chronic aspergillosis or candidiasis of non-neutropenic patients. At the
interim analysis of clinical efficacy in 25 patients, favorable clinical response (complete or
partial resolution of clinical signs and symptoms, as determined by the investigator) was
achieved in 70% (12/17). Mycological response was available in three patients at the end of
therapy (EOT) and all three had negative cultures. The compound was generally well tolerated
in those patients. Visual disturbance, skin rash and elevated liver function tests were observed
and reported as adverse events possibly related to therapy. In two patients, elevation of liver
function tests (LFTs) above the protocol-specified maximum resulted in their withdrawal from
the study.
The third study was an open, non-comparative study of voriconazole (6 mg/kg IV Q12H for one
day then 3 mg/kg IV Q12H for 6-27 days followed by 200 mg PO Q12H for up to a total of 24
weeks) in acute invasive aspergillosis of neutropenic and other immunocompromised patients.
Interim analysis of clinical efficacy in 71 patients indicated a favorable clinical response
(complete/partial resolution or stable clinical signs and symptoms, as determined by the
investigator) was achieved in 83% (54/65). Mycological response at EOT was available in 31
patients; three patients had their infection eradicated, four had persistent infection and 24 were
not evaluable. The drug was generally well tolerated by these severely ill patients. LFT
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elevations above the protocol-specified maximum resulted in withdrawal of three patients from
the study.
The safety and efficacy of voriconazole in children treated within the compassionate release
program who were intolerant of, or refractory to, conventional antifungal therapy was recently
reported [38]. Seventy-two patients (ages 9 months to 15 years, median 7 years) received
voriconazole; 63 had a proven or probable fungal infection. Among these 63 patients, 27 had
hematological malignancies and 14 had chronic granulomatous disease as the most frequent
underlying conditions. Forty-two patients had aspergillosis, 8 scedosporiosis, 4 invasive
candidiasis, and 4 had other invasive fungal infections. The median duration of voriconazole
therapy was 93 days. At EOT 27 patients (44%) had a complete or partial response. Four
patients (7%) had a stable response, 25 (43%) failed therapy, and 4 (7%) were discontinued from
voriconazole because of intolerance. Success rates were highest in patients with CGD (57%) and
lowest in patients with hematological malignancies (25%). Two patients experienced treatment-
related serious adverse events (ulcerated lips with rash, elevated hepatic transaminases, or
bilirubin). Voriconazole-related adverse events included rash (8), increased hepatic
transaminases or bilirubin (5), blurred vision (2), and vomiting (1). These data support the use of
voriconazole for treatment of invasive fungal infections in pediatric patients who are intolerant
of, or refractory to, conventional antifungal therapy.
The results of an open, randomized comparison of voriconazole versus amphotericin B followed
by other licensed antifungal therapy for primary treatment of invasive aspergillosis were recently
described [39]. Patients with invasive aspergillosis were randomized to receive amphotericin B
1 mg/kg or voriconazole intravenously at 6 mg/kg Q12 hours (2 doses) then 4 mg/kg Q12H.
Oral formulation at a dosage of 200 mg Q12H could be given following 4 mg/kg IV dosing.
Other licensed antifungal therapy was allowed after initial randomization therapy. Blinded
teams assessed eligibility and response, and followed modified EORTC/MSG definition criteria
for probable or proven infection. Favorable outcomes were complete response of clinical and
radiological findings or partial response, which was significant clinically and > 50% radiological
improvement. Unfavorable outcomes were unchanged or worsened condition. The primary
outcome was assessed at week 12. Secondary endpoints included outcome of study therapy and
survival through week 12. Three hundred ninety-two patients were enrolled over three years in
92 centers in 19 countries. One hundred forty-four voriconazole and 133 amphotericin B
patients had confirmed invasive aspergillosis and received > 1 dose of therapy. Underlying
diseases represented were allogeneic bone marrow transplant in 26 and 23%, autologous bone
marrow transplant or hematologic disease in 56 and 63%, and other in 18 and 14% of
voriconazole and amphotericin B patients, respectively. Pulmonary aspergillosis was present in
83% of the voriconazole and 84% of the amphotericin B treated patients. Disseminated disease
occurred in 8.3% voriconazole versus 7.5% amphotericin B-treated and CNS disease in 1.4%
versus 0.8%, respectively. At week 12, a complete/partial response of 52.8% with voriconazole
versus 31.6% with amphotericin B was observed (95% CI for the difference was 32.9% to
10.4%). Survival on the voriconazole arm was 70.8% for voriconazole versus 57.9% on the
amphotericin B arm (Hazard ratio 0.59; 95 CI 0.40 to 0.88). Study therapy was continued for a
median of 77 days on the voriconazole arm versus 11 days on the amphotericin B arm. End of
therapy response was 53.5% on the voriconazole arm versus 21.8% on the amphotericin B arm
(95% CI for the difference was 42% to 21%). These data suggest voriconazole was more
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effective than amphotericin B followed by other licensed antifungal therapy at week 12.
Moreover, voriconazole improved survival in patients with invasive aspergillosis.
Recently reported data on the efficacy of voriconazole against rare or resistant fungal pathogens
(C. neoformans, F. solani, P. lilacinus, Trichosporon spp, S.imitis and H. capsulatum) appear
promising [40-43]. Patients with documented invasive infections caused by rare or resistant
fungal pathogens and enrolled into voriconazole clinical studies or for compassionate use were
included in the analysis. Fifty-nine subjects were analyzed; those receiving primary therapy
(n=8 success=3, failure=5) and those receiving salvage therapy (n=51 success=21 failure=30).
Outcomes were grouped according to underlying condition: AIDS/HIV (n=13 success=3,
failure=10), hematologic malignancy (n=15 success=5, failure=8), drug or disease induced
immune suppression (n=11 success=4, failure=7), injury/trauma or post surgical (n=5 success=1,
failure=4), non-malignant hematological disorders (n=6 success=3, failure=3). Fifteen of the 59
patients had hematologic diseases (n=15 success=7, failure=8). Successful outcomes were seen
in 17 of 44 patients without these risk factors. Outcomes based on pathogens were also
analyzed: Cryptococcus spp was successfully treated in 4 of 13 patients, Fusarium spp in 6 of 16
infections, and infections with other rare fungi, 14 of 30. Therefore, voriconazole appears to be a
promising antifungal agent in severely immunocompromised patients who have failed or are
intolerant to other treatment options, with potent activity against a wide variety of resistant and
rare fungal pathogens.
The recently completed MSG-42 study of voriconazole versus liposomal amphotericin B (L-
AMB) for empirical antifungal therapy in persistently febrile neutropenic patients suggests
voriconazole is a safe and effective alternative therapy in this population [44]. Voriconazole was
compared to L-AMB in a randomized, multicenter, international trial. Eight hundred forty-nine
randomized patients (voriconazole n=421, L-AMB n=428) receiving at least one dose of study
drug were evaluable for success. Composite success rates were 26% with voriconazole and 31%
with L-AMB (95% CI for difference; -10.6% to 1.6%). These were independent of
administration of colony stimulating factors or antifungal prophylaxis. Documented
breakthrough fungal infections were fewer among patients treated with voriconazole 8 (1.9%)
versus 21 (5.0%). Severe infusion-related reactions (p<0.01) as well as nephrotoxicity (p<0.001)
were less in patients receiving voriconazole versus L-AMB. Hepatoxicity was similar for both
drugs. More cases of transient visual changes (22% versus 1%) (p<0.001) and hallucination
(4.3% versus 0.5%) occurred on the voriconazole arm than on the L-AMB arm. Ninety-two
patients (22%) changed to oral formulation of voriconazole with a reduction of mean duration of
hospitalization by one day in all patients and by two days in high-risk patients (p<0.05). The
authors concluded that voriconazole is an effective alternative for empirical antifungal therapy in
patients at risk.
1.4. Rationale for Study
Given the high mortality rate associated with documented fungal infections in BMT patients
despite aggressive therapy with amphotericin B, strategies to prevent infections are warranted [7,
8] and may be more effective than trying to treat a documented established infection. Allogeneic
BMT patients are at special risk for infection due to aggressive or prolonged immunosuppressive
therapy and are subject to a high case fatality rate. Antifungal agents such as fluconazole and
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voriconazole can be administered orally, have good activity against several fungal pathogens and
are less toxic than amphotericin B. The availability of intravenous formulations of both agents
permit continued compliance with the regimen in the event that the patient cannot tolerate oral
medications.
Although voriconazole has a wider antifungal spectrum than fluconazole, there are more drug
interactions requiring greater vigilance over the immunoprophylaxis regimen, and there is the
potential for greater toxicity. Whether or not, on balance, the potential benefit outweighs these
potential risks can only be determined in a prospective, randomized trial.
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CHAPTER 2
2.
STUDY DESIGN
2.1. Study Overview
This is a randomized, double-blind, multicenter, prospective, comparative study of fluconazole
versus voriconazole in the prevention of fungal infections in allogeneic hematopoietic transplant
recipients and cord blood recipients in children under the age of 12. Prior to the start of the pre-
transplant conditioning regimen, patients will give written informed consent and be screened for
eligibility. Patients who meet all entry criteria will be assigned randomly to voriconazole or
fluconazole within 72 hours of Day 0. Patients will begin study drug on Day 0 (after completion
of the conditioning regimen). Day 0 is defined as the day infusion of the stem cell product is
initiated. Study drug will be continued until Day 100 following transplant or until one or more
criteria for study drug early withdrawal are met as defined in Section 2.4.6. Continuation of
study drug beyond Day 100 is permitted for patients who meet criteria specified in Section 2.4.8.
The development of any fungal infection during prophylaxis will be classified according to the
definitions listed in Section 3.1.1.
2.2. Hypotheses and Specific Objectives
2.2.1.
Primary Hypothesis
Voriconazole prophylaxis will be associated with fewer invasive fungal infections and reduce
morbidity and mortality due to fungal infection. This will result in an improvement of fungal-
free survival (survival without invasive fungal infection).
2.2.2.
Secondary Hypothesis
Reduction in fungal infectious rates will be associated with improvement in post-transplant
survival.
2.2.3.
Study Objectives
This trial is designed to compare the efficacy of fluconazole 400 mg/day PO (or IV at the same
dose if the patient is unable to tolerate it PO) with voriconazole 200 mg PO BID (or IV at the
same dose if the patient is unable to tolerate it PO) in prevention of fungal infections in
allogeneic hematopoietic transplant recipients during the first 180 days after transplant. Children
aged < 12 years will receive age-appropriate dosing, as indicated in Section 2.4.1. The primary
objective is to compare the fungal-free survival rates between the two study arms during the first
180 days. Secondary objectives will be to compare invasive fungal infection rates, overall
mortality due to fungal infection, engraftment rates, acute and chronic GVHD rates, reasons for
failure (e.g., plasma concentrations, tolerance, fungal sensitivity, etc.), and to perform
exploratory analyses of quantitative aspects of the galactomannan assay. The relative safety of
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the two antifungals also will be assessed through the collection of post-transplant toxicities,
serious adverse event reports and routine laboratory monitoring.
2.3. Patient Eligibility
2.3.1.
Eligibility Criteria
Patients fulfilling all of the following criteria will be eligible for this study:
1. Patients who receive an allogeneic peripheral blood or marrow transplant from a family
or unrelated donor, or for children under the age of 12, a cord blood transplant from
either a sibling or other donor.
2. Patients must have a 5 or 6 of 6 HLA-matched donor. The match may be determined at
serologic level for HLA-A and HLA-B loci. For sibling donors, matching may be
determined at serologic level for HLA-DR; for unrelated donors, matching for HLA-
DRB1 must be at the high-resolution molecular level.
3. Patients two years of age or older.
4. Patients and/or legal guardian able to provide informed consent
5. Patients with one of the following underlying diseases:
a) AML, with or without a history of myelodysplastic syndrome, in first or second
complete remission (see Section 3.4) or in early relapse (< 30% blasts in bone
marrow with no circulating blasts in peripheral blood and no extramedulary
leukemia); or
b) ALL, in first or second complete remission (see Section 3.4); or
c) AUL (acute undifferentiated leukemia) in first or second complete remission (see
Section 3.4); or
d) Acute biphenotypic leukemia in first or second complete remission (see Section 3.4);
or
e) CML in either chronic or accelerated phase; or
f) One of the following myelodysplastic syndrome(s) defined by the following:
1) Refractory anemia
2) Refractory anemia with ringed sideroblasts
3) Refractory cytopenia with multilineage dysplasia
4) Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
5) Refractory anemia with excess blasts-1 (5-10% blasts)
6) Refractory anemia with excess blasts-2 (10-20% blasts)
7) Myelodysplastic syndrome, unclassified
8) MDS associated with isolated del (5q)
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9) CMML; or
g) Lymphoma (including Hodgkin’s) with chemosensitive disease (≥ 50% response to
chemotherapy) and receiving a related donor transplant
6. Patients receiving myeloablative conditioning regimens.
7. Patients with adequate physical function, within six weeks of initiation of conditioning
(preferably within four weeks) unless otherwise specified, as measured by:
a) Cardiac:
Asymptomatic or, if symptomatic, then left ventricular ejection
fraction at rest must be > 40% and must improve with exercise, or
shortening fraction > 26%
b) Hepatic:
< 5 x ULN ALT (within 72 hours of Day 0)
< 2.5 mg/dL total serum bilirubin
c) Renal:
Serum creatinine within normal range for age or if serum
creatinine above upper limit of normal range for age then renal
function (creatinine clearance) > 50% LLN for age
d) Pulmonary:
DLCO, FEV1, FVC (capacity) > 45% of predicted value (corrected
for hemoglobin) or O2 saturation > 85% of room air
8. Patients must have baseline galatomannan blood samples drawn within 30 days prior to
randomization with the results available prior to randomization (72 hours prior to
transplant)
9. Patients must have chest CT scans within six weeks prior to randomization if the results
of the baseline galactomannan blood sample are not available prior to randomization (72
hours prior to transplant)
2.3.2.
Exclusion Criteria
Patients with the following will be ineligible for randomization on this study:
1. Patients with an invasive yeast infection within the eight weeks prior to conditioning
regimen initiation. Patients are eligible if colonized or have had superficial infection.
Patients with a history of candidemia > 8 weeks prior to conditioning must have a
negative blood culture within 14 days of conditioning (within 7 days is recommended),
no clinical signs of candidemia, and may not still be requiring antifungal therapy.
2. Patients with a presumptive, proven or probable aspergillus or other mould infection or
deep mycoses (including hepatosplenic candidiasis) within 4 months prior to conditioning
regimen initiation.
3. Patients with an uncontrolled viral or bacterial infection at the time of study registration.
4. Women who are pregnant (positive -HCG) or breastfeeding. Women of child-bearing
age must avoid becoming pregnant while receiving antifungal agents.
5. Patients with a Karnofsky performance status < 70% or Lansky < 50% for patients < 16
years old unless approved by the Medical Monitor or protocol Chair.
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6. Patients with a history of allergy or intolerance to azoles (fluconazole, itraconazole,
voriconazole, posaconazole, ketoconazole, miconazole, clotrimazole).
7. Patients requiring therapy
with rifampin, rifabutin,
carbamazepine,
cisapride
(Propulsid®), terfenadine; (Seldane®), or astemizole (Hismanal®), ergot alkaloids, long-
acting barbiturates, or who have received > 3 days treatment with rifampin or
carbamazepine within 7 days prior to conditioning regimen initiation. Patients on
therapeutic anticoagulation with coumadin (1 mg/day for port prophylaxis is permitted).
8. Patients receiving sirolimus.
9. Patients with prolonged QTc syndrome at study entry.
10. Patients who are HIV positive.
11. Patients receiving another investigational drug unless cleared by the medical monitors.
12. Patients who have received a prior allogeneic or autologous transplant.
13. Patients with active CNS disease.
14. Patients on fungal prophylaxis during conditioning regimen (it is recommended that
fungal prophylaxis be suspended once patient is enrolled).
15. Patients with prior malignancies except resected basal cell carcinoma or treated
carcinoma in-situ. Cancer treated with curative intent < 5 years previously will not be
allowed unless approved by the Medical Monitor or Protocol Chair. Cancer treated with
curative intent > 5 years previously will be allowed.
2.4. Treatment Plan
The immediate pre-transplant 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
operations manuals of the Clinical Centers. All patients enrolled on this protocol will be
hospitalized in accordance with isolation procedures for recipients of allogeneic blood and
marrow transplants as defined by the given institution.
2.4.1.
Drug Dosages
The study drugs will be masked by overencapsulation to obscure their identity. Patients
randomized to voriconazole will receive one dose in the morning and one dose in the evening.
Fluconazole is appropriately efficacious if administered once daily. Those patients randomized
to fluconazole will receive their full daily dose in the morning followed by placebo in the
evening.
Study drug will begin on Day 0, day of transplant. Patient should be given an AM and PM dose.
If necessary, the AM dose may be administered prior to stem cell infusion.
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If a patient misses a dose, it should be taken within four hours of the scheduled time. If more
than four hours have passed, the patient should not take an additional dose until his next
scheduled dose.
In efforts to maintain the blind, both intravenous voriconazole and fluconazole will be
administered in equivalent volumes as specified in Appendix F.
Adults: The dose of oral voriconazole is 200 mg twice daily. When voriconazole must be given
intravenously, it will be given at a dose of 200 mg every 12 hours for the duration of intravenous
therapy. Doses will not be reduced for renal dysfunction.
The dose of fluconazole is 400 mg by mouth or intravenous drip. Doses will be reduced for
renal dysfunction in accordance with Section 2.4.3 and Appendix G.
Children (age < 12 years old): Oral doses will be given as follows: In patients weighing > 20
kg, voriconazole will be administered at a dose of 100 mg twice daily. Patients weighing < 20
kg will receive oral voriconazole at a dosage of 50 mg twice daily. If intravenous administration
is needed, voriconazole will be at a dose of 4 mg/kg (total body weight) every 12 hours (not to
exceed the equivalent oral dose) for the duration of intravenous therapy (see Appendix F).
For oral administration, patients weighing > 20 kg will receive fluconazole at a dose of 200 mg
once daily. For those weighing < 20 kg, a dose of 100 mg once daily will be used. Doses will be
reduced for renal dysfunction in accordance with Section 2.4.3 and Appendix G. When
intravenous administration is received, fluconazole will be given at 6 mg/kg/day total body
weight (with maximal IV dose not to exceed the equivalent oral dose per weight) once daily (see
Appendix F).
Both study drugs will be given orally whenever possible. Both voriconazole and fluconazole are
well absorbed after oral administration with bioavailability exceeding 90%. Study drugs should
be taken at least one hour after or one hour before a meal. The intravenous formulation will be
given only when the oral medication cannot be tolerated. Oral study drug should be resumed as
quickly as possible when oral medication can be given.
Total duration of the prophylaxis study drug will be 100 days, or until study drug early
withdrawal criteria have been met (Section 2.4.6) including criteria for a presumptive, probable
or proven fungal infection (Section 3.1.1). Study drug will be continued beyond Day 100 in
patients who meet criteria in Section 2.4.8.
Fungal prophylaxis must not be given after protocol-specified treatment plan is completed on
Day 100 (or 180).
2.4.2.
Administration Procedures
1. Voriconazole
Voriconazole will be administered orally twice daily. Voriconazole capsules should be
taken at least one hour before or one hour after a meal. Taken concomitantly with food,
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bioavailability of voriconazole is reduced. If oral drug is not possible, it will be given
intravenously at a dosage of 200 mg Q12H over two hours in patients > 12 years. Each
voriconazole dose will be diluted to a total volume of 200 mL in patients > 12 years.
Volumes of the formulation required to provide 4 mg/kg doses for children (age < 12
years) of various body weights, and the dilution and infusion instructions are in Appendix
F. To maintain the blind in children, a standardized volume defined in Appendix F will
be used for all doses. Accordingly, dilutions to the specified volume, if necessary, should
be made.
2. Fluconazole
Fluconazole will be administered orally once daily. Fluconazole capsules should be
taken at least one hour before or one hour after a meal. If oral drug is not possible, it will
be given intravenously once daily in a total volume of 200 mL in patients > 12 years. For
adults, each 200 mL infusion will be administered over 2 hours. In patients < 12 years,
intravenous doses will be prepared in accordance with Appendix F in standardized
volumes and administered over two hours.
3. Incompatibilities
Concomitant medications should not be infused in the same line as voriconazole,
fluconazole or amphotericin B.
4. Accountability
The investigator (and/or hospital pharmacist) will ensure that all study drug is stored in a
secured area under recommended storage conditions and is dispensed by qualified staff
members. All study drug will be accounted for on medication inventory sheets.
The BMT CTN clinical monitor will be allowed at intervals, and upon request during the
study, to check unused supplies. Accounting for the use of supplies will be by reference
to each center's record of supplies received, the dispensing records for the total number of
patients enrolled at each center and the unused and returned supplies.
Patients who are discharged from the hospital during the time they are receiving oral
voriconazole or fluconazole therapy will be provided with ample supply of study
medication between visits. The patient will be requested to return all containers of study
drug, including empty containers and containers with unused capsules, at the next visit.
Unused drug may be returned to patient if therapy continued.
The investigator is responsible for maintaining drug accountability records. Drug
accountability records will be reviewed during monitoring visits. Study drug must be
administered only to patients enrolled in this study as per the protocol.
5. Labeling
The investigator or pharmacist will record the patient number on the label of all
containers containing voriconazole or fluconazole capsules before dispensing to the
patient. The lot number of the bottle should be recorded on the patient's dispensing
records at the time they are dispensed.
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6. Cardiac Monitoring
In subjects assessed by the treating physician to be at risk for cardiac arrhythmia, the
following procedure must be performed: Continuous cardiac monitoring during the first
three days of study medication. If the cardiac monitoring reveals a significant arrhythmia,
the administration of study medication must be held, and the subject must undergo further
assessment by a cardiologist to evaluate the significance of the findings. The
cardiologist’s assessment and opinion on the significance of any abnormal finding will be
summarized in a report and submitted on an Adverse Event Form. If the PI and
cardiologist conclude that it is not related to the study drug, study drug can be resumed.
Otherwise, the patient will be withdrawn from study drug.
2.4.3.
Dosage and Formulation Adjustments
Oral intolerance: Oral study medication will be temporarily discontinued in patients who
become unable to take or to tolerate oral medications; the parenteral antifungal formulation
should be substituted in the dose according to Section 2.4.1. Patients will be changed back to
oral medications as soon as tolerable. If the patient is an outpatient and requires IV study drug
for more than 14 days and cannot tolerate oral study drug, the patient must be taken off study
drug.
Empirical therapy with Amphotericin B or Caspofungin: Patients who develop a possible
invasive fungal infection as defined in Section 3.1.1, but do not meet the criteria for failure of
prophylaxis, may be treated empirically with an amphotericin B formulation or caspofungin
according to the provisions of Section 2.4.10. These patients will remain on study and continue
to be assessed for more definitive evidence of fungal infection. During empirical therapy, the
study drug should be continued. Prior to initiation of any empirical trial of amphotericin B or
caspofungin, at least two blood samples for the diagnostic galactomannan assay should have
been collected during the last seven days (with at least one within 48 hours). No systemic
antifungal agent, other than one of the amphotericin B formulations or caspofungin, is permitted
while the patient is on study.
Renal dysfunction: In the setting of renal dysfunction, fluconazole doses will be adjusted as
follows: estimated CrCl < 50ml/min = 50% dose reduction. For pediatric patients with CrCl
< 20ml/min/1.73m2, fluconazole dose reduction = 75%. Calculations of creatinine clearance
should be made based on the method of Cockgroft and Gault [45] for adult males [CrCl = (140-
age in years) X kg weight (ideal) /serum creatinine x72]. For adult females, the equation is
multiplied by 0.85. Ideal body weight (IBW) is to be calculated as follows: Male IBW = 50kg +
2.3 kg/inch over 5 feet, Female IBW = 45.5 kg + 2.3 kg/inch over 5 feet. If less than 5 feet,
subtract 2.3 kg/inch. For children, the Schwartz calculation will be used (CrCl = k value X
height (cm)/plasma creatinine). K values for children and adolescent girls = 0.55, adolescent
boys = 0.70. Guidelines for oral dose adjustment are given in Appendix G. No dose adjustments
for renal dysfunction will be made in the voriconazole arm. For patients with moderate renal
insufficiency (estimated CrCl < 50 mL/min), accumulation of the voriconazole IV vehicle can
occur. Oral voriconazole should be administered to these patients unless a benefit/risk
assessment justifies the use of IV voriconazole. However, if CrCl declines to 25 mL/min and
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persists for more than 14 days and the patient must receive IV drug and is unable to switch to
oral drug, then the study drug should be discontinued. Study drug should be discontinued in the
setting of hemodialysis (see Section 2.4.6.1.f).
To maintain the blind in patients receiving intravenous study drug, for patients randomized to
receive voriconazole who meet the renal impairment criteria, the volume of voriconazole will be
adjusted to mimic the volume the patient would receive if randomized to fluconazole. To
maintain the blind in patients receiving oral study drug, the number of voriconazole capsules
taken in the morning will be adjusted to mimic the number the patient would receive if
randomized to fluconazole (see Appendix G).
The physician must order dose adjustments for all patients randomized into the study using an
order conforming to type listed in Appendix H. The pharmacist will make the appropriate
adjustments based on randomization and the type of renal impairment.
2.4.4.
Study Drug Supply
An initial supply of study drug (oral and IV, adult and pediatric doses, if appropriate) will be
automatically sent to the investigational pharmacy upon enrollment of the transplant center’s first
patient onto Segment A (see Section 4.1.1). The transplant center’s investigational pharmacist
will be responsible for subsequent ordering, receiving, storing, distributing and accounting of the
study drug. He/she will be responsible for recording the receipt and administration of all trial
drug supplies, for ensuring the supervision of the storage and allocation of these supplies, and for
maintaining the drug distribution and accountability logs. These logs must be available for
inspection during routine site monitoring visits. The investigator will ensure that all protocol
drugs are stored in a secured area under recommended storage conditions and are dispensed by
qualified staff members.
2.4.5.
Pharmaceutical Information
1. Source
Voriconazole and fluconazole are manufactured by Pfizer, Inc., Groton, CT.
2. Toxicity
Voriconazole: Voriconazole had been administered to over 3000 healthy volunteers or
patients with fungal infections in single or multiple dosing regimens, by oral and
intravenous routes at the time of FDA review for licensure. The following safety issues
have been identified. There were 286 serious adverse events recorded. Of these, a total
of eight were reported by the investigators to be potentially causally related to
voriconazole. Other events were assessed by the investigators to be related to the disease
under study or to other factors. The eight events that were causally related to study drug
were: three cases of elevated liver function test (LFT) values, three cases of skin
reactions, one case of exacerbated hypoglycemia and one case of atypical pneumonia
with hypoglycemia.
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Overall, 30% of volunteers and patients have reported adverse events related to vision,
regardless of route of administration. The most consistent description offered was of a
transient altered/increased perception of light or blurred vision. The events generally
lasted less than one hour, with onset occurring between 30 and 60 minutes after an oral
dose. Of these, three of four were mild. The remainder were moderate, with 1-2% being
severe. All of these events resolved. Abnormal vision is therefore reversible, even
during continued therapy, and is not considered to represent a serious risk.
Ophthalmologic tests (visual evoked response), performed in volunteers, did not reveal
any abnormalities and provide no basis for a potential mechanism. Also there have been
no ophthalmologic or brain/optic nerve histological changes in animals treated for up to
six months with high doses of voriconazole. These data suggest that pathological
changes to the visual pathways are unlikely.
Analysis of the data from patient studies has shown cases of elevated alkaline
phosphatase (ALP) and bilirubin, potentially indicative of cholestasis, which appear to be
temporally related to onset of voriconazole therapy. Occasionally, when these levels rose
to greater than three times the upper limit of normal (ULN) therapy was discontinued; a
total of 16 patients fulfilled this criterion. One of these cases resulted in prolonged
hospitalization and therefore was considered to be a serious adverse event.
Also, a number of cases of elevated transaminases (alanine aminotransferase and
aspartate aminotransferase, ALT and AST, respectively) have occurred. When levels
reached five times the ULN, therapy was discontinued in nine patients from two studies.
Two of these cases were hospitalized for observation and therefore were considered
serious events. Elevations in liver function tests (LFTs) have only rarely occurred in
studies of voriconazole in healthy volunteers.
There have been a small number of skin reactions recorded with the total incidence of
rash being 7%. These reactions were largely localized to the sun exposed areas of the
skin and may, therefore, indicate a photosensitizing potential with voriconazole. Other
azole antifungal agents have been reported to cause skin reactions.
In addition to the visual disturbances, elevated liver function tests, and skin reactions
discussed above, the following treatment-related adverse events have occurred at a rate of
< 1% in human volunteers and patients that have received voriconazole to date:
abdominal pain, headache, nausea, dizziness, asthenia, hypokalemia and injection site
reactions.
The following serious adverse events have been reported in patients receiving other azole
antifungal agents, and could potentially occur in patients receiving voriconazole: cardiac
dysrhythmias (reported in patients receiving itraconazole in combination with terfenadine
or astemizole), and anaphylaxis (reported with fluconazole and ketoconazole).
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Pediatric patients have received voriconazole in Phase II studies. Patients received
between 200-1000 mg per day and tolerated voriconazole without any attributable serious
adverse events.
Fluconazole: Sixteen percent of over 4,000 patients treated with fluconazole in clinical
trials of seven days or more experienced adverse events. Discontinuation of therapy was
required in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to
laboratory test abnormalities. Treatment-related clinical adverse events occurring at an
incidence of 1% or greater included nausea in 7.7%, headache in 1.9%, skin rash in 1.8%,
vomiting in 1.7%, abdominal pain in 1.7%, and diarrhea in 1.5%.
In both combined clinical trials and marketing experience there have been rare cases of
serious hepatic reactions thought probably causally associated. The spectrum of these
reactions has ranged from mild transient elevations in transaminases to clinical hepatitis,
colestasis, and fulminant hepatic failure including fatalities. Generally, liver function
returned to baseline on discontinuation of fluconazole.
Other side effects noted with uncertain causal association include seizures, exfoliative
skin disorders including Stevens Johnson syndrome and toxic epidermal necroliasis,
alopecia, leukopenia, including neutropenia, thrombocytopenia, hypercholesteremia,
hypertriglyceridemia, and hypercalcemia.
In children, 13% of 577 patients experienced treatment-related adverse events. These
included vomiting in 5%, abdominal pain in 3%, nausea in 2% and diarrhea in 2%.
Treatment was stopped in 2.3% of patients due to adverse reactions and in 1.4% of
patients due to laboratory test abnormalities. The majority of the laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
3. Formulation and Preparation
a) Voriconazole
Voriconazole for oral use is presented as 50 mg and 200 mg tablets. Tablets will be
overencapsulated by the BMT CTN Central Pharmacy to maintain the blind.
Capsules must not be opened or altered. Voriconazole for intravenous injection is
presented in a 30 mL vial as a lyophilized powder for reconstitution equivalent to 200
mg Voriconazole per vial. The lyophile must be stored at room temperature (15o-
30oC). After reconstitution with 19 mL of water for injection USP, each mL contains
10 mg of voriconazole and 160 mg of SBECD. The pH of the reconstituted solution
ranges from 5.5 to 7.5. Refer to Appendix F for reconstitution guidelines for IV
administration.
b) Fluconazole
Fluconazole for oral use is presented as 100 mg and 200 mg tablets. Tablets will be
overencapsulated by the BMT CTN Central Pharmacy to maintain the blind.
Capsules must not be opened or altered. Oral fluconazole suspension is not available
for this trial. Fluconazole for injection is packaged in Viaflex Plus plastic containers
containing 200 mg of fluconazole in a volume of 100 mL in sodium chloride (a
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concentration of 2 mg/mL). Refer to Appendix F for reconstitution guidelines for IV
administration. Intravenous fluconazole will be stored and prepared according to the
manufacturer’s instructions provided in the package insert.
c) Placebo
The oral formulations of voriconazole and fluconazole differ in appearance.
Accordingly, all oral medications will be masked by overencapsulation to prevent
identification. Patients receiving oral fluconazole will receive active masked drug in
the morning and an identical appearing placebo in the evening. Similarly, patients
receiving IV fluconazole therapy will receive an equivalent volume of normal saline
(weight-adjusted as per Appendix F) for the evening infusion.
4. Stability and Storage
The safe storage of study drug supplies will be arranged by the investigator until they are
dispensed to the patient(s). They will be stored in the hospital’s investigational pharmacy
under the supervision of the investigational pharmacist.
a) Voriconazole
Voriconazole capsules should be stored at controlled room temperature between 15º-
30ºC (59º-86ºF).
Vials containing unreconstituted lyophilized voriconazole should be stored at
controlled room temperature between 15º-30oC (59º-86ºF). Vials of reconstituted
voriconazole solution must be stored between 2º-8ºC (37º-46ºF) for no more than 24
hours. They should not be frozen. The reconstituted solution does not contain a
preservative, and each vial is intended for single use only.
b) Fluconazole
Fluconazole capsules should be kept below 30ºC (86ºF).
Fluconazole for injection is packaged in Viaflex® Plus plastic containers and should
be stored between 5º-25ºC (41º-77ºF).
2.4.6.
Early (Premature) Withdrawal of Study Drug
2.4.6.1.
Patient early withdrawal from study treatment
Patients will be prematurely withdrawn from study treatment prior to day 100 (or 180) if:
1. There is evidence at any time during the study of a presumptive, probable or proven
invasive fungal infection as defined by criteria (Section 3.1.1).
2. Any of the following toxicities occur. However, if another etiology is judged by the local
PI to be the likely cause of the toxicity and an interval of no more than 14 days has
lapsed, then the study drug can be resumed at original dose. If the same toxicity recurs,
the patient will be permanently withdrawn from the study treatment.
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a) For hepatic toxicity: If ALT exceeds ten times the upper limit of normal and is felt to
be at least possibly related to study drug, the study drug should be held until the
causality clarifies and until the toxicity resolves to a Grade II or less. If ALT exceeds
five times the upper limit of normal and is felt to be at least possibly related to study
drug, the study drug may be held at the discretion of the treating physician until the
causality clarifies and until the toxicity resolves to less than two and a half times the
upper limit of normal.
b) For visual toxicity: Photopsia (visual disturbances) is an occasional side effect of
voriconazole. It typically is transient and is not associated with organic or enduring
sequelae. It does not represent grounds for withdrawal. If a patient experiences loss
of vision (blindness), it is unlikely that it is due to the study drug; however, the study
drug should be held until etiology is established. Cyclosporine and tacrolimus can
cause loss of vision and should be held. Retinal hemorrhage is also a potential cause
of visual loss and platelet transfusions and optimization of coagulation parameters
should be considered where appropriate. Ophthalmic evaluation should be promptly
carried out.
c) For cutaneous toxicity: A skin rash can occasionally occur. This may be provoked or
exacerbated by sun exposure. Other potential causes of rash should be investigated,
including graft-versus-host disease and drug sensitivity. A skin biopsy may be useful
in the evaluation of other causes. This ordinarily will not constitute grounds for
withdrawal unless there is skin necrosis or ulceration or generalized exfoliative
dermatitis.
d) For neurologic toxicity: An infrequent observation in patients receiving voriconazole
is hallucinations. A preliminary analysis suggests this is due to potentiation of opiate
or benzodiazepine effect. If such should occur, attempts should be made to reduce
opiate and/or benzodiazepine dosages. If necessary after at least 24 hours after
reduction of the dose(s) of concomitant opiates or benzodiazepines, study drug can be
held (without withdrawal) up to 14 days as specified above to allow reduction of
doses of these concomitant medications.
e) For cardiac arrhythmia: If a significant arrhythmia occurs, study medication must be
held, and the subject must undergo further assessment by a cardiologist to evaluate
the significance of the findings. The cardiologist’s assessment and opinion on the
significance of any abnormal finding will be summarized in a report and submitted
with an Adverse Event Form. If the PI and cardiologist conclude that it is not related
to the study drug, study drug can be resumed as specified above. Otherwise, the
patient will be withdrawn from study treatment.
f) For renal insufficiency: The patient experiences serious renal impairment requiring
hemodialysis and IV study drug.
g) For any other Grade III or IV toxicity according to the NCI Common Terminology
Criteria for Adverse Events (CTCAE) Version 3.0 which is not typically expected in
the course of BMT and may be possibly related to study drug.
3. Systemic amphotericin B (or one of the lipid formulations) or caspofungin is given for
more than 14 consecutive days.
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If a patient is prematurely withdrawn from study drug prior to Day 100 for reasons
other than a presumptive, probable or proven fungal infection, fluconazole will be
allowed for fungal prophylaxis until Day 100 with permission of the Medical
Monitor or Protocol Chair. No other antifungal agents are allowed.
4. The patient requires terfenadine, astemizole, cisapride or sirolimus, maintenance
phenytoin/anticonvulsant therapy, or any of the drugs prohibited at study entry (Section
2.3.2).
5. The patient is an outpatient and requires IV study drug for more than 14 consecutive days
and cannot tolerate oral study drug. IV study drug must be prepared by the
investigational pharmacist at the transplant center (and not by home health care) in order
to maintain the blind.
6. The patient’s creatinine clearance declines to < 25 mL/min and persists for more than 14
days and the patient requires IV study drug and cannot tolerate oral study drug.
7. The patient has failed to engraft and requires chemotherapy.
8. The patient has relapsed and requires chemotherapy.
9. The patient becomes pregnant.
10. The patient withdraws consent.
The medical monitor or one of the protocol chairs should be contacted for advice about any of
the above considerations for holding or withdrawal of the study drug due to adverse events.
All early study drug withdrawals should be reported to Data Coordinating Center within three
business days. Even if withdrawal from study drug occurs for any of the above reasons, all study
assessments should continue through the remainder of the one-year period.
If a patient is prematurely withdrawn from study drug prior to Day 100 (or 180) for reasons other
than a probable or proven invasive fungal infection, only fluconazole will be allowed as
prophylaxis until Day 100 (or 180) with permission of the Medical Monitor or Protocol Chair.
No other antifungals are allowed for prophylaxis.
Refer to NCI’s Common Terminology Criteria for Adverse Events (CTCAE) as a guideline for
toxicity assessment. The CTCAE Document Version 3.0 can be accessed at the following web
site: http://ctep.cancer.gov/reporting/ctc.html.
2.4.6.2.
Breaking the blind
Study drug assignment may be revealed only for reasons relating to the patient’s safety or when
critical therapeutic decisions are contingent upon knowing the assigned study drug. A decision
to break the blind must be discussed with the medical monitor or one of the protocol chairs in
advance. Withdrawal of a patient from the study treatment is not a sufficient reason to break the
study blind. Suggestions for antifungal therapy for patients withdrawn due to presumptive,
probable or proven infection are provided in Section 2.4.9.
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2.4.7.
Contraindications, Drug Interaction and Monitoring
2.4.7.1
Voriconazole and fluconazole
Voriconazole is metabolized by three separate CYP 450 isoenzymes, including CYP34A,
CYP2C9 and CYP2C19. Fluconazole is also metabolized by the cytochrome P450 34A enzyme
system and may interact with several medications. Clinically and potentially significant drug
interactions that have been observed with fluconazole, as well as voricoazole (i.e., both azoles),
include the following:
Co-administration of terfenadine, cisapride, astemizole, quinidine, pimozide and dofetilide
with voriconazole and fluconazole is contraindicated. Serious cardiovascular adverse events,
including death, ventricular tachycardia, torsades de pointes and prolonged QTc have been
observed in patients taking other azoles concomitantly with these drugs. Voriconazole causes
increased concentrations of terfenadine, cisapride and astemizole.
Other medications with documented drug interactions with fluconazole and voriconazole whose
serum concentrations should be closely monitored, or the end effect closely monitored (e.g.,
blood sugar levels with sulfonylureas), include phenytoin, phenobarbital, digoxin, omeprazole,
warfarin and sulfonylureas (can increase plasma levels which may lead to hypoglycemia) [46-
51].
1. Oral Hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use
of fluconazole or voriconazole with oral hypoglycemic agents. One fatality has been
reported from hypoglycemia in association with combined fluconazole and glyburide use.
Fluconazole reduces the metabolism of tolbutamide, glyburide and glipizide, and
increases the plasma concentration of these agents. Blood glucose concentrations should
be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary.
2. Coumadin-Type Anticoagulants: Prothrombin time may be increased with concomitant
fluconazole or voriconazole and coumadin-type anticoagulants. Careful monitoring of
prothrombin time is recommended.
3. Phenytoin: Fluconazole or voriconazole increase the plasma concentrations of phenytoin.
Careful monitoring of phenytoin concentrations is recommended.
4. Cyclosporine: Fluconazole or voriconazole may significantly increase cyclosporine
levels in renal transplant patients with or without renal impairment. Careful monitoring
of cyclosporine concentrations and serum creatinine is recommended [52].
5. Rifampin: Rifampin enhances the metabolism of fluconazole. Depending on clinical
circumstances, consideration should be given to increasing the dose of fluconazole if
administered with rifampin.
6. Theophylline: Fluconazole (and probably voriconazole) increases the
serum
concentrations of theophylline. Careful monitoring of serum theophylline concentrations
is recommended.
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7. Rifabutin: There have been reports of uveitis in patients to whom fluconazole and
rifabutin were co-administered. Patients should be carefully monitored. The
concomitant administration of voriconazole and rifabutin is contraindicated (see
inclusion criteria).
8. Tacrolimus: There have been reports of nephrotoxicity in patients in whom fluconazole
or voriconazole and tacrolimus were co-administered. Patients should be carefully
monitored.
Grapefruit juice should be avoided since it is known to interfere with the cytochrome P450
system. Certain herbal medicines (e.g., St. John’s Wort) should be avoided for similar reasons.
2.4.7.2
Voriconazole drug interactions
Co-administration of voriconazole and immunosuppressive agents metabolized by cytochrome
P450 3A4 may result in alterations in drug metabolism as follows:
1. Cyclosporine: In stable transplant recipients, voriconazole increased cyclosporine Cmax
and AUC (area under the blood concentration time curve to the last quantifiable
measurement) by at least 13% and 170%, respectively. Trough cyclosporine
concentrations increased by an average of 2.5 fold [52]. These observations have led to
the recommendation that when initiating voriconazole in patients already receiving
cyclosporine, the cyclosporine dose be halved and blood cyclosporine levels carefully
monitored [59]. When voriconazole is discontinued, blood cyclosporine levels must be
carefully monitored and the dose increased as necessary.
2. Tacrolimus: In healthy volunteers, voriconazole increased tacrolimus (0.1 mg/kg single
dose) Cmax and AUC by 117% and 221%, respectively. These observations have led to
the recommendation that when initiating voriconazole in patients already receiving
tacrolimus, the tacrolimus dose should be reduced to at least one third of the original dose
and blood tacrolimus levels carefully monitored. When voriconazole is discontinued,
blood tacrolimus levels must be carefully monitored and the dose increased as necessary.
3. Sirolimus: In healthy volunteers, voriconazole increased sirolimus Cmax and AUC by
6.6 fold and 11.1 fold, respectively. Voriconazole should not be co-administered with
sirolimus.
4. Benzodiazepines: In vitro studies demonstrate the potential for voriconazole to inhibit
the metabolism of benzodiazepines (and thereby increasing plasma exposure). Frequent
monitoring for adverse events and toxicity (especially prolonged sedation) related to
benzodiazepines metabolized by cytochrome P450 3A4 (e.g., midazolam, triazolam,
alprazolam) is recommended. Adjustment of benzodiazepine dosage may be needed.
5. Statins: In vitro studies demonstrate the potential for voriconazole to inhibit metabolism
(thereby increasing plasma exposure). Frequent monitoring for adverse events and
toxicity related to statins is advised. Increased statin concentrations in plasma have been
associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
6. Calcium channel blockers: Voriconazole may increase the serum concentrations of this
class of drugs (e.g., diltiazem, verapamil, felodipine). Frequent monitoring for adverse
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events and toxicity related to calcium channel blockers is advised. Adjustment of
calcium channel blocker dosage may be required.
2.4.8.
