Comparison of Fluconazole vs Voriconazole to Treat Fungal Infections for Blood and Marrow Transplants (BMT CTN 0101)
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||A Randomized Double-blind Trial of Fluconazole Versus Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow Transplant Patients (BMT CTN #0101)|
- Fungal-free Survival (Percentage of Participants Alive and Free From Proven, Probable, or Presumptive Invasive Fungal Infection) at 180 Days Post-transplant [ Time Frame: 180 days ] [ Designated as safety issue: No ]
- Frequency of Invasive Fungal Infections (IFI) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]Incidence of proven, probably, or presumptive IFI
- Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days [ Time Frame: 100, 180, and 365 days ] [ Designated as safety issue: Yes ]
- Overall Survival [ Time Frame: 100, 180, and 365 days ] [ Designated as safety issue: Yes ]
- Relapse Free Survival [ Time Frame: 100, 180, and 365 days ] [ Designated as safety issue: Yes ]
- Frequency of Use of Amphotericin B or Caspofungin [ Time Frame: 1 year ] [ Designated as safety issue: No ]
- Duration of Use of Amphotericin B or Caspofungin [ Time Frame: 180 days ] [ Designated as safety issue: Yes ]
- Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) [ Time Frame: 100 and 365 days ] [ Designated as safety issue: Yes ]
- Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy [ Time Frame: 1 year ] [ Designated as safety issue: No ]Although there were 82 Galactomannan (GM) positives, 4 were excluded due to piperacillin/tazobactam administration, without other documentation of IFI, and were deemed false positives.
- Time to Neutrophil Engraftment [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
- Time to Platelet Engraftment [ Time Frame: 180 days ] [ Designated as safety issue: Yes ]
- Failure to Engraft [ Time Frame: day 42 ] [ Designated as safety issue: Yes ]
- 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 Greater Than 14 Consecutive Days [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
|Study Start Date:||November 2003|
|Study Completion Date:||September 2007|
|Primary Completion Date:||September 2006 (Final data collection date for primary outcome measure)|
Active Comparator: Fluconazole
The dose of fluconazole is 400 mg by mouth or intravenous drip.
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.
Other Name: Diflucan
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.
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.
Other Name: Vfend
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00075803
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|Study Director:||Mary Horowitz, MD||Center for International Blood and Marrow Transplant Research|