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Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801)

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ClinicalTrials.gov Identifier: NCT01106833
Recruitment Status : Active, not recruiting
First Posted : April 20, 2010
Results First Posted : August 14, 2018
Last Update Posted : September 14, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Information provided by (Responsible Party):
Medical College of Wisconsin

Brief Summary:
This study is designed as a combined Phase II/III, randomized, open label, multicenter, prospective comparative study of sirolimus plus prednisone versus sirolimus/calcineurin-inhibitor plus prednisone for the treatment of chronic GVHD. Patients will be stratified by transplant center and will be randomized to an experimental arm of one of the two pre-specified experimental arms (sirolimus + prednisone or the comparator arm of sirolimus + calcineurin inhibitor + prednisone) in a 1:1 ratio.

Condition or disease Intervention/treatment Phase
Chronic GVHD Drug: Sirolimus + calcineurin inhibitor + prednisone Drug: Sirolimus + prednisone Phase 2 Phase 3

Detailed Description:

Background: Chronic GVHD is a medical condition that can become very serious. Chronic GVHD is a common development after allogeneic transplant that occurs when the donor cells attack and damage tissues. The primary purpose of this study is to compare treatment regimens that contain sirolimus without a calcineurin inhibitor to a comparator regimen of sirolimus with a calcineurin inhibitor and evaluate how well chronic GVHD responds to treatment. The combinations of medications in this study are:

  • Sirolimus + calcineurin inhibitor + prednisone
  • Sirolimus + prednisone

The goal is to select a treatment regimen for further comparison in the Phase III trial.

Design Narrative: The intent is to enroll subjects at the start of initial therapy for chronic GVHD, or before their chronic GVHD is refractory to glucocorticoid therapy, or is chronically dependent upon glucocorticoid therapy and multiple secondary systemic immunosuppressive agents. Patients will be stratified by transplant center and will be randomized to one of two arms.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 151 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT CTN Protocol #0801)
Actual Study Start Date : April 2010
Actual Primary Completion Date : February 14, 2017
Estimated Study Completion Date : March 2019


Arm Intervention/treatment
Active Comparator: calcineurin inhibitor
Sirolimus + calcineurin inhibitor + prednisone
Drug: Sirolimus + calcineurin inhibitor + prednisone

The target serum level for sirolimus is 3-12 ng/mL. The target serum level for tacrolimus is 5-10 ng/mL. The target serum level for cyclosporine is 120-200 ng/mL.

Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.

Other Names:
  • Rapamune
  • Prograf
  • Neorall
  • Gengraf

Experimental: Sirolimus and prednisone
Sirolimus + prednisone
Drug: Sirolimus + prednisone

The target serum level for sirolimus is 3-12 ng/mL.

Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.

Other Name: Rapamune




Primary Outcome Measures :
  1. Proportion of Participants With Treatment Success [ Time Frame: 6 months and 24 months post-randomization ]
    Treatment success was evaluated at 6 months in Phase II and is defined as a complete or partial response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death. In Phase III, treatment success was evaluated at 24 months and is defined as a complete response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death.


Secondary Outcome Measures :
  1. Percentage of Participants With Overall Survival [ Time Frame: 6 months and 24 months post-randomization ]
    Overall survival is defined as survival of death from any cause.

  2. Percentage of Participants With Progression-free Survival [ Time Frame: 6 months and 24 months post-randomization ]
    Progression-free Survival is defined as survival without malignancy relapse. Relapse and death are considered failures for this endpoint.

  3. Percentage of Participants With Failure-free Survival [ Time Frame: 6 months and 24 months post-randomization ]
    Failure-free Survival is defined as survival without malignancy progression or initiation of secondary therapy for chronic GVHD. Progression, initiation of secondary therapy for chronic GVHD, and death are considered failures for this endpoint.

  4. Percentage of Participants With Relapse [ Time Frame: 6 months and 24 months post-randomization ]
    Relapse is defined as recurrence of the primary malignancy. Death is considered a competing risk for this endpoint.

  5. Percentage of Participants With Secondary Immunosuppressive Therapy Initiated [ Time Frame: 6 months and 24 months post-randomization ]
    The percentage of participants initiating secondary immunosuppressive therapy for chronic GVHD is described. Death is considered a competing risk for this endpoint.

  6. Percentage of Participants With Discontinuation of Systemic Immunosuppressive Therapy at Two Years [ Time Frame: 2 years post-randomization ]
    The percentage of participants discontinuing all systemic immunosuppressive therapy by two years post-randomization is described. Death is considered a competing risk for this endpoint.

  7. Prednisone Dose [ Time Frame: Baseline, 6 months, and 1 year post-randomization ]
    Daily dose of prednisone is described by treatment arm at baseline, 6 months, and 1 year post-randomization.

  8. Change in Prednisone Dose From Baseline [ Time Frame: 6 months and 1 year post-randomization ]
    Change in the daily dose of prednisone from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization.

  9. Serum Creatinine Level [ Time Frame: Baseline, 6 months, and 1 year post-randomization ]
    Creatinine level is described by treatment arm at baseline, 6 months, and 1 year post-randomization.