Duration of Study Drug
Study drug will be continued without interruption through Day 100 unless the patient has met the
early drug withdrawal criteria or has met the criterion for a presumptive, probable or proven
fungal infection. In three circumstances, study drug may be continued beyond Day 100 and
should be given in those instances until Day 180. An assessment between Day 90 and 100
should be made to determine if either of the following three conditions are met:
Any patient who is receiving at least 1.0 mg/kg/d of prednisone or other steroid
equivalent (based on actual or ideal body weight) during that assessment should continue
study drug until Day 180.
Recipients of T cell depleted transplants receiving post-transplant immunosuppression
between Day 90 and 100 should continue to receive study drug until Day 180.
Recipients of T cell depleted transplants with CD4+ counts < 200/uL should continue
study drug until Day 180.
2.4.9.
Recommendations for Treatment of Documented Fungal Infections
In the event of the patient demonstrating a presumptive, probable or proven invasive fungal
infection as per the criteria of Section 3.1, the patient has reached the primary study endpoint,
should stop study drug and the clinician is free to treat the infections according to local
institutional guidelines. The following are offered as suggestions.
One option is to use amphotericin B and voriconazole together. This would provide adequate
therapy for most fungal pathogens irrespective of which study drug the patient was assigned to
and this strategy would ordinarily not require breaking the blind. Voriconazole is to be given at
a dose of 6 mg/kg/dose IV twice daily for two days, then at a dose of 4 mg/kg/d thereafter. One
can switch to the equivalent dose orally once the patient is stable and taking oral drugs
satisfactorily. The dose of amphotericin B is 1.0 mg/kg/d if the conventional formulation is used
or is 4.0-5.0 mg/kg/d if a lipid formulation is used. If the pathogen is mucormycoses, an
amphotericin B formulation is the therapy of choice; voriconazole is not active against this
pathogen and is not needed.
For patients with proven mucormycoses or probable fungal infection with filamentous fungal
forms on cytologic or histologic section, which cannot exclude mucormycetes, an amphotericin
B formulation (or other investigational therapy) is recommended. Voriconazole is not active
against mucormycosis.
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2.4.10. Guidelines for Empirical Antifungal Therapy with Amphotericin B or Caspofungin
Usage for Patients not “Off Study”
Limited empirical antifungal therapy may be given using amphotericin B (or one of the lipid
formulations of amphotericin B) or caspofungin. No other systemic antifungal is permitted
without approval of the medical monitor. Empirical antifungal therapy is intended for patients
strongly suspected to have invasive fungal infections where exhaustive diagnostic evaluation has
excluded other etiologies but has also failed to demonstrate a presumptive, probable or proven
invasive fungal infection as defined in Table 3.1.1a and b. It is generally intended for patients in
whom the criteria for possible invasive fungal infection in Tables 3.1.1a and b are met. The
guidelines for empirical therapy for the most common situations are below. In no case should it
be continued beyond 14 consecutive days. During an empirical trial of antifungal therapy,
efforts should continue to be undertaken to ascertain the etiology of the fever through cultures
and biopsies of pertinent tissue specimens.
2.4.10.1.
Required tests prior to use of empirical antifungal therapy
All focal lesions suspicious for fungi must be biopsied if clinically possible. Cultures of urine
and blood must be obtained. Isolator culture methods are preferred if available in your
institution. At least two blood samples for the diagnostic galactomannan assay should have been
obtained during the seven days (with at least one within 48 hours) before institution of empirical
antifungal therapy and should continue to be drawn along with blood samples for investigational
fungal diagnostic assays during the empirical therapy. In addition, one Pharmokinetics (PK)
blood sample should be obtained prior to the start of empirical antifungal therapy.
2.4.10.2.
Pre-engraftment requirements and amphotericin B/caspofungin dose
If the patient is neutropenic, has persistent fever (≥ 38°C) of unknown origin refractory to at
least 96 hours of broad-spectrum antibiotics or fever that recurs after 96 hours of antibiotics, and
a specific etiology cannot be established, an empirical trial of either amphotericin B at a dose of
1.0 mg/kg/d (or one of the lipid formulations at a dose of 4-5 mg/kg/d) or caspofungin (in
accordance with manufacturer prescribing guidelines) is permitted. Generally, the loading dose
for caspofungin is 70 mg on day one and 50 mg/day on subsequent days for patients over 12
years of age. This may be continued until resolution of neutropenia (ANC > 500) but should not
be continued beyond 72 hours after resolution of neutropenia and not longer than 14 consecutive
days.
2.4.10.3.
Post-engraftment requirements and amphotericin B/caspofungin dose
If the patient is post-engraftment and meets the criteria for possible infection in Table 3.1.1b and
attempts to document etiology have failed, an empirical trial of an amphotericin B formulation or
caspofungin is permitted. Continued radiographic procedures, cultures, biopsies, and other
pertinent diagnostic evaluations should be performed in an effort to elucidate the suspected
infection. If these measures fail, then the empirical trial should be terminated after no more than
14 days. If the physician feels that additional therapy is warranted this should be discussed with
the medical monitor or one of the protocol chairs. The dose of amphotericin B or one of the lipid
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formulations of amphotericin B should be 1.0 mg/kg/d (for conventional amphotericin B) or 4-5
mg/kg/d for the lipid formulations. The dose of caspofungin should be in accordance with
manufacturing guidelines, generally, 70 mg on the first day followed by 50 mg/day on
subsequent days for patients over 12 years of age.
2.4.10.4.
Continuation of study drug during empirical antifungal therapy
There are no data to suggest antagonism of voriconazole or fluconazole with amphotericin B or
caspofungin. So as to avoid fluctuations in the drug levels of concomitant immunosuppressive
agents, it is recommended that the study drug be continued during empirical therapy.
If the clinician does not discontinue empirical amphotericin B or caspofungin within the 14 days,
then the study drug will be withdrawn. The patient will continue to be monitored for all study
assessments for the remainder of the study duration (one year) and continue to have
galactomannan assays performed according to the study schedule.
2.4.11. Other Antifungal Therapy
Topical antifungal therapy is permitted and should be documented on the appropriate case report
form. Nebulized or inhaled amphotericin B is not permitted. Systemic amphotericin B (or one
of its lipid preparations) and caspofungin are the only systemic antifungal agents permitted on
study but are only permitted as specified as empirical therapy for possible infection (or for
presumptive, probable or proven invasive infection) as specified above in Section 2.4.10.
If a patient is prematurely withdrawn from study drug prior to Day 100 (or 180) for reasons other
than a probable or proven invasive fungal infection, only fluconazole will be allowed as
prophylaxis until Day 100 (or 180) with permission of the Medical Monitor or Protocol Chair.
No other antifungals are allowed for prophylaxis.
Fungal prophylaxis must not be given after protocol-specified treatment plan is completed on
Day 100 (or 180).
If a patient develops a presumptive, proven or probable fungal infection as specified in Table
3.1.1a and b, the clinician can employ other antifungal therapy as appropriate.
2.4.12. Use of the Galactomannan Assay
The galactomannan assay is used with host and clinical factors to determine the likelihood of
invasive aspergillus infection. The galactomannan assay detects only aspergillus and
penicillium. The sensitivity and specificity of the galactomannan assay are reported as 90% and
98% respectively [32]. The positive and negative predictive values are 88% and 98%
respectively [32]. Many invasive fungi other than aspergillus can cause invasive infection
without galactomannan positivity. Thus, a negative test does not exclude the possibility of
infection by fungi.
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A positive galactomannan assay satisfies only the microbiologic criterion for invasive fungal
infection as defined in Tables 3.1.1a and b. In the event that a positive result is obtained,
additional radiographic, cultural, and other diagnostic tests should be performed, and a repeat
specimen for the galactomannan assay should be sent. The study drug should be continued while
these investigations are underway.
There have been reports of false positive results using the galactomannan assay in patients
receiving concomitant piperacillin-tazobactem (Zosyn). In addition, certain lots of Zosyn have
tested positive. However, piperacillin alone does not test positive. As a result, positive
galactomannan results in patients receiving piperacillin/tazobactam (Zosyn) should NOT be
considered a microbiological criterion to support documentation of an invasive fungal infection.
Other diagnostic methods should be pursued. Subsequent positive galactomannan results should
not be considered as microbiological criteria until the patient has been off of Zosyn for 5 days.
One other secondary endpoint to be evaluated is the utility of the galactomannan assay to
determine response to therapy. Accordingly, if the patient develops a presumptive, probable or
proven invasive fungal infection, twice weekly monitoring of treatment galactomannan samples
should be collected at onset and after initiation of treatment for the infection for four weeks, then
once every two weeks for eight weeks for a total of 12 samples. These samples will be frozen
and batch shipped to the Repository. The assays will be performed after completion of study
enrollment at Dr. Kieren Marr’s laboratory at FHCRC. The investigators will be blinded to the
results.
For the galactomannan assays, all specimens are to be collected, processed, and transported in
accordance with the procedures in Appendices C and D.
2.4.13. Supportive Care
Blood products must be irradiated.
Antibiotics and intravenous immunoglobulin should be given according to institutional practice.
Growth factors should be given according to institutional practice.
Granulocyte transfusions are not permitted as part of routine care.
2.4.13.1.
Prophylaxis against infections
Patient should be given prophylaxis for:
1. Pneumocystis carinii: According to institutional practice.
2. Herpes viruses (HSV, VZV): According to institutional practice until neutrophil
engraftment for HSV+ recipients.
3. Encapsulated bacteria: According to institutional practice.
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The Manual of Procedures for Infection should be followed for patients with cytomegalovirus
(CMV) infections. In general, the guidelines for CMV prevention jointly developed by the
CDC/IDSA/ASBMT should be used. These can be accessed from the CDC website:
http://www.cdc.gov/mmwr/PDF/RR/RR4910.pdf.
2.4.13.2.
Identification of opportunistic infections
In the event that a patient develops fever, sinusitis, interstitial pneumonia, diarrhea, or hepatitis,
all efforts will be made to identify the responsible organism. Cultures will include routine
bacterial, mycobacterial, fungal, and viral cultures. Bronchial lavages and open lung biopsies
will also be evaluated for pneumocystis carinii. If possible, these samples will also be evaluated
for RSV, other respiratory viral pathogens, and legionella. Stool samples will also be evaluated
for C. difficile toxin, cryptosporidium, and rotavirus. Samples will not be routinely sent for EM
studies. If a GI biopsy is performed, evaluation for CMV with immunofluorescence and PCR
should be considered.
When a fungal infection is suspected, radiographic studies and invasive diagnostic procedures
will be obtained as deemed necessary by the investigator. CT scans of the chest are
recommended in persistently febrile patients. CT scans of the sinuses are recommended in
patients with symptoms of sinusitis. Biopsies should be obtained whenever possible of tissue
from sites suspected to be infected. If biopsy is not feasible, BAL or a percutaneous needle
biopsy should be performed for evaluation of pulmonary infiltrates. Assays for bacteria, CMV,
fungi, PCP and respiratory viruses should be performed. If visual symptoms occur, an
ophthalmologic consult should be obtained if signs or symptoms are persistent. Blood and urine
fungal cultures should be obtained in all febrile patients and fungal cultures and stains obtained
of all specimens of suspected infection.
For non-fungal infections, a Post-Transplant Infection Report Form should be completed for
each infectious episode with a severity grade assigned for each known agent contributing to the
episode. A Fungal Infection Report Form incorporating the fungal infection-specific definitions
will be used for fungal infections.
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2.4.14. Diagnosis of GVHD
2.4.14.1.
Acute GVHD
Acute GVHD generally develops within the first three months after transplantation and appears
as a characteristic dermatitis often accompanied by hepatic cholestasis and enteritis. The clinical
appearance of skin GVHD can be mimicked by toxicity of the transplant conditioning regimen
and by drug reactions. Therefore, documentation of the diagnosis by skin biopsy is
recommended. Severity of liver GVHD is usually described according to the serum bilirubin
level. Hepatic GVHD cannot be assessed solely on clinical grounds in patients who have
concurrent drug toxicity, viral hepatitis, or toxicity caused by the pre-transplant chemotherapy
and irradiation. Liver biopsy can be helpful but often cannot be done because of clinical
contraindications such as thrombocytopenia. Gastrointestinal GVHD is characterized by watery
diarrhea with anorexia, nausea and vomiting accompanied in more severe cases by abdominal
cramps, gastrointestinal hemorrhage, and ileus. Eating often exacerbates symptoms. The
volume of diarrhea has been used as an indicator of the severity of gut GVHD, but this can be
inaccurate and highly variable from day to day. In many cases, it can be difficult to distinguish
GVHD from infectious enteritis, and endoscopic biopsy is often helpful and should be done
wherever possible. Prospective data related to symptoms of acute GVHD will be collected.
2.4.14.2.
Chronic GVHD
Manifestations of chronic GVHD typically do not occur until three to twelve months after
transplantation. Initial symptoms frequently include nausea, anorexia and weight loss, ocular
and oral sicca, and skin changes. Rash characteristically appears with pigmentary changes,
vitiligo, mottling, erythema, plaques, papules, nodules, poikiloderma, or exfoliation progressing
to sclerosis and contractures. Hair loss and onychodystrophy may also indicate chronic GVHD.
Cough and dyspnea with wheezing, rales, and abnormal PFTS may indicate pulmonary
involvement. Diarrhea and abdominal pain may occur but are relatively infrequent. Liver
involvement may be indicated by increased bilirubin and alkaline phosphatase and less
frequently by increased transaminase levels.
2.4.15. Risks and Toxicities
Recipients of allogeneic blood or marrow transplants incur risks from pre-transplant conditioning
and post-transplant therapy, which must be weighed against the risk of the disease for which the
transplant is prescribed. Major risks following transplantation include: 1) Infection which can be
of a fungal, bacterial, viral or parasitic nature. Often, these infections are life-threatening,
particularly when caused by viral or fungal agents, and are associated with a high mortality rate
in the transplant population; 2) GVHD, either acute or chronic in nature, may occur following
allogeneic blood or marrow transplants. 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 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., antibiotics, antifungal medications, etc.), and as a result of destructive processes (e.g.,
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infection, GVHD, etc.) or radiotherapy, and may have a fatal outcome; 5) for patients
transplanted for malignant disorders, Relapse of the underlying disease may occur, especially in
patients with advanced disease status at time of transplant; 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.
Damage to major body organs may include the brain, eyes, heart, lung, liver, and kidneys.
Possible late effects may include growth retardation deformities, cataracts, changes in endocrine
function, sterility, learning disabilities or brain damage, bone and joint abnormalities, and
secondary malignancy.
For specific study drug risks/interactions refer to Sections 2.4.5 and 2.4.7.
For toxicity assessment, refer to NCI’s Common Terminology Criteria for Adverse Events
(CTCAE) as a guideline for toxicity assessment. The CTCAE Document Version 3.0 can be
accessed at the web site: http://ctep.cancer.gov/reporting/ctc.html.
2.4.16. Genetic Variation Study Sampling: Single Nucleotide Polymorphisms from Donor
Subtle differences in different molecules of innate immunity may contribute to either the
predisposition or clinical course of infection with filamentous fungi. The allelic frequencies of
24 different genes [MBL2 (mannose-binding lectin 2), CCR5 (chemokine receptor 5), IL1RN
(interleukin-1 receptor antagonist), IL1A (interleukin-1 alpha), IL1B (interleukin-1 beta), IL6
(interleukin-6), IL8 (interleukin-8), IL8RA (interleukin-8 receptor type A), IL8RB (interleukin-8
receptor type B), IL10 (interleukin-10), TNFA (tumor necrosis factor alpha), TNFB (tumor
necrosis factor beta), MPO (myeloperoxidase), NRAMP1 (natural resistance-associated
macrophage protein 1), CHIT1 (chitotriosidase 1), FCGR2A (Fc-gamma receptor 2a), FCGR3A
(Fc-gamma receptor 3a), FCGR3B (Fc-gamma receptor 3b), MICA (MHC, major
histocompatibility complex, class I chain-related gene A), MICB (MHC class I chain-related
gene B), TLR4 (toll-like receptor 4), CD14, HBD-1 (beta defensin), IL-18 (interleukin 18) and
their intragenic polymorphic forms will be analyzed and this data will be compared to the
incidence and severity of fungal infection. The purpose of this study is to identify a group of
molecules of innate immunity, which may influence the risk and severity of invasive fungal
infection. Single Nucleotide Polymorphisms (SNPs) of the genes encoding the following two
cytochrome P450 proteins (3A4 and 2C19) will also be studied for a total of 26 genes.
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CHAPTER 3
3.
STUDY ENDPOINTS
3.1. Primary Endpoint
The primary endpoint for this study of prevention of invasive fungal infections in allogeneic
blood and marrow transplants is fungal-free survival (proportion of patients alive and free from
proven, probable or presumptive invasive fungal infection) at 180 days post-transplant.
Fungal infections graded as colonization, superficial infection or possible invasive infection
(defined below) will not be counted as events for this endpoint. A fungal infection will be
defined in accordance with the following consensus EORTC/MSG1 criteria [53]:
Colonization: Defined as fungus or mould present in surveillance cultures in the absence of
clinical findings of fungal infection.
Superficial Infection: Includes cutaneous fungal infections, oropharyngeal candidiasis and
vulvovaginal candidiasis defined as:
1. Typical signs of mucocutaneous fungal infection
2. Positive fungal culture of scrapings, swab or exudate
3. Hyphae or pseudohyphae noted on Gram or other stain, or biopsy demonstrating invasive
fungal elements
4. Patients who develop superficial infections will be treated with topical antifungals and
continued on study medication
Invasive Infection: Defined as per Table 3.1.1a and 3.1.1b.
1 European Organization for Research and Treatment of Cancer-Invasive Fungal Infection Cooperative
Group/National Institutes of Allergy and Infectious Dieases-Mycoses Study Group.
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Table 3.1.1a
Definitions of Invasive Fungal Infections in Patients with Cancer and Recipients of
Hematopoietic Stem Cell Transplants
Category, Type of Infection
Description
Proven invasive fungal infections
Deep tissue infections
Mouldsa
Histopathologic or cytopathologic examination showing hyphae from needle
aspiration or biopsy specimen with evidence of associated tissue damage
(either microscopically or unequivocally by imaging); or positive culture
result for a sample obtained by sterile procedure from normally sterile and
clinically or radiologically abnormal site consistent with infection,
excluding urine and mucous membranes
Yeastsa
Histopathologic or cytopathologic examination showing yeast cells (Candida
species may also show pseudohyphae or true hyphae) from specimens of
needle aspiration or biopsy excluding mucous membranes; or positive
culture result on sample obtained by sterile procedure from normally sterile
and clinically or radiologically abnormal site consistent with infection,
excluding urine, sinuses, and mucous membranes; or microscopy (India ink,
mucicarmine stain) or antigen positivityb for Cryptococcus species in CSF
Fungemia
Mouldsa
Blood culture that yields fungi, excluding aspergillus species and Penicillium
species other than Penicillium marneffei, accompanied by temporally
related clinical signs and symptoms compatible with relevant organism
Yeastsa
Blood culture that yields Candida species and other yeasts in patients with
temporally related clinical signs and symptoms compatible with relevant
organism
Endemic fungal infectionsc
Systemic or confined to lungs
Must be proven by culture from site affected, in host with symptoms
attributed to fungal infection; if culture results are negative or unattainable,
histopathologic or direct microscopic demonstration of appropriate
morphological forms is considered adequate for dimorphic fungi
(Blastomyces, Coccidioides and Paracoccidiodes species) having truly
distinctive appearance; Histoplasma capsulatum variant capsulatum may
resemble Candida glabrata
Disseminated
May be established by positive blood culture result or positive for urine or
serum antigen by means of RIA [17]
Probable invasive fungal infections
At least 1 host factor criterion (see Table 3.1.1b); and 1 microbiological
criterion; and either a) 1 major (or 2 minor) clinical criteria from abnormal
site consistent with infection for sites other than lower respiratory tract, or
b) one of the clinical criteria for lower respiratory tract site
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Category, Type of Infection
Description
Presumptive invasive fungal infection
At least 1 host factor criterion (see Table 3.1.1b) and 1 clinical criterion
for lower respiratory tract infection as listed below. A microbiological
criterion is NOT required. The clinical criterion for lower respiratory
tract infection must be consistent with the microbiological findings, if
any, temporally related to current episode and other potential causes
must have been eliminated, along with:
The presence of one of the following “specific” imaging signs on
CT: (1) Halo sign, (2) wedge-shaped infiltrate, (3) air crescent
sign, OR
The presence of a new non-specific focal infiltrate, PLUS at least
one of the following: pleural rub, pleural pain, or haemoptysis,
AND no evidence of other etiology demonstrated by
bronchoscopic examination
Or if lacking a host criterion, but otherwise meets the microbiological
and clinical criteria for a presumptive, probable or proven invasive
fungal infection. The clinical criterion for lower respiratory tract
infection must be consistent with the microbiological findings, if any,
temporally related to current episode and other potential causes must
have been eliminated, along with:
The presence of one of the following “specific” imaging signs on
CT: (1) well-defined nodule with or without a halo sign, (2) halo
sign, (3) wedge-shaped infiltrate, (4) air crescent sign, (5) cavity
within area of consolidation OR
The presence of a new non-specific focal infiltrate, PLUS at least
one of the following: pleural rub, pleural pain, or haemoptysis
AND no evidence of other etiology demonstrated by
bronchoscopic examination
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Table 3.1.1a cont’d
Category, Type of Infection
Description
Possibled invasive fungal infections
At least 1 host factor criterion; and 1 microbiological criterion; or either a) 1
major (or 2 minor) clinical criteria from abnormal site consistent with
infection for sites other than lower respiratory tract, or b) one of the clinical
criteria for lower respiratory tract site
Notes for Table 3.1.1a
a Append identification at genus or species level from culture, if available.
b False-positive cryptococcal antigen reactions due to infection with Trichosporan beigelli (1), infection with Stomatococcus
mucilaginosis (2), circulating rheumatoid factor (3), and concomitant malignancy (4) may occur and should be eliminated if
positive antigen test is only positive result in this category.
c Histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis.
d This category is not recommended for use in clinical trials of antifungal agents but might be considered for studies of
empirical treatment, epidemiological studies, and studies of health economics
Table 3.1.1b
Host Factor, Microbiological, and Clinical Criteria for Invasive Fungal Infections in
Patients with Cancer and Recipients of Hematopoietic Stem Cell Transplants
Type of Criteria
Criteria
Host factors
Neutropenia (< 500 neutrophils/mm3 for > 10 days)
Persistent fever (≥ 38°C) for > 96 h refractory to appropriate broad-
spectrum antibacterial treatment in high-risk patients
Body temperature either > 38oC or < 36oC and any of the following
predisposing conditions: prolonged neutropenia (> 10 days) in previous
60 days, recent or current use of significant immunosuppressive agents
in previous 30 days, proven or probable invasive fungal infection during
previous episode of neutropenia, or coexistence of symptomatic AIDS
Signs and symptoms indicating graft-versus-host disease, particularly
severe (Grade > 2) or extensive chronic disease
Prolonged (> 3 weeks) use of corticosteroids in previous 60 days
Microbiological
Positive result of culture for mould (including aspergillus, Fusaruim, or
Scedosporium species or Zygomycetes) or Cryptococcus neoformans or
an endemic fungal pathogena from sputum or bronchoalveolar lavage
fluid samples
Positive result of culture or findings of cytologic/direct microscopic
evaluation for mould from sinus aspirate specimen
Positive findings of cytologic/direct microscopic evaluation for mould or
Cryptococcus species from sputum or bronchoalveolar lavage fluid
samples
Positive result for aspergillus antigen in blood samples as defined in
Section 3.2
Positive result for aspergillus antigen in specimens of bronchoalveolar
lavage fluid or CSF
Positive result for cryptococcal antigen in blood sampleb
Positive findings of cytologic or direct microscopic examination for fungal
elements in sterile body fluid samples (e.g., Cryptococcus species in
CSF)
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Table 3.1.1b cont’d
Type of Criteria
Criteria
Microbiological (cont’d)
Positive result for Histoplasma capsulatum antigen in blood, urine, or CSF
specimens [17]
Two positive results of culture of urine samples for yeasts in absence of
urinary catheter
Candida casts in urine in absence of urinary catheter
Positive result of blood culture for Candida species
Clinical
Must be related to site of microbiological criteria and temporally related to
current episode
Lower respiratory tract infection
The presence of one of the following “specific” imaging signs on
CT: (1) well defined nodule(s) of at least 1 cm in diameter with
or without a halo sign, (2) wedge-shaped infiltrate, (3) air
crescent sign, or (4) cavity within area of consolidationc, OR
The presence of a new non-specific focal infiltrate, PLUS at least
one of the following: pleural rub, pleural pain or hemoptysis
Sinonasal infection
Major
Suggestive radiological evidence of invasive infection in sinuses (i.e.,
erosion of sinus walls or extension of infection to neighboring structures,
extensive skull base destruction)
Minor
Upper respiratory symptoms (e.g., nasal discharge, stuffiness); nose
ulceration or eschar of nasal mucosa or epistaxis; periorbital swelling;
maxillary tenderness; black necrotic lesions or perforation of hard palate
CNS infection
Major
Radiological evidence suggesting CNS infection (e.g., mastoiditis or other
parameningeal foci, extradural empyema, intraparenchymal brain or
spinal cord mass lesion)
Minor
Focal neurological symptoms and signs (including focal seizures,
hemiparesis, and cranial nerve palsies); mental changes; meningeal
irritation findings; abnormalities in CSF biochemistry and cell count
(provided that CSF is negative for other pathogens by culture or
microscopy and negative for malignant cells)
Disseminated fungal infection
Papular or nodular skin lesions without any other explanation; intraocular
findings suggestive of hematogenous fungal chorioretinitis or
endophthalmitis
Chronic disseminated candidiasis
Small, peripheral, target-like abscesses (bull’s-eye lesions) in liver and/or
spleen demonstrated by CT, MRI, or ultrasound, as well as elevated
serum alkaline phosphatase level; supporting microbiological criteria are
not required for probable category
Candidemia
Clinical criteria are not required for probable candidemia; there is no
definition for possible candidemia
Notes for Table 3.1.1.b
a H. capsulatum variant capsulatum, Blastomyces dermatitidis, Coccidioides immitis, or Paracoccidioides brasiliensis.
b See Table 3.1.1a footnote b for causes of false-positive reactions that must be considered and eliminated from consideration.
c In absence of infection by organisms that may lead to similar radiological findings including cavitation, such as
Mycobacterium, Legionella, and Nocardia species.
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3.2. Secondary Endpoints
The secondary endpoints are:
1. Frequency of invasive fungal infections
2. Time to invasive fungal infection
3. Six-month and one-year patient survival
4. Empirical use of amphotericin B or caspofungin, frequency and duration of use
5. Time to and severity of acute and chronic graft-versus-host disease (GVHD)
6. Utility of galactomannan assay in diagnosis of aspergillus and response to therapy
7. Time to neutrophil engraftment
8. Time to platelet engraftment
9. Freedom from possible, presumptive, probable, or proven invasive fungal infection,
death, or withdrawal of study drug due to toxicity, intolerance, or an empirical trial of
amphotericin B or caspofungin > 14 consecutive days.
Other complications that are ordinarily seen during the course of BMT will be captured in BMT
CTN and IBMTR follow-up forms. Planned data to be collected, tabulated and analyses to be
performed include: association of CD4 counts with infection risk, rates of hepatotoxicity and
hepatic GVHD in the two cohorts, drug levels on Day 14 and 28 as they relate to subsequent
infection and toxicities, in vitro fungal susceptibility and occurrence of breakthrough infection
and response to therapy, and rates of possible fungal infections, fever of uncertain etiology, and
pulmonary infiltrates of uncertain etiology. Galactomannan levels will be collected, tabulated
and analyses of these data with various endpoints will be performed.
Neutrophil Engraftment: Neutrophil engraftment is defined as achieving ANC 500/mm3 for
three consecutive measurements over three or more days by Day 42. The first of the three
measurements may occur on Day 42. A patient receiving a second stem cell infusion prior to
Day 42 will be considered a graft failure.
Platelet Engraftment: Platelet engraftment will be defined as the first day of a minimum of
three consecutive measurements over three or more days such that the patient:
1. Has achieved a platelet count > 50,000/mm3, and
2. Is platelet transfusion independent for a minimum of seven days.
Acute and Chronic GVHD: Acute GVHD usually develops within the first three months after
transplantation and appears as a characteristic dermatitis often accompanied by cholestasis and
enteritis. Initial symptoms of chronic GVHD frequently include nausea and anorexia with ocular
and oral sicca. Rash characteristically appears with pigmentary changes progressing to sclerosis
and contractures. Other organs may be involved. Symptoms may mimic those seen in patients
with scleroderma and other autoimmune disorders.
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The staging of acute GVHD will follow NMDP guidelines but will include weekly capture of
symptoms and characterization of alternative causes. The highest level of organ abnormalities,
the etiologies contributing to the abnormalities and biopsy results pertaining to GVHD will be
identified. Staging and grading of acute GVHD are listed in the BMT CTN Manual of
Procedures (MOP).
Chronic GVHD typically does not occur until three or more months after transplantation. Details
regarding the definition and diagnosis are listed in the BMT CTN MOP.
Infection Grading: Definitions for fungal infections are provided in Section 3.1.1. Non-fungal
infections will be graded according to the severity scale defined in the BMT CTN Data
Management Handbook.
Galactomannan Positivity: A positive galactomannan assay is defined as two positives on the
same specimen or two consecutive positives on different specimens, i.e., a repeat test on the first
specimen was not performed. Sera with an index less than 0.5 are considered to be negative.
Sera with an index greater than or equal to 0.5 are considered to be initially positive.
Whenever a sample has an index 0.5, positivity must be confirmed by re-testing the sample,
including repeating the heat treatment on a new aliquot, and by testing another sample obtained
from the patient. This confirmation is necessary in order to eliminate any false-positive results
due to contamination of the sample after collection.
3.3. Safety Monitoring Endpoints
The rates of neural, cardiac, hepatic, and renal toxicities will be monitored up to 100 days post-
transplant, separately in each treatment arm. The definitions of these toxicities are described
below:
1. Neural toxicity is defined as convulsions.
2. Cardiac toxicity, defined as grade III toxicity on the Bearman scale, is severe EKG
abnormalities with no or partial response to medical intervention; or, heart failure with no
or minor response to medical intervention; or, decrease in voltage by more than 50%.
3. Hepatic toxicity, defined as grade III toxicity on the Bearman scale, is severe hepatic
dysfunction with bilirubin > 20 mg/dL; or, hepatic encephalopathy; or, ascites
compromising respiratory function.
4. Renal toxicity is defined as use of dialysis.
Monitoring will be performed monthly until enrollment to that treatment arm is closed. Each
month, the null hypothesis that the rate of convulsions is less than or equal to 10% will be tested
against the alternative that it is greater than 10%. Similarly, the rate of hepatic and renal
toxicities will be compared to thresholds of 8% and 10% respectively. The expected threshold
for cardiac toxicity is 2% and a formal monitoring plan was not developed. If the calculated
rates are significantly greater than the threshold rates (as defined in section 5.3.2), the NHLBI
will be consulted to determine if the Data Safety and Monitoring Board should convene to
review the data.
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3.4
Definition of Morphologic Complete Remission
Complete remission (CR) will be defined as all of the following according to the revised
recommendations of the international working group [61]:
1. A bone marrow aspirate containing spicules with < 5% blasts with a count of at least 200
nucleated cells and no Auer rods seen. If spicules are absent in the aspirate, a bone
marrow biopsy should confirm that < 5% blasts are present.
2. No evidence of a persistently abnormal leukemic population by flow cytometry.
3. ANC > 1000/L and platelet count > 100,000/L.
4. No extramedullary leukemia.
5. No blasts in peripheral blood.
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CHAPTER 4
4.
PATIENT ENROLLMENT AND EVALUATION
4.1. Enrollment and Randomization
4.1.1 Screening and Enrollment Procedures
Patients will be registered using the BMT CTN Electronic Data Capture System
(AdvantageEDCSM). The following procedures should be followed:
1. An authorized user at the clinical center completes the initial screening by entering
patient demographics, Segment O information (date informed consent signed) and
Segment A information (inclusion/exclusion criteria and HLA typing information) of the
Eligibility form preferably within 10 days prior to the initiation of the conditioning
regimen and no later than 72 hours prior to transplant (Day 0).
2. If patient is eligible, an ALT test should be obtained within 72 hours of Day 0.
3. An authorized user at the clinical center completes the enrollment process by entering
Segment B (dates of conditioning and proposed transplant, ALT value, baseline GM
sample and CT scan) of the Eligibility Form within 72 hours of Day 0.
4. If the patient is eligible, a study number and random treatment assignment is generated.
If a connection is interrupted during a randomization session, the process is completely canceled
and logged. A backup manual registration and randomization system will also be available to
provide for short-term system failure or unavailability.
4.1.2 Randomization
Patients will be randomized within 72 hours prior to Day 0. Patients will be stratified by center
and donor type (related vs. unrelated). Patients will be assigned to either voriconazole or
fluconazole in a 1:1 ratio.
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.
Follow-up Assessments: The timing of follow-up visits is based on the date of allogeneic blood
or marrow transplant. Following randomization, the Transplant Center can print a Patient Visit
Schedule listing target dates for assessments. Weeks 1-14, Day 120, and Day 150 visits are
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primarily for fungal assessments. The subsequent visits are for follow-up reports.
Galactomannan (GM) and investigational fungal diagnostic assays will be done up to twice
weekly during the first 100 days. In addition, blood for GM and fungal diagnostic assays will be
collected from patients with possible, presumptive, probable or proven infection as stated in
Section 4.2.2. All efforts should be made to obtain the samples. Failure to obtain all of the
samples does not constitute a protocol deviation.
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 submitted to
the DCC within the specified time will be considered delinquent. Transplant Centers can view
past due forms via the web-based electronic data capture system. A missing form will continue
to appear until the form is entered into AdvantageEDC, or until an exception is granted and
entered into the Missing Form Exception File, as detailed in the Data Management Handbook
and User’s Guide.
Reporting Patient Deaths: The Recipient Death Information must be entered into the web-
based electronic data capture system within one business day of knowledge of a 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 should be updated.
CIBMTR Data Reporting: All transplant centers will be required to pre-register all of their
transplant patients, not just those participating in BMT CTN protocols, with the Center for
International Blood and Marrow Transplant Research (CIBMTR). The IBMTR Day 100 Report
Form (including the Core, Graft and Disease Inserts) and IBMTR Follow-up Form (including the
Core and Disease Inserts) for patients participating in the BMT CTN protocols will be submitted
directly to the CIBMTR at the times specified in the Data Management Handbook and User’s
Guide.
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Table 4.2.1
FOLLOW-UP SCHEDULE
Assessment Time
Target Day1
(Days Post-BMT)
1 week2
7 days
2 week
14 days
3 week
21 days
4 week
28 days
5 week
35 days
6 week
42 days
7 week
49 days
8 week
56 days
9 week
63 days
10 week
70 days
11 week
77 days
12 week
84 days
13 week
91 days
100 day
100 days
120 day
120 days3
150 day
150 days3
6 month
180 days3
9 month
270 days3
12 month
365 days3
1 Target day range = 2 days up to Day 100, 14 days for Day 120 and 150, and 28 days for
Day 180, 270 and 365 post-transplant.
2 Samples for galactomannan (GM) assays will be drawn twice weekly on two non-consecutive
days, preferably three days apart (e.g., Mondays and Thursdays), during the first 60 days, once
weekly during Days 61-100 unless ONE of the following is met: (1) patient received a T cell
depleted transplant and received post-transplant GVHD prophylaxis, or (2) patient is on
steroids, or (3) patient has or has had acute GVHD requiring systemic therapy. These select
patients will have GM samples collected twice weekly during Days 61-100. Any patient that
has possible, presumptive, probable or proven infection will have additional samples collected
for GM assays as described in Section 4.2.2. Investigational fungal diagnostic blood samples
will be collected at each of these time points.
3 Data will be collected by telephone contact with the patient and/or treating physician if patient
is unable to return to the transplant center.
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4.2.2.
Assessments
Pre-transplant required for study
1. History, physical examination, weight, height, and BSA according to institutional
practice (preferably within one week of initiation of the conditioning regimen). Vital
signs within 48 hours of initiation of the conditioning regimen.
2. Serum creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase, and total bilirubin within 30 days of initiation of the conditioning regimen
(preferably within 7 days)
3. A CT scan of the chest (with contrast) and/or sinuses (without contrast) must be obtained
within three weeks (one week preferable) prior to initiation of conditioning regimen if the
patient has respiratory or sinus symptoms, or a history of pulmonary infection within the
preceding three months
4. Patients with signs or symptoms of respiratory infection or hepatosplenic candidiasis
(e.g., elevated alkaline phosphatase) should be evaluated with appropriate CT scans
within three weeks (one week preferable) prior to initiation of conditioning regimen
5. A pregnancy test must be obtained in women of childbearing age within 30 days prior to
start of the conditioning regimen (test must be negative to be eligible for study)
6. Karnofsky or Lansky performance status within one week of initiation of the conditioning
regimen
7. Whole blood (5 mL) to be cryopreserved at the transplant center for future testing (e.g.,
infectious disease testing) if consent obtained. This should be collected in a red top tube
and processed per Appendix C.
8. Whole blood or stem cell product from donor (5 mL) for SNPs assay if consent obtained.
This should be collected in a green top tube and processed per Appendix C.
9. EKG to exclude prolonged QTc syndrome
Pre-transplant generally performed for transplant eligibility
1. CBC (including hemoglobin and hematocrit), differential, platelet count within 48 hours
of initiation of the conditioning regimen
2. Serum creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase, and total bilirubin within one week of initiation of conditioning regimen
3. Urinalysis < 48 hours of initiation of the conditioning regimen
4. ABO and Rh typing
5. Serum chemistries including sodium, potassium, chloride, bicarbonate, blood urea
nitrogen, phosphate, calcium, albumin, and total protein < one week of initiation of
conditioning regimen and ≤ 72 hours of Day 0
6. Cardiac evaluation: echocardiogram or MUGA with ejection fraction (or shortening
fraction if appropriate) in accordance with institutional policies
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7. Pulmonary function evaluation: pulmonary function tests in accordance with institutional
policies
8. Serology for CMV, HSV, HIV, toxoplasmosis, varicella, hepatitis B-surface antigen,
hepatitis B-core antibody and hepatitis C in accordance with institutional policies
9. Sample of peripheral blood (3 mL) from donor and recipient to be stored for chimerism
studies at the home institution. This should be collected in a purple top tube and
processed according to local institutional practices.
10. A lumbar puncture is recommended if the patient has a history of CNS disease.
Post-transplant required for study
1. Pre-engraftment: CBC at least 3 times weekly until neutrophil engraftment (once ANC
≥ 500/mm3 for three consecutive days). Differential if WBC ≥ 500/mm3.
2. CBC and Absolute CD4 counts measured at Day 100 post-transplant.
3. Peripheral blood samples (5 mL) for analysis of fluconazole or voriconazole
concentrations collected at Day 14 and Day 28, and at onset of possible, presumptive,
probable or proven infection (prior to start of amphotericin B or caspofungin) and at time
of any suspected study drug toxicities delineated in Section 2.4.6. Blood is to be
collected during one of the windows relative to study drug administration as delineated in
Appendix C. Pediatric patients less than 12 years old will provide 2.5 mL of blood.
4. Serum creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase, and total bilirubin, on a weekly basis during the first 100 days or more
frequently if dictated by the condition of the patient, and if the patient is still on study
drug at Day 120, 150 and 180.
5. Blood samples (5 mL for adult, 2.5 mL for pediatric patients less than 12 years old) will
be obtained twice weekly on two non-consecutive days, preferably three days apart (e.g.,
Mondays and Thursdays), from Day 0 to Day 60 for diagnostic galactomannan testing
and processed in accordance with Appendices C and D. In addition, blood samples will
be obtained once weekly from Days 61 to 100 unless ONE of the following is met: (1)
patient received a T cell depleted transplant and received post-transplant GVHD
prophylaxis, or (2) patient is on steroids, or (3) patient has or has had acute GVHD
requiring systemic therapy. Blood samples from these patients will be collected twice
weekly from Days 61 to 100. In addition, at least two samples within the week before
(and one within the last 48 hours) should be collected at initiation of empirical antifungal
therapy for possible infection. Collection of blood for diagnostic galactomannan (GM)
assays should be continued twice weekly in patients receiving empirical antifungal
therapy (per Section 2.4.10) for possible invasive fungal infection.
6. Collection of blood for diagnostic GM samples should be continued once to twice weekly
until Day 100 in patients who have been prematurely withdrawn from study drug for
reasons other than presumptive, probable or proven fungal infection (see Section 2.4.6.1).
7. For patients prematurely withdrawn from study drug due to presumptive, probable or
proven aspergillus infection, monitoring of treatment blood GM samples (5 mL for adult,
2.5 mL for pediatric patients < 12 years old) should be collected at onset and twice
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weekly for four weeks and then once every two weeks for eight weeks (for a total of 12
samples) to monitor response. Collection of blood for diagnostic GM samples after
treatment of presumptive, probable or proven infection is at the discretion of the
investigator.
8. Blood samples (10 mL for adult; 5.0 mL for pediatric patients less than 12 years old) for
investigational fungal diagnostic (IFD) assays will be collected at the same frequency as
the diagnostic GM blood samples. Collection of IFD blood samples for patients with
presumptive, probable or proven fungal infection will be at the same frequency as the
monitoring of treatment GM samples and then 1-2x weekly until Day 100.
9. The center may make adjustments in blood volumes collected from patients less than 12
years old to meet the institution’s Human Investigation Committee Guidelines.
10. For any patient receiving a bronchoalveolar lavage, a 1 mL sample should be taken and
stored in a cryovial at –70C.
Post-transplant generally performed for transplant recipient
1. CMV surveillance should be performed according to institutional policy.
2. Post-engraftment: CBC and platelet count 3 times weekly until discharge from initial
hospitalization; Post-discharge: CBC and platelet count weekly until PRBC and platelet
transfusion independent, and at Day 100, 180, and 365. Differential should be done if
WBC is between 500-1500/mm3 at any time post-engraftment and at Day 100, 120, 150,
180 and 365.
3. Vital signs taken at least weekly up to Day 100 post-transplant and obtained from local
health provider at Day 120, 150, 180 and 365.
4. Clinical assessment weekly until Day 100, then by telephone contact at Day 120, 150,
180 and 365 to ascertain whether any signs, symptoms or clinical events have occurred
that suggest infection.
5. Serum chemistries including sodium, potassium, chloride, bicarbonate, blood urea
nitrogen, phosphate, calcium, and albumin, total protein on a weekly basis during the first
100 days or more frequently if dictated by the condition of the patient, and at Day 120,
150 and 180.
6. Serum creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase and total bilirubin at Day 120, 150 and 180.
7. Karnofsky/Lansky assessments by history and physical examination at Day 180 and 365.
8. Cyclosporine (or tacrolimus) blood levels should be assessed closely during the first one
to two weeks of study and doses adjusted in accordance with institutional policy. This is
important for patient safety because of drug interactions (see Section 2.4.7).
Measurement of cyclosporine or tacrolimus levels three times or more during the first
week may be necessary initially until drug levels are optimized. Clinical and laboratory
assessments of cyclosporine or tacrolimus toxicities should also be monitored closely.
9. Sample of peripheral blood (3 mL) or bone marrow from patient for chimerism studies to
document engraftment.
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4.2.3.
Fungal Infection (possible, presumptive, probable or proven)
1. Specimens from sites of suspected infection and blood will be obtained and analyzed for
fungi as clinical symptoms warrant. All isolates of yeast or mould organisms from blood
or tissue, if available, should be obtained by the PI, stored at the local institution and
shipped to the Study Repository in accordance with Appendix C. Antifungal
susceptibility testing will be conducted by the University of Florida.
2. CT scans of chest and sinuses should be obtained at diagnosis and preferably at least after
6 and 12 weeks of therapy and otherwise as clinically appropriate.
