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Acute Graft-versus-Host Disease Treatment (BMT CTN 0802)

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01002742
First received: October 23, 2009
Last updated: April 21, 2016
Last verified: March 2016
  Purpose
The study is a Phase III, randomized double blind, placebo controlled, and trial evaluating the addition of Mycophenolate mofetil (MMF) vs. placebo to systemic corticosteroids as initial therapy for acute Graft Vs Host Disease (GVHD). The primary endpoint will be GVHD free survival at Day 56 post randomization.

Condition Intervention Phase
Graft-versus-Host Disease
Immune System Disorders
Drug: Mycophenolate Mofetil
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating Corticosteroids With Mycophenolate Mofetil vs. Corticosteroids With Placebo as Initial Systemic Treatment of Acute Graft-Vs-Host-Disease (BMT CTN #0802)

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • GVHD-free Survival [ Time Frame: Day 56 ] [ Designated as safety issue: Yes ]
    Success is defined as alive and free of GVHD at day 56 after randomization, all others are considered to be a study failure.


Secondary Outcome Measures:
  • Percentage of Surviving Participants With Complete Response (CR) [ Time Frame: Days 14, 28, and 56 ] [ Designated as safety issue: No ]
    CR is defined as a score of 0 for the GVHD grading in all evaluable organs.

  • Incidence of GVHD Flares Requiring Increased Therapy [ Time Frame: Day 90 ] [ Designated as safety issue: Yes ]
    Flares are defined as any progression of acute GVHD after an initial response (i.e., earlier CR or PR) that requires re-escalation of steroid dosing, or initiation of additional topical or systemic therapy.

  • Incidence of Discontinuation of Immune Suppression Without Flare [ Time Frame: Day 56, Day 180 and Day 360 post-treatment ] [ Designated as safety issue: No ]
  • Cumulative Steroid Dose [ Time Frame: Days 28 and 56 ] [ Designated as safety issue: No ]
    The cumulative steroid dose for each patient will be calculated by adding the doses (end of each week's dose) for each of the first four weeks of treatment, divided by the number of days of survival during this interval. The cumulative steroid dose was calculated for all patients per treatment arm and compared.

  • Incidence of Topical/Non-absorbable Therapy [ Time Frame: Day 56 ] [ Designated as safety issue: No ]
  • Overall GVHD-free Survival Post-randomization [ Time Frame: Months 6 and 12 ] [ Designated as safety issue: No ]
  • Incidence of Chronic GVHD [ Time Frame: 12 months post-randomization ] [ Designated as safety issue: Yes ]
  • Incidence of Systemic Infections [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
    Number of participants that experienced at least one infection.

  • Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Incidence of Cytomegalovirus (CMV) Reactivation [ Time Frame: Year 1 ] [ Designated as safety issue: Yes ]
  • Cumulative Incidence of a Severe/Life-threatening/Fatal Infections [ Time Frame: Year 1 ] [ Designated as safety issue: Yes ]
  • Disease-Free Survival (DFS) Post-Randomization [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    DFS includes death or progression/relapse of malignancy

  • Treatment Related Mortality (TRM) [ Time Frame: Year 1 ] [ Designated as safety issue: Yes ]
  • Change in Patient Reported Outcomes From Enrollment to Day 56 [ Time Frame: Day 56 ] [ Designated as safety issue: No ]

Enrollment: 236
Study Start Date: January 2010
Study Completion Date: June 2013
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Placebo
Corticosteroids with placebo
Drug: Placebo

Oral dosing should be delivered in 250 mg units blinded placebo. For those < 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period.

  • Patients who weight > 60 kg should receive placebo 1 gm PO/IV every 8 hours.
  • Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours.
  • Patients who weight <40 kg should receive 20 mg/kg IV or PO every 8 hours.
Other Name: Inactive drug
Experimental: Mycophenolate Mofetil
Corticosteroids with Mycophenolate Mofetil
Drug: Mycophenolate Mofetil

Oral dosing should be delivered in 250 mg units. For those < 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period.

  • Patients who weight > 60 kg should receive MMF 1 gm PO/IV every 8 hours.
  • Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours.
  • Patients who weight <40 kg should receive 20 mg/kg IV or PO every 8 hours.
Other Names:
  • Cellcept®
  • MMF

Detailed Description:

Corticosteroids have been used as primary therapy for acute GVHD for many years. Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid therapy for previously untreated patients with acute GVHD.