  10. Change in Serum Creatinine Level From Baseline [ Time Frame: 6 months and 1 year post-randomization ]
    Change in creatinine level from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization.

  11. Patient-reported Chronic GVHD Severity [ Time Frame: Baseline, 6 months, 1 year, and 2 years post-randomization ]
    Each patient's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe.

  12. Provider-reported Chronic GVHD Severity [ Time Frame: Baseline, 6 months, 1 year, and 2 years post-randomization ]
    Each patient's care provider's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe.

  13. NIH Consensus Criteria Chronic GVHD Severity [ Time Frame: Baseline, 6 months, 1 year, and 2 years post-randomization ]
    Chronic GVHD severity was determined at baseline and at 6 months, 1 year, and 2 years post-randomization per the 2005 NIH Consensus Criteria (Filipovich et al. 2005). Severity is categorized as none, mild, moderate, and severe.

  14. SF-36 Physical Component Summary [ Time Frame: Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization ]
    The Medical Outcome Study SF-36 Physical Component Summary (PCS) is a subscale of the SF-36 intended to measure physical well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.

  15. SF-36 Mental Component Summary [ Time Frame: Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization ]
    The Medical Outcome Study SF-36 Mental Component Summary (MCS) is a subscale of the SF-36 intended to measure mental well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.

  16. FACT-BMT Score [ Time Frame: Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization ]
    The Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale (FACT-BMT) is a quality of life instrument that assesses the effects of bone marrow transplantation (BMT) on a patient's physical, social/family, emotional, and functional well-being while taking into consideration BMT-specific concerns. The assessment has 37 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-148, with higher scores indicating higher levels of overall well-being.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Suitable candidates are patients with classic chronic GVHD or overlap syndrome (classic chronic plus acute GVHD)that is: a)Previously untreated (newly diagnosed) as defined by having received < 14 days of prednisone (or equivalent) before enrollment/randomization to study therapy; b)Previously treated but inadequately responding after ≤ 16 weeks of initial therapy with prednisone and/or calcineurin inhibitor (CNI) ± additional non-sirolimus agent (started at the time of chronic GVHD diagnosis).
  • Patient or guardian willing and able to provide informed consent.
  • Stated willingness to use contraception in women of childbearing potential.
  • Stated willingness of patient to comply with study procedures and reporting requirements.

Exclusion Criteria:

  • Patients with late persistent acute GVHD or recurrent acute GVHD only.
  • Inability to begin prednisone therapy at a dose of greater than 0.5 mg/kg/day.
  • Receiving sirolimus for treatment of chronic GVHD (sirolimus for prophylaxis or treatment of acute GVHD is acceptable).
  • Already receiving sirolimus (for prophylaxis or treatment of acute GVHD) with prednisone at ≥ 0.25 mg/kg/day (or equivalent) ± additional agents.
  • Receiving therapy for chronic GVHD for more than 16 weeks.
  • Invasive fungal or viral infection not responding to appropriate antifungal or antiviral therapies.
  • Inadequate renal function defined as measured creatinine clearance less than 50 mL/min/1.73 m^2 based on the Cockcroft-Gault formula (adults) or Schwartz formula (age less than or equal to 12 years). Adults: estimated creatinine clearance rate (eCCr) (mL/min/) = (140 - age) x mass (kg) x (0.85 if female)/72 x serum creatinine (mg/dL; Creatinine clearance (mL/min/1.73m^2) = eCCr x 1.73/Body Surface Area (BSA) (m^2); Children: eCCr (mL/min/1.73 m^2) = k x height (cm) / serum creatinine (mg/dL) k = 0.33 (pre-term), 0.45 (full term to 1 year old), 0.55 (age 1-12 years).
  • Inability to tolerate oral medications.
  • Absolute neutrophil count less than 1500 per microliter.
  • Requirement for platelet transfusions.
  • Pregnancy (positive serum β-HCG) or breastfeeding.
  • Receiving any treatment for persistent, progressive or recurrent malignancy.
  • Progressive or recurrent malignancy defined other than by quantitative molecular assays.
  • Known hypersensitivity to sirolimus.

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): NCT01106833


  Show 31 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Investigators
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
  Study Documents (Full-Text)

Documents provided by Medical College of Wisconsin:
Study Protocol  [PDF] July 9, 2012
Statistical Analysis Plan  [PDF] May 20, 2016


Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01106833     History of Changes
Other Study ID Numbers: BMTCTN0801
U01HL069294 ( U.S. NIH Grant/Contract )
BMT CTN 0801 ( Other Identifier: Blood and Marrow Transplant Clinical Trials Network )
U01HL06929406 ( Other Grant/Funding Number: National Cancer Institute (NCI) )
5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted: April 20, 2010    Key Record Dates
Results First Posted: August 14, 2018
Last Update Posted: September 14, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/

Keywords provided by Medical College of Wisconsin:
Chronic Graft-versus-Host Disease (cGVHD)

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Prednisone
Sirolimus
Everolimus
Calcineurin Inhibitors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action