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

NCT ID: NCT00075803

Last Updated: 2023-01-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-11-30
• Study Completion Date: 2007-09-30

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.

Detailed Description

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.

Conditions

Lymphoma; Infection; Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Fluconazole

The dose of fluconazole is 400 mg by mouth or intravenous drip.

Group Type: ACTIVE_COMPARATOR

Fluconazole

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Voriconazole

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Diflucan; Vfend

Eligibility Criteria

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

• Minimum Eligible Age: 2 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

UCSD Medical Center

La Jolla, California, United States

Stanford Hospital and Clinics

Stanford, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Florida College of Medicine (Shands)

Gainesville, Florida, United States

H. Lee Moffitt Cancer Center

Tampa, Florida, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Indiana University Medical Center

Indianapolis, Indiana, United States

Johns Hopkins/SKCCC

Baltimore, Maryland, United States

Dana Farber Cancer Institute/Brigham & Womens

Boston, Massachusetts, United States

Dana Farber Cancer Institute/Children's Hospital of Boston

Boston, Massachusetts, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

Karmanos Cancer Institute/BMT

Detroit, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Kansas City Cancer Centers

Kansas City, Missouri, United States

Cardinal Glennon Children's Hospital

St Louis, Missouri, United States

Washington University/Barnes Jewish Hospital

St Louis, Missouri, United States

Washington University/St. Louis Children's Hospital

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States

Oregon Health Sciences University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States

University of Texas/MD Anderson CRC

Houston, Texas, United States

Texas Transplant Institute

San Antonio, Texas, United States

Utah BMT/Univ of Utah Med School

Salt Lake City, Utah, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Countries

United States

References

Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolanos-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA; Blood and Marrow Transplant Clinical Trials Network. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9;116(24):5111-8. doi: 10.1182/blood-2010-02-268151. Epub 2010 Sep 8.

Reference Type: RESULT

PMID: 20826719 (View on PubMed)

Mauskopf J, Chirila C, Graham J, Gersten ID, Leather H, Maziarz RT, Baden LR, Bolanos-Meade J, Brown JM, Walsh TJ, Horowitz MH, Kurtzberg J, Marr KA, Wingard JR. Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. Am J Health Syst Pharm. 2013 Sep 1;70(17):1518-27. doi: 10.2146/ajhp120599.

Reference Type: RESULT

PMID: 23943184 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

BMT CTN 0101

Identifier Type: OTHER

Identifier Source: secondary_id

U01HL069294

Identifier Type: NIH

Identifier Source: secondary_id

View Link

5U24CA076518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMTCTN0101

Identifier Type: -

Identifier Source: org_study_id

NCT00322088

Identifier Type: -

Identifier Source: nct_alias