BMT CTN study 0302 (NCT00224874)was a randomized Phase II study evaluating etanercept, mycophenolate mofetil, denileukin diftitox or pentostatin in addition to corticosteroids. The results of that study suggested that mycophenolate mofetil produced the highest rates of CR at Day 28 and overall survival, supporting its evaluation in a Phase III study. Day 56 GVHD-free survival for the four treatment arms (all combining corticosteroids with one of the four study drugs) ranged from 39-71% across the four study arms.

  Eligibility

Ages Eligible for Study:   Child, Adult, Senior
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute GVHD developing after allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells or cord blood. Recipients of non-myeloablative and myeloablative transplants are eligible.
  • Acute GVHD after planned donor lymphocyte infusion or planned T cell add back are eligible.
  • De novo acute GVHD requiring systemic therapy. GVHD is defined as the presence of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting in a context in which acute GVHD is likely to occur and where other etiologies such as drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled out. Note that patients with stage I and II skin only (overall grade I) or isolated upper gastrointestinal (GI) involvement are eligible if the treating physician deems that systemic high-dose corticosteroid treatment is indicated.
  • The patient must have had no previous systemic immune suppressive therapy for treatment of acute GVHD except for a maximum 72 hours of prior corticosteroid therapy at >0.5mg/kg methylprednisolone or equivalent after the onset of acute GVHD.
  • Clinical status at enrollment to allow tapering of steroids to not less than 0.25 mg/kg/day prednisone (0.2 mg/kg/day methylprednisolone) at Day 28 of therapy.
  • Absolute neutrophil count (ANC) greater than 500/µL.
  • Written informed consent and/or assent from patient, parent or guardian.
  • Documentation that the assent document and education materials have been provided to, and reviewed with, patients between the ages of 7 and 17.
  • Patients of all ages are eligible.
  • Biopsy confirmation of GVHD is recommended, but not required. Enrollment should not be delayed for biopsy or pathology results unless these are to be used to decide about whether to treat for GVHD.

Exclusion Criteria:

  • Patients receiving mycophenolate mofetil or mycophenolic acid (Myfortic) within seven days of screening for enrollment.
  • Patients with uncontrolled infections will be excluded. If a bacterial or viral infection is present, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. If a fungal infection is present, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
  • Relapsed/persistent malignancy requiring rapid immune suppression withdrawal.
  • Patients with GVHD after an unplanned Donor Lymphocyte Infusion (DLI), i.e., DLI that was not part of their original transplant therapy plan, or DLI given for treatment of persistent or recurrent malignancy after transplantation.
  • Patients unlikely to be available at the transplantation center on Day 28 and 56 of therapy.
  • A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation.
  • Patients receiving other drugs for the treatment of GVHD.
  • Patients receiving methylprednisolone > 0.5 mg/kg/day (or 0.6 mg/kg/day prednisone) within 7 days before the onset of acute GVHD. If steroid therapy has been administered for treatment of a non-GVHD related condition and tapered to ≤ 0.5 mg/kg/day methylprednisolone (0.6 mg/kg/day prednisone) for seven or more days before the onset of acute GVHD, the patient is eligible.
  • Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study. Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding, therefore breast feeding patients are not eligible.
  • Adults unable to provide informed consent.
  • Patients on dialysis.
  • Patients with severe hepatic Veno-Occlusive Disease (VOD) or sinusoidal obstruction syndrome who in the judgement of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment.
  • Patients with a history of intolerance/allergy to MMF.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01002742

  Show 36 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Investigators
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
  More Information

Additional Information:
Publications:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01002742     History of Changes
Other Study ID Numbers: BMTCTN0802  U01HL069294  BMT CTN 0802  U01HL069294-06 
Study First Received: October 23, 2009
Results First Received: January 6, 2016
Last Updated: April 21, 2016
Health Authority: United States: Food and Drug Administration
United States: Federal Government
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript.

Keywords provided by Medical College of Wisconsin:
GVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Mycophenolic Acid
Mycophenolate mofetil
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 29, 2016