3. For patients with possible aspergillus infection, at least two blood samples within the
week before (and one within the last 48 hours) should be collected for diagnostic
galactomannan assays upon initiation of empirical antifungal therapy with amphotericin
B or caspofungin for possible infection. Collection of blood for diagnostic
galactomannan assays should be continued twice weekly in patients receiving empirical
antifungal therapy (per Section 2.4.10) for possible invasive fungal infection. These
samples should be shipped immediately to a certified reference lab. Investigational
fungal diagnostic samples should be collected at the same frequency as the diagnostic
galactomannan samples.
4. For patients with presumptive, probable or proven aspergillus infection, monitoring of
treatment galactomannan samples should be collected at onset and twice weekly for four
weeks and then once every two weeks for eight weeks (for a total of 12 samples) to
monitor response. These samples should be frozen and batched shipped quarterly to the
repository. Investigational fungal diagnostic samples should be collected at the same
frequency as the monitoring of treatment galactomannan samples and then 1-2x weekly
until Day 100.
5. Peripheral blood sample (5 mL for adult patients, 2.5 mL for pediatric patients less than
12 years old) for analysis of fluconazole or voriconazole concentrations to be collected
and processed as per Appendix C.
6. The center may make adjustments in blood volumes collected from patients less than 12
years old to meet the institution’s Human Investigation Committee Guidelines.
7. Paraffin blocks of tissue specimens demonstrating fungal infection should be saved and
shipped to the Study Repository in accordance with Appendix C.
4.2.4.
Discontinuation of Study Drug
1. Upon discontinuation of study drug, all patients will be assessed with regards to drug
efficacy in terms of the fungal definition criteria described in Section 3.1.1.
2. A physical examination including vital signs will be performed within 72 hours of
discontinuing study drug.
3. If previously positive, CT scans of chest or sinus should be performed within a 72-hour
window of study drug discontinuation and if abnormality suspected or proven to be
fungal in nature is still present then pertinent studies should be repeated approximately
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two weeks following study drug completion and subsequently repeated until resolution of
clinical or radiographic signs of infection, generally at no more than 6 week intervals.
4. Other follow-up diagnostic tests should be obtained as deemed appropriate by each
center's principal investigator.
5. Peripheral blood sample (5 mL for adult patients, 2.5 mL for pediatric patients less than
12 years old) for analysis of fluconazole or voriconazole concentrations (as per Appendix
C).
6. Any patient removed from study drug still should continue to have all study assessments
performed up through Day 365.
4.2.5.
GVHD Monitoring
GVHD should be monitored in accordance with BMT Clinical Trials Network guidelines as
specified in the Manual of Procedures, i.e., weekly until Day 70.
Follow-up GVHD assessments should be obtained at Day 90, 120, 180 and 365.
4.2.6.
Serious Adverse Event Reporting
Unexpected grade 3-5 Adverse Events (AEs) will be reported through an expedited AE reporting
system via the web-based electronic data capture system, AdvantageEDC. Unexpected grade 4-5
AEs must be reported within 24 hours of knowledge of the event. Unexpected grade 3 AEs must
be reported within 3 business days of knowledge of the event. Toxicities will be reported using
NCI’s Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 at regular
intervals as defined on the Form Submission Schedule. Decision to discontinue or re-administer
the study drug will be made on a case-by-case basis after discussion with the Medical Monitor or
one of the Protocol Chairs.
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Table 4.2.2 REQUIRED ASSESSMENTS
X = Required
Days Post Transplant
O = Generally Performed
Baseline 7
7
14
28
30
42
60
90
100
120
150
180
270
365
Pregnancy test (females only)
X
CT scan of the chest1
X
CT scans of sinus and abdomen2
X
X-At time of possible, presumptive, probable or proven fungal infection, Refer to Section 4.2.3
History, physical exam, weight, height, BSA, and
Karnofsky/Lansky performance status
X
O3
O3
CBC4, differential5 and platelet count4
X
X-Refer to Section 4.2.2 for frequency
O
O
O
O
O
CD4 Counts
X
EKG
X
Vital signs and clinical assessment
X
Generally performed weekly until Day 100
O
O
O
O
Serum chemistries
X
X-Refer to Section 4.2.2 for frequency but at least one per week until
Day 100
X9
X9
X9
Diagnostic galactomannan assay8 and investigational fungal
diagnostic (IFD) assay10
X
X-Refer to Section 4.2.4 for frequency; twice weekly until Day 60 and at least once weekly Day 61-100. Also prior to
and during empirical trials of amphotericin B or caspofungin for possible fungal infection.
Monitoring of treatment galactomannan assay8 and IFD
assay
X-At onset and twice weekly for 4 weeks and then once every 2 weeks for 8 weeks for a total of 12 samples for
patients with presumptive, probable or proven aspergillus infection. IFD continue 1-2x weekly until Day 100.
Whole blood sample: 5 mL (Pharmacokinetics)
X
X
X-Day 14 and 28 and at onset of possible, presumptive, probable or proven fungal infection
or serious suspected drug toxicity as described in Section 2.4.6.
Donor whole blood or stem cell product 5 mL for SNPs
X
Whole blood 5 mL6
X
Bronchoalveolar Lavage
X-At any time procedure is performed
Fungal Isolates
X-At time of possible, presumptive, probable or proven infection and every seven days if available following the
initiation of antifungal therapy or if infection relapses after therapy discontinued
Paraffin Blocks of Infected Tissues
X-At time of infection
1 Obtain within 6 weeks (one week preferable) prior to randomizaton if the results of a baseline galactomannan
assay are not available prior to randomization.
2 Refer to Section 4.2.2.4 for conditions.
3 Physical exam only.
4 Post-discharge CBC & platelet count must be done weekly until PRBC and platelet transfusion independent and at
Day 100, 180, 365.
5 Differential must be done if WBC = 500-1500/mm3 at any time post-engraftment and at Day 100, 180, 270, 365.
6 To be cryopreserved at the transplant center for future testing.
7 Baseline refers to prior to conditioning. Hepatic function tests
should be repeated within 72 hours of start of study drug. See
Section 4.2.2.
8 Refer to Section 4.2.2 for frequency in patients with possible,
presumptive, probable or proven infections.
9 If patient is on study drug until Day 180.
10 Investigational fungal diagnostic assays are not required at baseline.
.
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CHAPTER 5
5. STATISTICAL CONSIDERATIONS
5.1. Study Design
The study is designed as a Phase III, randomized, blinded, multicenter, prospective comparative
study of fluconazole versus voriconazole in the prevention of fungal infections in allogeneic
transplant recipients. The target enrollment is 600 patients.
Accrual
It is estimated that three years of accrual will be necessary to enroll the targeted sample size.
Both Core and non-Core Centers will enroll patients on this study. Accrual will be reported by
race, ethnicity, gender, and age (pediatric patients will be defined as < 18 years).
Randomization
Patients will be registered using the electronic data capture system, AdvantageEDC. Only
patients who have completed the screening process as described in Chapter 4 will be eligible for
randomization. All patients will be randomized within 3 days prior to the day of transplant.
Randomization will be performed in a 1:1 ratio using random block sizes for the voriconazole
and fluconazole arms. Randomization will be stratified by transplant center and donor type
(sibling versus unrelated donor).
Primary Endpoint
The primary endpoint is the fungal-free survival proportion at 180 days post-transplant. The
primary analysis will be performed using the intent-to-treat principle so that all randomized
patients will be included in the analysis. Death or the occurrence of a presumptive, probable or
proven invasive fungal infection by Day 180 will be considered events for this endpoint.
Primary Hypothesis
The primary hypothesis of the study is that the voriconazole treatment will improve Day 180
fungal-free survival as compared to the fluconazole treatment.
Ho:
pv = pf
Ha:
pv pf
5.2. Sample Size and Power Considerations
Fungal-free survival at 180 days will be compared between the standard and experimental
therapy arms using the standardized difference in the Kaplan Meier estimates of survival. The
final analysis will be performed after all patients have been followed for a minimum of 180 days
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post-transplant. At this time point, all individuals will have been completely observed for the
primary outcome. However, the Kaplan Meier test will be used rather than a binomial test of
proportions in order to ensure consistency with the results of interim analysis conducted with
incomplete follow-up. The sample size of 300 patients per group is sufficient to maintain type I
error of 5% across all planned interim analyses (see below) while providing > 80% statistical
power for a two-sided test to detect an increase in the proportion surviving fungal-free at 180
days from 0.50 in the standard therapy arm to 0.62 in the experimental arm.
5.3. Interim Analysis and Stopping Guidelines
Interim analyses for efficacy will be conducted at times coincident with regularly scheduled
meetings of the NHLBI-appointed Data and Safety Monitoring Board (DSMB) at approximately
six month intervals. Monitoring of key safety endpoints will be conducted monthly, and if rates
significantly exceed pre-set thresholds, the NHLBI will be consulted to determine if the DSMB
should be advised and if an ad-hoc meeting will be convened. Policies and composition of the
DSMB are described in the BMT CTN's Manual of Procedures.
5.3.1.
Interim Analysis for Efficacy
Analyses will be performed as described below for the primary endpoint. Toxicity, adverse
events, and other safety endpoints will be monitored regularly and reported to the DSMB at each
interim analysis.
At the time of each interim analysis, the test statistic based on the Kaplan-Meier proportion will
be compared to the critical value shown below. All patients randomized prior to the time of the
interim analyses will be used to compute the Kaplan-Meier estimate. If the test statistic exceeds
the critical value, the DSMB will discuss the continuation of the trial.
At each interim analysis time point, a two-sided test to detect either an increase or decrease in the
proportion of patients with fungal-free survival at 180 days will be performed, as described
above for the final analysis. In order to preserve the over-all type I error rate at 5%, the critical
value for the test statistic will be inflated above 1.96, the value that would be used if no repeated
testing were used. Equivalently, the nominal p-value at which an observed difference is declared
significant will be reduced below 0.05. The actual critical values and nominal p-values will be
computed using statistical methods for group sequential testing with O’Brien Fleming
boundaries.
As an example, Table 5.3.1a shows the critical values and nominal p-values for tests conducted
at 1.0, 1.5, 2.0, 2.5, 3.0 and 3.5 years after the study opens to enrollment. The column labeled
“followed to 180 days” shows the average number of individuals who have reached the 180-day
post-transplant follow-up time point, assuming uniform accrual over a three-year period. The
fraction of patients followed to 180 days, as compared to a denominator comprised of the total
sample of 600, quantifies the “statistical information” from which the critical values, nominal p-
values and cumulative type I error are computed.
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Table 5.3.1a Critical Values and Nominal P-Values
Calendar Time
Followed to 180 Days
Critical Value
Nominal P-value
Cumulative Type I Error
1.0
100
5.3660
.00000
.00000
1.5
200
3.7107
.00021
.00021
2.0
300
2.9697
.00284
.00305
2.5
400
2.5386
.00905
.01210
3.0
500
2.2522
.01605
.02815
3.5
600
2.0447
.02185
.05000
In practice, the rate of accrual or timing of DSMB meetings may not be as anticipated. To
permit necessary flexibility in scheduling interim analyses, the critical values will be recomputed
to correspond to the actual available statistical information using the “use-function” approach of
Lan and DeMets.
Operating Characteristics of the Design
Under the assumption that time to infection or death is exponentially distributed, the statistical
power to reject the null hypothesis of equal 180 day survival is shown below under a variety of
scenarios.
Table 5.3.1b – Power to Reject the Null Hypothesis under Various Scenarios
N
Proportion Surviving
Power at Interim and Final Analyses
Overall
Power
per
Fungal-Free at Day 180
By Year of Scheduled Analysis
Arm
Standard
Experiment
1.0
1.5
2.0
2.5
3.0
3.5
275
.50
.50
.0000
.0003
.0030
.0114
.0167
.0239
.0553
275
.50
.62
.0000
.0337
.1847
.2609
.2053
.1198
.8044
300
.50
.50
.0000
.0005
.0039
.0099
.0170
.0218
.0531
300
.50
.62
.0006
.0400
.2061
.2736
.2085
.1068
.8355
325
.50
.50
.0000
.0002
.0036
.0102
.0155
.0224
.0519
325
.50
.62
.0001
.0475
.2251
.2829
.2088
.1021
.8665
* from simulation with 10,000 replications, assuming exponential time to failure
5.3.2.
Guidelines for Safety Monitoring
The rates of neural, hepatic and renal toxicities will be monitored up to 100 days post-transplant,
separately in each treatment arm for all transplanted patients. Patients will be analyzed
according to their randomized treatment assigment. Refer to Section 3.3 for definitions of these
safety monitoring endpoints. Monitoring will be performed monthly until enrollment to that
treatment arm is closed. We expect approximately 20 patients to be on study at the time of the
first look. Each month, the null hypothesis that the rate of convulsions is less than or equal to
10% will be tested against the alternative that it is greater than 10%. Similarly, the rate of
hepatic and renal toxicities will be compared to thresholds of 8% and 10% respectively.
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An extension to the Sequential Probability Ratio Test (SPRT) will be used for each endpoint, as
described in greater detail below and in Appendix I. This sequential testing procedure conserves
type I error across all of the monthly examinations for a single endpoint, but not across the
multiple safety endpoints. Thus for a single endpoint, the type I error is approximately 5%, and
across all three safety endpoints, the study-wise type I error is < 15% per arm for a total of 30%
study-wide.
The rationale for not conserving type I error across multiple safety endpoints is twofold. First,
adjusting the size of the test for multiple comparisons would reduce statistical power to detect
adverse outcomes, which seems imprudent. Secondly, the procedure is a guideline for requiring
additional review by the Data and Safety Monitoring Board, and is not a formal “stopping rule”
that would mandate automatic closure of study enrollment.
The SPRT can be represented graphically. At each monthly interim analysis, the total time on
study is plotted against the total number of endpoints, (e.g., patients with convulsions). 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 100-day rates of convulsions.
If the graph falls below the lower boundary, the SPRT rejects the null hypothesis, and concludes
that there are more convulsions than predicted by the observed time on study. Otherwise, the
SPRT continues until enrollment to the treatment arm reaches the target goal.
This procedure assumes an exponential distribution for the time until failure during the first 100
days, but censors follow-up time after 100 days. Only endpoints that occur on or before the
patient has been followed for 100 days post-randomization are counted. Total time on study is
computed as time from randomization to event, or to 100 days, whichever comes first, summed
for all individuals on study. Death is a competing risk for the event, and time on study will be
censored at the time of death.
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 the following SPRTs:
A SPRT contrasting 10% versus 15% 100-day rate of convulsions, with nominal type I
and II errors of 9% and 15%, respectively. The common slope of the parallel lines is
2.076 and the intercepts are –10.755 and 8.635.
A SPRT contrasting 8% versus 13% 100-day rate of hepatic toxicity, with nominal type I
and II errors of 7% and 15%, respectively. The common slope of the parallel lines is
2.513 and the intercepts are –12.233 and 8.939.
A SPRT contrasting 10% versus 15% 100-day rate of use of dialysis, with nominal type I
and II errors of 9% and 15%, respectively. The common slope of the parallel lines is
2.076 and the intercepts are –10.755 and 8.635.
Note that since the test uses only the lower boundary, and is truncated by a finite sample size,
both the size and power of the test will be lower than nominal levels.
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The actual operating characteristics of the truncated test, shown in Table 5.3.2, were determined
in a simulation study that assumed uniform accrual of 300 individuals over a three-year time
period, and exponential time to failure after randomization. Since 100,000 replications were
used, the estimates have two digits of precision.
Table 5.3.2
Operating Characteristics of Sequential Testing Procedure
from a Simulation Study with 100,000 Replications
Neural Toxicity (Convulsions)
True 100-Day Rate
10%
15%
20%
Probability Reject Null
0.06
0.79
1.00
Mean Month Stopped
35.8
21.8
10.7
Mean # Endpoints in 100 days
28.4
25.2
15.3
Mean # Patients Enrolled
290.9
179.8
89.1
Hepatic Toxicity
True 100-Day Rate
8%
13%
18%
Probability Reject Null
0.05
0.81
1.00
Mean Month Stopped
36.1
21.2
10.2
Mean # Endpoints in 100 days
22.9
21.3
13.0
Mean # Patients Enrolled
292.7
175.3
85.3
Renal Toxicity (Use of Dialysis)
True 100-Day Rate
10%
15%
20%
Probability Reject Null
0.06
0.79
1.00
Mean Month Stopped
35.8
21.8
10.7
Mean # Endpoints in 100 days
28.4
25.2
15.3
Mean # Patients Enrolled
290.9
179.8
89.1
For example, the testing procedure for convulsions rejects the null hypothesis in favor of the
alternative 6% of the time when the true 100 day convulsion rate is 10%, and 79% of the time
when the rate is 15%. This corresponds to a type I error rate of = .06 and a type II error rate of
= .21. When the true 100 day convulsion rate is 15%, on average, the Data and Safety
Monitoring Board will be consulted 21.8 months after opening, when 25.2 convulsions have
been observed in 179.8 patients.
Since the expected rate of serious cardiac events is 2%, a formal monitoring rule will not be
used.
5.4. Demographic and Baseline Characteristics
Demographics and baseline characteristics will be summarized for all patients. Characteristics to
be examined are: age, gender, race/ethnicity, performance status, HLA match, primary disease,
risk status, prior history of fungal infections, source of stem cells, donor age, donor gender, and
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donor ethnicity. Between group comparisons will be performed for continuous variables via a t-
test and for categorical variables, via the chi-square test.
5.5. Analysis of Secondary Endpoints
1. Frequency of invasive fungal infections by Day 180: The Cochran-Mantel Haenszel
(CMH) test will be used to compare the proportion of patients with invasive fungal
infection between the treatment groups.
2. Time to invasive fungal infection: Cumulative incidence curves will be computed by
treatment. A stratified log-rank test will be used to compare the two arms. Also, a Cox
proportional hazards model will be fit to control for important prognostic variables.
3. Patient survival: Survival distribution will be estimated by the Kaplan- Meier curve. The
two treatment arms will be compared using the stratified log-rank test. A Cox
proportional hazard model will be fit to control for important prognostic variables. All
patients will be followed for a minimum of one year post transplant for mortality.
4. Empirical use of amphotericin B or caspofungin: This will be assessed by
measurement of proportions of patients with empirical use of amphotericin B or
caspofungin and total number of days on amphotericin B or caspofungin and compared
between the two treatment groups via the CMH and 2-way ANOVA respectively. Rank
(or other) data transformation may be used for the number of days on amphotericin B or
caspofungin for the 2-way ANOVA. The impact of use of amphotericin B or
caspofungin on the incidence of systemic fungal infections will be examined using
logistic regression. Duration of amphotericin B or caspofungin and the proportion of
patients who received > 14 days of consecutive amphotericin B or caspofungin use will
be assessed.
5. Time to acute or chronic graft-versus-host disease (GVHD): Cumulative incidence
curves will be computed by treatment. A stratified log-rank test will be used to compare
the two arms. Also, a Cox proportional hazards model will be fit to control for important
prognostic variables.
6. Exploratory analyses of quantitative aspects of galactomannan assay in diagnosis
and treatment of aspergillus in the presence of different patient conditions: The
objectives of the analyses are (1) to explore quantitative aspects of the assay to optimize
sensitivity and specificity in the setting of different host factors and manifestations of
aspergillus, (2) to determine if cases first detected by the galactommanan assay have
improved treatment outcomes as compared to cases first documented by other diagnostic
tests, and if galactomannan kinetics are predictive of clinical response to antifungal
therapy.
Objective 1
It is hypothesized that the performance of the assay will be dependent on circulating
fungal burden, which is potentially impacted by multiple host factors, and various
manifestations of aspergillus. Specifically, it is anticipated that pulmonary infections
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may be less likely detected by GM than disseminated infection, and sinus infections
will be the least likely to be detected by GM early.
Host factors that will be considered include: age, neutropenia or ANC > 500, receipt
of mould-active antifungal therapy, primary graft failure versus engrafters, and
receipt of voriconizole vs. fluconozole. Manifestations of aspergillus that will be
considered include: (1) site of infection (lung, sinus, extra pulmonary); (2) stage of
infection (localized versus disseminated); and, (3) causative aspergillus species.
Patients who develop aspergillus infection will be classified according to whether the
infection was first detected by GM positivity or by conventional means. The effects
of the host and infection factors listed above on the probability of first detection by
GM will be explored by conditional logistic regression modeling. If infection status
is not ascertained in all patients, more complex models that incorporate non-response
will be considered.
The proportion of patients diagnosed with aspergillus infection, and the median time
to first detection of the first episode of aspergillus, will be compared according to
whether the infection was first detected by GM positivity or conventional means.
However, the results are not expected to differ because the GM result will be reported
in real time to clinicians and will trigger a clinical work-up.
It is anticipated that one-third of cases of “possible” aspergillosis will be upgraded to
“probable” by incorporation of the GM assay. To test this hypothesis, the proportion
of cases reclassified from “possible” to “probable,” and its associated confidence
interval, will be estimated. More generally, the rates of reclassification will be
investigated using methods appropriate for ordinal responses on paired samples.
The performance (e.g., sensitivity and specificity) of diagnostic criteria that
incorporate the GM assay will be compared to a “gold standard” of the conventional
diagnostic criteria, using Receiver Operator Curve (ROC) methodology. The
semiquantitative GM index will be compared with baseline to determine what relative
increase in GM index occurs at the time of diagnosis by other diagnostic tests. Other
thresholds for determining a positive GM response will be investigated.
Objective 2
It is hypothesized that cases first detected by GM positivity will be less advanced
infections and will be more likely associated with survival than those detected by
other conventional diagnostic means. For cases detected by conventional means,
67% die. It is believed that the case fatality rate for GM-detected cases will be lower.
A survival model with two time-dependent indicator variables, representing the
absorbing states of first diagnosis by GM positivity, and first diagnosis by
conventional means will be employed. The hypothesis that GM-detected cases will
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have improved survival will be tested using a likelihood ratio test to compare the
coefficients for these terms.
In patients treated for aspergillosis, the temporal change in galactomannan level will be
tested as a guide to response to treatment and compared with clinical, cultural, and
radiographic parameters of response.
7. Engraftment: Rate of primary graft failure will be estimated using cumulative incidence
estimates. The treatment arms will be compared using the stratified log-rank test.
Neutrophil and platelet engraftment will be computed with cumulative incidence
estimates. The number of autologous recoveries will be reported.
8. Freedom from possible, presumptive, probable or proven infection, death or
withdrawal of study drug. Cumulative incidence curves will be computed by treatment.
A stratified log-rank test will be used to compare the two arms. Also, a Cox proportional
hazards model will be fit to control for important prognostic variables.
Two-sided tests will be used throughout. A p-value of 0.05 or less will be considered
statistically significant.
5.6. Safety Analysis
All entered patients will be included in the safety analysis:
1. Serious Adverse Events: All reported serious adverse events potentially associated with
study drug will be carefully examined with respect to the severity and relationship to
study drug. Adverse events will be graded according to the NCI Common Terminology
Criteria for Adverse Events Version 3.0. The incidence for each reported study drug
associated adverse event delineated in Section 2.4.5 will be presented for each group.
2. Clinical Laboratory Tests: Laboratory tests will be performed during the study.
Descriptive statistics will be calculated for each laboratory test. Abnormal laboratory test
results will be summarized in the report. Laboratory data will be cross-classified into
below, within, and above the reference range according to their values at screening and
during the study.
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APPENDIX A
REFERENCES
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APPENDIX A
REFERENCES
1. Wingard JR. Fungal infections after bone marrow transplant. Biol Blood Marrow
Transplant 5:55-68, 1999.
2. Goodman JL, Winston DJ, Greenfield RA: A controlled trial of Fluconazole to prevent
fungal infections in patients undergoing bone marrow transplantation. N Eng J Med
326:845, 1992.
3. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of
Fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and
intensity of cytotoxic therapy. Clin Infect Dis 28:331, 1999.
4. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of Fluconazole prophylaxis for
fungal infections after marrow transplantation – a prospective, randomized, double-blind
study. J Infect Dis 171:1545, 1995.
5. Marr KA, Seidel K, Slavin M, et al. Outcome of blood and marrow transplantation in
patients who received prolonged Fluconazole prophylaxis: long-term follow-up of a
randomized, placebo-controlled trial. Blood 96:12055, 2000.
6. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for
patients with chronic myeloid leukemia. N Eng J Med 338:962, 1998.
7. Recommendations of CDC, the Infectious Diseases Society of America, and the American
Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic
infections among hematopoietic stem cell transplant recipients. Biol Blood Marrow
Transplant 6:659-734, 2000.
8. Wingard JR, Chairman of the IBMTR/ASBMT/NIH State of Science BMT Meeting,
Infectious Complications Working Group, April 1, 2000, personal communication.
9. Marco F, Pfaller MA, Messer S, et al. In vitro activities of Voriconazole (UK-109-496) and
four other antifungal agents against 394 clinical isolates of Candida sp. Antimicrob Agents
Chemother 42:161, 1998.
10. Johnston D, Zhou X, Fukuoka T, et al. Voriconazole is highly active against the 14-
demethylase of Candida krusei. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 26-29, 1999, San Francisco, CA, abstract 2073.
11. Clancy CJ, Fothergill, Rinaldi MG, et al. SCH56592 and Voriconazole against emerging
yeasts: in vitro efficacy compared with Fluconazole and Itraconazole. 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy, September 26-29, 1999, San
Francisco, CA, abstract 1518.
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12. Pai MP, Prause JL, Danziger LH, et al. In vitro activity of Voriconazole and other azoles
against Candida isolates. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 17029, 2000, Toronto, Canada, poster presentation.
13. Schlamm HT, Corey L, Brown J, et al. Voriconazole for salvage treatment of invasive
aspergillosis. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy,
September 17029, 2000, Toronto, Canada, abstract 304.
14. Perfect J, Lutsar I, Gonzalea-Ruiz A. Voriconazole (VORI) for the treatment of resistant
and rare fungal pathogens. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 17029, 2000, Toronto, Canada, abstract 303.
15. Green BA, Breen A, Corey L. Voriconazole for salvage therapy of fungal infections in
patients with hematological malignancies and stem cell transplantation. 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy, September 17029, 2000, Toronto,
Canada, Abstract 41.
16. Johnston D, Cannom RRM, Filler SG. Amino acid substitutions in the aspergillus fumigatus
ERG 11 gene product render it resistant to itraconazole yet susceptibility to Voriconazole is
maintained. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy,
September 17029, 2000, Toronto, Canada. Abstract.
17. Torre-Cisneros J, Gonzalez-Ruiz A, Hodges MR. Voriconazole for the treatment of
S.apiospermum and S.prolificans infection. 40th Interscience Conference on Antimicrobial
Agents and Chemotherapy, September 17029, 2000, Toronto, Canada, Abstract 305.
18. Sabo JA, Abdel-Rahman SM. Voriconazole: a new triazole antifungal. Ann Pharmacother
34:1032, 2000.
19. Dupont B, Ally R, Burke J, et al. A double-blind, randomized, multicenter trial of
Voriconazole (VORI) vs Fluconazole (FLU) for the treatment of esophageal candidiasis (EC)
in immunocoompromised adults. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 17-20, 2000, Toronto, Ontario, Canada, Abstract 706.
20. Walsh TJ, Pappas P, Winston D, et al. Voriconazole versus liposomal amphotericin B for
empirical antifungal therapy of persistently febrile neutropenic patients: a randomized,
international, multicenter trial. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 17-20, 2000, Toronto, Ontario, Canada, abstract L-1.
21. Denning DW, Patterson TF, Herbrecht R, et al. Utility of criteria to assess outcome of
invasive aspergillosis: consistency of response assessments in a clinical trial. 40th
Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17029,
2000, Toronto, Canada, abstract 1325.
22. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral intraconazole versus
intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic
hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Itern
Med. 2003; 138:705-713.
23. Marr, K, Crippa F, Leisenring W, et al. Intraconazole vs Fluconazole for antifungal
prophylaxis in allogeneic HSCT recipients: results of a randomized trial. Blood 2002; 11:
(311), 215a (Abstrat 806).
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24. Jantunen E, Ruutu P, Hiskanen L, et al. Incidence and risk factors for invasive fungal
infections in Allogeneic BMT patients. Bone Marrow Transplant 19:801, 1997.
25. Wald A, Leisenring W, van Burik J-A, et al. Epidemiology of aspergillus infections in a
large cohort of patients undergoing bone marrow transplantation. J Infect Dis 175:1459,
1997.
26. Grow WB, Moreb JS, Roque D, et al. Late onset of invasive aspergillosis infection in bone
marrow transplant patients at a university hospital. Blood 94:341a, Abstract #1524,1999.
27. Ribaud P, Chastang C, Latge JP, et al. Survival and prognostic factors of invasive
aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis 28:322-330, 1999.
28. Morrison VA, Haake RJ, Weisdorf DJ. The spectrum of non-candida fungal infections
following bone marrow transplantation. Medicine 72:78, 1993.
29. Marr KA, Balajee A, Leisenring W, et al. Utility of galactomannan detection for the
diagnosis of invasive aspergillosis in HSCT recipients. Blood 96:786a, Abstract 3400, 2000.
30. Iwen PC, Reed EC, Armitage JO, et al. Nosocomial invasive aspergillosis in lymphoma
patients treated with bone marrow or peripheral stem cell transplants. Infect Control Hosp
Epidemiol 14:131, 1993.
31. Wald A, Leisenring W, van Burik J-A, et al. Epidemiology of aspergillus infection in a
large cohort of patients undergoing bone marrow transplantation. J Infect Dis 175:1459,
1997.
32. Maertens JA, Verhaegen J, Lagrou K, et al. Screening for circulating galactomannan as a
non-invasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and
stem cell transplantation recipients: a prospective validation. Blood 97:1604-1610, 2001.
33. Salonen J, Lehtonen O-P, Terasjarvi M-R, et al. Aspergillus antigen in serum, urine and
bronchoalveolar lavage specimens of neutropenic patients in relation to clinical outcome.
Scand J Infect Dis 32:485-490, 2000.
34. Denning DW. Early diagnosis of invasive aspergillosis. Lancet 355:423, 2000.
35. Becker MJ, de Marie S, Willemse D, et al. Quantitative galactomannan detection is superior
to PCR in diagnosing and monitoring invasive pulmonary aspergillosis in an experimental rat
model. J Clin Microbiol 38:1434-1438, 2000.
36. Ally R, Schurman D, Kreisel W, et al. A randomized, double-blind, double-dummy,
multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis
in immunocompromised patients. Clin Infect Dis 33:1447-1454, 2001.
37. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the
treatment of acute invasive aspergillosis. Clin Infect Dis 34:563-571, 2002.
38. Walsh TJ, Lutsar I, Driscoll T, DuPont B, Roden M, Gharamani P, Hodges M, Groll AH,
and Perfect JR: Voriconazole in the treatment of aspergillosis, scedosporiosis, and other
invasive fungal infections in children. Ped Infect Dis J 21: 240-248, 2002.
39. Herbrecht R, Denning DW, Patterson TF, et al. Open, randomized comparison of
voriconazole (VRC) and amphotericin B (AmB) followed by other licensed antifungal
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therapy of invasive aspergillosis (IA). Abstract J-680. p. 378 41st Annual Intersci Conf
Antimicrob Agents Chemother. 2001.
40. McGinnis MR, Nordoff N, Li RK, et al. Sporothrix schenkii sensitivity to voriconazole,
itraconazole and amphotericin. Med Mycol 39:369-371, 2001.
41. Fernandez-Torres B, Carrillo AJ, Martin E, et al. In vitro activities of 10 antifungal drugs
against 508 dermatophyte strains. Antimicrob Agents Chemother 45:2524-2528, 2001.
42. Carrillo AJ, Guarro J. In vitro activities of four novel triazoles against scedosporium spp.
Antimicrob Agents Chemother 45:2151-2153, 2001.
43. Meletiadis J, Meis JF, Mouton JW, et al. In vitro activities of new and conventional
antifungal agents against clinical scedosporium isolates. Antimicrob Agents Chemother
46:62-68, 2001.
44. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin
B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J
Med 346:225-234, 2002.
45. Cockgroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.
Nephron 16:31-41, 1976.
46. Ghahramani P, Purkins L, Kleinermans, et al. Voriconazole potentiates warfarin-induced
prolongation of prothrombin time. 40th Interscience Conference on Antimicrobial Agents
and Chemotherapy, September 17029, 2000, Toronto, Canada, abstract 846.
47. Ghahramani P, Purkins L, Wood ND, et al. Drug interactions between Voriconazole and
phenytoin. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy,
September 17029, 2000, Toronto, Canada, abstract 847.
48. Ghahramani P, Wood ND, Purkins L, et al. Effect of omeprazole on the pharmacokinetics of
Voriconazole. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy,
September 17029, 2000, Toronto, Canada, abstract 843.
49. Ghahramani P, Purkins L, Wood ND, et al. The pharmacokinetics of Voriconazole and its
effect on prednisolone disposition. 40th Interscience Conference on Antimicrobial Agents
and Chemotherapy, September 17029, 2000, Toronto, Canada, abstract 842.
50. Ghahramani P, Purkins L, Wood ND, et al. Effects of rifampicin and rifabutin on the
pharmacokinetics of Voriconazole. 40th Interscience Conference on Antimicrobial Agents
and Chemotherapy, September 17029, 2000, Toronto, Canada, abstract 844.
51. Ghahramani P, Purkins L, Klleinermans D, et al. Voriconazole does not affect the
pharmacokinetics of digoxin. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 17029, 2000, Toronto, Canada, abstract 849.
52. Ghahramani P, Romero AJ, Wood ND, et al. The effect of Voriconazole on the
pharmacokinetics of cyclosporin. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 17029, 2000, Toronto, Canada, abstract 845.
53. Ascioglu S, Res JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in
immunocompromised patients with cancer and hematopoietic stem cell transplants: an
international consensus. Clin Infect Dis 34:7-14, 2002.
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54. National Committee for Clinical Laboratory Standards. Reference method for broth dilution
antifungal susceptibility testing of yeasts. Approved standard M27-A. National Committee
for Clinical Laboratory Standards, Wayne, Pa, 1997.
55. National Committee for Clinical Laboratory Standards. Reference method for broth dilution
antifungal susceptibility testing of conidium-forming filamentous fungi. Proposed standard
M38-P. National Committee for Clinical Laboratory Standards, Wayne, Pa, 1998.
56. Marr KA, Carter RA, Cripa F, et al. Eidemiology and outcome of mould infections in
hematopoietic stem cell transplant recipients. Clin Infect Dis 34:909-917, 2002.
57. Purkins L, Wood N, Chahramani P, et al. Pharmacokinetics and safety of voriconazole
following intravenous to oral-dose escalation regimens. Antimiccrob Agents Chemother
46:2546-2553, 2002.
58. Lazarus HM, Blumer JL, Yanovich S, et al. Safety and pharmacokinetics of oral
voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol
42:395-402, 2002.
59. Romero AJ, Pogamp PL, Nilsson L-G, et al. Effect of voriconazole pharmacokinetics on
cyclosporine in renal transplant patients. Clin Pharmacol Ther 71:226-234, 2002.
60. Walsh TJ, Wood N, Milligan P, et al. Pharmacokinetics of intravenous voriconazole in
children after single and multiple dose administration. Abstract A17. In: 41st Interscience
Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 22 to 25,
2001. Washington, DC: American Society for Microbiology, 2001:2.
61. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised
recommendations of the international working group for diagnosis, standardization of
response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute
myeloid leukemia. J Clin Oncol 21(24): 4642-9, 2003.
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APPENDIX B-1
CONSENT FORMS
PARTICIPANT INFORMED CONSENT
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Informed Consent to Participate in Research
If you are a parent, as you read the information in this Consent Form, you should put yourself
in your child’s place to decide whether or not to allow your child to take part. Therefore, for the
rest of the form, the word “you” refers to your child.
If you are a child, adolescent or adult who is reading this form, the word “you” refers to you.
You are being asked to take part in a research study. This form tells you about
the study. The Principal Investigator (the person in charge of this research) or a co-
worker of the Principal Investigator will also describe this study to you and answer all
of your questions. Before you decide whether or not to take part, read the information
below and ask questions about anything you do not understand. Your taking part is
entirely your choice.
1.
Name of the Subject (“Study Subject”)
2.
Title of Research Study
A Randomized Double-blind Trial of Fluconazole Versus Voriconazole for the
Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow
Transplant Patients
3.
Principal Investigator Contact Information
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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 sponsor of this study, The National Institutes of Health (NIH), is providing the
study drugs and research tests free of charge to study subjects through the Blood and
Marrow Transplantation Clinical Trials Network (BMT CTN), a group of 32 U.S.
transplant centers.
5.
What is the purpose of this study?
You are being asked to take part in this research study because you are having a
blood or bone marrow transplant (BMT) using cells from another person.
One of the most common side effects of BMT is a decrease in the number or
strength of infection fighting cells (white blood cells) in the body. Infections are caused by
bacteria, viruses or fungi. When white blood cell numbers are low or the cells are weak,
the body can’t fight infections. For this reason, all BMT patients take drugs to prevent
infection by these germs.
Fungal infections are one of the worst forms of infection. One of the drugs used to
both prevent and treat fungal infections is called fluconazole. Fluconazole prevents some,
but not all, types of fungal infections. Voriconazole is a newer antifungal drug that can
treat more types of fungal infections than fluconazole. But, voriconazole has more side
effects than fluconazole. Although voriconazole is used to treat severe fungal infections, it
has not yet been tested for the prevention of fungal infections.
The purpose of this study is to compare fluconazole and voriconazole in the
prevention of fungal infections in blood or marrow transplant patients where another
person is the donor. About 600 patients will take part in this study at many centers
around the country.
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6.
What will be done if you take part in this research study?
Before starting treatment in this study, your doctor will check your general health.
This will include a physical exam and taking blood (about 3 teaspoons or 10-20 mL for
adult patients). A CT scan of the chest will be required if the results of the baseline
galactomannan blood draw are not available. A CT scan is a type of x-ray that takes many
detailed pictures. A chest CT scan results in an estimated dose of 0.8 rem, equivalent to
2.25 years of naturally occurring background radiation in the United States. A CT scan of
the abdomen and/or sinuses may be required. An abdomen CT results in 1.1 rem,
equivalent to 3 years. A head (sinus) CT results in 0.55 rem, equivalent to 1.7 years of
background. If you are a female able to have children, a pregnancy test will also be
performed. If you are pregnant, you will not be able to take part in this study.
If you choose to take part in this study, you will be randomly assigned (much like
the toss of a coin) to receive either fluconazole or voriconazole. You and your study
doctor will not know whether you are receiving fluconazole or voriconazole. This is called
a double-blind study. In an emergency, the name of your drug can be obtained quickly.
Treatment will begin on the day of your transplant (Day 0).
Since voriconazole is given twice per day and fluconazole only once per day, a
placebo (a pill with no active drug or a salt water infusion) will be used to keep us from
knowing which drug you are receiving. You will take the assigned drug twice a day.
Whenever possible, the drug will be given as pills. If you are unable to take pills, the drug
will be given over two hours by an IV infusion through your catheter. If you have been
assigned to fluconazole, one of the pills (or infusions) will be a placebo since fluconazole is
normally taken once daily.
You will continue the study drug until 100 days after your transplant. At around
90 to 100 days, your doctor will test your immune function and review your
immunosuppressive drugs. If your risk of fungal infection is high, you will stay on study
drug until 180 days. The study drug will stop by 180 days. But your doctor can give you
an antifungal drug for longer if he/she believes you need it.
While you are in the study, your doctor will conduct routine and study-specific
tests (such as x-rays, CT scans, or blood tests) and check you for a fungal infection. The
table below shows when you will have study-required blood tests. The tests are described
after the table.
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Time
Amount of Blood
per Draw (adults)*
Type of Test / Purpose**
Standard of CareS / InvestigationalI
Pre transplant
1 teaspoon (5 mL)
1 teaspoon (5 mL)
1 teaspoon (5 mL)
Liver function testsS/ eligibility
Galactomannan assayS/ eligibility
Future testingI/ research
3x/week until
engraftment
1 teaspoon (5 mL)
CBCS/ blood chemistry
1x/week until Day 100.
Also on Day 120, 150
and 180 if patient
remains on study drug
1 teaspoon (5mL)
Liver function testsS/ check for bad side effects
Day 14 and 28
1 teaspoon (5 mL)
Pharmacokinetics (PK) I/ test for drug levels
2x/week, Days 1 – 60
1 tablespoon (15 mL)
Galactomannan (GM) assayS and Investigational
Fungal DiagnosticsI/ tests for fungal infections
1x/week***, Days 61 –
100
1 tablespoon (15 mL)
GM assayS and Investigational Fungal
DiagnosticsI/ tests for fungal infections
If you have bad side
effects
1 teaspoon (5 mL)
PKI/ test for drug levels
If doctor suspects you
have a possible fungal
infection
4 teaspoons (20 mL) at
onset
1 tablespoon (15 mL)
2x/week for up to 14
days while on empirical
antifungal therapy
PKI/ test for drug levels, GM assayS and
Investigational Fungal DiagnosticsI/ tests for
fungal infections
GM assayS and Investigational Fungal
DiagnosticsI/ tests for fungal infections
If you get a fungal
infection
4 teaspoons (20 mL) at
onset
1 tablespoon (15 mL)
2x/week for 4 weeks
and then once every 2
weeks for 8 weeks, for
a total of 12 samples
PKI/ test for drug levels, GM assayI and
Investigational Fungal DiagnosticsI/ tests for
fungal infections
GM assayI and Investigational Fungal
DiagnosticsI/ measure response to treatment
*
Pediatric patients less than 12 years old will provide one-half of the required amounts of blood.
The center may make adjustments in blood volumes collected from patients less than 12 years old
to meet the institution’s Human Investigation Committee Guidelines.
** Tests that are typically done for your care are considered standard of care. These tests will be
charged to you. Tests that are done solely for research purposes are considered investigational and
will not be charged to you.
*** Patients will be tested twice weekly from Days 61-100 if they (1) received a T cell depleted
transplant (a transplant where certain white cells have been removed to reduce the risk of GVHD)
and post transplant GVHD prophylaxis (medications designed to prevent GVHD), or (2) have or
have had GVHD (a condition in which the donated cells recognize the recipient’s cells as non-self
and attack them) requiring systemic therapy, or (3) are taking steroids.
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Blood (1 tablespoon or 15 mL) will be taken prior to the transplant to determine
eligibility for the study. A small sample (1 teaspoon or 5 mL) will be saved for future
testing.
Blood samples (1 teaspoon or 5 mL) will also be taken 3x/week to determine
engraftment (when the infused stem cells begin to multiply its own cells in your bone
marrow). Engraftment typically occurs within 1-4 weeks post-transplant.
Weekly blood tests (about 1 teaspoon or 5 mL) will be taken for the first 100 days
(and on Day 120, 150 and 180 if you remain on study drug) to check for bad side effects.
Blood (1 teaspoon or 5 mL) will also be taken to measure drug levels at about Day 14 and
28, plus if you develop any bad side effects possibly related to the study drug, and at the
start of a fungal infection. Usually, blood can be taken from your central venous catheter.
In addition, we will also take blood (about 1 tablespoon or 15 mL), twice a week for the
first 60 days of the study, and extra samples if your doctor suspects you have an infection
to see if new tests can detect a serious fungal infection earlier and more easily than current
tests.
Blood samples will also be taken once per week from Days 61-100 unless: (1) you
received a T cell depleted transplant and received post-transplant GVHD prophylaxis or,
(2) you are on steroids, or (3) you have or have had acute GVHD requiring systemic
therapy. Then blood samples will be taken twice weekly from Days 61-100. Other tests
will also be done to see which treatment is more effective in treating infections.
If your doctor suspects a fungal infection he/she may give you a drug
(amphotericin B, Ambisome, Abelcet, Amphotec or Caspofungin) to treat it while he/she
is reviewing your symptoms. You will continue to receive the study drug. If the tests do
not show a fungal infection, your doctor will stop the other drug within 14 days. If your
doctor believes that you need the other drug after 14 days, then he/she will continue it but
the study drug will stop. You will continue to be tested as part of the study for the full
year. Your doctor will still do the research tests, including the blood tests described above
just as if you were taking the study drug.
