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)”

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 Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Efficacy Study

Study Primary Completion Date: September 2006

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.

Intervention(s) in this Clinical Trial

• Drug: Fluconazole
  • Age Drug Route Renal Function Dosage 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
• Drug: Voriconazole
  • Age Drug Route Renal Function Dosage 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

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • fluconazole
• Experimental: 2
  • voriconazole

Primary Measures

• Fungal-free survival (proportion of participants alive and free from proven, probable, or presumptive invasive fungal infection) at 180 days post-transplant
  • Time Frame: 180 days
    

Secondary Measures

• Frequency of invasive fungal infections
  • Time Frame: 1 year
    
• Time to invasive fungal infection
  • Time Frame: 1 year
    
• survival
  • Time Frame: 1 year
    
• Frequency and duration of use of amphotericin B or caspofungin
  • Time Frame: 1 year
    
• Time to and severity of acute and chronic GVHD
  • Time Frame: 1 year
    
• Utility of galactomannan assay in diagnosis of aspergillus and response to therapy
  • Time Frame: 1 year
    
• Time to neutrophil engraftment
  • Time Frame: 28 days
    
• Time to platelet engraftment
  • Time Frame: 180 days
    
• 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
    

Inclusion Criteria:

• Must 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
• Must have a 5 or 6 of 6 human leukocyte antigens (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
• Must have one of the following underlying diseases:
• 1. Acute myelogenous leukemia (AML)
• 2. Acute lymphocytic leukemia (ALL)
• 3. Acute undifferentiated leukemia (AUL)
• 4. Acute biphenotypic leukemia in first or second complete remission
• 5. Chronic myelogenous leukemia (CML) in either chronic or accelerated phase
• 6. One of the following myelodysplastic syndrome(s) (MDS):
• 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. MDS, unclassified
• 8. MDS associated with isolated del (5q)
• 9. Chronic myelomonocytic leukemia (CMML)
• 7. Lymphoma (including Hodgkin's) with chemosensitive disease (at least 50% response to chemotherapy) and receiving a related donor transplant
• Receiving myeloablative conditioning regimens
• Adequate physical function (cardiac, hepatic, renal, and pulmonary), within 6 weeks of initiation of conditioning (preferably within 4 weeks) unless otherwise specified
• Baseline galactomannan blood samples drawn within 30 days prior to randomization with the results available prior to randomization (72 hours prior to transplant)
• Chest computed tomography (CT) scans within 6 weeks prior to randomization if the results of the baseline galactomannan blood sample are not available prior to randomization (72 hours prior to transplant)

Exclusion Criteria:

• Invasive yeast infection within the 8 weeks prior to conditioning regimen initiation.
• Patients are eligible if colonized or have had superficial infection. Patients with a history of candidemia greater than 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 require antifungal therapy
• Presumptive, proven, or probable aspergillus or other mold infection or deep mycoses (including hepatosplenic candidiasis) within 4 months prior to conditioning regimen initiation
• Uncontrolled viral or bacterial infection at the time of study registration
• Pregnant or breastfeeding. Women of child-bearing age must avoid becoming pregnant while receiving antifungal agents
• Karnofsky performance status less than 70% or Lansky status less than 50% for patients under 16 years old unless approved by the medical monitor or protocol chair
• History of allergy or intolerance to azoles (e.g., fluconazole, itraconazole, voriconazole, posaconazole, ketoconazole, miconazole, clotrimazole)
• Requiring therapy with rifampin, rifabutin, carbamazepine, cisapride (Propulsid®), terfenadine (Seldane®), astemizole (Hismanal®), ergot alkaloids, long-acting barbiturates, or who have received more than 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)
• Receiving sirolimus
• Prolonged QTc syndrome at study entry
• HIV positive
• Receiving another investigational drug unless cleared by the medical monitors
• Received a prior allogeneic or autologous transplant
• Active central nervous system disease
• On fungal prophylaxis during conditioning regimen (it is recommended that fungal prophylaxis be suspended once patient is enrolled)
• Prior cancer, other than resected basal cell carcinoma or treated carcinoma in-situ.
• Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the medical monitor or protocol chair. Cancer previously treated with curative intent over 5 years ago will be allowed

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 2 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Donna Salzman, MD Principal Investigator University of Alabama at Birmingham  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00075803

Study ID Number: 416

ClinicalTrials.gov Identifier: NCT00075803

Health Authority: United States: Federal Government