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Comparison of Fluconazole vs Voriconazole to Treat Fungal Infections for Blood and Marrow Transplants (BMT CTN 0101)

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ClinicalTrials.gov Identifier: NCT00075803
Recruitment Status : Completed
First Posted : January 13, 2004
Results First Posted : September 4, 2015
Last Update Posted : September 12, 2016
Information provided by (Responsible Party):

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Lymphoma Infection Leukemia Drug: Fluconazole Drug: Voriconazole Phase 3

Detailed Description:


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.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, 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)
Study Start Date : November 2003
Primary Completion Date : September 2006
Study Completion Date : September 2007

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Active Comparator: Fluconazole
The dose of fluconazole is 400 mg by mouth or intravenous drip.
Drug: 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.
Other Name: Diflucan
Experimental: Voriconazole
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.
Drug: 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, 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

Outcome Measures

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. Frequency of Invasive Fungal Infections (IFI) [ Time Frame: 1 year ]
    Incidence of proven, probably, or presumptive IFI

  2. Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days [ Time Frame: 100, 180, and 365 days ]
  3. Overall Survival [ Time Frame: 100, 180, and 365 days ]
  4. Relapse Free Survival [ Time Frame: 100, 180, and 365 days ]
  5. Frequency of Use of Amphotericin B or Caspofungin [ Time Frame: 1 year ]
  6. Duration of Use of Amphotericin B or Caspofungin [ Time Frame: 180 days ]
  7. Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) [ Time Frame: 100 and 365 days ]
  8. Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy [ Time Frame: 1 year ]
    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.

  9. Time to Neutrophil Engraftment [ Time Frame: 28 days ]
  10. Time to Platelet Engraftment [ Time Frame: 180 days ]
  11. Failure to Engraft [ Time Frame: day 42 ]
  12. 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 ]

Eligibility Criteria

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00075803

  Hide Study Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, California
UCSD Medical Center
La Jolla, California, United States, 92093
Stanford Hospital and Clinics
Stanford, California, United States, 94305
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Florida
University of Florida College of Medicine (Shands)
Gainesville, Florida, United States, 32610
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33624
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60614
United States, Indiana
Indiana University Medical Center
Indianapolis, Indiana, United States, 46202
United States, Maryland
Johns Hopkins/SKCCC
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Dana Farber Cancer Institute/Brigham & Womens
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute/Children's Hospital of Boston
Boston, Massachusetts, United States, 02114
United States, Michigan
University of Michigan Medical Center
Ann Arbor, Michigan, United States, 48109
Karmanos Cancer Institute/BMT
Detroit, Michigan, United States, 48201
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, United States, 64108
Kansas City Cancer Centers
Kansas City, Missouri, United States, 64111
Cardinal Glennon Children's Hospital
St. Louis, Missouri, United States, 63110
Washington University/Barnes Jewish Hospital
St. Louis, Missouri, United States, 63110
Washington University/St. Louis Children's Hospital
St. Louis, Missouri, United States, 63110
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
University Hospitals of Cleveland/Case Western
Cleveland, Ohio, United States, 44106
United States, Oregon
Oregon Health Sciences University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
University of Pennsylvania Cancer Center
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas/MD Anderson CRC
Houston, Texas, United States, 77030
Texas Transplant Institute
San Antonio, Texas, United States, 78229
United States, Utah
Utah BMT/Univ of Utah Med School
Salt Lake City, Utah, United States, 84132
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
More Information

Additional Information:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT00075803     History of Changes
Obsolete Identifiers: NCT00322088
Other Study ID Numbers: BMTCTN0101
BMT CTN 0101 ( Other Identifier: Blood and Marrow Transplant Clinical Trial Network )
U01HL069294 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted: January 13, 2004    Key Record Dates
Results First Posted: September 4, 2015
Last Update Posted: September 12, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Medical College of Wisconsin:
Myelodysplastic and Myeloproliferative Diseases

Additional relevant MeSH terms:
Communicable Diseases
Invasive Fungal Infections
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP3A Inhibitors