If you get a fungal infection, the study drug will be stopped and another therapy
will be discussed with you. This could include voriconazole if your doctor believes it to be
the best choice. Your blood will be tested twice weekly for four weeks and then once
every two weeks for eight weeks, for a total of 12 samples, to test your response to
treatment.
This study will employ a new test approved by the FDA for detecting fungal
infections in adults using blood samples. It is called the galactomannan test.
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Galactomannan is a part of the fungus that gets into the blood of infected patients. Some
(1 teaspoon or 5 mL) of the blood samples described above will be used for this test.
This galactomannan test will be used with other standard tests to check you for
certain kinds of fungal infection. The results will be used along with your medical history,
physical check up, and other laboratory tests to judge whether you have or may have an
infection. If you have a procedure on your lungs known as a bronchoscopy to test for an
infection, a small part of the fluid obtained will be saved for later testing by the
galactomannan test and other investigational tests to see if these new tests are better than
the tests used now. The galactomannan test will also be used to test response to treatment
if you develop an infection.
It is not yet clear if the galactomannan test will be better than the old tests and it is
possible that it may not be as good in patients receiving one of the study drugs and certain
other antifungal drugs, including amphotericin B and caspofungin. One good thing about
this new test is that it requires only a sample of blood rather than a biopsy of tissue or
other more uncomfortable tests. It also may show infection earlier. However, it may not
be as exact. This could mean that if the test is positive and you really are not infected, you
may receive treatment you don’t need or if the test is negative and you really are infected,
you may not receive treatment you need. For these reasons, your doctor will be using
several kinds of tests for your safety. Results from this study will be used to measure the
new test’s value.
After your treatment is complete, we would like to keep track of your progress
until 12 months after your transplant. To do this, we will contact you or your local doctor.
7.
Will You Provide Samples for Research?
Genetic material is any sample of blood, tissue, fluid, etc. that is obtained from
you. You will be asked to provide samples of blood, tissue and fluid to be used solely
for future research and testing in laboratories where we are studying fungal infections.
These samples will not require additional procedures. Your name will not be on these
samples. You do not have to agree to provide these research samples to participate in
the study.
If you agree, a small blood sample (1 teaspoon or 5 mL) will be drawn pre-
transplant and saved for future testing. Additional blood samples (2 teaspoons or 10
mL) will be taken, if you agree, each time samples are drawn to test for galactomannan.
Usually the blood can be drawn from your central venous catheter at the time of other
blood collections. If this is not possible, then it would be drawn directly from a vein.
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If you agree, small samples of tissue or fluid (1 mL) will be collected post-
transplant and saved for future testing. These samples will be taken from samples that
are collected for diagnosis of potential fungal infections. Additional procedures are not
required.
The samples collected for research purposes will be sent to laboratories that have
contracts with the National Marrow Donor Program (NMDP) to conduct these research
tests. They will be labeled with unique codes that do not contain information that could
identify you. A link to this code does exist. The link is stored at the Data Coordinating
Center for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The
staff at the laboratories where your samples are being tested do not have a link to this
code. Your samples will be stored at these laboratories until the entire sample has been
used for the research tests or until the end of the study.
If any of your samples are leftover after the research studies are completed, these
samples will either be destroyed or be sent to the National Heart Lung and Blood
Institute (NHLBI) sample repository in Maryland. If your leftover samples are sent to
the repository, they will be given an anonymous code. These leftover samples stored at
the repository can never be linked to you. Any research performed on these left-over
samples must first be approved by an advisory panel at the NHLBI.
If you agree to allow your blood, tissue and fluids to be kept for research, you are
free to change your mind at any time. We ask that you tell [the Principal Investigator] in
writing and let him/her know you are withdrawing your permission for your samples to
be used for research. The mailing address is on the first page of this form. Any unused
samples will be destroyed. You are free not to take part in this future research and still
take part in the other parts of the study. There will be no change in your care if you
decide not to give these extra samples. Please mark your choice below for each sample:
(1) Pre-transplant 5 mL blood sample
I agree to have a blood sample drawn pre-transplant for future research and testing.
I do not agree to have a blood sample drawn pre-transplant for future research and
testing.
(2) Post-transplant 10 mL blood samples taken each time blood samples are taken for
the galactomannan (GM) assay
I agree to have blood samples drawn post-transplant for future research and testing.
I do not agree to have blood samples drawn post-transplant for future research and
testing.
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(3) Post-transplant tissue and fluid samples each time samples are taken post-
transplant for diagnosis of fungal infections
I agree to have tissue and fluid samples collected post-transplant for future research
and testing.
I do not agree to have tissue and fluid samples collected post-transplant for future
research and testing.
____________________________________ _______________________
Signature Date
8.
What are the possible discomforts and risks?
Cancer treatments can cause bad side effects, some of which may be life
threatening or could kill you. The drugs used in this study may cause all, some, or none
of the side effects listed below. Also, there is always the chance of unexpected new side
effects.
The most common side effect in patients who have received voriconazole has
been a change in eyesight that was often described as a “brightness” in vision that
usually lasts less than one hour. Some patients treated with voriconazole have reported
temporary glare or blurred vision. The effect may begin within 30 minutes after taking
a dose of voriconazole and lasts an average of one-half hour but may last up to one
hour. You should not drive or operate machinery during these periods. The next most
common side effect was abnormal liver tests.
The following side effects have been reported in more than 1% of patients who
have received voriconazole: a reaction at the site of injection, photosensitivity (a rash
caused by sunlight), weakness, dizziness, headache, trouble sleeping, dry mouth,
nausea, stomach pain, and low potassium levels. Other side effects that have been
reported in at least one patient that was treated with voriconazole include: skin rash,
skin erythema (redness), psoriasis (scaling) with eosinophilia (an abnormal blood
condition), hypoglycemia (low blood sugar), hepatitis (liver disease), nausea, vomiting
and jaundice (yellow skin), pancreatitis (a disease of the pancreas with pain in the
stomach), decrease in the number of cells in the bone marrow (this was reported in a
patient who had leukemia before starting voriconazole), and irregular heartbeat. An
irregular heartbeat resulting in death occurred during treatment in a patient who had a
history of an irregular heartbeat before entering the study. The patient also had a
history of cancer and was on chemotherapy and many other drugs (including a
potassium infusion, which may have affected the heart beat). In addition, an irregular
heartbeat possibly related to taking voriconazole with the medications pimozide,
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quinidine, dofetilide, and quinupristin-dalfopristin (an antibiotic) has been reported.
One patient with leukemia, who was also taking this antibiotic, was hospitalized
because of faintness and palpitations (rapid heartbeats).
Voriconazole may increase or decrease levels of other commonly prescribed
drugs and non-prescription drugs. Drugs known to interact with voriconazole include
warfarin, phenytoin, cyclosporine, tacrolimus, sirolimus, rifabutin, ompreazole and
rifampin. Other drugs that may interact with voriconazole include ritonavir, lovastatin
(and other statins), benzodiazepines, sulfonylureas, clarithromycin, terfenadine,
astemizole, cisapride, dihydropyridine calcium channel blockers (verapamil, diltiazem),
certain chemotherapy drugs (vinca alkaloids) and cabamazepine. We ask that you
consult with your doctor before starting new drugs or increasing the dose of any drug
including non-prescription drugs or herbs such as St. John’s Wort. Grapefruit juice
should be avoided. Other drugs that you may be taking may need to be changed or
stopped in order for you to receive voriconazole.
The most frequent side effects after treatment with fluconazole affect the
gastrointestinal tract (stomach and intestines) such as nausea and vomiting. Other side
effects include dizziness, headache, skin rash, and liver problems. Serious side effects
which have been reported with fluconazole include: liver damage which included
deaths primarily in patients with serious medical conditions; elevated liver tests; severe
skin disorders; hepatitis (liver disease), jaundice (yellow skin), irregular heartbeats or
heart function changes; and acute allergic reactions.
The risks of drawing blood from a vein include discomfort at the site of puncture;
possible bruising and swelling around the puncture site; rarely, an infection; and,
uncommonly, faintness from the procedure.
Only you, the person for whom it has been prescribed, can take the study drug. If
the drug is not packaged in a childproof container, you should keep it out of the reach of
children and persons who have limited ability to read or understand. By federal law, this
drug cannot be given or transferred to anyone for whom it is not prescribed.
As noted earlier, a new test, the galactomannan test, will be used along with other
tests to see if you have an infection and will be used to test your response to treatment if
you develop an infection. It is possible that this test may be less exact in patients taking
one of the study drugs (voriconazole) when compared to the other (fluconazole). It is
hoped that information from the study will help show that the new test can quickly and
easily detect fungal infections.
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Throughout the study, the researchers will tell you of new information that might
affect your decision to remain in the study.
If you wish to discuss the information above or any other discomforts you may
experience, you may ask questions now or call the Principal Investigator or contact
person listed on the front page of this form.
9a.
What are the possible benefits to you?
Although this study cannot be guaranteed to be of benefit to you, it is hoped that
your taking part may prevent you from getting a fungal infection. A possible advantage
of this study is that one antifungal treatment may prevent fungal infections better than the
other. However, you may not benefit from this treatment. The use of the galactomannan
test along with other diagnostic tests may allow us to more quickly and more easily
diagnose fungal infections and determine how well you respond to treatment if you
develop an infection. However, there is no guarantee that this test is better than the
currently available tests.
9b.
What are the possible benefits to others?
Future patients may benefit from the results of this study.
10.
If you choose to take part in this study, will it cost you anything?
Your cost for care on this research study will not be higher than for standard
treatment for this disease. The BMT CTN will cover the cost of the study drug. You
will remain responsible for the costs of standard treatment for your disease. Your
insurance provider may not cover all or part of these costs. You or your family will
have to pay installments based on your verified ability to pay. Any questions about
these charges should be discussed with the Principal Investigator of the study.
11.
Will you receive payment for taking part in this research study?
No.
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12.
What if you are injured because of the study?
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. You or your insurance provider will pay hospital expenses. No other
compensation is offered. If you have any questions about study-related injuries, you may
call [insert name of person at institution] at [insert phone number].
13.
What other options or treatments are available if you do not want to be in this
study?
Taking part in this study is entirely up to you. 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.
The current standard therapy for preventing fungal infections in patients receiving
bone marrow or stem cell transplant is fluconazole. Your doctor will review other
treatments with you.
14a.
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 and for us to use your data. If you
withdraw from the study, you will continue to have access to health care at [participating
clinical facility]. If you decide to withdraw, we ask that you tell [the Principal
Investigator] in writing; his/her mailing address is on the first page of this form. If you do
withdraw your consent, there will be no penalty and you will not lose any benefits to
which you are otherwise entitled. You will be asked to return any unused study drug.
You will also be asked to return for a checkup before you stop your study drug. Even if
you withdraw, or your doctor withdraws you, from the study, you are asked to have
research tests conducted and allow the study investigators to collect that information.
If you have any questions about your rights as a study subject, you may call the
Institutional Review Board (IRB) office at (xxx) xxx-xxxx.
14b.
If you withdraw, can information about you still be used and/or collected?
If you withdraw from the study, we ask that you agree that we can continue using
all information about you that has already been collected as part of the study prior to your
withdrawal, and to continue to allow your doctor to tell us about your progress until 12
months after your transplant. You may, of course, say no.
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14c.
Can the Principal Investigator withdraw you from this research study?
You can be taken off the study (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. Ask your doctor if you would like more information about this.
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 and the study treatment could be harmful to the fetus.
You are unable to keep appointments or take study drugs as directed.
Other study-specific reasons; for example, if the dose of study drug you are taking
has been found to be unsafe.
The study is cancelled by the Food and Drug Administration (FDA) or the National
Institutes of Health (NIH).
15.
How will your privacy and the confidentiality of your research records be
protected?
Study records that have your name will be kept private as required by law. You
will not be identified by name in the central study records. Your records will be given a
unique code number. The key to the code will be kept in a locked file in the Principal
Investigator’s office. Authorized persons from [the participating clinical facility], 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 their confidentiality
to the extent permitted by law. This research study is sponsored by and conducted with
funds from the National Institutes of Health; therefore, the sponsor, the Blood and
Marrow Transplant Clinical Trials Network (BMT CTN), the investigators conducting this
study and the FDA also have the legal right to review your research records. Otherwise,
your research records will not be shown to anyone 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
name will not be disclosed.
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
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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.
16.
Expiration date for retention of records
The study results will stay in your research record at (insert Institution) 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.
17.
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 the scientific press. In addition, the sponsor is paying the Principal
Investigator to conduct this study.
18. HIPAA2 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 A Randomized, Double-blind,
Trial of Fluconazole vs. Voriconazole for Prevention of Invasive Fungal Infections in
Allogeneic Blood and Bone Marrow Transplant Patients.
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).
2 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health
information
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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. John Wingard, Study Chairperson and staff/laboratories at University of
Florida College of Medicine
Dr.
Thomas
Walsh,
Study
Chairperson
and
staff/laboratories
at
NIH/NCI/POB
Staff/laboratories identified in the protocol for the evaluation of other
laboratory samples; e.g., Dr. Patricia Fraser/Harvard
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
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
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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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19.
Consent and Assent Instructions
Consent:
Subjects 18 years and older must sign on the subject line below.
For subjects under 18, consent is provided by the Legally Authorized
Representative
Assent:
Is required for subjects under the age of 18, using the Assent Section on
the following page.
I have been informed about this study’s purpose, procedures, possible benefits and
risks. I have been given the chance to ask questions. My questions have all been
answered satisfactorily. I understand that I can ask other questions at any time.
I voluntarily agree to take part, or to allow my child to take part, in this study.
By signing this consent form, I have not given up any of the legal rights that I (my child)
otherwise would have as a subject in a research study.
Subject‘s Signature
Date
If you are not the subject, please print your name
and indicate one of the following:
The subject’s parent
The subject’s guardian
A surrogate
A durable power of attorney
A proxy
Other, please explain:
Legally Authorized Representative Signature
Date
As a representative of this study, I have explained the purpose, the procedures, the
benefits, and the risks that are involved in this research study:
Signature of person conducting informed consent
Date
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ASSENT SIGNATURES: For subjects under the age of 18 years.
Assent of Minor
I have been told what I will be asked to do if I am in this study. I have been told that I
don’t have to be in this study. I may quit the study at any time, and no one will be mad
at me. I have had a chance to discuss the study and ask questions. My questions have
been answered. I agree to be in the study and do what I am asked to do so long as I
continue in the study.
Signature of Minor
Date
Age (years)
Study Personnel
I have explained the purposes, procedures, and risks involved in this research study in
detail to:
Print name(s) of Parents/Authorized Consenting Party, and
, who in my opinion
IS/
IS NOT capable of assenting to
participate in this study.
Print child’s name
Signature of Person Conducting Assent
Date
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B-2
APPENDIX B-2
CONSENT FORMS
DONOR INFORMED CONSENT
FOR SNP ASSAY
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CO-PRINCIPAL INVESTIGATORS: John R. Wingard, M.D. and Thomas J. Walsh, M.D.
STUDY TITLE: A Randomized, Double-blind, Trial of Fluconazole vs. Voriconazole for
Prevention of Invasive Fungal Infections in Allogeneic Blood and Bone Marrow
Transplant Patients
INTRODUCTION
We invite you to take part in a research study sponsored by the National Institutes of
Health (NIH).
First, we want you to know that:
Taking part in NIH research is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time. In
either case, you will not lose any benefits to which you are otherwise entitled.
You 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 have such beliefs, please discuss them with your doctors or research team before you
agree to the study.
Now we will describe this research study. Before you decide to take part, please take as
much time as you need to ask any questions and discuss this study with your family,
friends, or your personal physician or other health professional.
PURPOSE
During the course of this study, we will attempt to learn about genetic factors that may
have an influence on infections due to invasive fungal infections. This type of infection
occurs in individuals with a breakdown in the body’s immune system, due to either
medications, (such as corticosteroids) or in those who have had bone marrow
transplantation. We are interested in studying the small variations or differences in genes,
called polymorphisms or variants that could effect the body’s ability to fight off invasive
fungal infections. We also will study genes that help the body eliminate fluconazole and
voriconazole from the blood stream. We have identified a collection of genes (twenty-six),
each of which has one or more polymorphism. We would like to analyze your DNA for
these twenty-six genes to see if any of these genes are associated with fungal infections.
We invite you to participate in this study so that we can learn more about these genetic
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factors that may influence the susceptibility and severity of fungal infections in those who
undergo blood or marrow transplantation.
PROCEDURES
Five (5) milliliters of blood or stem cell product will be used for the genetic analysis. We
ask that you submit a sample of no more than 5 mL, equivalent to one teaspoon. It may be
necessary to perform a buccal swab of the inside of your mouth to obtain genomic DNA if
blood is unable to be drawn. If you withdraw from the study, your samples will not be used
for other research studies or tested further.
Clinical information (e.g., HLA typing) about you/your child will be collected. NIH will
not have access to the names of the patients enrolled in this study. The clinical information
will be coded and compared to the genetic analysis of the twenty-six genes chosen for our
study: MBL2, CCR5, IL1RN, IL1A, IL1B, IL6, IL8, IL8RA, IL8RB, IL10, TNFA, TNFB,
MPO, NRAMP1, CHIT1, FCGR2A, FCGR3A, FCGR3B, MICA, MICB, TLR4, CD14,
HBD-1, IL-18 and two cytochrome P450 genes (3A4 and 2C19). In the laboratory, we will
isolate DNA from your blood or stem cell product and test for each of these genes by
standard techniques. We shall determine normal and variant sequences in DNA and
compare this information to the clinical information collected.
ALTERNATIVES
You may choose not to participate in this part of the study. The decision to participate in
this study will not affect the care given to you by your physicians.
RISK AND DISCOMFORT
It is possible that the information from this study could be important for family members
(even though no blood and no analysis of family members are proposed). However
individual results will not be reported directly to you.
There is a small risk of an infection or fainting from the blood draw. If blood is not
available, a buccal swab from the inside of your mouth needs to be performed by a health
care provider. This may result in minimal discomfort in the mouth during the time the
cotton swab is rubbed against the inside of the cheek of your mouth.
At no time will this information be made available to those not directly involved in the
study without your written consent. Patient information will not be made public. Only the
results of the proposed analysis will be collected, presented and published. At no time, will
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the name or an identifier of patients be available to anyone except those conducting the
study. The investigators who will conduct the genetic analysis will not have access to the
names of the patients enrolled in this study. The clinical information will be coded and
compared to the genetic analysis of the twenty-six genes chosen for the study.
BENEFITS
This study will increase our understanding of the factors that influence the risk for
developing and treating fungal infections during bone marrow transplantation. We hope
that it will eventually contribute to improvements in medical care, treatment and prevention
of these types of infection. There may be no direct benefit to you or your family from this
study. If there are any questions, we will attempt to answer them with the most recent
information.
SAMPLES FOR RESEARCH AND FUTURE TESTING
Genetic material is any sample of blood, tissue, fluid, etc. that is obtained from you. You
will be asked to provide a sample of blood, stem cell or buccal product to be used solely for
future research and testing in laboratories where we are studying fungal infections. This
sample will not require additional procedures. You do not have to agree to provide this
research sample to participate in the study.
A portion of your 5 mL blood sample, stem cell product or buccal swab product, if you
agree, will be saved for future testing and research related to infectious diseases or the
immune system. These tests may include genetic analysis of your DNA beyond the 26
genes identified in this document.
The samples collected for research purposes will be sent to laboratories that have contracts
with the National Marrow Donor Program (NMDP) to conduct these research tests. They will
be labeled with unique codes that do not contain information that could identify you. A link
to this code does exist. The link is stored at the Data Coordinating Center for the Blood and
Marrow Transplant Clinical Trials Network (BMT CTN). The staff at the laboratories where
your samples are being tested do not have a link to this code. Your samples will be stored at
these laboratories until the entire sample has been used for the research tests or until the end
of the study.
If any of your samples are leftover after the research studies are completed, these samples will
either be destroyed or be sent to the National Heart Lung and Blood Institute (NHLBI) sample
repository in Maryland. If your leftover samples are sent to the repository, they will be given
an anonymous code. These leftover samples stored at the repository can never be linked to
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you. Any research performed on these leftover samples must first be approved by an advisory
panel at the NHLBI.
If you agree to allow your blood, stem cell or buccal product to be kept for research, you are
free to change your mind at any time. We ask that you tell [the Principal Investigator] in
writing and let him/her know you are withdrawing your permission for your sample to be used
for research. The mailing address is on the first page of this form. Any unused sample will be
destroyed. You are free not to take part in this future research and still take part in the
other parts of the study. There will be no change in your care if you decide not to give
this extra sample. Please mark your choice below:
I agree to use of a sample of my blood, stem cell or buccal swab product for additional
research or future testing.
I do not agree to use a sample of my blood, stem cell or buccal swab product for any
additional research or future testing.
________________________________________________________ __________________
Signature
Date
HIPAA3 AUTHORIZATION TO USE AND DISCLOSE INDIVIDUAL HEALTH
INFORMATION FOR RESEARCH PURPOSES
1. 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 A Randomized, Double-blind, Trial of Fluconazole
vs. Voriconazole for Prevention of Invasive Fungal Infections in Allogeneic Blood and
Bone Marrow Transplant Patients.
2. 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, physical examination
findings, and genetic test results.
3 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health
information.
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3.
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):
___________________________________________________________________
___________________________________________________________________
___________________________________________________________________
4. Parties Who May Receive or Use My Individual Health Information: The individual health
information disclosed by parties listed in item 3 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. John Wingard, Study Chairperson and staff/laboratories at University of Florida
College of Medicine
Dr. Thomas Walsh, Study Chairperson and staff/laboratories at NIH/NCI/POB
Staff/laboratories identified in the protocol for the evaluation of other laboratory
samples; e.g., Dr. Patricia Fraser/Harvard
National Heart, Lung and Blood Institute (NHLBI) and 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
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.
5. 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.
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6. 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.
7. 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.
8. This authorization does not have an expiration date.
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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 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 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 NIH medical records. However, you should know that
the Act allows release of some information from your 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 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 have the right to pursue legal remedy if you believe that your 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.
4. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research
participant, or about any research-related injury, contact the Principal Investigator at (xxx) xxx-xxxx.
5. Consent Document. Please keep a copy of this document in case you want to read it again.
COMPLETE APPROPRIATE ITEM BELOW, A or B
A. Adult Patient's Consent.
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.
Signature of Adult Patient & Date Signed
THIS CONSENT DOCUMENT HAS BEEN APPROVED
FOR USE FROM _________ THROUGH __________.
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 give permission for my child to take part in this study.
(Attach NIH 2514-2, Minor’s Assent, if applicable)
Signature of Parent(s)/Guardian & Date Signed
If other than parent, specify relationship:
Child's Verbal Assent (if applicable).
The information in the above consent form has been
adequately described to my child in language that my child
can understand, and my child willingly agrees to participate
in the study.
Signature of Parent(s)/Guardian & Date Signed
Signature of Investigator & Date Signed
Signature of Witness & Date Signed
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APPENDIX C
LABORATORY PROCEDURES
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APPENDIX C
LABORATORY PROCEDURES
LABORATORY SPECIMEN COLLECTION, STORAGE AND SHIPPING
PROCEDURES
Standard procedures for collection, storage, and shipping of specimens will be followed
according to the NMDP and the NHLBI guidelines. Samples will be given a unique
alphanumeric code that contains no personal identifiers. Transplant Center Coordinators will
hold the link to the code. Laboratory staff will not have access to the link.
LABORATORY CONTRACTS AND REMAINING SAMPLES
All laboratory studies will be performed at laboratories under contract with the NMDP on behalf
of the BMT CTN. The laboratory contract specifies that any remaining sample must be stored at
the laboratory for the duration of the study. If the investigators choose to perform additional
studies on these remaining samples, a formal amendment will be made to the protocol. Any
amendments to the protocol are subject to the DSMB and IRB approval process.
At the end of the study, the BMT CTN will either instruct the laboratory to destroy any
remaining samples or to transfer the remaining samples to the NHLBI sample repository in
Maryland. These 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. An
NHLBI Biologic Specimen Repository Utilization Committee will advise the Institute on
requests for specimens to perform research with these anonymous samples. If an investigator
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
his/her research protocol. Samples sent to researchers cannot be linked with any remaining
sample at the repository.
PHARMACOKINETICS
Blood for analysis of fluconazole and voriconazole concentrations will be obtained on Day 14
and 28 of therapy, at onset of serious suspected study drug toxicities as delineated in Section
2.4.6 and at onset of possible, presumptive, probable or proven infection (prior to start of
antifungal therapy). Blood should be drawn in relationship to administration of the study drug in
one of three windows of time after the start of the infusion or administration of the oral dose:
Window 1 is 1-5 hours after start of the infusion; Window 2 is 5-8 hours after start of infusion;
Window 3 is 8-12 hours after start of the infusion. On the case report form, indicate the start
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time of the drug and the time of the blood draw. The form will calculate from which of the three
windows the blood was drawn. Testing of pharmacokinetic samples will be conducted at Dr.
Tom Walsh’s lab at NCI.
Collection and Processing: Collect 5 mL (2.5 mL for patients less than 12 years old) of blood in
green top vacutainer; centrifuge for 20 minutes within 120 minutes (preferably 60 minutes) of
collection at 450 x g or 1500 rpm; transfer plasma to a cryovial; sample may stored at 2-8ºC for
24 hours prior to cryopreservation at -70ºC; batch ship frozen samples on dry ice quarterly to the
repository.
ANTIFUNGAL SUSCEPTIBILITY TESTING
Collection and Processing Procedures: All fungal isolates will be collected and identified to the
species level at participating centers. Isolates will then be streaked onto Sabouraud dextrose agar
slants, grown at 35°C until confluent, and stored at –20°C until use. Serial isolates from a given
patient will be collected every seven days when possible following initiation of antifungal
therapy, or if infection relapses following the discontinuation of therapy. Frozen isolates will be
shipped in batch quarterly to the Study Repository in compliance with the shipping procedures
specified in the BMT CTN MOP. The antifungal susceptibility testing will be performed by Dr.
Nguyen at the University of Florida College of Medicine.
Assay Procedures: The antifungal susceptibility testing will be performed according to the
NCCLS recommendations (NCCLS M27-A for yeast and NCCLS M38-P for moulds) [54, 55].
The susceptibility testing will be performed in batch, and repeated twice on two different days to
ensure that the results are reproducible. The reference isolate Aspergillus flavus ATCC 204304
and the quality control strain Candida parapsilosis ATCC 22019 will be included in each batch
of testing as control isolates.
1. Hypothesis
The hypothesis, for patients treated with fluconazole, is that breakthrough fungal infections
will be caused by yeasts or moulds exhibiting elevated fluconazole minimum inhibitory
concentrations (MICs). A number of these organisms, however, will exhibit low MICs of
voriconazole. The hypothesis, for patients treated with voriconazole, is that breakthrough
fungal infections will be caused by yeasts or moulds exhibiting elevated MICs of both
fluconazole and voriconazole. These organisms will also exhibit elevated MICs of
itraconazole, consistent with broad azole cross-resistance. In addition, we hypothesize that
mould infections in patients receiving fluconazole will be primarily caused by aspergillus
spp., whereas mould infections in patients receiving voriconazole will be caused by Rhizopus
or moulds other than aspergillus spp.
2. Antifungal Agents
All isolates will be tested in vitro against fluconazole (Pfizer Inc., New York, NY),
itraconazole (Janssen Pharmaceutical, Titusville, NJ), and voriconazole (Pfizer Inc., New
York, NY). The antifungal agents will be provided by the manufacturers as assay powders.
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3. Assay Medium
The medium used will be RPMI 1640 medium without sodium bicarbonate and with L-
glutamine. It will be buffered to pH 7.0 with 0.165 M morpholinepropanesulfonic acid, and
sterilized by filtration.
4. Drug Concentration Ranges
Drug dilutions will be prepared at 100 times the final concentration in 100% dimethyl
sulfoxide followed by further dilutions (1:50) in RPMI-1640 medium to yield twice the final
concentrations required for the test. The final concentrations of the tested drugs will range
from 0.125 to 64 µg/mL for fluconazole and 0.03 to 16 µg/mL for itraconazole and
voriconazole. 100 µl of twofold serial dilutions of the antifungal drugs will be dispensed into
each well of sterile flat-bottomed plastic microtitre plates. Two drug-free-medium wells will
be used per row as sterility and growth controls. The plates will be prepared in batch and
stored at –70°C until used.
5. Inoculum Preparations
Yeasts: Two days before the susceptibility test, the yeast strains will be streaked for isolation
from the –70oC stock onto Sabouraud Dextrose Agar (SDA). These strains will be streaked
again onto SDA a day before the susceptibility test and incubated at 35oC. The yeast
suspension will then be prepared from five colonies of each culture to match the turbidity of a
McFarland 0.5 standard as determined by a standard spectrophotometric method. Further
dilutions will be made in RPMI 1640 medium to achieve a final yeast inoculum of 0.5 × 103
to 2.5 × 103 CFU/mL.
Moulds: Stock inoculum suspensions will be prepared as described in the NCCLS M38-P
document from 7-day-old cultures grown on potato dextrose agar slants and adjusted
spectrophotometrically to optical density that ranges from 0.09 to 0.3 (82 to 60%
transmittance). This stock solution will contain mainly conidia. The nongerminated conidial
inoculum suspensions will be diluted 1:50 in medium. The final concentration of stock
inoculum will range from 0.5 × 106 to 4.5 × 106 CFU/mL.
6. Determination of MICs
On the day of the test, the microtitre plates containing drug will be allowed to thaw at room
temperature. A 100 µl aliquot of the tested inoculum will be added to each well. The plates
will then be incubated at 350C and examined at the time points described. MIC will be
determined by visual inspection. For yeasts, the MIC will be determined at both 24 and 48h
according to a 0-to-4 scale, with 0 indicating an optically clear culture, 1 indicating a slightly
hazy culture, 2 indicating a prominent decrease in turbidity, 3 indicating a slight decrease in
turbidity, and 4 indicating no reduction in turbidity. The MIC will be defined as the lowest
concentration of a drug for which the score is 2 [54]. For moulds, the MIC will be
determined at 48h, and will be defined as the lowest drug concentration that yields a
prominent inhibition of growth compared to the growth control well [55].
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INVESTIGATIONAL FUNGAL DIAGNOSTIC ASSAYS TO DIAGNOSE
ASPERGILLUS AND OTHER INFECTIONS
New assays, including antigen, antibody, metabolite, and PCR techniques, are being developed
to improve diagnostic accuracy. Whole blood will be collected for storage and assay by future
investigational tests. These blood samples will be collected twice weekly on two non-
consecutive days, preferably three days apart (e.g., Mondays and Thursdays), during the first 60
days post-transplant and once weekly on Days 60-100 unless one of the following criteria is met:
(1) patient received a T cell depleted transplant and received post-transplant GVHD prophylaxis;
or, (2) patient is on steroids; or, (3) patient has or has had acute GVHD requiring systemic
therapy. Investigational fungal diagnostic samples will be collected twice weekly from these
select patients. Investigational fungal diagnostic samples will also be collected at onset of
possible, presumptive, probable and proven infections and twice weekly from patients receiving
empirical antifungal therapy for possible invasive infection. Investigational fungal diagnostic
samples will also be collected from patients with presumptive, probable or proven infection
twice weekly for four weeks, then once every two weeks for eight weeks and then once to twice
weekly until Day 100. The investigational assays will be conducted at Dr. John Wingard’s lab at
the University of Florida College of Medicine.
Collection and Processing:
Serum: Collect 5 mL (2.5 mL for patients less than 12 years old) of blood in red top vacutainer;
allow 15-30 minutes for clotting; centrifuge at 900 x g or 2100 rpm for 10 minutes; (clot and
serum should be distinct); carefully remove the serum without disturbing the clot (leaving behind
a small volume of serum if necessary) and transfer to a cryovial; sample may stored at 2-8ºC for
24 hours prior to cryopreservation at -70ºC; batch ship frozen samples on dry ice quarterly to the
repository.
Blood: Collect 5 mL (2.5 mL for patients less than 12 years old) of blood in green top
vacutainer; transfer whole blood, without centrifugation, to a cryovial; sample may stored at 2-
8ºC for 24 hours prior to cryopreservation at -70ºC; batch ship frozen samples on dry ice
quarterly to the repository.
GENETIC VARIATION STUDY SAMPLING SINGLE NUCLEOTIDE
POLYMORPHISMS (SNPs)
A major goal of human genetics is to understand the contribution of genetic diversity to disease
susceptibility and outcome. With the completion of a first generation map of the human genome,
a catalogue of known genes and their annotated sequence variations has begun to take shape1, 2.
DNA sequence variations include insertions, deletions, variable numbers of repeat sequences,
and single nucleotide polymorphisms (SNPs). The latter, SNPs, are the most common variants
that occur and create alleles that can be investigated for their association with a specific, defined
disease outcome3. Current estimates are that there could be as many as 10 million SNPs (defined
on the basis of the frequency of the minor allele being greater than 1% in at least one
population)4. Until recently, the ability to perform genetic association studies with SNPs has
been limited by the paucity of known SNPs. Advances in high-throughput sequence analysis and
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DNA chip arrays systems are generating an expanding set of reagents that can be used for
investigating the relationship between genetic variations and disease. For the past five years, we
have exclusively utilized the candidate SNP approach5. However, new technical developments
and comprehensive SNP catalogues should not only improve the utility of SNP association
studies, but also in the near future allow their use in classical linkage studies; however, for the
immediate future, this approach is not viable nor is it economically feasible to search for such
genetic markers. Accordingly, we will continue to concentrate on candidate SNPs to dissect
their genetic contribution to complex diseases6. The focus will shift from the study of previously
characterized SNPs of known biological importance, towards the identification of novel SNPs
and haplotypes in groups of genes belonging to key pathways. Haplotypes comprise a set of
genetic variants residing on one chromosome and represent ancestral segments inherited by
descent from shared ancestors7.
In order to validate SNPs and standardize assays, the laboratory devised a program that has been
adapted and supported by the Cancer Genome Anatomy Program (CGAP). This web-based
resource, the SNP500Cancer (http://snp500cancer.nci.nih.gov). SNP500Cancer is a new
database designed to publicly address the immediate needs for candidate SNPs and candidate
gene approaches to mapping complex diseases. SNP500Cancer provides bi-directional
sequencing information on a set of control DNA samples derived from anonymized subjects (102
Coriell samples representing four self-described ethnic groups: African/African-American,
Caucasian, Hispanic and Pacific Rim). All SNPs are chosen from public databases and reports,
and the choice of genes includes a bias towards nonsynonymous and promoter SNPs in genes
that have been implicated in one or more cancers. The website is searchable for SNPs by gene,
chromosome and by known dbSNP ID. For each analyzed SNP, gene location and over 200 bps
of surrounding annotated sequence (including nearby SNPs) are provided, with frequency
information in total and per sub-population. A calculation of Hardy-Weinberg Equilibrium is
included. Moreover, genotyping assays (5’-exonuclease, hybridization-triggered fluorescence,
and/or MALDI-TOF) were developed for SNPs with minor allele frequencies > ~5%. These
assays have been performed on the same 102 samples and the results compared for concordance
with the sequencing results. The website will soon post the conditions (including sequences for
probes, primers, etc.) for validated genotyping assays. Estimation of haplotypes is currently
provided for select genes, with the goal of expanding this effort rapidly. SNP500Cancer
provides an invaluable resource for investigators world-wide to select validated candidate SNPs
linked to established genotyping assays and sequence data. In addition, this project forms the
cornerstone for the assay validation pipeline of the Core Genotyping Facility.
In this prospective study, the purpose is to study genetic variants in genes of innate immunity,
which could contribute to fungal infections. Already, the paradigm has been established in a
number of infections, such as malaria, filariasis, RSV infection and most recently in candidiasis
in leukemia patients (Choi et al in press JID, 2003). Moreover, the initial rationale was based
upon the search for genetic determinants of infectious complications using immune SNPs in a
well-defined population receiving comparable therapy, but the design is suitable for investigating
pharmacogenomic questions at a later time8. The choice of genes was made because on the basis
of three criteria: (1) well defined SNPs altered function of the gene (either the protein sequence
or expression), (2) a frequency for the variants was greater than 5% (most are between 20 and
35% for the minor alleles), which provides adequate opportunity for statistical analysis and (3)
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prior association studies 8-9. A total of 20 genes will be studied by Dr. Tom Walsh at
NIH/NCI/POB. The genes were chosen from several pathways within innate immunity,
specifically, because these pathways are not substantially altered by changes in lymphocyte or
phagocyte populations following myelotoxic therapy. The 18 genes involved in intrinsic host
defense include MBL2, CCR5, IL1RN, IL1A, IL1B, IL6, IL8, IL8RA, IL8RB, IL10, TNFA, TNFB,
MPO, NRAMP1, CHIT1, FCGR2A, FCGR3A, and FCGR3B. The other two genes will be
studied for the metabolism of voriconazole (3A4 and 2C19). The products of the 20 following
genes mediate their respective functions (indicated in parentheses): MBL2 (involved in innate
host recognition of fungal pathogens); CCR5, IL8, IL8RA, and IL8RB (mediate recruitment of
PMNs); IL1RN, IL1A, IL1B, and IL6, TNFA, TNFB (pro-inflammatory cytokine mediators); IL10
(suppression of phagocytic host defenses); MPO (mediator of phagocytic oxidative injury);
NRAMP (mediates intracellular phagocytic injury and divalent metal efflux); CHIT1 (mediates
chitin and fungal cell wall hydrolysis); FCGR2A, FCGR3A, and FCGR3B (antibody receptors);
and 3A4 and 2C19 (cytochrome P450-dependent hepatic microsomal enzymes involved in
metabolic clearance of voriconazole). Additional genes mediating host response and metabolism
will be studied as new technology is developed.
Additional SNP analyses in six other genes involved in the innate immune response to fungal
infection will be conducted by Dr. Patricia Fraser at the Center for Blood Research at Harvard
Medical School. The six genes and their respective functions (indicated in parenthesis) include
MICA and MICB (augment cytolysis mediated by T cells and NK cells and co-stimulate
CD8+ T cells in pathogen-specific immune response), TLR4 and CD14 (TLR4 mediates cell
signaling from exposure to microbial pathogens such as fungi and complexes with CD14 which
facilitates monocyte activation by Aspergillus hyphae), HBD-1 (expresses antifungal properties)
and IL-18 (confers protection against pulmonary and disseminated infections).
Collection and Processing: Collect 5mL of blood or stem cell product (2.5 mL for patients less
than 12 years old) from related donor in green top vacutainer; transfer whole blood, without
centrifugation, to two cryovials; samples may be stored at 2-8ºC for 24 hours prior to
cryopreservation at -70ºC; batch ship frozen samples on dry ice to the repository.
Sample Analysis
1. Dr. Tom Walsh at NIH/NCI/POB and Dr. Patricia Fraser at the Center for Blood
Research at Harvard Medical School will conduct extraction of genomic DNA by
standard technique under SOPs filed at their laboratories.
2. Samples will be given a numerical number and a record linking the number to patient
information will be kept confidential. It will only be available for investigators
participating in this study. Samples will be linked to clinical data collected under the
supervision of Dr. Walsh. Genomic samples will not be shared with other investigators
unless approved by an IRB amendment and informed consent is given.
3. Sample tracking will be accomplished using a numerical code assigned each consecutive
patient enrolled on study. Clinical data will be entered on datasheets containing the
polymorphism/variant data on the 26 genes of the study.
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4. Genetic analysis will be performed on fragments amplified by the polymerase chain
reaction (PCR) and subjected to analysis designed to distinguish between known alleles
in the following genes: MBL2, CCR5, IL1RN, IL1A, IL1B, IL6, IL8, IL8RA, IL8RB, IL10,
TNFA, TNFB, MPO, NRAMP1, CHIT1, FCGR2A, FCGR3A, FCGR3B, 3A4, 2C19,
MICA, MICB, TLR4, CD14, HBD-1and IL-18. Each study will be confirmed at least
twice before entry into the spread sheet data bank.
Data Evaluation
1.a
Sample analysis will be performed as they are made available.
1.b
The genomic DNA of each patient will be genotyped for allelic variations in the 26
genes: MBL2, CCR5, IL1RN, IL1A, IL1B, IL6, IL8, IL8RA, IL8RB, IL10, TNFA,
TNFB, MPO, NRAMP1, CHIT1, FCGR2A, FCGR3A, FCGR3B, 3A4, 2C19, MICA,
MICB, TLR4, CD14, HBD-1and IL-18. The genotype determination for each gene
will be considered to be a separate variable for each patient.
1.c
Data will be analyzed with respect to each gene in terms of allelic frequency and
separately in terms of gene distribution (wild type, heterozygotes and homozygotes
for the gene being analyzed).
1.d
Frequencies will be compared to the general population norms- both published and
established in our laboratory. Comparison for statistical significance will be
evaluated within the cohort to determine if specific alleles are over or under-
represented.
2. Epidemiological data on the infectious complications of all enrolled will be evaluated and
entered into the database program for comparison with genotypic evaluation of individual
patients. Continuous and non-continuos variable analysis will be performed.
3. The primary outcome will be a direct comparison of the allelic frequencies of a specific
gene or combination of genes in the identified population to established controls (already
established in our laboratory and in the literature). Secondary outcomes that will undergo
statistical analysis are continuous variables (e.g., complications, response to therapy and
presenting parameters).
4. After univariate analyses are performed in an exploratory mode for the individual loci,
multivariate analyses of the possibly correlated outcomes will be performed. This
analysis will be performed with as few as two loci and as many as all 26 loci.
5. Complex trait analysis will be performed on the database. All of the variables included in
the infectious events will be analyzed with respect to cohorts of patients determined by
allelic frequency.
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Version 7.0 dated March 29, 2006
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PARAFFIN BLOCKS OF INFECTED TISSUE SPECIMENS
Paraffin blocks from tissues found to be infected should be saved and batch sent quarterly at
room temperature to the Study Repository in compliance with the shipping procedures specified
in the BMT CTN MOP. Dr. John Wingard at the University of Florida will analyze these
specimens for identification of fungal pathogen where cultures were negative but organisms were
seen microscopically.
INVESTIGATIONAL FUTURE TESTING
Blood for investigational future testing will be collected at baseline prior to initiation of
conditioning. The identification and location of test(s) to be performed have not been
determined.
Collection and Processing: Collect 5 mL (2.5 mL for patients less than 12 years old) of blood in
red top vacutainer; allow 15-30 minutes for clotting; centrifuge at 900 x g or 2100 rpm for 10
minutes; (clot and serum should be distinct); carefully remove the serum without disturbing the
clot (leaving behind a small volume of serum if necessary) and transfer equally to two cryovials;
samples may stored at 2-8ºC for 24 hours prior to cryopreservation at -70ºC; batch ship frozen
samples on dry ice quarterly to the repository.
DIAGNOSTIC GALACTOMANNAN ASSAYS
Incorporation of the “real-time” diagnostic GM assay along with classical criteria will improve
accuracy and may increase the number of documented invasive aspergillosis cases (by upgrading
possible cases not proven by classical criteria to proven or probable cases with the GM assay).
Blood samples for the GM assays will be collected twice weekly on non-consecutive days,
preferably three days apart (e.g., Mondays and Thursdays), during the first 60 days post-
transplant and once weekly on Days 60-100 unless one of the following criteria is met: (1)
patient received a T cell depleted transplant and received post-transplant GVHD prophylaxis; or,
(2) patient is on steroids; or, (3) patient has or has had acute GVHD requiring systemic therapy.
GM blood samples will be collected twice weekly from these select patients. Diagnostic GM
samples should also be collected at onset of possible infections and twice weekly from patients
receiving empirical trials of amphotericin B or caspofungin for possible invasive infection.
GM samples may be processed at contract laboratories or hospital laboratories associated with
the transplant center if the laboratory is certified by CLIA, CAP or JCAHO. Samples to be
processed at these certified laboratories must be collected twice weekly on two non-consecutive
days, preferably three days apart. Results are required within 72 hours of collection. It is
recommended that these certified laboratories complete Bio-Rad’s proficiency panel and use the
criteria for galactomannan positivity as defined in §3.2 of the protocol, i.e., two consecutive
positives on one sample.
