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

Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00075803
• Other study ID #: BMTCTN0101
• Secondary ID: BMT CTN 0101U01H
• Status: Completed
• Phase: Phase 3
• Start date: November 2003
• Est. completion date: September 2007

Study information

• Verified date: December 2022
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00322088

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: September 2007
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Infections
• Leukemia
• Lymphoma
• Mycoses

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Johns Hopkins/SKCCC	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
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	Roswell Park Cancer Institute	Buffalo	New York
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	University Hospitals of Cleveland/Case Western	Cleveland	Ohio
United States	Karmanos Cancer Institute/BMT	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine (Shands)	Gainesville	Florida
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Texas/MD Anderson CRC	Houston	Texas
United States	Indiana University Medical Center	Indianapolis	Indiana
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Kansas City Cancer Centers	Kansas City	Missouri
United States	UCSD Medical Center	La Jolla	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Cardinal Glennon Children's Hospital	Saint Louis	Missouri
United States	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri
United States	Washington University/St. Louis Children's Hospital	Saint Louis	Missouri
United States	Utah BMT/Univ of Utah Med School	Salt Lake City	Utah
United States	Texas Transplant Institute	San Antonio	Texas
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Stanford Hospital and Clinics	Stanford	California
United States	H. Lee Moffitt Cancer Center	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (5)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Marrow Donor Program

Country where clinical trial is conducted

United States, 

References & Publications (2)

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 inv — View Citation

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. R — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fungal-free Survival (Percentage of Participants Alive and Free From Proven, Probable, or Presumptive Invasive Fungal Infection) at 180 Days Post-transplant		180 days
Secondary	Frequency of Invasive Fungal Infections (IFI)	Incidence of proven, probably, or presumptive IFI	1 year
Secondary	Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days		100, 180, and 365 days
Secondary	Overall Survival		100, 180, and 365 days
Secondary	Relapse Free Survival		100, 180, and 365 days
Secondary	Frequency of Use of Amphotericin B or Caspofungin		1 year
Secondary	Duration of Use of Amphotericin B or Caspofungin		180 days
Secondary	Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD)		100 and 365 days
Secondary	Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy	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.	1 year
Secondary	Time to Neutrophil Engraftment		28 days
Secondary	Time to Platelet Engraftment		180 days
Secondary	Failure to Engraft		day 42
Secondary	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		1 year

External Links

•   Blood and Marrow Transplant Clinical Trials Network (BMT CTN)
•   National Marrow Donor Program