Collection and Processing: Collect 5 mL of blood (2.5 mL for patients less than 12 years old) in
gold top plastic serum separator tube; allow 15-30 minutes for clotting; centrifuge at 900 x g or
2100 rpm for 10 minutes but do not decant or transfer unless instructed otherwise by reference
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lab; store at 2-8°C for up to 72 hours if necessary; ship sample on cold packs immediately via
priority overnight to the reference lab according to the lab’s instructions.
INVESTIGATIONAL MONITORING OF TREATMENT GALACTOMANNAN ASSAYS
For patients with presumptive, probable or proven aspergillus infection, monitoring of treatment
GM samples will be collected at onset and twice weekly for four weeks and then once every two
weeks for eight weeks for a total of 12 samples. These samples will be processed at the Fred
Hutchinson Cancer Research Center at a later date. Results will not be made available to the
transplant center.
Collection and Processing: Collect 5 mL of blood (2.5 mL for patients less than 12 years old) in
gold or red top, plastic or glass serum separator tube; allow 15-30 minutes for sample to clot;
centrifuge at 900 x g or 2100 rpm for 10 minutes (clot and serum should be distinct); carefully
remove the serum without disturbing the clot (leaving behind a small volume of serum) and
transfer to cryovial; sample may stored at 2-8ºC prior to cryopreservation at -70ºC; batch ship on
dry ice quarterly to the repository.
INVESTIGATIONAL GALACTOMANNAN ASSAYS OF BAL
Whenever a bronchoscopy is performed, 1 mL of BAL (bronchoalveolar lavage) will be
collected in a cryovial, frozen at -70ºC, and batch shipped quarterly to the Repository. These
samples will be processed at the Fred Hutchinson Cancer Research Center at a later date.
Results will not be made available to the transplant center.
REPOSITORY INFORMATION
Room temperature and frozen samples should be batched and shipped quarterly to the Repository
in compliance with the shipping procedures specified in the BMT CTN MOP and the BMT CTN
0101 Laboratory Sample Information Guide:
Misti Dowell
NHLBI Repository
SeraCare BioServices
217 Perry Parkway
Gaithersburg, Maryland 20877
Phone: (301) 208-8100
Fax:
(301) 208-8829
Email:
nhlbi@bbii.com
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REFERENCES IN APPENDIX C
1.
Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science
2001; 291:1304-51.
2.
Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human
genome. Nature 2001; 409:860-921.
3.
Kruglyak L, Nickerson DA. Variation is the spice of life. Nat Genet 2001; 27:234-6.
4.
Taylor JG, Choi EH, Foster CB, Chanock SJ. Using genetic variation to study human
disease. Trends Mol Med 2001; 7:507-12.
5.
Chanock S. Candidate genes and single nucleotide polymorphisms (SNPs) in the study of
human disease. Dis Markers 2001; 17:89-98.
6.
Schork NJ, Fallin D, Thiel B, et al. The future of genetic case-control studies. Adv Genet
2001; 42:191-212.
7.
Fallin D, Cohen A, Essioux L, et al. Genetic analysis of case/control data using estimated
haplotype frequencies: application to APOE locus variation and Alzheimer's disease.
Genome Res 2001; 11:143-51.
8.
Chanock SJ, Foster CB. SNPing away at innate immunity. J Clin Invest 1999; 104:369-
70.
9.
Foster CB, Chanock SJ. Mining variations in genes of innate and phagocytic immunity:
current status and future prospects. Curr Opin Hematol 2000; 7:9-15.
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Table C-1
LABORATORY SCHEDULE
TEST
TYPE OF
SAMPLE
(collection container)
TYPE OF STORAGE
DATES SAMPLES OBTAINED
SHIPPING
SPECIFICATIONS
LOCATION OF
TEST PERFORMED
Pharmacokinetics
5 mL peripheral blood1
(green top tube)
Centrifuge for 20 min
within 120 min of
collection; transfer
plasma to cryovial
Store at –70oC
Day 14 & 28 of therapy, at onset of serious
suspected drug toxicities as delineated in Section
2.4.6 and at onset of possible, presumptive,
probable or proven infection (prior to start of
antifungal therapy).
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. Walsh’s Lab at NCI
Antifungal
Susceptibility Test
Fungal isolate from any
infected site, if
available
Streak on agar slant
Store at –20oC
Serial isolates every 7 days if available following
initiation of antifungal therapy, or if infection
relapses following discontinuation of therapy.
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. Nguyen’s Lab at
University of Florida
College of Medicine
Investigational
Fungal Diagnostic
Assays
5 mL peripheral blood1
(red top tube)
___________________
5 mL peripheral blood1
(green top tube)
Sit for 15-30 minutes to
allow for clotting
centrifuge for 10 min;
transfer serum to
cryovial
May store at 2o-8° C for
up to 24 hours
For longer storage
–70°C
___________________
Transfer to cryovial
without centrifugation
May store at 2 o-8° C
for up to 24 hours
For longer storage
–70°C
2x/week from Day 0 to Day 60. After Day 60,
samples will be collected once per week until Day
100 unless one of the following is met: (1) patient
received a T cell depleted transplant and received
post-transplant GVHD prophylaxis, or (2) patient is
on steroids, or (3) patient has or has had acute
GVHD requiring systemic therapy. These patients
will provide samples 2x/week until Day 100.
Samples will also be collected at onset of possible
fungal infection and 2x/week in patients receiving
an empirical trial of amphotericin B or caspofungin
for possible invasive fungal infection. For patients
with presumptive, probable or proven aspergillus
infection, 2x/week for 4 weeks and then once every
2 weeks for 8 weeks for a total of 12 samples, and
then 1-2x/week until Day 100.
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. John Wingard’s Lab
at University of Florida
College of Medicine
Donor SNPs (related
donor)
(Single Nucleotide
Polymorphisms)
5 mL peripheral blood
or stem cell product
from donor (green top
tube)
Transfer without
centrifugation equally
to two 3.6 mL cryovials
Store at –70ºC
At baseline prior to transplant.
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. Walsh’s Lab at NCI
and Dr. Fraser’s Lab at
Harvard
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TEST
TYPE OF
SAMPLE
(collection container)
TYPE OF STORAGE
DATES SAMPLES OBTAINED
SHIPPING
SPECIFICATIONS
LOCATION OF
TEST PERFORMED
Paraffin Blocks of
Infected Tissues
Paraffin blocks
Room temperature
At time of infection.
Ship at room temp.
quarterly to Repository as
specified in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. Wingard’s Lab at
the University of
Florida College of
Medicine
Diagnostic
Galactomannan
Assays2
5 mL peripheral blood1
(gold hemogard tube)
Sit for 15-30 minutes to
allow for clotting
Centrifuge for 10 min
(but do not decant or
transfer), leave in gold
hemogard collection
tube unless instructed
otherwise by reference
lab
Store at 2 o–8°C
2x/week from Day 0 to Day 60. After Day 60,
samples will be collected once per week until Day
100 unless one of the following is met: (1) patient
received a T cell depleted transplant and received
post-transplant GVHD prophylaxis; or, (2) patient
is on steroids; or, (3) patient has or has had acute
GVHD requiring systemic therapy. These patients
will provide samples 2x/week until Day 100.
Samples will also be collected prior to and at onset
of possible fungal infection and 2x/week in patients
receiving an empirical trial of amphotericin B or
caspofungin for possible invasive fungal infection.
Cold pack shipment
PRIORITY OVERNIGHT
to reference lab in
compliance with shipping
procedures specified in the
BMT CTN MOP/BMT
CTN 0101 Laboratory
Sample Information Guide
Certified contract lab
or certified hospital lab
associated with the
transplant center
Investigational
Monitoring of
Treatment
Galactomannan
Assays
5 mL peripheral blood1
(gold hemogard tube)
Sit for 15-30 minutes to
allow for clotting
Centrifuge for 10 min;
transfer serum to
cryovial
May store at 2º-8ºC for
up to 24 hours. Freeze
at –70ºC
For patients with presumptive, probable or proven
aspergillus infection, at onset and 2x/week for 4
weeks and then once every two weeks for a total of
12 samples.
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. Kieren Marr’s Lab
at Fred Hutchinson
Cancer Research Center
Investigational
Galactomannan
Assays of BAL
(bronchoalveolar
lavage)
1 mL BAL
(cryovial)
May store at 2º-8ºC for
up to 24 hours.
Freeze at –70ºC
Anytime bronchoscopy is performed.
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
Dr. Kieren Marr’s Lab
at Fred Hutchinson
Cancer Research Center
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TEST
TYPE OF
SAMPLE
(collection container)
TYPE OF STORAGE
DATES SAMPLES OBTAINED
SHIPPING
SPECIFICATIONS
LOCATION OF
TEST PERFORMED
Investigational
Future Testing
5 mL peripheral blood1
(red top tube)
Sit for 15-30 minutes to
allow for clotting
Centrifuge for 10 min;
transfer serum to two
cryovials.
May store at 2º-8ºC for
up to 24 hours. For
longer storage
–70ºC
Baseline.
Frozen shipment quarterly
to Repository as specified
in the BMT CTN
MOP/BMT CTN 0101
Laboratory Sample
Information Guide
TBD
Notes for Table C-1:
1 Collect 2.5 mL for pediatric patients less than 12 years old
2 Diagnostic GM samples must be collected twice weekly on two non-consecutive days preferably three days apart (e.g., Monday and Thursday).
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D-1
APPENDIX D
GALACTOMANNAN ASSAY
Platelia® Aspergillus Laboratory Protocol
with
Platelia® Aspergillus Kit Receipt Log
Platelia® Aspergillus Package Insert
Platelia® Aspergillus Worksheets
Platelia® Aspergillus Quick Reference Guide
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D-2
APPENDIX D
TABLE OF CONTENTS
INTENDED USE .............................................................................................................. D-3
SUMMARY AND EXPLANATION ..................................................................................... D-3
PRINCIPLE OF THE PROCEDURE ................................................................................. D-4
STUDY DESIGN .............................................................................................................. D-5
TECHNICAL INFORMATION ........................................................................................... D-9
MATERIALS AND METHODS .......................................................................................... D-9
A. Materials provided by Bio-Rad Laboratories ................................................................ D-9
B. Materials not Provided.............................................................................................. D-10
PRECAUTIONS ............................................................................................................. D-11
A. Health and Safety Precautions ................................................................................. D-11
B. Test Precautions ...................................................................................................... D-11
SPECIMEN COLLECTION / TESTING ........................................................................... D-12
A. Specimen Collection ................................................................................................ D-12
B. Specimen Testing .................................................................................................... D-12
C. Calculation of Results .............................................................................................. D-14
D. Limitations of the Procedure ..................................................................................... D-15
TRAINING / PROFICIENCY TESTING ........................................................................... D-15
A. Proficiency Testing Documentation Form .................................................................. D-17
DATA COLLECTION ...................................................................................................... D-18
ATTACHMENT A: PATELIA® ASPERGILLUS KIT RECEIPT LOG.................................. D-19
ATTACHMENT B: PATELIA® ASPERGILLUS PACKAGE INSERT ................................. D-21
ATTACHMENT C: PATELIA® ASPERGILLUS WORKSHEETS ...................................... D-45
ATTACHMENT D: PATELIA® ASPERGILLUS QUICK REFERENCE GUIDE .................. D-48
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D-3
PLATELIA® ASPERGILLUS LABORATORY PROTOCOL
for
“A Randomized Double-blinded Trial of Fluconazole vs. Voriconazole
for the Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow
Transplant Patients”
Read the entire protocol, including the appendices, before beginning the study. Instructions
for collecting, handling, and testing specimens are provided in detail in this protocol.
INTENDED USE
The Platelia® Aspergillus EIA Galactomannan Assay is a 1-stage immunoenzymatic assay utilizing the
sandwich microplate technique for the detection of galactomannan in human serum. This assay is to be
used and test results interpreted in conjunction with other conventional diagnostic procedures such as
microbiological culture, histologic examination of biopsy samples, and other signs and symptoms for
detection of aspergillus infection. Positive Platelia® Aspergillus EIA test results are an aid in the early
diagnosis of Invasive Aspergillosis, and, along with other diagnostic tests and clinical signs of disease,
allow for effective early treatment of disease. Negative Platelia® Aspergillus EIA test results, along with
other diagnostic tests, can be used to prevent the unnecessary use of anti-fungal agents in the absence
of Invasive Aspergillosis.
SUMMARY AND EXPLANATION
Aspergillus infections usually occur following inhalation of aspergillus spores, which are present in the
environment. Invasive forms, which have been on the increase for more than 10 years, constitute the
most serious infections. They mainly occur in neutropenic patients (following anticancer treatment) and in
patients treated with immunosuppressants (organ transplantations, particularly bone marrow
transplantation) and corticosteroids4. AIDS-related cases of aspergillus have also been reported5.
The efficacy of treatment depends on early introduction of treatment, but the diagnosis of Aspergillosis is
still very difficult. The test for anti-aspergillus antibodies is not adapted to the diagnosis of invasive
Aspergillosis in immunocompromised patients. Aspergillus is rarely isolated from blood culture. The
diagnosis is often based on nonspecific or late criteria (clinical symptoms, radiology, etc.)
At the present time, the test for soluble aspergillus antigens in the serum appears to be the only
serological method able to improve both the rapidity and specificity in the diagnosis of the infection6,7.
Among the various antigens present in body fluids of patients suffering from invasive Aspergillosis,
carbohydrates and particularly galactomannan appear to be well-suited for the diagnosis of the
infection8,9.
4 Denning DW, Stevens DA. 1990. Anti-fungal and surgical treatment of invasive Aspergillosis: review of 2121 published cases.
Rev. Infect. Dis. 12:1147 - 1201.
5 Lortholary O, Meyohas MC, Dupont B, et al. 1993. Invasive aspergillosis in patients with acquired immunodeficiency syndrome:
report of 33 cases. Am J. Med. 95:177 - 187.
6 Andriolet VT. 1993. Infections with Aspergillus species. Clin Infect Dis. 17 (suppl 2) : S481-6.
7 De Repentigny L, Kaufman L. Cole GT, Druse K, Latge JP, Matthews RC. 1994. Immunodiagnosis of invasive fungal infections. J.
Med Vet Mycol. 32 (S1): 239 - 252.
8 De Repentigny L. 1989. Serological techniques for diagnosis of fungal infection. Eur. J. Clin Microbiol Infect Dis. 8 (4) : 362 - 375.
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D-4
PRINCIPLE OF THE PROCEDURE
The Platelia® Aspergillus EIA is a one-stage immunoenzymatic sandwich microplate assay that detects
galactomannan in human serum. The assay uses the rat monoclonal antibody EBA-2, which is directed
against aspergillus galactomannan, and has been characterized during previous studies10 11 12. The
monoclonal antibody is used to sensitize the wells of the microplate, bind the antigen and as the detector
antibody in the conjugate reagent (peroxidase-linked monoclonal antibody). Serum samples are heat-
treated in the presence of EDTA in order to dissociate the immune-complexes and to precipitate serum
proteins, which could possibly interfere with the EIA. The treated serum samples and conjugate are
added to the wells coated with the monoclonal antibody, and incubated. A monoclonal antibody -
galactomannan - monoclonal antibody / peroxidase complex is formed in the presence of aspergillus
antigen. The strips are washed to remove any unbound material. Next, the substrate solution is added,
which will react with the complexes bound to the well to form a blue color reaction. The enzyme reaction
is stopped by the addition of acid, which changes the blue color to yellow. The optical absorbance of
specimens and controls is determined with a spectrophotometer set at 450 and 620/630-nm wavelength.
9 Latge JP. 1995. Tools and trends in the detection of Aspergillus fumigatus. Curr Top Med Mycol, in press.
10 Latge JP, Kobayashi H, Debeaupuis JP, Diaquin M, Sarfati J, Wieruszeski JM, Parra E, Bouchara JP, Fournet B. 1994.
Chemical and immunological characterization of the extracellular galactomannan secreted by Aspergillus fumigatus. Infect Immun.
62: 5424 -5433.
11 Stynen D, Sarfati J, Symoens F, Goris A, Nolard N, Latge JP. 1991. Rat monoclonal antibodies against exocellular carbohydrate
antigens of Aspergillus and dermatophytes. In: “Fungal Cell Wall and Immune Response”, 181 -193. Ed. By J.P. Latge and D.
Boucias, Springer Verlag.
12 Stynen D, Sarfati J, Goris A, Prevost MC, Lesour M, Kamphuis H, Darras V, Latge JP. 1992. Rat monoclonal antibodies against
Aspergillus galactomannan. Infect Immun. 60: 2237 - 2245.
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D-5
STUDY DESIGN
for
Laboratory Protocol for
BMT CTN Protocol 0101 – “A Randomized Double-blinded Trial of Fluconazole versus Voriconazole for
the Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow Transplant Recipients”
Objectives:
1) To perform exploratory analyses of quantitative aspects of the Platelia® Aspergillus EIA in
detecting galactomannan antigen in serum as an aid in the diagnosis of invasive Aspergillosis in
allogeneic blood and marrow transplant patients receiving prophylactic treatment with
Fluconazole or Voriconazole (diagnostic phase).
2) To perform exploratory analyses of quantitative aspects of the Platelia® Aspergillus EIA in
determining response to anti-fungal therapy in allogeneic blood and marrow transplant patients
with proven or probable invasive Aspergillosis (monitoring phase).
Population:
Allogeneic hematopoietic transplant recipients randomized to receive post-transplant prophylaxis with
either Fluconazole (N = 300) or Voriconazole (N = 300). The length of these studies is expected to be
three years.
Study Design:
This is a randomized, double-blinded, multicenter, prospective, comparative study of Fluconazole versus
Voriconazole prophylaxis in the prevention of invasive fungal infections in allogeneic hematopoietic
transplant recipients. The Platelia® Aspergillus assay for detection of galactomannan is being used in
conjunction with host and clinical factors (see Table 3.1.1 a and b in BMT CTN Protocol 0101) to
determine the likelihood of invasive aspergillus infection.
Sample Collection and Testing:
DIAGNOSTIC PHASE
A serum specimen for the Platelia® Aspergillus assay will be collected prior to the start of the conditioning
regimen. Serum blood samples will be obtained up to twice weekly from Day 0 to Day 100 for testing with
the Platelia® Aspergillus assay.
The Platelia® Aspergillus EIA will be performed “real-time” for this protocol, and positive or negative assay
results will be reported to the clinician. Positive results will elicit further clinical evaluation for the
presence of invasive aspergillus.
The assay testing will be performed at a certified reference laboratory. Testing will be performed in all
sera following the manufacturer’s package insert instructions. Results of each assay will be
communicated to each site’s clinical coordinator within three business days. Index Values and positive or
negative results will be reported.
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MONITORING PHASE
During this monitoring phase, two serum samples will be collected within 7 days of initiation of anti-fungal
therapy, with one of the samples collected 48 hours before. After anti-fungal therapy has been initiated
and during therapy monitoring, a serum sample will be collected twice a week for four weeks and then
once every two weeks for eight weeks. In all, 12 samples will be collected and tested with the Platelia®
Aspergillus assay after the initiation of drug therapy. Samples will be frozen at –70oC and batch shipped
quarterly to the Repository. These samples should be clearly marked “Monitoring of Treatment.” Results
of this testing will not be reported to the clinician.
Testing Algorithm:
DIAGNOSTIC PHASE
If a sample is negative in the Platelia® Aspergillus assay, the sample is reported as negative. If a sample
is initially positive in the Platelia® Aspergillus assay, the result is not reported and a new treatment of the
same sample will be retested as soon as possible. If the repeat test result using a new treatment is also
positive, the result will be reported as positive and another serum sample will be requested for testing
with the Platelia® Aspergillus assay. In addition, additional diagnostic procedures will be initiated. These
will be evaluated in conjunction with clinical signs to determine the likelihood of invasive aspergillus
infection.
MONITORING PHASE
The monitoring phase of the study will begin for any patient who is diagnosed with invasive aspergillosis
and begins anti-fungal therapy. Samples will be collected as described above. Testing will be performed
at a later date. Test results are to be blinded and not reported to the clinician.
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D-7
TESTING ALGORITHM
Diagnostic Phase
600 post-transplant patients
Fluconazole (N = 300) or Voriconazole (N = 300)
Platelia ® Aspergillus EIA
Negative Result
(Index < 0.5)
Positive Result
(Index > 0.5)
Report as Negative
Re-test Same Sample
(new treatment)
Do not report
Negative Result
(Index < 0.5)
Positive Result
(Index > 0.5)
Report as Positive
Collect a second sample and
test with Platelia® Aspergillus.
Sample QNS
for retest
Request another serum sample.
Initiate additional diagnostic
procedures. Evaluate in
conjunction with clinical signs to
determine if invasive aspergillus
infection.
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Fungal Prophylaxis Protocol – 0101
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D-8
TESTING ALGORITHM
Monitoring Phase
(No reporting of results)
Invasive Aspergillosis Patients on Anti-Fungal Therapy
Platelia ® Aspergillus EIA
Negative Result
(Index < 0.5)
Positive Result
(Index > 0.5)
No Report
Re-test Same Sample
(new treatment)
Negative Result
(Index < 0.5)
Positive Result
(Index > 0.5)
No Report
Collect a second sample and
test with Platelia® Aspergillus
Sample QNS
for retest
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Version 7.0 dated March 29, 2006
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TECHNICAL INFORMATION
Store the Platelia® Aspergillus assay kits at 2-8 °C. The kit lot number as well as the expiration date will
be on the box containing the reagents.
All printouts must be signed in blue or black ink by the person actually performing the Platelia®
Aspergillus assay and should be sent by facsimile or electronically weekly to the study monitor:
Lisa McLaughlin
Phone: 425-498-1774
Bio-Rad Laboratories
Fax:
425-498-1651
6565 185th N.E.
E-mail: lisa_McLaughlin@bio-rad.com
Redmond, WA 98052
The investigator, or a responsible party designated by the investigator, must maintain an inventory record
of devices/reagents received (see Attachment A to Appendix D) to assure that the materials will not be
used for any purpose other than what is stated in this protocol. These records must include all dates, lot
numbers, quantities received, and identification of the subject. If any portion of the device is lost, i.e.
wastage, the name of the responsible individual, the date, and the quantity must be documented. The
study reagents must be used only at the institution specified in this protocol.
Return the completed Platelia® Aspergillus Receipt Log and all unused devices/reagents in their original
containers to the attention of the study monitor at Bio-Rad Laboratories at the conclusion or termination of
the study. Return unused serum samples to the Repository.
MATERIALS AND METHODS
A. Materials Provided by Bio-Rad Laboratories
Platelia® Aspergillus Kits
7 Member panel for Training / Proficiency
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Platelia® Aspergillus Kit Composition [Product No. 62797 (96 Tests)]
Component
Contents
Quantity
R1 - Microwell Strip
Plate
96 wells coated with antigalactomannan
monoclonal antibody
1 plate containing 12 strips
with 8 wells each
R2 - Wash Solution,
10X Concentrate
Tris NaCl buffer
1% Tween 20
0.01% sodium merthiolate
1 x 100 mL
R3 - Negative Control
Freeze-dried human negative serum
Negative for anti-HIV-1, anti-HIV-2, anti-HCV
antibodies and HBs antigen
2 x 1 mL
R4 – Cut-off Control
Freeze-dried
human
serum
containing
galactomannan
Negative for anti-HIV-1, anti-HIV-2, anti-HCV
antibodies and HBs antigen
2 x 1 mL
R5 - Positive Control
Freeze-dried
human
serum
containing
galactomannan
Negative for anti-HIV-1, anti-HIV-2, anti-HCV
antibodies and HBs antigen
2 x 1 mL
R6 - Conjugate
Peroxidase-labeled
antigalactomannan
monoclonal antibody
0.01% sodium merthiolate
1 x 8 mL
R7 - Serum Treatment
Solution
EDTA acid solution
1 x 10.5 mL
R8 - Substrate buffer
Citric acid
Sodium acetate
0.009% Hydrogen peroxide
4% Dimethylsulfoxide (DMSO)
1 x 60 mL
R9 - Chromogen
Dimethylsulfoxide (DMSO)
Tetramethylbenzidine (TMB)*
1 x 1 mL
R10 - Stopping
Solution
1.5 N Sulphuric acid
1 x 12 mL
Plate sealers
Adhesive sheets for microplates
6
*NOTE: TMB (Tetramethylbenzidine) is a non-carcinogenic and non-mutagenic chromogen for
peroxidase. Store the kit at 2-8C. Bring all reagents to room temperature (15-30C) before use. Return
all reagents, except controls, to 2-8C immediately after use. After reconstitution, unused Negative
Control, Cut-off Control, and Positive Control must be frozen at -20C. Return unused strips/plates to
pouch and reseal. Do not remove desiccant. Strips should be used within 5 weeks of opening and
resealing the pouch. After dilution, wash solution can be kept for 15 days at 2-8C. All other reagents are
stable until expiration after opening. Reagents are supplied in sufficient quantity to perform 96
determinations in a maximum of 6 batches.
B. Materials Not Provided
1.
Distilled or deionized water, for dilution of Wash Solution.
2.
Sterile purified water, for reconstitution of control sera.
3.
Absorbent paper.
4.
Disposable gloves.
5.
Protective glasses.
6.
Sodium hypochlorite (bleach) and sodium bicarbonate.
7.
Pipettes or multi-pipettes, adjustable or fixed, to measure and dispense 50 µl, 100 µl, 300 µl, and
1000 µl.
8.
1.5 mL Eppendorf (Sarstedt Cat. # 72.692.105) or similar polypropylene tubes with airtight
stoppers, able to support heating to 100C.
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9.
Laboratory bench centrifuge for Eppendorf tubes capable of obtaining 10,000g (Brinkman Cat.#
22-36-280-1 or VWR Scientific Cat.# 20901-051or equivalent).
10.
Vortex agitator.
11.
Boiling water bath or heating block (VWR Scientific Cat. # 13259-005).
12.
Micro-plate incubator at 37 1C.
13.
Manual or semi-automatic or automatic plate washer.
14.
Microplate reader equipped with 450 nm and 620/630 nm filters.
15.
Printer.
PRECAUTIONS
A. Health and Safety Precautions
1.
The Positive Control, Cut-off Control, and Negative Control are heat-inactivated, human serum.
They have been tested and found to be negative for anti-HIV-1, anti-HIV-2, and anti-HCV
antibodies, as well as HBs antigen. However, all the reagents should be handled as though
capable of transmitting infection. All tests should be conducted using the precautions
recommended for bloodborne pathogens, as defined by OSHA regulations.
2.
Wear protective clothing and disposable gloves while handling the kit reagents and patient
samples. Wash hands thoroughly after performing the test.
3.
Do not pipette by mouth.
4.
Do not smoke, drink, or eat in areas where specimens or kit reagents are being handled.
5.
Avoid splashing samples or solutions containing them.
6.
Biological spills not containing acid should be wiped thoroughly with an effective disinfectant.
Disinfectants that can be used include (but are not limited to) a solution of 10% bleach (0.5%
solution of sodium hypochlorite), 70% ethanol, or 0.5% Wescodyne™. Spills containing acid
should be wiped dry or neutralized with sodium bicarbonate and then cleaned with one of the
chemical disinfectants. Materials used to wipe up spills should be disposed of as biohazardous
waste. CAUTION: Do not place solutions containing bleach in the autoclave.
7.
Dispose of all specimens and materials used to perform the test as though they contain an
infectious agent. Disposal should comply with all applicable waste disposal requirements.
8.
CAUTION: The Stopping Solution is an acid. Wipe up spills immediately and flush the areas with
water.
R36/38: Irritating to eyes and skin.
S:2-26-30: Keep out of reach of children. In case of contact with eyes, flush immediately and
thoroughly with water and consult a physician. Never pour water into this product.
9.
Avoid contact of Substrate Buffer, Chromogen, and Stopping Solution with eyes, skin, and
mucosa (risk of toxicity, irritation, and burns).
B. Test Precautions
Please follow these guidelines in order to maintain consistency and reliability of results when using the
Bio-Rad Laboratories PlateliaAspergillus:
1.
Do not use kit or any kit reagents after the stated expiration date.
2.
Do not mix reagents from other kits that have the same or different lot numbers.
3.
Store Platelia® Aspergillus kit reagents at 2 - 8C. Bring all reagents to room temperature before
use. Return to storage at 2 - 8C immediately after use.
4.
Mix thoroughly while reconstituting reagents, exercising care to avoid microbial contamination.
5.
Do not conduct the test in the presence of reactive vapors (acids, alkalis, aldehydes) or dust,
which could affect the enzymatic activity of the conjugate.
6.
Use clean, disposable polypropylene plastic containers to prepare the chromogen solution. If
glassware must be used, clean thoroughly and rinse with deionized water.
7.
Always use a fresh disposable pipette tip for each specimen and when making reagent dilutions.
8.
When aliquots of reagents are removed from their stock bottles, take care to avoid chemical and
microbial contamination. Always use a fresh disposable pipette or pipette tip for these transfers.
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9.
To ensure adequate washing of the wells, comply with the recommended number of wash cycles
and ensure that all wells are completely filled and then completely emptied.
10.
Use plastic disposable containers to dispense the conjugate and substrate solution. Do not use
the same container for the conjugate and substrate solutions.
11.
Do not allow conjugate or substrate solutions to come into contact with metal or metallic ions.
12.
Use clean, dust-free materials (tubes, tips, containers, etc.) to minimize the possibility of
contamination with aspergillus spores in the environment. Because galactomannan is heat-
stable, sterilization of material used does not guarantee the absence of contaminating antigen.
Pyrogen-free materials are optimal, but standard material can be used with adequate
precautions.
13.
Never perform the test in the same room where aspergillus or other molds are being cultured or
otherwise manipulated.
14.
Limit exposure of solutions (sera, treatment solution, conjugate) or open containers (plates,
tubes, pipettes) to free air. Do not leave microplate wells exposed to air. Perform the assay as
soon as possible after removing the strips from the packet. Remove only the number of strips
necessary for testing samples.
15.
Add Conjugate to the microplate wells before the sample is added. Do not pour any unused
conjugate back into the original container.
16.
The substrate-chromogen reaction solution must be colorless. The appearance of a blue color
after dilution indicates the reagent is contaminated and should not be used. Discard and prepare
fresh reagent.
SPECIMEN COLLECTION / TESTING
A. Specimen Collection:
Collect a blood sample according to current practice. The test is performed on undiluted serum. Extract
the serum from the clots as soon as possible to avoid hemolysis. Serum samples must be
uncontaminated with fungal spores or bacteria. Transport and store samples in sealed tubes, unexposed
to air. Samples can be stored at 2-8C unopened for up to 5 days prior to testing. After initial opening,
samples may be stored at 2-8C for 48 hours prior to testing. For longer storage, store the serum at
–70C.
B. Specimen Testing:
Procedural Comments:
Test patient samples according to the Platelia® Aspergillus package insert (See Attachment B of
Appendix D). Note: Samples should be tested in batches for best utilization of assay reagents. Each kit
has reagents in sufficient quantity to perform 96 determinations in a maximum of 6 batches.
BRING ALL REAGENTS TO ROOM TEMPERATURE (15 - 30C) BEFORE USE AND RETURN THEM
IMMEDIATELY AFTER USE TO 2 - 8C.
If samples have been frozen, thaw at room temperature and mix thoroughly (vortex) before testing.
Negative, Positive, and Cut-off Controls must be run on each plate to validate the test results.
Reagent preparation and storage / Reconstitution of Controls (Negative, Cut-off, and Positive
Controls
Working Wash Solution
Prepare Working Wash Solution as needed by adding one part Concentrated Wash Solution to 9 parts
deionized or distilled water. The Working Wash Solution can be stored for 15 days at 2-8C. Prepare a
sufficient amount of Working Wash Solution to complete the run (i.e., minimum of 160 mls for each 2
strips of 8 wells).
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Negative Control Serum
Reconstitute the contents of one bottle of control with 1000 µl (1 mL) of sterile purified water (preferably
pyrogen-free). The sera must be rehydrated just before performing the test. Mix thoroughly after allowing
2-3 minutes for re-hydration of the serum. Aliquot 300 µl into each of 3 Eppendorf tubes. Immediately
freeze at -20C the two tubes not used on the day of re-hydration. Note: control sera that have been
previously rehydrated and immediately frozen at -20C may be thawed and used without further
rehydration. Frozen rehydrated controls may be stored at -20C for up to 5 weeks. Handle the control
sera in the same manner as patient specimens.
Cut-off, and Positive Control Serum
PREPARE AS DESCRIBED ABOVE FOR THE NEGATIVE CONTROL.
Substrate-Chromogen Reaction Solution
Prepare Substrate-Chromogen Reaction Solution by adding one part Concentrated Chromogen Solution,
R9, to 50 parts Substrate Buffer, R8 (e.g., 200 µl of R9 + 10 mL of R8). Prepare 4 ml of Substrate-
Chromogen Reaction Solution per strip. The solution is stable for 6 hours when stored in the dark at
room temperature.
Treatment of Sera / Controls
1.
Pipette 300 µl of each test serum and control into individual 1.5 mL polypropylene tubes.
2.
Add 100 µl of treatment solution (R7) to each tube.
3.
Mix tubes thoroughly by vigorous homogenization or vortex to mix thoroughly. Heat tubes in
boiling water bath or heat block for 3 minutes at 100C.
4.
Centrifuge tubes at 10,000 x g for 10 minutes.
5.
Test the supernatants using the following procedure. After preparation, the supernatant may be
removed and stored at 2-8C for up to 72 hours prior to testing. If analysis of the results indicate
retesting is required, another aliquot of serum must be treated for testing.
EIA Procedure
1.
Prepare a Platelia® Aspergillus Worksheet (see Attachment C of Appendix D) and indicate the
identification of test sera and controls in the microplate on the platemap. Use one well for the
Negative Control Serum (R3), two wells for the Cut-off Control (R4), and one well for the Positive
Control Serum (R5).
See suggested platemap below:
1
2
3
4
5
6
7
8
9
10
11
12
A
R3
5
B
R4
6
C
R4
7
D
R5
8
E
Sample 1
9
F
2
10
G
3
11
H
4
etc.
= Null strip / empty well
2.
Remove the plate holder and microwell strips (R1) from the plate pouch. Return any strips to the
pouch that will not be used, with the desiccant, and reseal the pouch.
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3.
Add 50 µl of conjugate (R6) to each well. Next, add 50 µl of treated serum supernatant to each
well, as designated above. Do not add serum samples to the wells before the conjugate.
4.
Cover plate with plate sealer, ensuring that entire surface is covered and watertight.
5.
Incubate the microplate in a water bath or dry microplate incubator for 90 + 5 minutes at
37C( +1C).
6.
Remove the plate sealer. Wash the plate 5 times, using a minimum of 370 µl of Working Wash
Solution. After the last wash, invert the microplate and gently tap on absorbent paper to remove
remaining liquid.
7.
Add 200 µl of Substrate-Chromogen Reaction Solution (R8 + R9) to each well, avoiding exposure
to bright light.
8.
Incubate microplate in the dark at room temperature (18 to 25C) for 30 5 minutes. Do not use
adhesive film during this incubation.
9.
Add 100 µl of Stopping Solution (R10) to each well, utilizing the same order for addition of
Substrate Solution.
10.
Thoroughly wipe the bottoms of each plate.
11.
Read the optical density of each well at 450 nm (reference filter of 620/630 nm). Micro-plates
must be read within 30 minutes of addition of Stopping Solution. Avoid exposure of plate to light
before reading.
C. Calculation of Results
The presence or absence of galactomannan antigen in the test sample is determined by calculation of an
index for each sample. The Index (I) is the OD value of the specimen divided by the mean optical density
of the wells containing the cut-off control specimen.
Calculation of the Mean Cut-off Control OD:
Add the OD values of the two wells containing Cut-off control (R4) and divide the total by 2.
Calculation of an index (I) for R3 and R5 control:
Calculate the following ratio for R3 and R5 controls:
OD R3 /or R5 control
I = ---------------------------------------------------------
Mean Cut-off Control OD
Assay Validation
Calculate an index (I) for the Positive and Negative controls as described above. In order for the assay to
be valid, the following criteria must be met:
Cut-off Control: The optical density of each Cut-off control must be between 0.3 and 0.8
Positive Control: Index (I) must be greater than 2.0
Negative Control: Index (I) must be less than 0.4
Interpretation of Results
The presence or absence of galactomannan antigen in the test sample is determined by calculation of an
index for each patient specimen. The Index (I) is the OD value of the specimen divided by the mean
optical density of the wells containing the cut-off control specimen
Calculation of an index (I) for each patient sample
Calculate the following ratio for each patient sample:
OD patient sample
I = ---------------------------------------------------------
Mean Cut-off Control OD
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Sera with an Index less than 0.5 are considered to be negative.
Sera with an Index greater than or equal to 0.5 are considered to be positive.
Whenever a sample has an Index 0.5, positivity must be confirmed by re-testing the sample, including
repeating the heat treatment on a new aliquot, and/or by testing another sample obtained from the
patient.
D. Limitations of the Procedure
1.
A negative test cannot rule out the diagnosis of invasive Aspergillosis. Patients at risk for invasive
Aspergillosis should be tested twice a week.
2.
The Platelia® Aspergillus Procedure and the Interpretation of Results must be followed when
testing samples for the presence of aspergillus antigen. The user of the kit is advised to read the
package insert carefully prior to conducting the test. In particular, the test procedure must be
carefully followed for sample and reagent pipetting, plate washing, and timing of the incubation
steps.
3
Failure to add specimen or reagent as instructed in the procedure could result in a falsely
negative test. Repeat testing should be considered where there is clinical suspicion of infection
or procedural error.
4.
Contamination of negative patient specimen wells by positive control/patient specimen wells is
possible if the contents of one well spill over into another well due to rough handling of the
microplate or poor pipetting technique while adding reagents.
TRAINING / PROFICIENCY TESTING
The purpose of training is to provide the technologist with familiarity in using the Bio-Rad Platelia®
Aspergillus and instruments. Proficiency in running the assay will be assessed and demonstrated by
testing a panel of specimens provided by Bio-Rad Laboratories with the Bio-Rad Platelia® Aspergillus EIA
kit. Testing will be done according to package insert instructions (See Attachment B of Appendix D).
Each technologist who will be testing study specimens with the Platelia® Aspergillus EIA must
demonstrate proficiency in running the assay before testing study specimens.
Proficiency will be assessed and demonstrated by testing a 7 member -training panel provided by Bio-
Rad Laboratories. Each of the 7 panel members will be pretreated by heating 300l of serum with 100l
Treatment Solution to 100C as instructed in the Platelia® Aspergillus assay package insert. After
centrifugation, the supernatant will be assayed in triplicate. See the suggested plate map below.
Complete testing according to package insert instructions.
The within plate accuracy and reproducibility for each panel member will be calculated by the monitor.
1
2
3
4
5
6
7
8
9
10
11
12
A
R3
X
AF
AI
B
R4
X
AF
C
R4
Z
AF
D
R5
Z
AH
E
W
Z
AH
F
W
AC AH
G
W
AC
AI
H
X
AC
AI
R3 = Negative Control Serum R4 = Cut-off Control R5 = Positive Control Serum
W,X,Z,AC,AF,AH,AI = Panel Members = Empty well
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The study monitor will complete the Proficiency Testing Documentation Form (page D-17) for each
technologist who will be testing specimens with the Platelia® Aspergillus antigen assay and will indicate
on the form if proficiency testing is acceptable or unacceptable. If proficiency testing is unacceptable, the
technologist must repeat proficiency testing as instructed by the study monitor. If proficiency testing is
acceptable, the technologist can begin testing study specimens on the date indicated on the form.
Testing of study specimens can begin when proficiency testing is acceptable and a copy of the
signed and dated Proficiency Testing Documentation Form is received from the study monitor.
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Proficiency Testing Documentation Form
Site: __________________________________________________________
Name of Technologist: _______________________________Date of Testing ________________
Platelia®Aspergillus Lot #_________________________Expiration Date____________________
R3 =___________
R4 =1.___________ 2.___________ Mean = _____________
R5 =___________
Cutoff = mean optical density of R4 (Cut-off Control) = ____________
Panel
Member
Mean Index (I)
Interpretation
SD
CV%
Acceptable Range
Index (I)
Acceptable
CV%
W
0.10-0.21
< 25%
X
2.60-3.45
< 10%
Z
3.88-5.44
< 10%
AC
2.75-3.56
< 10%
AF
1.68-2.27
< 10%
AH
0.85-1.33
< 15%
AI
0.47-0.78
< 25%
___ Proficiency Testing Not Acceptable. Repeat proficiency testing.
___ Proficiency Testing Acceptable. Testing of specimens can begin on:____________________
(Attach a copy of the printout of OD values).
Signature of the Study Monitor:___________________________________ Date:___________________
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DATA COLLECTION
Platelia® Aspergillus Data
Data will be collected following the NIH Clinical Protocol guidelines.
Patient Clinical Data
Blood samples will be collected as part of the clinical protocol (“A Randomized Double-blind Trial of
Fluconazole vs. Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood and
Marrow Transplant Patients”). These samples will be tested with the Platelia® Aspergillus assay and the
results correlated with patient clinical data.
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APPENDIX D
ATTACHMENT A: PLATELIA® ASPERGILLUS KIT RECEIPT LOG
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PLATELIA® ASPERGILLUS KIT RECEIPT LOG
DATE
RECEIVED
PLATELIA® ASPERGILLUS
LOT NUMBER
NUMBER OF KITS
RECEIVED
______________________________________ ________________________
Investigator’s Signature
Date
(Make copies of this form if additional space is needed)
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APPENDIX D
ATTACHMENT B: PLATELIA ASPERGILLUS PACKAGE INSERT
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PLATELIA® ASPERGILLUS EIA
96 TESTS:
62793
480 TESTS:
62794
THE PLATELIA® ASPERGILLUS EIA IS AN IMMUNOENZYMATIC SANDWICH
MICROPLATE ASSAY FOR THE DETECTION OF ASPERGILLUS
GALACTOMANNAN ANTIGEN IN SERUM
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1. INTENDED USE
The Platelia Aspergillus EIA is an immunoenzymatic sandwich microplate assay for the
detection of Aspergillus galactomannan antigen in serum.
2. INDICATIONS FOR USE
The Platelia Aspergillus EIA is a test which, when used in conjunction with other diagnostic
procedures such as microbiological culture, histological examination of biopsy samples and
radiographic evidence, can be used as an aid in the diagnosis of Invasive Aspergillosis.
3. SUMMARY AND EXPLANATION
Aspergillus infections usually occur following inhalation of Aspergillus spores which are present
in the environment. Invasive forms, which have been on the increase for the past 10 years,
constitute the most serious infections. They mainly occur in neutropenic patients (following anti-
cancer treatment) and in patients treated with immuno-suppressants (organ transplantations,
particularly bone marrow transplantation) and corticosteroids2.
Aspergillus is rarely isolated from blood culture. The diagnosis is often based on nonspecific
diagnostic or radiological evidence (clinical symptioms, CT scan, chest x-ray, etc.).
At the present time, the test for soluble Aspergillus antigen in serum appears to be a serological
method able to aid in the diagnosis of Invasive Aspergillosis1,3,6,17,21.
4. PRINCIPLE OF THE PROCEDURE11
The Platelia Aspergillus EIA is a one-stage immunoenzymatic sandwich microplate assay
which detects galactomannan in human serum. The assay uses the rat monoclonal antibody
EBA-2, which is directed against Aspergillus galactomannan, and has been characterized
during previous studies8,12. The monoclonal antibody is used, (1) to coat the wells of the
microplate and bind the antigen, and (2) as the detector antibody in the conjugate reagent
(peroxidase-linked monoclonal antibody).
Serum samples are heat-treated in the presence of EDTA in order to dissociate the immune
complexes and to precipitate serum protieins that could possibly interfere with the test7. The
treated serum samples and conjugate are added to the wells coated with the monoclonal
antibody, and incubated. A monoclonal antibody - galactomannan - monoclonal antibody /
peroxidase complex is formed in the presence of Aspergillus antigen.
The strips are washed to remove any unbound material. Next, the substrate solution is added,
which will react with the complexes bound to the well to form a blue color reaction. The enzyme
reaction is stopped by the addition of acid, which changes the blue color to yellow. The optical
absorbance of specimens and controls is determined with a spectrophotometer set at 450 and
620/630 nm wavelength.
5. REAGENTS
Platelia Aspergillus
product No. 62793 (96 Tests)
product No. 62794 (480 Tests)
Store the kit at 2-8C. Bring all reagents to room temperature (18-25C) before use. Return all
reagents, except controls, to 2-8C immediately after use. After reconstitution, unused Negative
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Control, Cut-off Control, and Positive Control must be frozen at -20C. Return unused
strips/plates to pouch and reseal. Do not remove desiccant. Strips should be used within 5
weeks of opening and resealing the pouch. After dilution, wash solution can be kept for 15 days
at 2-8C. All other reagents are stable until expiration after opening. Reagents are supplied in
sufficient quantity to perform 96 determinations in a maximum of 6 batches or 480 tests in a
maximum of 12 batches.
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Component
Contents
Quantity
96
Test Kit
480
Test Kit
R1
Microwell
Strip Plate
96 wells (12 strips of 8 wells each)
coated with antigalactomannan
monoclonal antibody
1 Plate /
12 x 8 Wells
5 Plates /
12 x 8 Wells
R2
Wash
Solution 10X
Concentrate
Tris NaCl buffer
1% Tween® 20
0.01% thimerosal
1 x 100 mL
3 x 100 mL
R3
Negative
Control
Serum
Freeze-dried human negative serum
Negative for anti-HIV-1, anti-HIV-2,
anti-HCV antibodies and HBsAg
2 x 1 mL
4 x 1 mL
R4
Cut-off
Control
Serum
Freeze-dried human serum containing
galactomannan
Negative for anti-HIV-1, anti-HIV-2,
anti-HCV antibodies and HBsAg
2 x 1 mL
4 x 1 mL
R5
Positive
Control
Serum
Freeze-dried human serum containing
galactomannan
Negative for anti-HIV-1, anti-HIV-2,
anti-HCV antibodies and HBsAg
2 x 1 mL
4 x 1 mL
R6
Conjugate
Anti-galactomannan monoclonal
antibody/peroxidase labeled
0.01% thimerosal
1 x 8 mL
4 x 8 mL
R7
Treatment
Solution
EDTA acid solution
1 x 10.5 mL
5 x 10.5 mL
R8
Substrate
Buffer
Citric acid
Sodium acetate
0.009% Hydrogen peroxide
4% Dimethylsulfoxide (DMSO)
1 x 60 mL
3 x 60 mL
R9
Chromogen
Dimethylsulfoxide (DMSO)
Tetramethylbenzidine (TMB)*
1 x 1 mL
3 x 1 mL
R10
Stopping
Solution
1.5 N Sulphuric acid (H2SO4)
1 x 12 mL
5 x 12 mL
Plate sealers
Adhesive sheets for microplates
1 x 6 sheets
2 x 6 sheets
*Note: TMB (Tetramethylbenzidine) is a non-carcinogenic and non-mutagenic chromogen for peroxidase.
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Version 7.0 dated March 29, 2006
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6. WARNINGS FOR USERS
1. For in vitro diagnostic use.
2. For professional use only.
3. Use of this test kit with samples other than human serum is not recommended.
4. The Positive Control, Cut-off Control, and Negative Control are heat-inactivated, human
serum. They have been tested and found to be negative for anti-HIV-1, anti-HIV-2, and anti-
HCV antibodies, as well as HBsAg with French approved tests. However, all the reagents
should be handled as though capable of transmitting infection. All tests should be
conducted using the precautions recommended for blood borne pathogens, as defined by
OSHA regulations.
5. Wear protective clothing and disposable gloves while handling the kit reagents and patient
samples. Wash hands thoroughly after performing the test.
6. Do not pipette by mouth.
7. Do not smoke, drink, or eat in areas where specimens or kit reagents are being handled.
8. Avoid splashing samples or solutions containing them.
9. Biological spills not containing acid should be wiped thoroughly with an effective
disinfectant. Disinfectants that can be used include (but are not limited to) a solution of 10%
bleach (0.5% solution of sodium hypochlorite), 70% ethanol, or 0.5% Wescodyne™. Spills
containing acid should be wiped dry or neutralized with sodium bicarbonate and then
cleaned with one of the chemical disinfectants. Materials used to wipe up spills should be
disposed of as biohazardous waste. CAUTION: Do not place solutions containing bleach in
the autoclave.
10. Dispose of all specimens and materials used to perform the test as though they contain an
infectious agent. Disposal should comply with all applicable waste disposal requirements.
11. CAUTION: The Stopping Solution is an acid. Wipe up spills immediately and flush the areas
with water.
R36/38: Irritating to eyes and skin.
S:2-26-30: Keep out of reach of children. In case of contact with eyes, flush
immediately and thoroughly with water and consult a physician. Never pour
water into this product.
12. Avoid contact of Substrate Buffer, Chromogen, and Stopping Solution
with eyes, skin, and mucosae (risk of toxicity, irritation, and burns).
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Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
D-27
7. PRECAUTIONS FOR USERS
1. FROZEN SERUM SAMPLES STORED IN UNKOWN CONDITIONS MAY GIVE FALSE
POSITIVE RESULTS DUE TO CONTAMINATION WITH FUNGUS AND/OR BACTERIA.
2. Do not use kit or any kit reagents after the stated expiration date.
3. With the exception of the 10x Wash Solution (R2) and the Stopping Solution (R10), do not
mix reagents from other kits that have the same or different lot numbers. Note: Platelia
10X Wash Solution (R2) may be used on any Platelia brand assay.
4. Bring all reagents to room temperature for at least 15 minutes before use.
5. Mix thoroughly while reconstituting reagents, exercising care to avoid microbial
contamination.
6. Do not conduct the test in the presence of reactive vapors (acids, alkalis, aldehydes) or
dust, which could affect the enzymatic activity of the conjugate.
7. Use clean, disposable polypropylene plastic containers to prepare the chromogen solution.
If glassware must be used, clean thoroughly and rinse with deionized water.
8. For manual pipetting of controls and specimens, use individual pipette tips to prevent
carryover of samples.
9. To ensure adequate washing of the wells, comply with the recommended number of wash
cycles and ensure that all wells are completely filled and then completely emptied. Washing
should not be performed manually with a squeeze bottle.
10. Do not use the same container for the conjugate and substrate solutions.
11. Do not allow conjugate or substrate solutions to come into contact with metal or metallic
ions.
12. Avoid exposing the Chromogen or the Substrate-Chromogen Reaction Solution to strong
light during storage or incubation. Do not allow the chromogen solutions to come into
contact with an oxidizing agent.
13. Avoid contact of the Stopping Solution with any oxidizing agent. Do not allow the Stopping
Solution to come into contact with metal or metallic ions.
14. Use clean, dust-free materials (tubes, tips, containers, etc.) to minimize the possibility of
contamination with Aspergillus spores from the environment. Because galactomannan is
heat-stable, sterilization of material used does not guarantee the absence of contaminating
antigen. Pyrogen-free materials are optimal, but standard material can be used with
adequate precautions.
15. Limit exposure of solutions (sera, treatment solution, conjugate) or open containers (plates,
tubes, pipettes) to the air.
16. Do not pour any unused conjugate back into the original container.
17. The Substrate-Chromogen Reaction Solution must be colorless. The appearance of a blue
color after dilution indicates the reagent is contaminated and should not be used. Discard
and prepare fresh reagent.
8. REAGENT PREPARATION AND STORAGE
Wash Solution
Prepare Working Wash Solution as needed by adding one part Concentrated Wash Solution to
9 parts deionized or distilled water. The Working Wash Solution can be stored for 15 days at 2-
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
D-28
8C. Prepare a sufficient amount of Working Wash Solution to complete the run (i.e., minimum
of 160 mls for each 2 strips of 8 wells).
Negative Control Serum
Reconstitute the contents of one bottle of control with 1000 µl (1 mL) of sterile, purified water.
The sera must be rehydrated just before performing the test. Mix thoroughly after allowing 2-3
minutes for rehydration of the serum. Aliquot 300 µl into each of 3 Eppendorf tubes.
Immediately freeze at -20C any remaining Eppendorf tubes that will not used after rehydration.
Note: Control sera that have been previously rehydrated and immediately fozen at -20C may
be thawed and used without further rehydration. Frozen rehydrated controls may be stored at -
20C for up to five weeks. Handle the control sera in the same manner as patient specimens.
Cut-off Control Serum and Positive Control Serum
Prepare as described above for Negative Control Serum.
Substrate-Chromogen Reaction Solution
Prepare Substrate-Chromogen Reaction Solution by adding one part Concentrated Chromogen
Solution, R9, to 50 parts Substrate Buffer, R8 (e.g., 200 µl of R9 + 10 mL of R8). Prepare
4 mL of Substrate-Chromogen Reaction Solution per strip. The solution is stable for 6 hours
when stored in the dark at room temperature.
9. SPECIMEN COLLECTION
Collect blood samples according to standard laboratory procedures. The test is performed on
serum. Serum samples must be uncontaminated with fungal spores and/or bacteria. Transport
and store samples in sealed tubes, unexposed to air. Unopened samples can be stored at 2-
8C for up to 5 days prior to testing. After initial opening, samples may be stored at 2-8C for 48
hours prior to testing. For longer storage, store the serum at –70C.
10. PROCEDURE
Materials provided
See REAGENTS section.
Materials required but not provided
1. Distilled or deionized water, for dilution of Wash Solution.
2. Sterile, purified water for reconstitution of control sera.
3. Absorbent paper.
4. Disposable gloves.
5. Protective glasses.
6. Sodium hypochlorite (bleach) and sodium bicarbonate.
7. Pipettes or multipipettes, adjustable or fixed, to measure and dispense 50 µl, 100 µl, 300 µl,
and 1000 µl.
8. 1.5 mL Eppendorf (Sarstedt Cat. #72.692.105) or similar polypropylene tubes with airtight
stoppers, able to support heating to 100C.
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Version 7.0 dated March 29, 2006
D-29
9. Laboratory bench centrifuge for polypropylene tubes capable of obtaining 10,000g
(Brickman Cat. #22-36-280-1 or VWR Scientific Cat. #20901-051 or equivalent).
10. Round, floating micro-centrifuge rack for 1 L beaker (VWR Scientific Cat. # 60986-100 or
Nalgene #5974-1015 or equivalent).
11. Vortex agitator.
12. Boiling waterbath.
13. Microplate incubator at 37 1C.
14. Manual or semi-automatic plate washer.
15. Microplate reader equipped with 450 nm and 620/630 nm filters.
Procedural Comments
1. Negative, Positive, and Cut-off Controls must be tested on each run to validate the test
results.
Treatment of the sera
1. Pipette 300 µl of each test serum and control into individual 1.5 mL polypropylene tubes.
2. Add 100 µl of Treatment Solution (R7) to each tube.
3. Mix tubes thoroughly by vigorous homogenization or vortexing to mix thoroughly. Heat
tubes for 3 minutes in boiling waterbath at 100C.
4. Carefully remove hot tubes from the boiling waterbath and place in a centrifuge. Centrifuge
tubes at 10,000 x g for 10 minutes.
5. Test the supernatants using the following procedure. After preparation, the supernatant
may be removed and stored at 2-8C for up to 72 hours prior to testing. If analysis of the
results indicates retesting is required, another aliquot of serum must be treated for testing.
EIA Procedure
1. Bring reagents to room temperature (18 - 25C) for at least 15 minutes before use.
2. Prepare Wash Solution, Substrate-Chromogen Reaction Solution, and Negative, Positive,
and Cut-off Controls.
3. Prepare a chart for identification of test sera and controls in the microplate. Use one well for
the Negative Control Serum (R3), two wells for the Cut-off Serum (R4), and one well for the
Positive Control Serum (R5).
4. Remove the plateholder and microwell strips (R1) from the plate pouch. Return any strips
that will not be used to the pouch, with the desiccant, and reseal the pouch.
5. Add 50 µl of Conjugate (R6) to each well. Next, add 50 µl of treated serum supernatant to
each well, as designated above. Do not add serum samples to the wells before the
conjugate.
6. Cover plate with plate sealer, or other means to prevent evaporation, ensuring that entire
surface is covered and watertight.
7. Incubate the microplate in a dry microplate incubator for 90 ± 5 minutes at 37C (± 1 C).
8. Remove the plate sealer. Wash the plate 5 times, using a minimum of 370 µl of Working
Wash Solution. After the last wash, invert the microplate and gently tap on absorbent paper
to remove remaining liquid.
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Version 7.0 dated March 29, 2006
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9. Add 200 µl of Substrate-Chromogen Reaction Solution (R8 + R9) to each well, avoiding
exposure to bright light.
10. Incubate microplate in the dark at room temperature (18 to 25C) for 30 5 minutes. Do
not use adhesive film during this incubation step.
11. Add 100 µl of Stopping Solution (R10) to each well, utilizing the same order for addition of
Substrate Solution. Mix well.
12. Thoroughly wipe the bottoms of each plate.
13. Read the optical density of each well at 450 nm (reference filter of 620/630 nm).
Microplates must be read within 30 minutes of addition of Stopping Solution.
11. QUALITY CONTROL (VALIDITY CRITERIA)
Cut-off Control: The O.D. of each Cut-off Control Serum must be ≥ 0.3 and ≤ 0.8.
Positive Control: The index of the Positive Control Serum must be greater than 2.
I =
OD Positive Control (R5)
> 2
Mean Cut-off Control OD
Negative Control: The index of the Negative Control Serum must be less than 0.4.
I =
OD Negative Control (R3)
< 0.4
Mean Cut-off Control OD
Failure of any of the controls to meet the validity criteria described above renders the assay
invalid, and patient specimen results should not be reported. The operator may decide to
repeat the assay, after reviewing the procedure, or may contact the manufacturer for
assistance. If a repeat assay is performed, then a new aliquot of the same sample should be
used in the repeat assay.
Example Calculation:
Sample
Absorbence (OD)
Negative Control (R3) OD
0.117
Cut-off Control (R4) OD
0.596
0.576
Positive Control (R5) OD
2.602
Calculations
Mean Cut-off Control Value
To calculate the mean Cut-off Control (R4) OD, add the OD values for each Cut-off Control
replicate together and divide the result by 2:
(0.596 + 0.576) 2 = 0.586
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Version 7.0 dated March 29, 2006
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Negative Control Index
To calculate the index of the Negative Control, divide the OD of the Negative Control by the
mean Cut-off Control OD:
I =
0.117
= 0.20
0.586
Positive Control Index
To calculate the index of the Positive Control, divide the OD of the Positive Control by the mean
Cut-off Control OD:
I =
2.602
= 4.44
0.586
Validity
In the above example:
Each Cut-off Control OD is ≥ 0.3 and ≤ 0.8, indicating that the Cut-off Control is valid.
The index of the Negative Control is < 0.4, indicating that the Negative Control is valid.
The index of the Positive Control is > 2, indicating that the Positive Control is valid.
The test run in this example is considered to be valid since the results meet the validity criteria
for each control.
12. INTERPRETATION OF RESULTS
The presence or absence of Aspergillus antigen in the test sample is determined by calculation
of an index for each patient specimen. The Index (I), is the OD value of the specimen divided
by the mean optical density of the wells containing Cut-off Control Serum.
Calculation of the mean Cut-off Control optical density:
Add the optical densities of the two wells containing Cut-off Control Serum (R4) and divide the
total by 2.
Calculation of an index (I) for each test serum:
Calculate the following ratio for each test serum:
I =
OD sample
Mean Cut-off Control OD
Sera with an index < 0.5 are considered to be negative for galactomannan antigen.
Note: A negative result may indicate that the patient’s result is below the detectable level
of the assay.
Note: Negative results do not rule out the diagnosis of Invasive Aspergillosis. Repeat testing is
recommended if the result is negative, but the disease is suspected.
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Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
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Sera with an index > 0.5 are considered to be positive for galactomannan antigen.
Note: The Platelia Aspergillus EIA is intended to be used as an aid in the diagnosis of
Invasive Aspergillosis. Positive results obtained with the Platelia Aspergillus EIA
should be considered in conjuction with other diagnostic procedures such as
microbiological culture, histological examination of biopsy samples and radiographic
evidence.
For all positive patients, it is recommended that a new aliquot of the same sample be repeated
as well as collection of a new sample from the patient for follow-up testing.
Note: An absorbance value of less than 0.000 OD may indicate a procedural or instrument error
which should be evaluated. That result is invalid and the specimen must be re-run.
Example Calculation:
Sample
Absorbence (OD)
Negative Control (R3) OD
0.117
Cut-off Control (R4) OD
0.596
0.576
Positive Control (R5) OD
2.602
Patient Sample #1
0.134
Patient Sample #2
0.436
Patient Sample #3
1.196
Calculations
Refer to the Quality Control (Validity Criteria) section for an example of calculations to
determine the validity of the assay controls.
Mean Cut-off Control Value
To calculate the mean Cut-off Control (R4) OD, add the OD values for each Cut-off Control
replicate together and divide the result by 2:
(0.596 + 0.576) 2 = 0.586
Patient Sample #1
To calculate the index of Patient #1, divide the OD of Patient Sample #1 by the mean Cut-off
Control OD:
I =
0.134
= 0.23
0.586
In this example, Patient Sample #1 is negative, since the Index of 0.23 is < 0.5.
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Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
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Patient Sample #2
To calculate the index of Patient #2, divide the OD of Patient Sample #2 by the mean Cut-off
Control OD:
I =
0.436
= 0.74
0.586
In this example, Patient Sample #2 is positive, since the Index of 0.74 is > 0.5.
Patient Sample #3
To calculate the index of Patient #3, divide the OD of Patient Sample #3 by the mean Cut-off
Control OD:
I =
1.196
= 2.04
0.586
In this example, Patient Sample #3 is positive, since the Index of 2.04 is > 0.5.
13. LIMITATIONS OF THE PROCEDURE
1. A negative test cannot rule out the diagnosis of Invasive Aspergillosis. Patients at
risk for Invasive Aspergillosis should be tested twice a week.
2. The Platelia Aspergillus Procedure and the Interpretation of Results must be followed when
testing samples for the presence of Aspergillus antigen. The user of the kit is advised to
read the package insert carefully prior to conducting the test. In particular, the test
procedure must be carefully followed for sample and reagent pipetting, plate washing, and
timing of the incubation steps.
3. Failure to add specimen or reagent as instructed in the procedure could result in a falsely
negative test. Repeat testing of additional samples should be considered where there is
clinical suspicion of Invasive Aspergillosis or procedural error.
4. Contamination of negative patient specimen wells by positive control/patient specimen wells
is possible if the contents of one well spill over into another well due to rough handling of the
microplate or poor pipetting technique while adding reagents.
5. The performance of the Platelia Aspergillus EIA has not been evaluated with neonate or
pediatric serum samples.
6. The Platelia Aspergillus EIA may exhibit reduced detection of galactomannan in patients
with chronic granulomatous disease (CDG) and Job’s syndrome19,20.
7. The concomitant use of mold-active anti-fungal therapy in some patients with Invasive
Aspergillosis may result in reduced sensitivity with the Platelia Aspergillus EIA.
8. The Platelia Aspergillus EIA has not been evaluated for use with plasma or other sample
types such as urine, BAL, or CSF.
9. The performance of the Platelia Aspergillus EIA has not been established for manual
reading and/or visual result determination.
10. Other genera of fungi such as Penicillium and Paecilomyces have shown reactivity with the
rat, EBA-2 monoclonal antibody used in the assay for the detection of Aspergillus
galactomannan15. These species are rarely implicated in invasive fungal disease.
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Version 7.0 dated March 29, 2006
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14. EXPECTED VALUES
The expected prevalence of Invasive Aspergillosis varies with the patient population; rates from
5-20% have been reported2,5. A clinical study was conducted on a total of 1890 serum samples
from 179 bone marrow transplant (BMT) and leukemic patients diagnosed with and without
Invasive Aspergillosis, at three testing centers in North America to determine the performance
characteristics of the Platelia Aspergillus EIA. The average prevalence rate for this study was
14%. The distribution of index values for these populations is represented in the following
charts.
Patients diagnosed with Invasive Aspergillosis (control population)
A total of 1362 frozen serum samples obtained from 148 bone marrow transplant (BMT) and
leukemic patients at three testing centers in North America were tested with the Platelia
Aspergillus EIA test. The distribution of index values is shown in the following chart.
This scatter plot depicts
galactomannan assay
results for the 1362 serum
samples from 148 control
patients in this study
(patients undergoing
immunosuppressive therapy
for HSCT, or to treat
hematological malignancy).
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Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
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Patients diagnosed with Invasive Aspergillosis
This scatter plot depicts
galactomannan assay results for
the 528 serum samples from 31
patients in this study diagnosed
with proven or probable Invasive
Aspergillosis as defined by
EORTC/NIAID definitions. Not
every serum sample from each
patient is expected to be positive.
The expected prevalence of
Invasive Aspergillosis varies with
the patient population; rates from 5-
20% have been reported 2,5. The
prevalence rate for this study was
14%.
The following graphs represent examples of a patient without clinical signs or symptoms of
Invasive Aspergillosis (negative for Aspergillus) and a patient with proven or probable Invasive
Aspergillosis (positive for Aspergillus) respectively.
Negative Patient
Positive Patient
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Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
D-36
15. SPECIFIC PERFORMANCE CHARACTERISTICS
A. Reproducibility Studies
Inter-assay and Intra-assay variability for the Platelia Aspergillus EIA were determined in a
study using a panel of 6 pooled patient serum samples (one negative, one low positive, two
positive, and two high positive) obtained from actual clinical trial sites. Each of the 6 panel
members was tested in triplicate (x3) on 3 different days, on one lot, at two sites (total number
of replicates at each site = 9). Each of the 6 panel members was tested in duplicate (x2) on 3
different days, on 1 lot, at a third site (total number of replicates at the third site = 6). One (1)
operator performed all precision testing at each site. The data were analyzed according to the
National Committee for Clinical Laboratory Standards (NCCLS). The mean optical density (D)
and mean index value, standard deviation (SD), percent coefficient of variation (%CV), within
run precision (intra-assay) and within site (inter-assay) precision for each panel member at each
site are illustrated below in the following tables.
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Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
D-37
Site 1
Panel Member
Neg
Low Pos
Pos #1
Pos #2
High Pos #1
High Pos #2
Neg Control
CO Control
Pos Control
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
N
9
9
9
9
9
9
9
9
9
9
9
9
3
3
6
6
3
3
Mean
0.052
0.09
0.445
0.74
0.702
1.17
0.931
1.563
1.227
2.06
2.887
4.83
0.046
0.08
0.606
1.00
2.216
3.67
Within Run
(intra-assay)1SD
0.002
0.00
0.022
0.03
0.059
0.09
0.044
0.08
0.051
0.09
0.089
0.17
N/A
N/A
0.02
0.03
N/A
N/A
% CV
N/A
N/A
4.8%
4.4%
8.4%
7.6%
4.7%
5.1%
4.2%
4.4%
3.1%
3.6%
N/A
N/A
3.7%
3.4%
N/A
N/A
Total
(inter-assay)2SD
0.036
0.04
0.051
0.08
0.070
0.14
0.044
0.25
0.058
0.29
0.169
0.58
N/A
N/A
0.102
0.03
0.317
0.12
% CV
N/A
N/A
11.5%
10.4%
10.0%
11.6%
4.7%
15.7%
4.7%
14.3%
5.9%
11.9%
N/A
N/A
16.9%
2.8%
14.3%
3.3%
Site 2
Panel Member
Neg
Low Pos
Pos #1
Pos #2
High Pos #1
High Pos #2
Neg Control
CO Control
Pos Control
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
N
9
9
9
9
9
9
9
9
9
9
9
9
3
3
6
6
3
3
Mean
0.040
0.10
0.280
0.70
0.364
0.89
0.602
1.49
0.801
2.01
1.361
3.43
0.074
0.18
0.415
1.00
1.197
2.97
Within Run
(intra-assay)1SD
0.006
0.01
0.041
0.09
0.023
0.07
0.045
0.11
0.046
0.10
0.047
0.11
N/A
N/A
0.00
0.01
N/A
N/A
% CV
N/A
N/A
14.5%
13.0%
6.4%
7.6%
7.5%
7.1%
5.7%
4.8%
3.5%
3.2%
N/A
N/A
1.1%
1.1%
N/A
N/A
Total
(inter-assay)2SD
0.006
0.03
0.058
0.19
0.083
0.18
0.057
0.28
0.042
0.53
0.079
1.00
N/A
N/A
0.094
0.01
0.068
0.54
% CV
N/A
N/A
20.8%
27.0%
22.7%
19.8%
9.5%
18.7%
5.3%
26.5%
5.8%
29.2%
N/A
N/A
22.7%
0.9%
5.7%
18.2%
Site 3
Panel Member
Neg
Low Pos
Pos #1
Pos #2
High Pos #1
High Pos #2
Neg Control
CO Control
Pos Control
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
OD
Index
N
6
6
6
6
6
6
6
6
6
6
6
6
3
3
6
6
3
3
Mean
0.049
0.10
0.388
0.81
0.652
1.36
0.830
1.73
1.158
2.41
2.378
4.96
0.059
0.12
0.480
1.00
1.652
3.45
Within Run
(intra-assay)1SD
0.003
0.01
0.009
0.02
0.082
0.17
0.068
0.14
0.094
0.20
0.126
0.25
N/A
N/A
0.028
0.06
N/A
N/A
% CV
N/A
N/A
2.4%
2.4%
12.5%
12.2%
8.2%
8.2%
8.1%
8.2%
5.3%
5.1%
N/A
N/A
5.8%
5.8%
N/A
N/A
Total
(inter-assay)2SD
0.012
0.03
0.078
0.13
0.068
0.15
0.104
0.25
0.082
0.15
0.111
0.34
N/A
N/A
0.028
0.04
0.056
0.23
% CV
N/A
N/A
20.0%
15.8%
10.5%
11.1%
12.5%
14.3%
7.1%
6.2%
4.7%
6.8%
N/A
N/A
5.8%
4.1%
3.4%
6.6%
N/A = not applicable
1NCCLS EP5-A, Vol. 19, No. 2, Page 24, Equation (C2)
2NCCLS EP5-A, Vol. 19, No. 2, Page 25, Equation (C3) and Equation (C4)
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Version 7.0 dated March 29, 2006
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B. Cross Reactivity
A study to evaluate the effect of potentially interfering medical conditions unrelated to Invasive
Aspergillosis was performed with one lot of the Platelia Aspergillus EIA kit. The following
serum samples were tested for cross-reactivity with the Platelia Aspergillus EIA. A total of 151
sera were tested.
Pathology
#Samples Tested
# Positives
Rheumatoid Factor
10
0
ANA Positive
10
0
IgG Hypergammaglobulinemia
10
0
IgM Hypergammaglobulinemia
10
0
Cancer*
11
0
Non-Viral Cirrhosis (primary biliary;
alcohol induced; drug induced)
10
0
Multiple Transfusions
10
0
Multiparous Females
10
0
HAV
10
0
HCV
10
0
Rubella
10
0
CMV
10
0
Syphilis (RPR+)
10
0
Toxoplasmosis
10
0
Mycoplasma
10
0
*One each of bladder, breast (2), colon, endometrial, lung, prostate, renal, and squamous (3).
C. Clinical Testing
Clinical testing to evaluate the sensitivity, specificity, and predictive value of the Platelia
Aspergillus EIA was conducted at three sites located in the U.S. and Canada. The study was
conducted retrospectively using a total of 1890 serum samples collected from 179 patients from
the following populations*:
patients without signs of Invasive Aspergillosis (control patients)
patients with probable Invasive Aspergillosis
patients with proven Invasive Aspergillosis
* The Invasive Fungal Infection Cooperative Group (IFICG) of the European Organization for
Research (EORTC) and the Mycosis Study Group (MSG) of the National Institute of Allergy and
Infectious Diseases (NIAID) have defined criteria for diagnosis of Invasive Aspergillosis (IA) in
patients with hematologic malignancy or hematopoetic stem cell transplant.
Proven Invasive Aspergillosis is defined by positive microbiological culture obtained by sterile
procedure from the site affected, and histopathological demonstration of the appropriate
morphological forms in a host with symptoms attributed to the fungal infection.
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Probable Invasive Aspergillosis is defined as a least one microbiological criterion, and one
major or two minor clinical criteria from a site consistent with infection, in a host with symptoms
attributed to the fungal infection.
Possible Invasive Aspergillosis is defined as at least one microbiological criterion, or one
major or two minor clinical criteria from a site consistent with infection, in a host with symptoms
attributed to the fungal infection.
Given the relative rarity of Probable and Proven Invasive Aspergillosis, we offer the following
definition of clinical sensitivity and specificity for the purposes of this study.
SENSITIVITY
Results from this study have been analyzed in terms of patient sensitivity. Sensitivity testing
was conducted using the Platelia Aspergillus EIA at three sites on a combined total of 31 Bone
Marrow Transplant (BMT) and Leukemia patents diagnosed with Proven or Probably Invasive
Aspergillosis.
1. Proven Aspergilliosis (as defined by IFICG / EORTC; see above)
Combined Sites
N = 11 (patients)
11 patients:
6 patients diagnosed with Proven Invasive Aspergillosis of the lung
5 patients diagnosed with Proven Invasive Aspergillosis of the sinus
Sensitivity: 81.8% (9/11).
Note: The 95% confidence interval could not be calcuated due to insuffient sample size.
2. Probable Aspergillosis (as defined by IFICB / EORTC; see above)
Combined Sites
N = 20 (patients)
20 patients:
16 patients diagnosed with Probable Invasive Aspergillosis of the lung
4 patients diagnosed with Probable Invasive Aspergillosis of the sinus
Sensitivity: 80.0% (16/20)
Note: The 95% confidence interval could not be calculated due to insufficient sample size.
3. Combined Proven and Probable Aspergillosis (as defined byIFICG / EORTC; see
above)
Combined Sites
N = 31 (patients)
31 patients:
22 patients diagnosed with Proven or Probable Invasive Aspergillosis of the lung
9 patients diagnosed with Proven or Probable Invasive Aspergillosis of the sinus
Sensitivity: 80.7% (25/31). The 95% confidence interval is 64.0 – 97.3%
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SPECIFICITY
Specificity testing was conducted using the Platelia Aspergillus EIA at three sites on a
combined total of 1362 samples obtained from 148 Bone Marrow Transplant (BM) and
Leukemia patients without signs of Invasive Aspergillosis (control patients).
Site 1
N = 33 patients
449 sera obtained from:
16 BMT patients without signs of Invasive Aspergillosis
11 BMT patients colonized with Aspergillus and/or Candida sp.
1 BMT patient diagnosed with Invasive Fusariosis
3 BMT patients diagnosed with Candidemia
1 patient with blood cultures positive for Lecythophora mutabilis
1 patient diagnosed with Invasive Pseudoallescheria boydii
Site 1
Specificity
95% Confidence Interval
Patients (27/33)
81.8%
66.1 – 97.5%
Patients after repeat testing (31/33)
Site 2
N = 77 patients
560 sera obtained from:
67 Leukemic patients without signs of Invasive Aspergillosis
8 Leukemic patients with Fungemia (Candida, Fusarium, Trichosporon, or Aureobasidium)
1 Leukemic patient diagnosed with Probable Fusarium pneumonia
1 Leukemic patient diagnosed with Candida pneumonia
Site 2
Specificity
95% Confidence Interval
Patients (71/77)
93.4%
87.1 – 99.8%
Patients after repeat testing (74/77)
Site 3
N = 38 patients
353 sera obtained from:
28 BMT patients without signs of Invasive Aspergillosis
5 Leukemic patients receiving a second course of cytotoxic therapy
5 BMT patients being treated for Graft Versus Host Disease
Site 3
Specificity
95% Confidence Interval
Patients (34/38)
89.5%
77.8 – 100%
Patients after repeat testing (38/38)
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Combined Sites
N = 148 patients*
Combined Sites
Specificity
95% Confidence Interval
Patients (132/148)
89.2%
83.8 – 94.6%
Patients after repeat testing (143/148)
PREDICTIVE VALUE
Positive and negative predictive values have been analyzed for the patient population in this
study, based on the actual average 14% prevalence rate observed in this study. Positive and
negative predictive values have been calcualted for both the initial test result and after repeat
testing.
Actual Prevalence of 14%
PPV
NPV
Patients
54.8%
96.6%
Patients after repeat testing
68.3%
95.5%
The expected prevalence of Invasive Aspergillosis varies with the patient population; rates from
5-20% have been reported2,5. For patient populations on the lower end of the published
prevalence, the positive and negative prevalence have been re-calculated using a 5%
prevalence rate.
Calculated Prevalence of 5%
PPV
NPV
Patients
12.5%
96.0%
Patients after repeat testing
31.3%
96.3%
*Note: A total of 1362 sera obtained from 148 patients were tested. 1343 of the 1362 sera were
intitially negative, resulting in a sample agreement of 98.6% with a 95% confidence interval of
97.9 – 99.3%. On repeat testing, 1355 of the 1362 sera were negative.
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16. APPENDIX D BIBLIOGRAPHY
1. de Repentigny L., L. Kaufman, G.T. Cole, D. Kruse, J.P. Latge, R.C. Matthews. 1994.
Immunodiagnosis of Invasive Fungal Infections. J Med Vet Mycol. 32: 239-252.
2. Denning, D.W. 1998. Invasive Aspergillosis. Clin. Infect. Dis. 26: p. 781-803.
3. Erjavec, Z. and P.E. Verweij, 2002. Recent progress in the diagnosis of fungal infections in
the immunocompromised host. Drug Resist. Updat. 5: p. 3-10.
4. Herbrecht, R., V. Letscher-Bru, C. Oprea, B. Lioure, J. Waller, F. Campos, O. Villard,
K.L. Liu, S. Natarajan-Ame, P. Lutz, P. Dufour, J.P. Bergerat, and E. Candolfi. 2002.
Aspergillus galactomannan detection in the diagnosis of Invasive Aspergillosis in cancer
patients. J. Clin. Oncol. 20: p. 1898-1906.
5. Herbrecht, R., D. Denning, T. Patterson, J. Bennett, R. Greene, J. Oestmann, W. Kern,
K. Marr, P. Ribaud, O. Lortholary, R. Sylvester, R. Rubin, J. Wingard, P. Stark, C.
Durand, D. Caillot, E. Thiel, P. Chandrasekar, M. Hodges, H. Schlamm, P. Troke, B.
DePauw. 2002. Voriconazole Versus Amphotericin B for Primary Therapy of Invasive
Aspergillosis. N Engl J Med. 347, 6: p. 408-415.
6. Latge, J.P. 1995. Tools and trends in the detection of Aspergillus fumigatus. Curr Top
Med Mycol 6, p. 245-281.
7. Latge, J.P. 1999. Aspergillus fumigatus and Aspergillosis. Clin Microbiol Rev 12[2], 310-
50.
8. Latge, J.P., H. Kobayashi, J.P. Debeaupuis, M. Diaquin, J. Sarfati, J.M. Wieruszeski, E.
Parra, J.P. Bouchara, and B. Fournet. 1994. Chemical and immunological
characterization of the extracellular galactomannan of Aspergillus fumigatus. Infect. Immun.
62: p. 5424-5433.
9. Maertens, J., J. Verhaegen, H. Demuynck, P. Brock, G. Verhoef, P. Vandenberghe, J.
Van Eldere, L. Verbist, and M. Boogaerts. 1999. Autopsy-controlled prospective
evaluation of serial screening for circulating galactomannan by a sandwish enzyme-linked
immunosorbent assay for hematological patients at risk for invasive Aspergillosis. J. Clin.
Microbiol. 37: p. 3223-3228.
10. Maertens, J., J. Verhaegen, K. Lagrou, J. Van Eldere, and M. Boogaerts. 2001.
Screening for circulating galactomannan as a noninvasive diagnostic tool for Invasive
Aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a
prospective validation. Blood 97: p. 1604-1610.
11. Stynen D, A. Goris, J. Sarfati, and J.P. Latge. 1995. A new sensitive sandwich enzyme-
linked immunosorbent assay to detect galactofuran in patients with Invasive Aspergillosis.
J. Clin Microbiol. 33: 497-500.
12. Stynen D., J. Sarfati, A. Goris, M.C. Prevost, M. Lesourd, H. Kamphuis, V. Darras, and
J.P. Latge. 1992. Rat monoclonal antibodies against Aspergillus galactomannan. Infect.
Immun. 60: p. 2237-2245.
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13. Sulahian, A., F. Boutboul, P. Ribaud, T. Leblanc, C. Lacroix, and F. Derouin. 2001.
Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of
Invasive Aspergillosis in two adult and pedatric hematology units during a 4-year
prospective study. Cancer 91: p. 311-318.
14. Sulahian, A., M. Tabouret, P. Ribaud, J. Sarfati, E. Gluckman, J.P. Latge, and F.
Derouin. 1996. Comparison of an enzyme immunoassay and latex agglutination test for
detection of galactomannan in the diagnosis of Invasive Aspergillosis. Eur. J. Clin.
Imcrobiol. Infect. Dis. 15: p. 139-145.
15. Swanink, C.M., J.F. Meis, A.J. Rijs, J.P. Donnelly, and P.E. Verweij. 1997. Specificity of
a sandwish enzyme-linked immunosorbent assay for detecting Aspergillus galactomannan.
J Clin. Microbiol. 35: p. 257-260.
16. Verweij, P.E., E.C. Dompeling, J.P. Donnelly, A.V. Schattenberg, and J.F. Meis. 1997.
Serial monitoring of Aspergillus antigen in the early diagnosis of Invasive Aspergillosis.
Preliminary investigations with two examples. Infection 25: p. 86-89.
17. Verweij, P.E. and J.F. Meis. 2000. Microbiological diagnosis of Invasive Fungal Infections
in transplant recipients. Transpl. Infect. Dis. 2: p. 80-87.
18. Verweij, P.E., D. Stynen, A.J. Rijs, B.E. de Pauw, J.A. Hoogkamp-Korstanje, and J.F.
Meis. 1995. Sandwish enzyme-linked immunosorbent assay compared with Pastorex latex
aggluination test for diagnosing Invasive Aspergillosis in immunocompromised patients. J.
Clin. Microbiol. 33: p. 1912-1914.
19. Verweij, P.E., C.M. Weemaes, J.H. Curfs, S. Bretagne, J.F. Meis. 2000. Failure to detect
circulating Aspergillus markers in a patient with chronic granulomatous disease and Invasive
Aspergillosis. J Clin. Microbiol. 38: p. 3900-3901.
20. Walsh, T.J., R.L. Schaufele, T. Sein, J. Gea-Banacloche, M. Bishop, N. Young, R.
Childs, J. Barrett, H.L. Malech, and S.M. Holland. 2002. Reduced expression of
galactomannan antigenemia in patients with Invasive Aspergillosis and chronic
granulomatous disease or Job’s syndrome. Abstracts of the 40th Annual Meeting of the
Infectious Diseases Society of America. Arlington, VA. P. 105; Abstr. 345.
21. Yeo, S.F. and B. Wong. 2002. Current Status of Nonculture Methods for Diagnosis of
Invasive Fungal Infections. Clin. Microbiol. Rev. 15: p. 465-484.
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APPENDIX D
ATTACHMENT C: PLATELIA ASPERGILLUS WORKSHEETS
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R1 Microwell Plates
Date p ouch op ened:
R2 Concentrated Wash
Date d iluted:
Fresh
(c irc le
Frozen
one)
Fresh
(c irc le
Frozen
one)
Fresh
(c irc le
Frozen
one)
R6 Conjugate
R7 Serum Treatment Solution
R8 Peroxidase Substrate Buffer
R9 Chromogen
R10 Stopping Solution
Boiling water bath or heat block
Temp:
Centrifuge for Eppendorf tubes
Revolution:
xG
Washer
Incubator
Temp:
Reader
Wa velength:
Heat in water bath or heat block
3 minutes
Heat in water bath or heat block
3 minutes
Heat in water bath or heat block
3 minutes
Centrifuge at 10,000 g
10 minutes
Centrifuge at 10,000 g
10 minutes
Centrifuge at 10,000 g
10 minutes
Incubation of conjugate and treated sera
90 minutes
Substrate-chromogen incubation
30 minutes +/- 5
Stopping solution added
Plate read
within 30 min of stop
N/A
N/A
N/A
TREATMENT OF SERA TREATMENT OF SERA TREATMENT OF SERA
EIA PROCEDURE EIA PROCEDURE EIA PROCEDURE
START TIME
FINISH TIME
ACCEPTABLE
PROCEDURE TIMING VERIFICATION
ASSAY STEP
/
R3 Negative Control Serum
R4 Threshold Control Serum
R5 Positive Control Serum
Date rec onst:
Date rec onst:
Date rec onst:
INSTRUMENTATION USED
INSTRUMENT
MANUFACTURER
SERIAL NO.
COMMENTS
(THIS PAGE TO BE HAND-WRITTEN)
REAGENT
COMMENTS
LOT #
Run No:______________________________ Date Performed:____________________ Technologist:____________________
Platelia Aspergillus Kit Lot #:_________________________ Expiration Date:_________________________
KIT REAGENTS
Clinical Trial Site:______________________________________________________________________
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1
2
3
4
5
6
A
B
C
D
E
F
G
H
7
8
9
10
11
12
A
B
C
D
E
F
G
H
(THIS PAGE TO BE HAND-WRITTEN)
Run No:______________________________ Date Performed:____________________ Technologist:____________________
Platelia Aspergillus Kit Lot #:_________________________ Expiration Date:_________________________
Clinical Trial Site:____________________________________________________________
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APPENDIX D
ATTACHMENT D: QUICK REFERENCE GUIDE
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APPENDIX E
HUMAN SUBJECTS
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APPENDIX E
HUMAN SUBJECTS
Subject consent: Candidates for the study will be identified as described in Section 2.0 of the
protocol. The PI or his/her designee at each transplant center will contact the candidates and
enroll them onto the study. The study coordinator at each center will provide the patient with
information about the purpose of the study and obtain consent. A template of the consent form
will be provided by the network to each center. Each center will customize the template
according to their local requirements and submit it for review by the local IRB. Each center
must provide evidence of IRB approval.
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 network.
Participation of women and minorities, children and other populations: Women and ethnic
minorities will be included in this study. The lower age limit of participants is age 2.
Accrual will be monitored within each center with the expectation that the enrolled patient
population is representative of the transplanted patient population at each center. Representation
will be examined by comparing gender, race, ethnicity and age distributions. Accrual of
minority patients will be expected to be in proportion to the number of minority patients
transplanted at each center. The DCC and NHLBI will discuss enrollment anomalies with the
centers.
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APPENDIX F
VORICONAZOLE AND FLUCONAZOLE
DILUTION AND INFUSION INSTRUCTIONS
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APPENDIX F
VORICONAZOLE AND FLUCONAZOLE
DILUTION AND INFUSION INSTRUCTIONS
A. VORICONAZOLE DILUTION AND INFUSION INSTRUCTIONS
Voriconazole is manufactured and supplied by Pfizer Pharmaceuticals, Groton, Connecticut,
USA and will be supplied by the Blood and Marrow Transplant Clinical Trials Network (BMT
CTN). Voriconazole is packaged as a lyophilized powder for injection, 200 mg in 30 mL vials,
with each vial also containing 3200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).
Prior to reconstitution vials should be stored at room temperature 15o-30oC. The drug does not
contain a preservative, and is suitable for single use only. If not used immediately, the in-use
storage times and conditions prior to use are the responsibility of the individual user and should
not be longer than 24 hours at 2o-8oC (37o-46oF).
RECONSTITUTION FOR PEDIATRIC DOSES - Under aseptic conditions:
1. Voriconazole should be reconstituted with 19 mL Sterile Water for Injection, USP. Each
mL will contain 10 mg voriconazole.
2. Use the table below to determine the number of vials needed for each dose.
3. The volume of 10 mg/mL concentrated voriconazole solution required based on the
patients weight should be calculated (see below) and withdrawn into a syringe.
VORICONAZOLE - Patients < 12 years
Body Weight (kg)
Dose
Volume of Voriconazole Concentrated
(10 mg/mL) Solution Required for
~4 mg/kg Dose (Number of Vials)
10
50 mg
5 mL (1)
10 – 14.99
50 mg
5 mL (1)
15 – 19.00
100 mg
10 mL (1)
20 – 24.99
100 mg
10 mL (1)
25 – 29.99
100 mg
10 mL (1)
30 – 34.99
150 mg
15 mL (1)
35 – 39.99
150 mg
15 mL (1)
40
200 mg
20 mL (1)
* NOTES:
1. Dose capped for children weighing > 40 kg.
2. It is expected that weight fluctuations during study periods will not be substantial enough to
warrant dosing changes.
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4. This volume should be withdrawn and injected into an empty Viaflex bag, and then
further diluted with an approved solution (these solutions will not be provided by the
BMT CTN).
5. Approved diluent: Sodium Chloride 0.9%, USP.
6. The final volume is dependent upon the age of the patient. For pediatric patients the
final concentration of voriconazole will vary, with the final volume varying according to
body weight.
Body Weight (kg)
VORICONAZOLE - Patients < 12 Years
Volume concentrated
solution (10mg/mL)
Additional Fluid for Final
Reconstitution
Total Volume
10
5.0 mL
45 mL
50 mL
10 – 14.99
5.0 mL
45 mL
50 mL
15 – 19.99
10.0 mL
40 mL
50 mL
20 – 24.99
10.0 mL
65 mL
75 mL
25 – 29.99
10.0 mL
65 mL
75 mL
30 – 34.99
15.0 mL
85 mL
100 mL
35 – 39.99
15.0 mL
85 mL
100 mL
40
20.0 mL
80 mL
100 mL
NOTE: for children < 30 kg, a single vial of voriconazole 200 mg may be used to prepare both AM and PM
doses. In such circumstances doses should be prepared at the same time and given an expiration of 24 hours
under refrigerated conditions.
Administration: Voriconazole is to be administered over 2 hours.
RECONSTITUTION FOR ADULT (patients aged 12 years or greater) DOSES - Under
aseptic conditions:
1. Voriconazole should be reconstituted with 19 ml Sterile Water for Injection, USP. Each
mL will contain 10 mg voriconazole.
2. Use the table below to determine the number of vials needed for each dose.
3. The volume of 10 mg/mL concentrated voriconazole solution required based on the
patients weight should be calculated (see below) and withdrawn into a syringe.
Volume of Voriconazole Concentrated (10 mg/mL) Solution required:
All adult patients (i.e., those 12 years of age or greater) will receive a standard intravenous
dose of voriconazole of 200 mg twice daily. The volume of concentrated solution to make
each dose is 20mL.
4. This volume should be withdrawn and injected into an empty Viaflex bag, and then
further diluted with an approved solution (these solutions will not be provided by the
BMT CTN).
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5. Approved diluent: Sodium Chloride 0.9%, USP.
6. The final volume is dependent upon the age of the patient.
Age
VORICONAZOLE – Adult Patients ( 12 years)
Volume
concentrated
solution (10 mg/mL)
Additional Fluid for Final
Reconstitution
Total Volume
> 12 years
(Normal Renal
Function)
20.0 mL
180 mL
200 mL
> 12 years
(CrCl
< 50 mL/min)
20.0 mL
80 mL
100 mL
Notes: Voriconazole should not be infused into the same catheter as other drug infusions,
including parenteral nutrition. Infusion of blood products and infusion of electrolyte
supplementation must not occur simultaneously with voriconazole infusion.
B. FLUCONAZOLE DILUTION AND INFUSION INSTRUCTIONS
Fluconazole (Diflucan) is manufactured by Pfizer, Inc., Groton, Connecticut and will be
supplied by the Blood and Marrow Transplant Clinical Trials Network. Fluconazole for
injection is packaged in Viaflex Plus plastic containers containing 200 mg of fluconazole in a
volume of 100 mL in sodium chloride (concentration 2 mg/mL).
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RECONSTITUTION FOR PEDIATRIC (< 12 years of age) PATIENTS:
1. The dose of fluconazole required should be calculated, and the corresponding volume of
fluid should be withdrawn from the manufacturer’s Viaflex bag (see below for
volumes).
FLUCONAZOLE – Patients < 12 years
Body
Weight (kg)
Volume of Fluconazole
Concentrated (2 mg/mL)
Solution Required for 6 mg/kg
Dose in Pediatrics
(Number of Bags)
Additional Fluid
for Final
Reconstitution
Total Volume
< 10
30 mL (1)
20 mL
50 mL
10 – 14.99
30 mL (1)
20 mL
50 mL
15 – 19.99
45 mL (1)
5 mL
50 mL
20 – 24.99
60 mL (1)
15 mL
75 mL
25 – 29.99
75 mL (1)
Nil
75 mL
30 – 34.99
90 mL (1)
10 mL
100 mL
> 35
100 mL (2)
Nil
100 mL
2. This solution should be injected into an empty Viaflex bag, and further diluted as
directed in the table above with an approved diluent (see below)
3. Approved diluent: Sodium Chloride 0.9%, USP.
RECONSTITUTION FOR PEDIATRIC (< 12 years of age) PATIENTS WITH
CREATININE CLEARANCE <50mL/min/1.73m2:
FLUCONAZOLE – Patients < 12 years (CrCl <50 mL/min/1.73m2)
Body
Weight (kg)
Volume of Fluconazole
Concentrated (2 mg/mL)
Solution Required for 3 mg/kg
Dose in Pediatrics
(Number of Bags)
Additional Fluid
for Final
Reconstitution
Total Volume
< 10
15 mL (1)
35 mL
50 mL
10 – 14.99
15 mL (1)
35 mL
50 mL
15 – 19.99
22.5 mL (1)
27.5 mL
50 mL
20 – 24.99
30 mL (1)
45 mL
75 mL
25 – 29.99
37.5 mL (1)
37.5 mL
75 mL
30 – 34.99
45 mL (1)
55 mL
100 mL
> 35
50 mL (1)
50 mL
100 mL
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RECONSTITUTION FOR PEDIATRIC (< 12 years of age) PATIENTS WITH
CREATININE CLEARANCE < 20mL/min/1.73m2:
FLUCONAZOLE – Patients < 12 years (CrCl < 20 mL/min/1.73m2)
Body
Weight (kg)
Volume of Fluconazole
Concentrated (2 mg/mL)
Solution Required for 1.5 mg/kg
Dose in Pediatrics
(Number of Bags)
Additional Fluid
for Final
Reconstitution*
Total Volume
< 10
7.5 mL (1)
42.5 mL
50 mL
10 – 14.99
7.5 mL (1)
42.5 mL
50 mL
15 – 19.99
11.25 mL (1)
38.75 mL
50 mL
20 – 24.99
15 mL (1)
60 mL
75 mL
25 – 29.99
18.75 mL (1)
56.25 mL
75 mL
30 – 34.99
22.5 mL (1)
77.5 mL
100 mL
≥ 35
25 mL (1)
75 mL
100 mL
4. This solution should be injected into an empty Viaflex bag, and further diluted as
directed in the table above with an approved diluent (see below)
5. Approved diluent: Sodium Chloride 0.9%, USP.
RECONSTITUTION FOR ADULT (> 12 years of age) PATIENTS:
1. A total volume of 200 mL should be withdrawn from the manufacturer’s Viaflex bag.
This solution is to be transferred into an empty sterile Viaflex bag (250 mL bag).
2. No further dilution is required.
Administration: Doses should be administered over 2 hours for both adults and pediatrics.
C. PLACEBO SOLUTION INSTRUCTIONS FOR FLUCONAZOLE-RANDOMIZED
PATIENTS
PLACEBO – Patients < 12 years
Body Weight (kg)
Volume of Sodium Chloride
< 10
50 mL
10 – 14.99
50 mL
15 – 19.99
50 mL
20 – 24.99
75 mL
25 – 29.99
75 mL
30 – 34.99
100 mL
35
100 mL
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
F-7
PLACEBO SOLUTION FOR FLUCONAZOLE RANDOMIZED
ADULT ( 12 years of age) PATIENTS
PLACEBO – Patients 12 years
Volume of Sodium Chloride
12 years age
(Normal Renal
Function)
200 mL
12 years age
(CrCl < 50 mL/min)
100 mL
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
G-1
APPENDIX G
DOSING TABLES
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
G-2
ORAL DOSING TABLE
Age
Drug
Route
Renal
Function
Dosage
Pills in AM
Pills in PM
Adult
fluconazole
PO
normal
400 mg/d
voriconazole
PO
normal
200 mgQ12H
Adult *
fluconazole
PO
< 50 mg/min
200 mg/d
voriconazole
PO
< 50 mg/min
200 mgQ12H
Age < 12 and
> 20 kg
fluconazole
PO
normal
200 mg/d
voriconazole
PO
normal
100 mgQ12H
Age < 12 and
> 20 kg *
fluconazole
PO
< 50 mg/min
100 mg/d
voriconazole
PO
< 50 mg/min
100 mgQ12H
Age < 12 and
< 20 kg
fluconazole
PO
normal
100 mg/d
voriconazole
PO
normal
50 mgQ12H
* RENAL INSUFFICIENCY based on calculated creatinine clearance of < 50 mL/min
RENAL INSUFFICIENCY in a patient age < 12 and < 20kg should be treated by IV infusion in order to achieve a
dosage of 50 mg/d fluconazole. To maintain blind, voriconazole patient should be treated by IV.
LEGEND:
Real Drug
200mg flu
200mg vori
100mg flu
50mg vori
Placebo
200 mg flu / 200 mg vori
100 mg flu / 50 mg vori
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
G-3
IV DOSING TABLE
Age
Drug
Route
Renal
Function
Agents
Number of Doses/Dose#
Time
Adult
[ 12]
Fluconazole
IV
Normal
1 FLUC
NS
400 mg/200 mL
200 mL NS
AM
PM
Voriconazole
IV
Normal
1 VORI
1 VORI
200 mg/200 mL
200 mg/200 mL
AM
PM
Adult
[ 12]
Fluconazole
IV
< 50mL/min 1 FLUC
NS
200 mg/100 mL
100 mL NS
AM
PM
Voriconazole
IV
< 50mL/min 1 VORI
1 VORI
200 mg/100 mL
200 mg/100 mL
AM
PM
Pediatric
[< 12 years]
Fluconazole
IV
Normal
1 FLUC
NS
6 mg/kg/weight adjusted
volume*
Weight adjusted volume*
AM
PM
Voriconazole
IV
Normal
1 VORI
1 VORI
4 mg/kg/weight adjusted
volume*
4 mg/kg/weight adjusted
volume*
AM
PM
Pediatric
[< 12 years]
Fluconazole
IV
< 50mL/min 1 FLUC
NS
3 mg/kg/weight adjusted
volume*
Weight adjusted volume*
AM
PM
Fluconazole
IV
< 20mL/min 1 FLUC
NS
1.5 mg/kg/weight adjusted
volume*
Weight adjusted volume*
AM
PM
Voriconazole
IV
< 50mL/min 1 VORI
1 VORI
4 mg/kg/weight adjusted
volume*
4 mg/kg/weight adjusted
volume*
AM
PM
# Doses to be rounded up to the nearest 5kg bracket.
* See Appendix F for volume guidelines.
If the patient is an outpatient, and requires study IV drug for more than 2 weeks and cannot tolerate
oral study drug, the patient must be taken off study drug.
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
H-1
APPENDIX H
ORDER FORM FOR DOSE ADJUSTMENT OF STUDY DRUG
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
H-2
DATE
TIME
PHYSICIAN’S ORDERS (Provider ID # Required)
SMS #
Orders for IRB#******, A Randomized , Double-blind
Trial of Fluconazole vs. Voriconazole for the Prevention of Invasive Fungal
Infections in Allogeneic Blood and Marrow Transplant Patients.
1. Subject meets inclusion/exclusion criteria and is enrolled in IRB # ***
2. Patient’s serum creatinine:________mg/dL, patient weight (kg):___________
3. Calculate Creatinine Clearance using Cockroft-Gault equation in 2.4.3 protocol
for adults and Schwartz equation for pediatrics or 24-hour urine Creatinine
Clearance.
Creatinine Clearance (mL/min):__________________mL/min
4. Dosage adjustments:
If CrCl 50 mL/minute – no dose adjustment required
If CrCl < 50 mL/minute - adjust the doses of study medications as follows:
Fluconazole: dose reduction of 50% PO and IV.
Initial dose:_________mg, new dose ___________mg. OR
If CrCl < 20 mL/min/1.73m2 for pediatric patients (i.e. < 12 years)
Fluconazole: dose reduction of 75% PO and IV.
Initial dose:_________mg, new dose ___________mg.
Voriconazole: no dose adjustment PO. Accumulation of the voriconazole
IV vehicle can occur. Oral voriconazole should be administered to these
patients unless a benefit/risk assessment justifies the use of IV voriconazole.
Medications to be reconstituted in the same volume of fluid to maintain the
blind.
Rev. 8/00
15-0610-1
DO NOT WRITE BELOW THIS LINE
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
I-1
APPENDIX I
DERIVATION OF THE SPRT FOR UNCENSORED EXPONENTIAL
SURVIVAL TIMES
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
I-2
APPENDIX I
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED
EXPONENTIAL DATA
Background – The Sequential Probability Ratio Test
Let
)
(.,
f
be the density function for random variable X. According to Neyman and Pearson, the most
powerful test of
o
H
:
0
versus
1
1 :
H
decides in favor of
1
H or
0
H if
c
Ln
or
c
Ln
,
respectively, where
n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1
is the likelihood ratio, and
c is determined to have the
size . When the sample size is not fixed in advance, further improvement is possible by using Wald’s
Sequential Probability Ratio Test (SPRT). The SPRT continues to sample as long as
A
L
B
n
for some
constant
A
B
1
, stops sampling and decides in favor of
1
H as soon as
A
Ln
, and stops sampling and
decides in favor of
0
H as soon as
B
Ln
.
The usual measures of performance of such a procedure are the error probabilities
and of rejecting
0
H when
0
, and of accepting
0
H when
1
, respectively, and the expected sample size
)
(
)
|
(
N
E
N
E
j
j
. Wald and Wolfowitz showed that among all tests, sequential or not, for which
)
reject
(
Pr
0
0
H
and
)
reject
(
Pr
0
1
H
, and for which
)
(N
E j
are finite, j=0,1, the SPRT with error
probabilities
and minimizes
)
(
0 N
E
and
)
(
1 N
E
. If, in addition, the
,...
2
,1 x
x
are independent and
identically distributed (i.i.d.) with density function
)
,
(
x
f
, with monotone likelihood ratio in
)
(x
, then
any SPRT for testing
0
against
)
(
0
1
has non-decreasing power function.
For the SPRT with error probabilities
and , the SPRT boundaries are given approximately by
/)
1(
A
and
)
1
/(
B
. The operating characteristics of the SPRT are given by
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0
h
h
h
B
A
A
O
where
)
(
h
is the non-trivial solution to the equation
1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h
.
The formula
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(
z
E
B
O
A
O
N
E
provides the average sample number for an
arbitrary . The sample size distribution is very highly skewed,
2
)]
(
[
)
(
N
E
N
Var
. Thus we will consider
a truncated test with maximum sample size of
0
N and simulate to obtain the operating characteristics of
the test.
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
I-3
Derivation of the SPRT for Uncensored Exponential Survival Times
For example, we wish to construct a sequential test for the composite null hypothesis that the rate of
convulsions at 100 days is less than or equal to 10% versus the alternative hypothesis that it is greater than
or equal to 10%. For the derivation of the uncensored SPRT, we will require that the type I error of the
test be less than 5%, and that the test provide 80% power to reject the null hypothesis under a specified
alternative that the true rate is 15%. A maximum sample size of 300 patients will be permitted.
Let us assume that the survival times,
nT
T
T
,...,
,
2
1
, are completely observed (uncensored) and are i.i.d. with
exponential density function
T
e
T
f
)
,
(
. These assumptions will be relaxed to incompletely observed
data subsequently. In the exponential parameterization, a 100-day survival rate of 90% translates into a
mean survival of 2.599 years (
0
.3848), and 85% translates into a mean survival of 1.685 years
(
1
.5936).
The SPRT is derived with reference to a simple null and alternative hypothesis, in this case,
o
H
:
0
.3848 versus
1
1 :
H
= .5936. However, since the log-likelihood ratio for the exponential,
n
i
n
i
n
i
i
i
i
T
n
x
f
x
f
)
(
))
log(
)
(log(
)
,
(
log
)
;
(
log
0
1
0
1
0
1
, is a monotone function of
n
i
iT ,
the power of the test is non-decreasing in . Thus the SPRT is a one-sided level .05 test of a composite
null (
3848
.
:
0
o
H
) versus a composite alternative (
3848
.
:
1
o
H
), with power of
80
.
1
at the selected alternative
1
.5936.
The SPRT can be represented graphically. The continuation region is bounded by two parallel lines with
common slope
)
/(
)
log
(log
1
0
1
0
2.076, and intercepts
)
/(
log
1
0
A
-13.28 and
)
/(
log
1
0
B
7.462, for the lower and upper bounds, respectively. As each individual unit is put on
trial and observed to fail, the cumulative sum of failure times,
n
i
iT , is recomputed, and plotted against
the current sample size, n . When this graph crosses the lower boundary, the null hypothesis is rejected.
The maximum sample size of 300 patients requires that the SPRT be truncated. We choose to truncate the
SPRT by declaring that if the test has failed to terminate after 300 patients, that the null hypothesis will be
accepted. Since the probability that the untruncated SPRT would reject the null at a sample size of 300 is
negligible, it makes little difference how the final boundary value is selected, and this rule is chosen for
simplicity.
Derivation of a Modified SPRT for Censored Exponential Data
The assumption of uncensored exponential survival times is flawed. However, we consider it reasonable
to assume the hazard for convulsions is constant over the first 100 days post-transplant, and we will
restrict our attention to this time interval. Furthermore, it is not practical to conduct a clinical study by
putting each individual on trial, and waiting until that individual is observed to fail. We relax our
assumptions as follows. Firstly, each individual’s time on study will be computed as time from transplant
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
I-4
to failure, or to the 100 day time point, whichever comes first. Secondly, we will put individuals on trial
as soon as they become available, without waiting for the previous individual to fail.
Let us consider the impact of relaxing these assumptions one at a time. In a fixed sample size trial with
uncensored exponential failure times, mean survival time is estimated by the sample mean of the failure
times, or total time on study divided by the number of individuals enrolled. When censoring is
introduced, the estimate becomes the total time on study divided by the number of observed (non-
censored) failures. This suggests that in an exponential SPRT test modified to incorporate censoring, we
replace the observed failure times,
nT
T
T
,...,
,
2
1
, with censored failures times,
nx
x
x
,...,
,
2
1
, and the current
sample size, n , with the number of observed failures, d .
Now we relax the second assumption, and put individuals on trial as soon as they become available,
without waiting for the previous individual to fail. Assume that three years are required for accrual of 300
patients to the study, and that the final analysis takes place 100 days after the last patient is entered.
Putting all of this together, we propose a modified truncated SPRT, where at any interim time point, s ,
ranging from 0 to 3 years 100 days, the sum of observed time on study,
n
i
i s
X
)
(
is plotted against the
number of observed failures,
)
(s
d
. In practice, monitoring will be scheduled monthly after the start of
enrollment to the study. A further modification to the SPRT was to only use the lower boundary for
stopping since the primary focus of the monitoring is to protect against unacceptable 100-day convulsion
rates.
Operating Characteristics of the Modified SPRT Test for Censored Exponential Data
Recall that the uncensored SPRT targeted a drop in convulsion-free survival at Day 100 from 90% to
85%, with type I and II errors of 5% and 20%. Since only the lower boundary is used for monitoring, the
continuation region of the test was bounded below by a line with a slope of 2.076 and intercept of –13.28.
The effect of truncation is to reduce the power of the test. In order to compensate for this, we raise the
lower boundary to make it easier to cross. Under the further assumption of uniform accrual over a three
year period, and monthly interim analyses over the course of the study, the operating characteristics of the
modified SPRT were obtained from a simulation study. These simulation show that an intercept of –
10.555, corresponding to setting parameters
and to 9% and 15%, result in empirical type I and II
error rates of 5% and 20%.
BMT CLINICAL TRIALS NETWORK
Fungal Prophylaxis Protocol – 0101
Version 7.0 dated March 29, 2006
I-5
Table I-1 Operating Characteristics of Sequential Testing Procedures from a
Simulation Study with 100,000 Replications
Neural Toxicity (Convulsions)
True 100-Day Rate
10%
15%
20%
Probability Reject Null
0.06
0.79
1.00
Mean Month Stopped
35.8
21.8
10.7
Mean # Endpoints in 100 days
28.4
25.2
15.3
Mean # Patients Enrolled
290.9
179.8
89.1
While the motivation for this testing procedure is largely heuristic rather than theoretical, the simulation
results validate the approach. When the true rate of convulsions on or before Day 100 was 10%, the test
crossed the lower boundary in 5977 of 100,000 replications, for an estimated type I error rate of 6%.
When the true rate of convulsions on or before Day 100 was 15%, the test failed to cross the boundary in
the in 21483 of 100,000 replications, for an estimated type II error rate of 21%. The test is almost certain
(100%) to reject the null hypothesis when the true rate is 20%, and on average, the boundary will be
crossed at 10.7 months, with probability less than 1% of crossing in the first 3 months.
It is interesting to note that the SPRT derived above for exponential failure times with censoring at 100
days, has operating characteristics which are similar to those of a more traditional SPRT, derived for
binomial variates with success probability equal to the 100 day failure rate. Using time to failure rather
than a simple binary indicator of failure, leads to little improvement in power when failure times are
censored relatively soon after entry on study. We speculate that if the constant hazard rate over the first
100 days were high, the exponential test would reject faster than the binomial test, but have not conducted
simulation studies to demonstrate this.
| 2
|
arm 1: The dose of fluconazole is 400 mg by mouth or intravenous drip. arm 2: The dose of oral voriconazole is 200 mg twice daily. When voriconazole must be given intravenously, it will be given at a dose of 200 mg every 12 hours for the duration of intravenous therapy.
|
[
1,
0
] | 2
|
[
0,
0
] |
intervention 1: Fluconazole will be administered orally once daily. Fluconazole capsules should be taken at least one hour before or one hour after a meal. If oral drug is not possible, it will be given intravenously once daily in a total volume of 200 mL in patients \> 12 years. For adults, each 200 mL infusion will be administered over 2 hours. In patients \< 12 years, intravenous doses will be prepared. intervention 2: Voriconazole will be administered orally twice daily. Voriconazole capsules should be taken at least one hour before or one hour after a meal. Taken concomitantly with food, bioavailability of voriconazole is reduced. If oral drug is not possible, it will be given intravenously at a dosage of 200 mg every 12 hours over two hours in patients \> 12 years. Each voriconazole dose will be diluted to a total volume of 200 mL in patients \> 12 years. Volumes of the formulation required to provide 4 mg/kg doses for children age \< 12 years.
|
intervention 1: Fluconazole intervention 2: Voriconazole
| 33
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
La Jolla | California | United States | -117.2742 | 32.84727
Stanford | California | United States | -122.16608 | 37.42411
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Gainesville | Florida | United States | -82.32483 | 29.65163
Tampa | Florida | United States | -82.45843 | 27.94752
Chicago | Illinois | United States | -87.65005 | 41.85003
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
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
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
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
Buffalo | New York | United States | -78.87837 | 42.88645
New York | New York | United States | -74.00597 | 40.71427
Durham | North Carolina | United States | -78.89862 | 35.99403
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Cleveland | Ohio | United States | -81.69541 | 41.4995
Portland | Oregon | United States | -122.67621 | 45.52345
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
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
Seattle | Washington | United States | -122.33207 | 47.60621
| 0
|
NCT00075803
|
[
3
] | 13
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| true
| 0ALL
| false
|
Phase II Study of Avastin Plus Rituximab for Patients with Relapsed and Chemotherapy - or Rituxan Refractory Aggressive B-Cell Non-Hodgkin's Lymphoma.
|
Bevacizumab is a new research drug that may help to stop or slow the growth of blood vessels in your tumor. These blood vessels are needed by the tumor to grow. Rituxan is a commercially available drug that is commonly used to treat relapsed and refractory lymphoma.
Before treatment starts, you will be asked questions about your medical history and about any surgeries you have had. You will have a complete physical exam including blood (around 3 tablespoons) and urine tests. You will have a sample of bone marrow collected to learn if the lymphoma has spread to the bone marrow. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. You will have either a CT scan or a MRI of the neck, chest, abdomen, and pelvis, and you will have a gallium or PET scan. You will be asked about any medications that you are taking, including over-the-counter medications. Women who are able to have children must have a negative blood pregnancy test.
Additional blood samples (2 tablespoons) will be collected from you before starting therapy and every 2 months during this study for tests to help your doctors and researchers to learn more about how Bevacizumab works.
During the study, you will be given a dose of rituximab by vein once a week for 8 weeks in a row, and a dose of Bevacizumab every other week. The drugs will be contained in a bag and will be given to you through a needle in one of your veins. This method of giving the drugs is called an infusion. The infusion of Bevacizumab may take 1 to 2 hours, and the infusion of rituximab may take up to 3 to 6 hours. This method of giving a drug is called an infusion. In the first week, infusions of rituxan and Bevacizumab will be given on the same day.
During the infusion of each drug, you will have your vital signs checked often and you will be watched for any side effects. If you experience side effects, the infusion may be slowed down or stopped until the symptoms have gone away.
Within 2 weeks after your 8th dose of rituximab, (4th dose of Bevacizumab) you will have a follow-up visit scheduled to evaluate the status of the disease. During the follow-up visit, you will have a physical exam and blood (around 4 tablespoons) will be collected for lab tests. You will have a CT scan or a MRI, gallium or PET scan, and bone marrow biopsy (if needed). If the disease gets worse or you experience any intolerable side effects, you will be taken off the study. If you are taken off the study or your doctor decides that you should stop study treatment, you will be asked to return to M. D. Anderson for all of the scheduled follow-up visits to check for long term side effects of the drug and to check on the status of the disease.
If the disease remains stable or shrinks after 8 weeks of therapy, you may continue to receive Bevacizumab treatments every 2 weeks for a maximum of a total of 6 months. Even if the treatment is shown to be of benefit to you, your doctor may not continue to give you additional treatments with Bevacizumab beyond the total of 6 months.
After treatment, you will have follow-up visits scheduled to check on the status of the disease. These visits will be scheduled every 3 months for 1 year, then every 4 months for 1 more year, then every 6 months until the disease gets worse. During these visits, you will have a physical exam, blood tests (around 2 tablespoons), and either a CT scan or a MRI. You will also have a sample of bone marrow collected.
This is an investigational study. Bevacizumab has been authorized by the FDA for use in research only. Rituximab is FDA approved and is commercially available. There will be no cost for Bevacizumab or for any tests and procedures that are not considered part of standard of care. Up to 40 patients will take part in this study. All patients will be enrolled at M. D. Anderson.
|
Lymphoma
|
Non-Hodgkin's Lymphoma B-Cell Lymphoma Lymphoma Avastin Bevacizumab Rituximab Rituxan
| null | 1
|
arm 1: Avastin 10 mg/kg given intravenously every 2 weeks for 4 doses, and Rituximab 375 mg/m\^2 intravenously weekly for 8 doses.
|
[
0
] | 2
|
[
0,
0
] |
intervention 1: 10 mg/kg given intravenously every 2 weeks for 4 doses. intervention 2: 375 mg/m\^2 given intravenously weekly for 8 doses, 30 minutes to 1 hour following Bevacizumab.
|
intervention 1: Avastin intervention 2: Rituximab
| 1
|
Houston | Texas | United States | -95.36327 | 29.76328
| 0
|
NCT00081861
|
[
3
] | 131
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 1FEMALE
| false
|
This is a Phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial of pertuzumab in combination with gemcitabine relative to placebo in combination with gemcitabine in subjects with advanced ovarian, primary peritoneal, or fallopian tube cancer that is resistant to platinum-based chemotherapy.
| null |
Ovarian Cancer Peritoneal Cancer Fallopian Tube Cancer
|
Omnitarg Cancer Platinum-Resistant
| null | 2
|
arm 1: Participants received placebo intravenously on Day 1 of every 3 week cycle for up to 1 year (up to 17 treatment cycles). In addition, participants received gemcitabine 800 mg/m\^2 intravenously on Days 1 and 8 of every 3 week cycle for up to 1 year (up to 17 treatment cycles). arm 2: Participants received pertuzumab intravenously on Day 1 of every 3 week cycle for up to 1 year (up to 17 treatment cycles). Participants received pertuzumab at a loading dose of 840 mg in Cycle 1 followed by a dose of 420 mg in Cycles 2 and beyond. In addition, participants received gemcitabine 800 mg/m\^2 intravenously on Days 1 and 8 of every 3 week cycle for up to 1 year (up to 17 treatment cycles
|
[
2,
1
] | 3
|
[
0,
0,
0
] |
intervention 1: Placebo was provided as a single-use formulation for infusion. intervention 2: Gemcitabine was provided as a solution for infusion. intervention 3: Pertuzumab was provided as a single-use formulation for infusion.
|
intervention 1: Placebo intervention 2: Gemcitabine intervention 3: Pertuzumab
| 41
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Huntsville | Alabama | United States | -86.58594 | 34.7304
Muscle Shoals | Alabama | United States | -87.66753 | 34.74481
Tucson | Arizona | United States | -110.92648 | 32.22174
Berkeley | California | United States | -122.27275 | 37.87159
Greenbrae | California | United States | -122.5247 | 37.94854
Los Angeles | California | United States | -118.24368 | 34.05223
Los Angeles | California | United States | -118.24368 | 34.05223
Oxnard | California | United States | -119.17705 | 34.1975
Sacramento | California | United States | -121.4944 | 38.58157
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
Norwalk | Connecticut | United States | -73.4079 | 41.1176
Stamford | Connecticut | United States | -73.53873 | 41.05343
Jacksonville | Florida | United States | -81.65565 | 30.33218
Orlando | Florida | United States | -81.37924 | 28.53834
Savannah | Georgia | United States | -81.09983 | 32.08354
Boise | Idaho | United States | -116.20345 | 43.6135
Coeur d'Alene | Idaho | United States | -116.78047 | 47.67768
Chicago | Illinois | United States | -87.65005 | 41.85003
Urbana | Illinois | United States | -88.20727 | 40.11059
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Wichita | Kansas | United States | -97.33754 | 37.69224
Lexington | Kentucky | United States | -84.47772 | 37.98869
Baltimore | Maryland | United States | -76.61219 | 39.29038
Baltimore | Maryland | United States | -76.61219 | 39.29038
Boston | Massachusetts | United States | -71.05977 | 42.35843
Boston | Massachusetts | United States | -71.05977 | 42.35843
Detroit | Michigan | United States | -83.04575 | 42.33143
Cherry Hill | New Jersey | United States | -75.03073 | 39.93484
Voorhees Township | New Jersey | United States | -74.49062 | 40.4795
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Columbus | Ohio | United States | -82.99879 | 39.96118
Columbus | Ohio | United States | -82.99879 | 39.96118
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Corvallis | Oregon | United States | -123.26204 | 44.56457
Portland | Oregon | United States | -122.67621 | 45.52345
Providence | Rhode Island | United States | -71.41283 | 41.82399
Annandale | Virginia | United States | -77.19637 | 38.83039
Roanoke | Virginia | United States | -79.94143 | 37.27097
| 0
|
NCT00096993
|
[
5
] | 552
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The purpose of this study is to evaluate the ability of a treatment strategy, that includes cinacalcet for the management of secondary hyperparathyroidism, to control parathyroid hormone (PTH) compared with the standard of care.
| null |
End Stage Renal Disease
|
Secondary HyperParaThyroidism (SHPT) Dialysis, End Stage Renal Disease (ESRD) KDOQI, Cinacalcet Clinical Trial, Amgen
| null | 2
|
arm 1: Subjects randomised to the standard care arm are to receive appropriate therapy in accordance with the investigator's practice in an attempt to achieve the K/DOQI PTH, serum calcium, phosphorus, and Ca x P treatment targets. arm 2: Treatment with cinacalcet will be initiated at a dose of 30 mg/day. Possible daily doses of cinacalcet are 30, 60, 90, 120, and 180 mg. Dose escalation of cinacalcet may occur based on iPTH values.
|
[
4,
5
] | 2
|
[
0,
10
] |
intervention 1: Treatment with cinacalcet will be initiated at a dose of 30 mg/day. Possible daily doses of cinacalcet are 30, 60, 90, 120, and 180 mg. intervention 2: Subjects randomised to the standard care arm are to receive appropriate therapy in accordance with the investigator's practice in an attempt to achieve the K/DOQI PTH, serum calcium, phosphorus, and Ca x P treatment targets.
|
intervention 1: cinacalcet intervention 2: Standard of care
| 0
| null | 0
|
NCT00110890
|
[
4
] | 149
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The primary purpose of this study is to determine the dose requirements of rocuronium bromide when administered as a bolus dose (a single, large dose) for intubation (insertion of a tube through the nose or mouth into the trachea to provide artificial ventilation) and when administered by either continuous infusion or bolus doses for maintenance of muscle relaxation in term neonates (birth to \<28 days old), infants (28 days to \<=3 months) and toddlers (\>3 months to \<=2 years), children (2 years to less than or equal to 11 years of age), and adolescents (\>11 years to less than or equal to 17 years of age).
| null |
Anesthesia
| null | 2
|
arm 1: Rocuronium bolus maintenance arm 2: Rocuronium continuous infusion maintenance
|
[
0,
0
] | 2
|
[
0,
0
] |
intervention 1: Subjects received a bolus dose of rocuronium for intubation followed by bolus doses for maintenance of muscle relaxation intervention 2: Subjects received a bolus dose of rocuronium for intubation followed by continuous infusion of rocuronium for maintenance of muscle relaxation
|
intervention 1: Rocuronium bolus maintenance intervention 2: rocuronium continuous infusion maintenance
| 0
| null | 0
|
NCT00124735
|
|
[
4
] | 90
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
Pompe disease (also known as glycogen storage disease Type II) is caused by a deficiency of a critical enzyme in the body called acid alpha-glucosidase (GAA). Normally, GAA is used by the body's cells to break down glycogen (a stored form of sugar) within specialized structures called lysosomes. In patients with Pompe disease, an excessive amount of glycogen accumulates and is stored in various tissues, especially heart and skeletal muscle, which prevents their normal function. The overall objective is to evaluate the safety, efficacy, and pharmacokinetics (PK) of alglucosidase alfa treatment in patients with late-onset Pompe disease as compared to placebo.
| null |
Pompe Disease (Late-onset) Glycogen Storage Disease Type II (GSD-II) Acid Maltase Deficiency Disease Glycogenosis 2
|
Glycogen Storage Disease Type II GSD-II Pompe Disease
| null | 2
|
arm 1: Intravenous (IV) infusions of alglucosidase alfa at 20 milligrams (mg)/kilogram (kg) of body weight every other week (qow) for 78 weeks. arm 2: Intravenous (IV) infusions of placebo every other week (qow) for 78 weeks.
|
[
1,
2
] | 2
|
[
2,
0
] |
intervention 1: IV infusion of 20mg/kg; qow for 78 weeks. intervention 2: Placebo Comparator; qow for 78 weeks.
|
intervention 1: alglucosidase alfa intervention 2: Placebo
| 8
|
Beverly Hills | California | United States | -118.40036 | 34.07362
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
St Louis | Missouri | United States | -90.19789 | 38.62727
New York | New York | United States | -74.00597 | 40.71427
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Paris | N/A | France | 2.3488 | 48.85341
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
Rotterdam | N/A | Netherlands | 4.47917 | 51.9225
| 0
|
NCT00158600
|
[
5
] | 20
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
The purpose of this study is to assess the safety and feasibility of concurrent treatment of nicotine dependence (cigarette smoking) and acute depression. Participants who meet DSM-IV criteria for both nicotine dependence and acute major depression will be given pharmacological treatment for both disorders at the same time, along with a brief behavioral intervention for smoking cessation.
|
The purpose of this study is to assess the safety and feasibility of concurrent treatment of nicotine dependence (cigarette smoking) and acute depression. Participants who meet DSM-IV criteria for both nicotine dependence and acute major depression will be given pharmacological treatment for both disorders at the same time, along with a brief behavioral intervention for smoking cessation.
|
Major Depressive Disorder Nicotine Dependence
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: None
|
intervention 1: bupropion and smoking cessation behavioral intervention
| 1
|
Stanford | California | United States | -122.16608 | 37.42411
| 0
|
NCT00186446
|
|
[
3
] | 298
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 1FEMALE
| null |
The purpose of this study is to evaluate the efficacy and safety of E7389 in Patients with locally advanced or metastatic breast cancer, previously treated with anthracycline, taxane, and capecitabine as prior therapy, and who are refractory to the last prior therapy for their disease.
| null |
Breast Cancer
| null | 1
|
arm 1: None
|
[
0
] | 1
|
[
0
] |
intervention 1: E7389 1.4 mg/m\^2 intravenous bolus given over 2-5 minutes on Days 1 and 8 every 21 days.
|
intervention 1: E7389
| 65
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Birmingham | Alabama | United States | -86.80249 | 33.52066
Hot Springs | Arkansas | United States | -93.05518 | 34.5037
Little Rock | Arkansas | United States | -92.28959 | 34.74648
La Verne | California | United States | -117.76784 | 34.10084
Denver | Colorado | United States | -104.9847 | 39.73915
Denver | Colorado | United States | -104.9847 | 39.73915
Littleton | Colorado | United States | -105.01665 | 39.61332
Plantation | Florida | United States | -80.23184 | 26.13421
Port Saint Lucie | Florida | United States | -80.35033 | 27.29393
Tamarac | Florida | United States | -80.24977 | 26.21286
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
Decatur | Illinois | United States | -88.9548 | 39.84031
Niles | Illinois | United States | -87.80284 | 42.01892
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Munster | Indiana | United States | -87.51254 | 41.56448
South Bend | Indiana | United States | -86.25001 | 41.68338
Kansas City | Kansas | United States | -94.62746 | 39.11417
Frederick | Maryland | United States | -77.41054 | 39.41427
Minneapolis | Minnesota | United States | -93.26384 | 44.97997
Columbia | Missouri | United States | -92.33407 | 38.95171
Missoula | Montana | United States | -113.994 | 46.87215
Henderson | Nevada | United States | -114.98194 | 36.0397
Albany | New York | United States | -73.75623 | 42.65258
East Setakuet | New York | United States | N/A | N/A
Huntington Station | New York | United States | -73.41151 | 40.85343
New York | New York | United States | -74.00597 | 40.71427
Syracuse | New York | United States | -76.14742 | 43.04812
Hudson | North Carolina | United States | -81.49593 | 35.84846
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Middletown | Ohio | United States | -84.39828 | 39.51506
Toledo | Ohio | United States | -83.55521 | 41.66394
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Oklahoma City | Oklahoma | United States | -97.51643 | 35.46756
Tulsa | Oklahoma | United States | -95.99277 | 36.15398
Eugene | Oregon | United States | -123.08675 | 44.05207
Portland | Oregon | United States | -122.67621 | 45.52345
Portland | Oregon | United States | -122.67621 | 45.52345
Portland | Oregon | United States | -122.67621 | 45.52345
Charleston | South Carolina | United States | -79.93275 | 32.77632
Knoxville | Tennessee | United States | -83.92074 | 35.96064
Amarillo | Texas | United States | -101.8313 | 35.222
Bedford | Texas | United States | -97.14307 | 32.84402
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
El Paso | Texas | United States | -106.48693 | 31.75872
El Paso | Texas | United States | -106.48693 | 31.75872
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
Plano | Texas | United States | -96.69889 | 33.01984
Tyler | Texas | United States | -95.30106 | 32.35126
Weslaco | Texas | United States | -97.99084 | 26.15952
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Fairfax | Virginia | United States | -77.30637 | 38.84622
Salem | Virginia | United States | -80.05476 | 37.29347
Spokane | Washington | United States | -117.42908 | 47.65966
Vancouver | Washington | United States | -122.66149 | 45.63873
Yakima | Washington | United States | -120.5059 | 46.60207
Hamilton | Ontario | Canada | -79.84963 | 43.25011
Thunder Bay | Ontario | Canada | -89.25018 | 48.38202
Toronto | Ontario | Canada | -79.39864 | 43.70643
Montreal | Quebec | Canada | -73.58781 | 45.50884
Montreal | Quebec | Canada | -73.58781 | 45.50884
| 0
|
NCT00246090
|
|
[
3
] | 146
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
The purpose of this study is to evaluate the effectiveness and safety of CNTO 1275 (ustekinumab) in patients with psoriatic arthritis.
|
This study is a randomized (the study drug is assigned by chance), double-blind (neither physician nor the patient knows the treatment that the patient receives), parallel-group (each group of patients will be treated at the same time), multicenter study to evaluate the effectiveness and safety of CNTO 1275 compared to placebo in the treatment of patients with active psoriatic arthritis. Patients will be randomized in 1:1 ratio to 1 of 2 treatment groups (CNTO 1275 63 mg and placebo). Patients will be randomly assigned to receive study medication up to Week 12 and will be followed through Week 36 to monitor safety and efficacy. Patients randomly assigned to placebo will crossover to receive CNTO 1275 63 mg at Weeks 12 and 16. Patients randomly assigned to CNTO 1275 will receive placebo at Weeks 12 and 16 to maintain the blind. The duration of participation for an individual patient in the study will be up to 36 weeks.
|
Psoriatic Arthritis
|
Psoriatic arthritis CNTO 1275 Ustekinumab Interleukin-23, IL-12, IL-23 Monoclonal antibodies
| null | 2
|
arm 1: Group 1: Patients will receive CNTO 1275 63 mg at Weeks 0, 1, 2, and 3. At Weeks 12 and 16, patients will receive placebo to maintain the blind. arm 2: Group 2: Patients will receive placebo at Weeks 0, 1, 2, and 3. At Weeks 12 and 16, patients will receive CNTO 1275 63 mg.
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: The patients will receive 90 mg (or 63 mg after filtration) subcutaneous injection on Weeks 0, 1, 2, and 3; Placebo subcutaneous injection on Weeks 12 and 16. intervention 2: The patients will receive placebo subcutaneous injection on Weeks 0, 1, 2, and 3; At weeks 12 and 16 the patients will receive CNTo1275 90 mg (or 63 mg after filtration) subcutaneous injection
|
intervention 1: CNTO 1275 63 mg intervention 2: Placebo
| 25
|
Macon | Georgia | United States | -83.6324 | 32.84069
Boise | Idaho | United States | -116.20345 | 43.6135
Normal | Illinois | United States | -88.99063 | 40.5142
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Covington | Louisiana | United States | -90.10042 | 30.47549
Boston | Massachusetts | United States | -71.05977 | 42.35843
Ann Arbor | Michigan | United States | -83.74088 | 42.27756
Las Vegas | Nevada | United States | -115.13722 | 36.17497
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
New York | New York | United States | -74.00597 | 40.71427
Wilmington | North Carolina | United States | -77.94604 | 34.23556
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Calgary | Alberta | Canada | -114.08529 | 51.05011
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Surrey | British Columbia | Canada | -122.82509 | 49.10635
Barrie | Ontario | Canada | -79.66634 | 44.40011
Hamilton | Ontario | Canada | -79.84963 | 43.25011
Toronto | Ontario | Canada | -79.39864 | 43.70643
Windsor | Ontario | Canada | -83.01654 | 42.30008
Aarhus C | N/A | Denmark | 10.21231 | 56.16558
Hellerup | N/A | Denmark | 12.57093 | 55.73204
København NV | N/A | Denmark | 12.52343 | 55.71258
Hus | N/A | Finland | N/A | N/A
Tampere | N/A | Finland | 23.78712 | 61.49911
Geneva | N/A | Switzerland | 6.14569 | 46.20222
| 0
|
NCT00267956
|
[
4
] | 145
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| false
|
The primary objective of this study is to evaluate the long term safety and tolerability of an iron maintenance dosing strategy utilizing VIT45 in the treatment of anemia of non-dialysis dependent chronic kidney disease (NDD-CKD). This study is a long term extension to protocol 1VIT04004 (NCT00317239).
|
The primary objective of this study is to evaluate the long term safety and tolerability of an iron maintenance dosing strategy utilizing VIT45 in the treatment of anemia of non-dialysis dependent chronic kidney disease (NDD-CKD). This study is a long term extension to protocol 1VIT04004.
In this study patients that complete protocol 1VIT 04004 or are discontinued will be offered to participate in this extension study.
|
Anemia
|
Anemia CKD Chronic Kidney Disease Iron Maintenance Dose
| null | 1
|
arm 1: maximum dose of 1,000 mg over 15 minutes IV administered within 7 days of the qualifying visit
|
[
0
] | 1
|
[
0
] |
intervention 1: maximum dose of 1,000 mg over 15 minutes IV administered within 7 days of the qualifying visit
|
intervention 1: Ferric Carboxymaltose (FCM)
| 1
|
Norristown | Pennsylvania | United States | -75.3399 | 40.1215
| 0
|
NCT00317226
|
[
4
] | 622
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 1FEMALE
| false
|
This is a four-arm, randomized, double-blind, parallel group, placebo-controlled study to compare the effects of two doses of DR-2041(Synthetic Conjugated Estrogens, A) Vaginal Cream on vulvovaginal atrophy in postmenopausal women with or without a hysterectomy and/or oophorectomy.
|
The study will include a screening period up to 4 weeks and a 12- week treatment period. The overall study duration for participants will be approximately 16 weeks. Study participants will undergo physical and gynecological exams, and blood tests for clinical laboratory assessments. All patients with a uterus will undergo transvaginal ultrasound.
|
Menopause
|
vaginal atrophy vaginal dryness vaginal itching vaginal pain
| null | 4
|
arm 1: None arm 2: None arm 3: None arm 4: None
|
[
0,
0,
2,
2
] | 4
|
[
0,
0,
10,
10
] |
intervention 1: 1 gram administered vaginally daily for the 1st 7 days then twice a week thereafter intervention 2: 2 grams administered vaginally daily for the 1st 7 days then twice a week thereafter intervention 3: 1 gram administered vaginally daily for the 1st 7 days then twice a week thereafter intervention 4: 2 grams administered vaginally daily for the 1st 7 days then twice a week thereafter
|
intervention 1: DR-2041a intervention 2: DR-2041b intervention 3: Placebo intervention 4: Placebo
| 97
|
Huntsville | Alabama | United States | -86.58594 | 34.7304
Mobile | Alabama | United States | -88.04305 | 30.69436
Montgomery | Alabama | United States | -86.29997 | 32.36681
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Phoenix | Arizona | United States | -112.07404 | 33.44838
Tucson | Arizona | United States | -110.92648 | 32.22174
Carmichael | California | United States | -121.32828 | 38.61713
Fresno | California | United States | -119.77237 | 36.74773
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Diego | California | United States | -117.16472 | 32.71571
San Ramon | California | United States | -121.97802 | 37.77993
Colorado Springs | Colorado | United States | -104.82136 | 38.83388
Pueblo | Colorado | United States | -104.60914 | 38.25445
New London | Connecticut | United States | -72.09952 | 41.35565
Clearwater | Florida | United States | -82.8001 | 27.96585
Clearwater | Florida | United States | -82.8001 | 27.96585
Gainesville | Florida | United States | -82.32483 | 29.65163
Jacksonville | Florida | United States | -81.65565 | 30.33218
Leesburg | Florida | United States | -81.87786 | 28.81082
Miami | Florida | United States | -80.19366 | 25.77427
Pinellas Park | Florida | United States | -82.69954 | 27.8428
Stuart | Florida | United States | -80.25283 | 27.19755
Tampa | Florida | United States | -82.45843 | 27.94752
Tampa | Florida | United States | -82.45843 | 27.94752
Venice | Florida | United States | -82.45426 | 27.09978
West Palm Beach | Florida | United States | -80.05337 | 26.71534
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Weston | Florida | United States | -80.39977 | 26.10037
Alpharetta | Georgia | United States | -84.29409 | 34.07538
Atlanta | Georgia | United States | -84.38798 | 33.749
Augusta | Georgia | United States | -81.97484 | 33.47097
Decatur | Georgia | United States | -84.29631 | 33.77483
Douglasville | Georgia | United States | -84.74771 | 33.7515
Sandy Springs | Georgia | United States | -84.37854 | 33.92427
Chicago | Illinois | United States | -87.65005 | 41.85003
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
Lexington | Kentucky | United States | -84.47772 | 37.98869
Louisville | Kentucky | United States | -85.75941 | 38.25424
Madisonville | Kentucky | United States | -87.49889 | 37.3281
Shreveport | Louisiana | United States | -93.75018 | 32.52515
Baltimore | Maryland | United States | -76.61219 | 39.29038
Livonia | Michigan | United States | -83.35271 | 42.36837
Lincoln | Nebraska | United States | -96.66696 | 40.8
Las Vegas | Nevada | United States | -115.13722 | 36.17497
Lebanon | New Hampshire | United States | -72.25176 | 43.64229
Lawrenceville | New Jersey | United States | -74.7296 | 40.29733
Moorestown | New Jersey | United States | -74.94267 | 39.96706
New Brunswick | New Jersey | United States | -74.45182 | 40.48622
Albuquerque | New Mexico | United States | -106.65114 | 35.08449
Johnson City | New York | United States | -75.95881 | 42.11563
Williamsville | New York | United States | -78.73781 | 42.96395
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Winston-Salem | North Carolina | United States | -80.24422 | 36.09986
Jamestown | North Dakota | United States | -98.70844 | 46.91054
Minot | North Dakota | United States | -101.29627 | 48.23251
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
Columbus | Ohio | United States | -82.99879 | 39.96118
Mayfield Heights | Ohio | United States | -81.4579 | 41.51922
Medford | Oregon | United States | -122.87559 | 42.32652
Portland | Oregon | United States | -122.67621 | 45.52345
Portland | Oregon | United States | -122.67621 | 45.52345
Allentown | Pennsylvania | United States | -75.49018 | 40.60843
King of Prussia | Pennsylvania | United States | -75.39602 | 40.08927
Media | Pennsylvania | United States | -75.38769 | 39.91678
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Rosemont | Pennsylvania | United States | -75.3238 | 40.02567
Strafford | Pennsylvania | United States | -75.40436 | 40.05094
Warwick | Rhode Island | United States | -71.41617 | 41.7001
Charleston | South Carolina | United States | -79.93275 | 32.77632
Charleston | South Carolina | United States | -79.93275 | 32.77632
Columbia | South Carolina | United States | -81.03481 | 34.00071
Watertown | South Dakota | United States | -97.11507 | 44.89941
Memphis | Tennessee | United States | -90.04898 | 35.14953
Nashville | Tennessee | United States | -86.78444 | 36.16589
Austin | Texas | United States | -97.74306 | 30.26715
Austin | Texas | United States | -97.74306 | 30.26715
Corpus Christi | Texas | United States | -97.39638 | 27.80058
Dallas | Texas | United States | -96.80667 | 32.78306
Houston | Texas | United States | -95.36327 | 29.76328
Houston | Texas | United States | -95.36327 | 29.76328
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
Waco | Texas | United States | -97.14667 | 31.54933
Williston | Vermont | United States | -73.06818 | 44.43755
Newport News | Virginia | United States | -76.42975 | 36.98038
Spokane | Washington | United States | -117.42908 | 47.65966
Tacoma | Washington | United States | -122.44429 | 47.25288
| 0
|
NCT00361569
|
[
4
] | 638
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| null | 0ALL
| null |
The primary purpose of this study is to evaluate the efficacy and safety of two doses of DVS SR (50 and 100 mg/day) in the treatment of adults with Major Depressive Disorder.
| null |
Depressive Disorder, Major
|
MDD Major Depressive Disorder Depression
| null | 4
|
arm 1: None arm 2: None arm 3: None arm 4: Active control to assess assay sensitivity
|
[
0,
0,
2,
5
] | 4
|
[
0,
0,
0,
0
] |
intervention 1: 50 mg tablet, once daily dosing for 8 weeks intervention 2: 100 mg tablet, once daily dosing for 8 weeks intervention 3: Matching placebo tablets and capsules, once daily dosing for 8 weeks intervention 4: 60 mg capsule, once daily dosing for 8 weeks
|
intervention 1: Desvenlafaxine Succinate Sustained-Release (DVS SR) intervention 2: Desvenlafaxine Succinate Sustained-Release (DVS SR) intervention 3: Placebo intervention 4: Duloxetine 60 mg/day
| 22
|
Beverly Hills | California | United States | -118.40036 | 34.07362
Burbank | California | United States | -118.30897 | 34.18084
Encino | California | United States | -118.50119 | 34.15917
Los Alamitos | California | United States | -118.07256 | 33.80307
Newport Beach | California | United States | -117.92895 | 33.61891
Northridge | California | United States | -118.53675 | 34.22834
Orange | California | United States | -117.85311 | 33.78779
Pasadena | California | United States | -118.14452 | 34.14778
Upland | California | United States | -117.64839 | 34.09751
South Miami | Florida | United States | -80.29338 | 25.7076
St. Petersburg | Florida | United States | -82.67927 | 27.77086
Edwardsville | Illinois | United States | -89.95316 | 38.81144
Farmington Hills | Michigan | United States | -83.37716 | 42.48531
Flint | Michigan | United States | -83.68746 | 43.01253
Okemos | Michigan | United States | -84.42747 | 42.72226
Clementon | New Jersey | United States | -74.98294 | 39.8115
Dayton | Ohio | United States | -84.19161 | 39.75895
Portland | Oregon | United States | -122.67621 | 45.52345
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Seattle | Washington | United States | -122.33207 | 47.60621
Brown Deer | Wisconsin | United States | -87.96453 | 43.16334
| 0
|
NCT00384033
|
[
3
] | 177
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| false
|
This study will evaluate the safety, tolerability, and effect on body weight of leptin, injected subcutaneously, in combination with pramlintide, injected subcutaneously.
| null |
Overweight Obesity
|
overweight obesity pramlintide leptin Amylin
| null | 4
|
arm 1: Placebo-pramlintide 600 microliters (µL) twice a day (BID) and metreleptin (recombinant-methionyl human leptin) 5 milligram (mg) BID, 20 weeks arm 2: Lead-in period: 2 weeks pramlintide acetate 180 mcg BID, then 2 weeks pramlintide acetate 360 mcg BID Study period: Pramlintide acetate 360 mcg BID and placebo-metreleptin 1 mL BID, 20 weeks arm 3: Lead-in period: 2 weeks pramlintide acetate 180 mcg BID, then 2 weeks pramlintide acetate 360 mcg BID Study period: Pramlintide acetate 360 mcg BID and metreleptin (recombinant-methionyl human leptin) 5 mg BID, 20 weeks arm 4: During the Lead-In Period before a participant was randomized to a study arm, the participant received 180 mcg pramlintide acetate twice a day (BID) for 2 weeks, followed by 360 mcg pramlintide acetate BID for 2 weeks (total of 4 weeks in the Lead-In Period).
|
[
0,
0,
0,
5
] | 5
|
[
0,
0,
0,
0,
0
] |
intervention 1: subcutaneous injection, twice a day, 360mcg intervention 2: subcutaneous injection, twice a day, 5mg intervention 3: twice a day intervention 4: twice a day intervention 5: subcutaneous injection twice a day, 180 mcg
|
intervention 1: pramlintide acetate 360 mcg intervention 2: metreleptin intervention 3: placebo-pramlintide 600 uL intervention 4: placebo-metreleptin 1 mL intervention 5: Pramlintide acetate 180 mcg
| 12
|
DeLand | Florida | United States | -81.30312 | 29.02832
Chicago | Illinois | United States | -87.65005 | 41.85003
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Overland Park | Kansas | United States | -94.67079 | 38.98223
Baton Rouge | Louisiana | United States | -91.18747 | 30.44332
Detroit | Michigan | United States | -83.04575 | 42.33143
Edina | Minnesota | United States | -93.34995 | 44.88969
Butte | Montana | United States | -112.53474 | 46.00382
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Portland | Oregon | United States | -122.67621 | 45.52345
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Olympia | Washington | United States | -122.90169 | 47.04491
| 0
|
NCT00392925
|
[
4
] | 278
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
A phase III study to evaluate the efficacy and safety of SLIT for grass pollen allergens compared with placebo for reduction of symptoms and rescue medication usage in children.
| null |
Allergy
|
Sublingual immunotherapy Grass pollen tablet Allergic rhinoconjunctivitis
| null | 2
|
arm 1: 300 IR grass pollen allergen extract tablet arm 2: Placebo tablet
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: One sublingual tablet daily during 4 months before pollen season and during pollen season intervention 2: One sublingual tablet daily during 4 months before pollen season and during pollen season
|
intervention 1: 300 IR grass pollen allergen extract tablet intervention 2: Placebo tablet
| 1
|
Berlin | N/A | Germany | 13.41053 | 52.52437
| 0
|
NCT00409409
|
[
3
] | 344
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| true
|
This is a study for patients with flu who also have a fever as well as other flu symptoms. Patients must have had symptoms for less than 48 hours in order to participate. Patients will have two out of three chances of getting an active study treatment and the other third will receive a placebo (dummy drug). Nobody will know who gets the active drug and who gets the inactive drug. All patients will get supplies to treat symptoms of flu. Patients will need to be seen 5 more times after they are enrolled in the study.
|
Peramivir is a neuraminidase inhibitor that was previously shown to be effective in the treatment of human experimental influenza using an oral formulation. Parenteral formulations of peramivir (for intramuscular and intravenous injection) entered clinical development at the time of this Phase 2 study. A series of Phase 1 studies in human volunteers was completed that provided safety and pharmacokinetic results that supported the initiation of this Phase 2 multinational, randomized, double-mask study that compared the antiviral efficacy and safety of peramivir administered intramuscularly versus placebo in adults with uncomplicated acute influenza. Because of the unique pharmacokinetic and pharmacodynamic properties of peramivir - a long terminal half life in plasma and an extended duration of binding to the neuraminidase enzyme - subjects were randomized in a 1:1:1 ratio to receive a single dose of one of three treatments: peramivir 150 mg, peramivir 300 mg, and placebo. Study drug was administered as one 2-mL intramuscular injection in each gluteal muscle (total of 4 mL, injected in divided doses). This multinational study was originally to be conducted at approximately 80 sites in the US and Canada. When enrollment during the North American influenza season of 2006-2007 did not achieve the target, the study was extended to sites in Australia, New Zealand, South Africa, and Hong Kong.
|
Influenza
|
influenza flu
| null | 3
|
arm 1: None arm 2: None arm 3: None
|
[
0,
0,
2
] | 3
|
[
0,
0,
0
] |
intervention 1: Single dose administered as bilateral 2-mL intramuscular injections in each gluteal muscle (one injection of peramivir 150 mg and one injection of placebo). intervention 2: Single dose administered as bilateral 2-mL intramuscular injections in each gluteal muscle (2 injections of peramivir 150 mg). intervention 3: Single dose administered as bilateral 2-mL intramuscular injections in each gluteal muscle (2 injections of placebo).
|
intervention 1: Peramivir 150 mg intervention 2: Peramivir 300 mg intervention 3: Placebo
| 69
|
Birmingham | Alabama | United States | -86.80249 | 33.52066
Jonesboro | Arkansas | United States | -90.70428 | 35.8423
Anaheim | California | United States | -117.9145 | 33.83529
Anaheim | California | United States | -117.9145 | 33.83529
Carmichael | California | United States | -121.32828 | 38.61713
El Centro | California | United States | -115.56305 | 32.792
Orange | California | United States | -117.85311 | 33.78779
Sacramento | California | United States | -121.4944 | 38.58157
San Diego | California | United States | -117.16472 | 32.71571
San Francisco | California | United States | -122.41942 | 37.77493
Boulder | Colorado | United States | -105.27055 | 40.01499
Washington D.C. | District of Columbia | United States | -77.03637 | 38.89511
Coral Gables | Florida | United States | -80.26838 | 25.72149
DeLand | Florida | United States | -81.30312 | 29.02832
Gainesville | Florida | United States | -82.32483 | 29.65163
Jacksonville | Florida | United States | -81.65565 | 30.33218
Jacksonville | Florida | United States | -81.65565 | 30.33218
Sarasota | Florida | United States | -82.53065 | 27.33643
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Atlanta | Georgia | United States | -84.38798 | 33.749
Indianapolis | Indiana | United States | -86.15804 | 39.76838
Overland Park | Kansas | United States | -94.67079 | 38.98223
Bardstown | Kentucky | United States | -85.4669 | 37.80923
Lexington | Kentucky | United States | -84.47772 | 37.98869
Metairie | Louisiana | United States | -90.15285 | 29.98409
Edina | Minnesota | United States | -93.34995 | 44.88969
St Louis | Missouri | United States | -90.19789 | 38.62727
St Louis | Missouri | United States | -90.19789 | 38.62727
St Louis | Missouri | United States | -90.19789 | 38.62727
Bozeman | Montana | United States | -111.03856 | 45.67965
Alliance | Nebraska | United States | -102.87215 | 42.10163
Omaha | Nebraska | United States | -95.94043 | 41.25626
Cherry Hill | New Jersey | United States | -75.03073 | 39.93484
East Brunswick | New Jersey | United States | -74.41598 | 40.42788
Brooklyn | New York | United States | -73.94958 | 40.6501
Raleigh | North Carolina | United States | -78.63861 | 35.7721
Akron | Ohio | United States | -81.51901 | 41.08144
Cincinnati | Ohio | United States | -84.51439 | 39.12711
Ashland | Oregon | United States | -122.70948 | 42.19458
Lancaster | Pennsylvania | United States | -76.30551 | 40.03788
Philadelphia | Pennsylvania | United States | -75.16362 | 39.95238
Pittsburgh | Pennsylvania | United States | -79.99589 | 40.44062
Cranston | Rhode Island | United States | -71.43728 | 41.77982
Cranston | Rhode Island | United States | -71.43728 | 41.77982
Warwick | Rhode Island | United States | -71.41617 | 41.7001
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Dallas | Texas | United States | -96.80667 | 32.78306
Dallas | Texas | United States | -96.80667 | 32.78306
Garland | Texas | United States | -96.63888 | 32.91262
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Tomball | Texas | United States | -95.61605 | 30.09716
Tomball | Texas | United States | -95.61605 | 30.09716
Salt Lake City | Utah | United States | -111.89105 | 40.76078
Salt Lake City | Utah | United States | -111.89105 | 40.76078
West Jordan | Utah | United States | -111.9391 | 40.60967
Calgary | Alberta | Canada | -114.08529 | 51.05011
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Edmonton | Alberta | Canada | -113.46871 | 53.55014
Coquitlam | British Columbia | Canada | -122.78217 | 49.2846
Hawkesbury | Ontario | Canada | -74.61595 | 45.60009
Toronto | Ontario | Canada | -79.39864 | 43.70643
Mirabel | Quebec | Canada | -74.08251 | 45.65008
Ste-Foy | Quebec | Canada | N/A | N/A
Saskatoon | Saskatchewan | Canada | -106.66892 | 52.13238
| 0
|
NCT00419263
|
[
3
] | 1
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| null | false
| 0ALL
| false
|
SB-705498 has demonstrated efficacy in several preclinical and human experimental pain models. This study will investigate the efficacy of SB-705498 in patients with rectal pain. This will be a double-blind, placebo-controlled, two-way crossover study. 21 patients with faecal urgency (Group 1), and 21 patients with IBS (Group 2) will complete this study.
| null |
Irritable Colon
|
TRPV1 antagonist Fecal Urgency rectal pain IBS
| null | 0
| null | null | 1
|
[
0
] |
intervention 1: None
|
intervention 1: SB-705498
| 1
|
London | N/A | United Kingdom | -0.12574 | 51.50853
| 0
|
NCT00461682
|
[
2
] | 30
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 4QUADRUPLE
| true
| 0ALL
| false
|
The objectives of this study are:
* to establish the safety of subcutaneous administration of ceftriaxone at different concentrations, with and without HYLENEX recombinant, and to determine the maximum tolerated concentration;
* and to establish the pharmacokinetic comparability of subcutaneous administration of ceftriaxone with HYLENEX recombinant to subcutaneous administration without HYLENEX recombinant and to IV administration.
| null |
Healthy
|
ceftriaxone cephalosporins pharmacokinetics subcutaneous hyaluronoglucosaminidase hyaluronidase hyaluronan rHuPH20
| null | 6
|
arm 1: subcutaneous HYLENEX and ceftriaxone as 1st intervention, subcutaneous placebo and ceftriaxone as 2nd intervention, IV ceftriaxone as 3rd intervention arm 2: subcutaneous HYLENEX and ceftriaxone as 1st intervention, IV ceftriaxone as 2nd intervention, subcutaneous placebo and ceftriaxone as 3rd intervention arm 3: subcutaneous placebo and ceftriaxone as 1st intervention, subcutaneous HYLENEX and ceftriaxone as 2nd intervention, IV ceftriaxone as 3rd intervention arm 4: subcutaneous placebo and ceftriaxone as 1st intervention, IV ceftriaxone as 2nd intervention, subcutaneous HYLENEX and ceftriaxone as 3rd intervention arm 5: IV ceftriaxone as 1st intervention, subcutaneous HYLENEX and ceftriaxone as 2nd intervention, subcutaneous placebo and ceftriaxone as 3rd intervention arm 6: IV ceftriaxone as 1st intervention, subcutaneous placebo and ceftriaxone as 2nd intervention, subcutaneous HYLENEX and ceftriaxone as 3rd intervention
|
[
0,
0,
0,
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes) intervention 2: single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes) intervention 3: single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)
|
intervention 1: SC HYLENEX and Ceftriaxone intervention 2: SC Placebo and Ceftriaxone intervention 3: IV Ceftriaxone
| 0
| null | 0
|
NCT00493220
|
[
3
] | 183
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 4QUADRUPLE
| false
| 0ALL
| false
|
The objective of this study is to evaluate the efficacy of MCI-196 in patients with Type 2 Diabetes based on the changes in blood glucose-related parameters and safety after 12 weeks administration in double-blind, placebo-controlled manner. And in addition, the changes in lipid-related parameters are examined.
| null |
Type 2 Diabetes
|
Type 2 Diabetes anion-exchange resin
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: Three tablets of MCI-196 500mg tablet at a time, three times daily, 12 weeks administration (dose in a day: 4500mg) intervention 2: Three tablets of Placebo tablet at a time, three times daily, 12 weeks administration
|
intervention 1: MCI-196 intervention 2: Placebo of MCI-196 Tablet
| 0
| null | 0
|
NCT00497198
|
[
5
] | 70
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| false
| 0ALL
| true
|
The purpose of this study is twofold: (1) to assess the feasibility and safety of fixed dose combination zidovudine/lamivudine/abacavir in HIV infected subjects with tuberculosis in a resource-limited setting, and (2) to assess the impact of delayed versus early initiation strategies for fixed dose combination zidovudine/lamivudine/abacavir on the rate of tuberculosis-associated immune reconstitution inflammatory syndromes.
| null |
HIV Tuberculosis
|
HIV Tuberculosis Treatment Naive
| null | 2
|
arm 1: Initiation of fixed dose combination zidovudine/lamivudine/abacavir 2 weeks after commencing antituberculous therapy arm 2: Initiation of fixed dose combination zidovudine/lamivudine/abacavir 8 weeks after commencing antituberculous therapy
|
[
0,
0
] | 1
|
[
0
] |
intervention 1: All subjects will receive fixed dose combination zidovudine(300 mg) / lamivudine (150 mg) / abacavir (300 mg) by mouth twice daily. Medications will be provided as long as deemed beneficial by the site investigator and study subject for up to two years. Toxicity substitutions are allowed per protocol.
|
intervention 1: Fixed dose combination zidovudine/lamivudine/abacavir
| 1
|
Moshi | N/A | Tanzania | 37.33333 | -3.35
| 0
|
NCT00851630
|
[
5
] | 145
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 0NONE
| null | 0ALL
| null |
This is a multi-center, open-label study of 28 weeks duration in subjects with Mild Cognitive Impairment who have completed the double-blind study (E2020-A001-412).
| null |
Mild Cognitive Impairment
|
Mild Cognitive Impairment
| null | 2
|
arm 1: None arm 2: None
|
[
0,
2
] | 2
|
[
0,
0
] |
intervention 1: 5 mg or 10 mg of donepezil hydrochloride (Aricept) taken orally once a day. intervention 2: None
|
intervention 1: Aricept (donepezil hydrochloride) intervention 2: placebo
| 49
|
Alabaster | Alabama | United States | -86.81638 | 33.24428
Peoria | Arizona | United States | -112.23738 | 33.5806
Sun City | Arizona | United States | -112.27182 | 33.59754
Tucson | Arizona | United States | -110.92648 | 32.22174
Encinitas | California | United States | -117.29198 | 33.03699
Fresno | California | United States | -119.77237 | 36.74773
Garden Grove | California | United States | -117.94145 | 33.77391
Irvine | California | United States | -117.82311 | 33.66946
La Mesa | California | United States | -117.02308 | 32.76783
San Diego | California | United States | -117.16472 | 32.71571
Santa Monica | California | United States | -118.49138 | 34.01949
Sherman Oaks | California | United States | -118.44925 | 34.15112
Vista | California | United States | -117.24254 | 33.20004
New Haven | Connecticut | United States | -72.92816 | 41.30815
Deerfield Beach | Florida | United States | -80.09977 | 26.31841
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
Hialeah | Florida | United States | -80.27811 | 25.8576
Hollywood | Florida | United States | -80.14949 | 26.0112
Miami Beach | Florida | United States | -80.13005 | 25.79065
Plantation | Florida | United States | -80.23184 | 26.13421
Sarasota | Florida | United States | -82.53065 | 27.33643
St. Petersburg | Florida | United States | -82.67927 | 27.77086
Tampa | Florida | United States | -82.45843 | 27.94752
Tampa | Florida | United States | -82.45843 | 27.94752
Tampa | Florida | United States | -82.45843 | 27.94752
Venice | Florida | United States | -82.45426 | 27.09978
West Palm Beach | Florida | United States | -80.05337 | 26.71534
Lexington | Kentucky | United States | -84.47772 | 37.98869
Kalamazoo | Michigan | United States | -85.58723 | 42.29171
St Louis | Missouri | United States | -90.19789 | 38.62727
Kenilworth | New Jersey | United States | -74.2907 | 40.67649
Albany | New York | United States | -73.75623 | 42.65258
Lawrence | New York | United States | -73.72958 | 40.61566
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
Staten Island | New York | United States | -74.13986 | 40.56233
Columbus | Ohio | United States | -82.99879 | 39.96118
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
Bala-Cynwyd | Pennsylvania | United States | -75.23407 | 40.00761
Greensburg | Pennsylvania | United States | -79.53893 | 40.30146
Jenkintown | Pennsylvania | United States | -75.12517 | 40.09594
Charleston | South Carolina | United States | -79.93275 | 32.77632
Houston | Texas | United States | -95.36327 | 29.76328
San Antonio | Texas | United States | -98.49363 | 29.42412
Wichita Falls | Texas | United States | -98.49339 | 33.91371
Bennington | Vermont | United States | -73.19677 | 42.87813
| 0
|
NCT00934375
|
[
2
] | 40
|
RANDOMIZED
|
CROSSOVER
| 9OTHER
| 0NONE
| true
| 0ALL
| false
|
The object of this study is to compare the rate and extent of absorption of an investigational formulation of buprenorphine 8 mg sublingual tablets manufactured by Barr Laboratories, Inc. to an equivalent oral dose of the commercially available reference product, Subutex® manufactured by Reckitt Benckiser, following and overnight fast of at least 10 hours.
|
Criteria for Evaluation: FDA Bioequivalence Criteria
Statistical Methods: FDA Bioequivalence Statistical Methods
|
Healthy
|
Bioequivalence Healthy
| null | 2
|
arm 1: Buprenorphine 8 mg Sublingual Tablets arm 2: Subutex® 8 mg Sublingual Tablets
|
[
0,
1
] | 2
|
[
0,
0
] |
intervention 1: 8 mg Sublingual Tablets intervention 2: 8 mg Sublingual Tablets
|
intervention 1: Buprenorphine intervention 2: Buprenorphine
| 1
|
Austin | Texas | United States | -97.74306 | 30.26715
| 0
|
NCT01157169
|
[
4
] | 22
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 3TRIPLE
| true
| 0ALL
| false
|
This study examined the effects of modafinil on apathetic symptomatology, performance of activities of daily living (ADLs) and caregiver burden in individuals with Alzheimer's disease (AD).
| null |
Apathy Alzheimer's Disease
|
apathy Alzheimer's disease activities of daily living performance caregiver burden
| null | 2
|
arm 1: None arm 2: None
|
[
2,
0
] | 2
|
[
0,
0
] |
intervention 1: 100 mg in the morning for the first week and 200 mg in the morning for the remaining seven weeks intervention 2: 100 mg in the morning for the first week and 200 mg in the morning for the remaining seven weeks
|
intervention 1: Modafinil intervention 2: Placebo
| 1
|
Providence | Rhode Island | United States | -71.41283 | 41.82399
| 0
|
NCT01172145
|
[
2
] | 44
|
RANDOMIZED
|
CROSSOVER
| 0TREATMENT
| 0NONE
| true
| 1FEMALE
| false
|
The purpose of this study is examine and compare the uptake of YAZ (oral contraceptive containing drospirenone and ethinylestradiol) with or without levomefolate calcium (Metafolin, a registered vitamin supplement) in the body and to examine and compare the uptake of levomefolate calcium with or without YAZ in the body, in healthy volunteers not using hormonal contraception
| null |
Contraception
| null | 3
|
arm 1: single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) arm 2: single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium \[MTHF-Ca\]) arm 3: single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium \[MTHF-Ca\])
|
[
0,
0,
0
] | 3
|
[
0,
0,
0
] |
intervention 1: Treatment group A: Single 1 film-coated tablet (Ethinylestradiol \[EE\] 0.02mg / Drospirenone \[DRSP\] 3mg) taken orally under fasting condition at intervals of at least one menstrual cycle. intervention 2: Treatment group B: Single 1 film-coated tablet (Ethinylestradiol \[EE\] 0.02mg / Drospirenone \[DRSP\] 3mg / L-5-methyltetrahydrofolate \[L-5-MTHF\] 0.451mg) taken orally under fasting condition at intervals of at least one menstrual cycle. intervention 3: Treatment group C: Single 1 coated tablet (L-5-methyltetrahydrofolate \[L-5-MTHF\] 0.451mg) taken orally under fasting condition at intervals of at least one menstrual cycle.
|
intervention 1: EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) intervention 2: EE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca) intervention 3: L-5-MTHF 0.451mg (Metafolin)
| 1
|
Groningen | N/A | Netherlands | 6.56667 | 53.21917
| 0
|
NCT01253187
|
|
[
5
] | 20
|
NON_RANDOMIZED
|
SINGLE_GROUP
| 7BASIC_SCIENCE
| 0NONE
| true
| 1FEMALE
| true
|
The purpose of the study is to examine the impact of hot flushes on sleep, mood, and well-being. The investigators will cause hot flushes by giving study participants the hormone medication, leuprolide (Lupron), which is a manufactured (artificial) hormone that makes the body think that it has reached menopause temporarily. Most women begin to have hot flushes within 4 weeks after taking leuprolide and resume menses 3 months later. The investigators will administer questionnaires to evaluate changes in sleep and mood over the course of the study.
| null |
Hot Flashes
|
Lupron Premenopausal Hot flashes
| null | 2
|
arm 1: Subjects who developed hot flashes after receiving leuprolide acetate (3.75 mg intramuscular injection) arm 2: Subjects who did not develop hot flashes after receiving leuprolide acetate (3.75 mg intramuscular injection)
|
[
0,
0
] | 1
|
[
0
] |
intervention 1: Leuprolide acetate (Lupron Depot®) 3.75-mg intramuscular injection
Leuprolide is a widely used gonadotropin-releasing hormone agonist (GnRHa) that is indicated for treatment of endometriosis, uterine fibroids, precocious puberty, and prostate cancer, and is used off-label for in-vitro fertilization and premenstrual syndrome. In this protocol, leuprolide will be administered once during the mid-luteal phase of the menstrual cycle at a dose routinely used for treatment of endometriosis and uterine fibroids in women.
|
intervention 1: Leuprolide acetate
| 1
|
Boston | Massachusetts | United States | -71.05977 | 42.35843
| 0
|
NCT00455689
|
[
5
] | 186
|
RANDOMIZED
|
PARALLEL
| 0TREATMENT
| 2DOUBLE
| false
| 0ALL
| null |
This study will last up to 3 years. You will visit the clinic up to 14 times. Certain visits will include lung function tests and scans of your bones. The purpose of this study is to determine the effect of the steroid component of an inhaled product on bone mineral density in patients with Chronic Obstructive Pulmonary Disease (COPD).
| null |
Pulmonary Disease, Chronic Obstructive
|
Osteoporosis Bone Mineral Density Osteopenia Chronic Obstructive Pulmonary Disease COPD
| null | 2
|
arm 1: Participants randomized to this arm received salmeterol 50 microgram (mcg), formulated with lactose via the DISKUS™ inhaler one inhalation twice daily (BID) one inhalation in the morning and one inhalation in the evening for 156 Weeks. Each DISKUS contained 60 doses of study medication. Participant were provided with albuterol/salbutamol as relief medication. DISCUS is registered trademark product of GlaxoSmithKline. arm 2: Participants randomized to this arm received Fluticasone propionate/salmeterol combination product 250/50 mcg, formulated with lactose via the DISKUS inhaler one inhalation BID, one inhalation in the morning and one inhalation in the evening for 156 Weeks. Each DISKUS contained 60 doses of study medication. Participant were provided with albuterol/salbutamol as relief medication.
|
[
0,
0
] | 3
|
[
0,
0,
1
] |
intervention 1: Salmeterol xinafoate 50 mcg strength DISKUS inhaler (formulated with lactose), BID in the morning and evening. intervention 2: Fluticasone propionate/salmeterol xinafoate combination product 250/50mcg strength DISKUS inhaler (formulated with lactose), BID in the morning and evening. intervention 3: Each participant received study medication via the DISKUS, for one of two possible treatment groups. Each DISKUS contained 60 doses of study medication. Participants were instructed to administer medication BID (one inhalation in the morning and one inhalation in the evening) approximately 12 hours apart for 156-week treatment period.
|
intervention 1: Salmeterol 50 mcg BID intervention 2: Fluticasone Propionate/Salmeterol 250/50 mcg BID intervention 3: DISKUS inhaler
| 37
|
Berkeley | California | United States | -122.27275 | 37.87159
Fullerton | California | United States | -117.92534 | 33.87029
Rancho Mirage | California | United States | -116.41279 | 33.73974
San Diego | California | United States | -117.16472 | 32.71571
Walnut Creek | California | United States | -122.06496 | 37.90631
Fort Collins | Colorado | United States | -105.08442 | 40.58526
Wheat Ridge | Colorado | United States | -105.07721 | 39.7661
Hartford | Connecticut | United States | -72.68509 | 41.76371
Fort Lauderdale | Florida | United States | -80.14338 | 26.12231
Jacksonville | Florida | United States | -81.65565 | 30.33218
Sarasota | Florida | United States | -82.53065 | 27.33643
Tamarac | Florida | United States | -80.24977 | 26.21286
Atlanta | Georgia | United States | -84.38798 | 33.749
Chicago | Illinois | United States | -87.65005 | 41.85003
North Chicago | Illinois | United States | -87.84118 | 42.32558
Wichita | Kansas | United States | -97.33754 | 37.69224
Boston | Massachusetts | United States | -71.05977 | 42.35843
Cadillac | Michigan | United States | -85.40116 | 44.25195
Saint Charles | Missouri | United States | -90.48123 | 38.78394
Omaha | Nebraska | United States | -95.94043 | 41.25626
Bronxville | New York | United States | -73.83208 | 40.93815
Charlotte | North Carolina | United States | -80.84313 | 35.22709
Portland | Oregon | United States | -122.67621 | 45.52345
Charleston | South Carolina | United States | -79.93275 | 32.77632
Greer | South Carolina | United States | -82.22706 | 34.93873
Simpsonville | South Carolina | United States | -82.25428 | 34.73706
Spartanburg | South Carolina | United States | -81.93205 | 34.94957
Kingsport | Tennessee | United States | -82.56182 | 36.54843
Milan | Tennessee | United States | -88.75895 | 35.91979
Corsicana | Texas | United States | -96.46887 | 32.09543
San Antonio | Texas | United States | -98.49363 | 29.42412
San Antonio | Texas | United States | -98.49363 | 29.42412
Richmond | Virginia | United States | -77.46026 | 37.55376
Richmond | Virginia | United States | -77.46026 | 37.55376
Bellingham | Washington | United States | -122.48822 | 48.75955
Spokane | Washington | United States | -117.42908 | 47.65966
Spokane | Washington | United States | -117.42908 | 47.65966
| 1
|
NCT00355342
|
[
3
] | 21
|
NA
|
SINGLE_GROUP
| 0TREATMENT
| 0NONE
| false
| 0ALL
| null |
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with cyclophosphamide may kill more cancer cells.
PURPOSE: This phase II trial is studying how well giving rituximab together with cyclophosphamide works in treating patients with high risk, refractory, or relapsed multiple myeloma.
|
OBJECTIVES:
* Determine the effect of rituximab and high-dose cyclophosphamide on the growth of myeloma stem cells in patients with high-risk, refractory, or relapsed multiple myeloma.
OUTLINE: Patients receive rituximab IV on days -10 and -7; once weekly for 4 weeks (after completion of high-dose cyclophosphamide); and then once in months 3, 6, 9, and 12. Patients also receive high-dose cyclophosphamide on days -3 to 0.
PROJECTED ACCRUAL: Not specified.
|
Multiple Myeloma and Plasma Cell Neoplasm
|
stage I multiple myeloma stage II multiple myeloma stage III multiple myeloma refractory multiple myeloma
| null | 1
|
arm 1: Rituximab 375 mg/m\^2 on Days -10 and -7; Cyclophosphamide 50 mg/kg on days -3, -2, -1, and 0; Rituximab 375 mg/m\^2 weekly x4 after platelet counts recover; For patients achieving at least stable disease, rituximab maintenance 375 mg/m\^2 once each during months 3, 6, 9, and 12
|
[
0
] | 2
|
[
2,
0
] |
intervention 1: None intervention 2: None
|
intervention 1: rituximab intervention 2: cyclophosphamide
| 1
|
Baltimore | Maryland | United States | -76.61219 | 39.29038
| 0
|
NCT00258206
|
[
0
] | 35
|
NA
|
SINGLE_GROUP
| 2DIAGNOSTIC
| 0NONE
| false
| 0ALL
| false
|
Analysis of aldeyde biomarkers of exposure and host response The purpose of this prospective, open-label, clinical trial is to establish the feasibility and validity of exhaled breath condensate (EBC) biomarkers for use in studies designed to evaluate harm reduction strategies of smoking. This will be accomplished by measuring selected markers in EBC believed related to the pathogenesis of lung disease before and after a smoking cessation intervention.
|
Twenty subjects will be accrued in three groups based on smoking habit: 10-20, 20-30 and \>30 cigarettes/day. Eligibility criteria include male and female cigarette smokers ≥19 years of age, who are able to give informed consent, able to exhale into Eco Screen instrument for 15-20 minutes. All must be willing to make a serious quit attempt and be willing to use nicotine replacement therapy.
Subjects will be excluded if any of the following are present: regular use of anti-inflammatory medication; presence of any inflammatory disease of the respiratory tract including moderate or worse COPD (FEV1 \< 80% predicted and FEV1/FVC ratio \< 0.7). Subjects with normal lung function who meet criteria for diagnosis of chronic bronchitis will be excluded. Subjects with stable medical conditions, excluding inflammatory lung disease, will be permitted to participate, providing anti-inflammatory therapies are not used regularly and providing there has been no change in their clinical status in the two months prior to beginning the study.
Upon entering into the study, subjects will establish a quit date and will be treated with nicotine replacement therapy (NRT) products based on individual preference and will receive smoking cessation counseling. They will then be seen at 12 visits over the course of 25 weeks.
Evaluations will include vital signs, interval smoking history, food frequency questionnaire, exhaled carbon monoxide, blood drawn for chemistry and CBC, peripheral blood harvested and serum aliquoted and saved for future biochemical analysis, urine sample for isoprostane, pregnancy test for females, and exhaled breath condensate. Some visits may also include spirometry with and with out bronchodilators, 24 hour urine collections for NNAL and NNAL-glc quantification, health status assessed using St. George's Respiratory Questionnaire, the Functional Assessment of Chronic Illness Therapy - Fatigue, the Leicester Cough Questionnaire, the Clinical COPD Questionnaire and smoking related symptoms assessed using the Breathlessness, Cough, and Sputum Scale.
|
Smoking Cessation
|
Smoking cessation Biomarkers Aldehydes Exhaled breath Harm Reduction Cigarette smoking cessation reduction
| null | 1
|
arm 1: open label NRT self comparator design
|
[
0
] | 3
|
[
0,
0,
0
] |
intervention 1: None intervention 2: None intervention 3: None
|
intervention 1: nicotine polacrilex intervention 2: nicotine transdermal system intervention 3: nicotine inhaler
| 1
|
Omaha | Nebraska | United States | -95.94043 | 41.25626
| 0
|
NCT00482690
|
[
0
] | 24
|
NA
|
SINGLE_GROUP
| 2DIAGNOSTIC
| 0NONE
| false
| 0ALL
| false
|
The purpose of this prospective, open-label, clinical trial is to establish the feasibility and validity of exhaled breath condensate (EBC) biomarkers for use in studies designed to evaluate harm reduction strategies of smoking. This will be accomplished by measuring selected markers in EBC believed related to the pathogenesis of lung disease before and after a smoking cessation intervention.
|
Twenty subjects will be accrued in three groups based on smoking habit: 10-20, 20-30 and \>30 cigarettes/day. Eligibility criteria include male and female cigarette smokers ≥19 years of age, who are able to give informed consent, able to exhale into Eco Screen instrument for 15-20 minutes. All must be willing to make a serious quit attempt and be willing to use nicotine replacement therapy.
Subjects will be excluded if any of the following are present: regular use of anti-inflammatory medication; presence of any inflammatory disease of the respiratory tract including moderate or worse COPD (FEV1 \< 80% predicted and FEV1/FVC ratio \< 0.7). Subjects with normal lung function who meet criteria for diagnosis of chronic bronchitis will be excluded. Subjects with stable medical conditions, excluding inflammatory lung disease, will be permitted to participate, providing anti-inflammatory therapies are not used regularly and providing there has been no change in their clinical status in the two months prior to beginning the study.
Upon entering into the study, subjects will establish a quit date and will be treated with nicotine replacement therapy (NRT) products based on individual preference and will receive smoking cessation counseling. They will then be seen at 12 visits over the course of 25 weeks.
Evaluations will include vital signs, interval smoking history, food frequency questionnaire, exhaled carbon monoxide, blood drawn for chemistry and CBC, peripheral blood harvested and serum aliquoted and saved for future biochemical analysis, urine sample for isoprostane, pregnancy test for females, and exhaled breath condensate. Some visits may also include spirometry with and with out bronchodilators, 24 hour urine collections for NNAL and NNAL-glc quantification, health status assessed using St. George's Respiratory Questionnaire, the Functional Assessment of Chronic Illness Therapy - Fatigue, the Leicester Cough Questionnaire, the Clinical COPD Questionnaire and smoking related symptoms assessed using the Breathlessness, Cough, and Sputum Scale.
|
Cigarette Smoking
|
smoking reduction inflammation harm reduction lipid biomarkers
| null | 1
|
arm 1: any form of nicotine replacement would be allowed at subject discretion
|
[
0
] | 1
|
[
0
] |
intervention 1: on label use of Nicotine replacement therapy (NRT)
|
intervention 1: nicotine polacrilex, transdermal system or inhaler
| 1
|
Omaha | Nebraska | United States | -95.94043 | 41.25626
| 0
|
NCT00493831
|
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