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Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation

This study has been terminated.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01278745
First received: January 16, 2011
Last updated: August 18, 2014
Last verified: August 2014
  Purpose

All people who have a heart transplant are at risk for developing cardiac allograft vasculopathy (CAV). CAV means narrowing of the heart transplant vessels, which is associated with poor heart transplant function. People who develop antibodies after transplant have a higher risk of developing CAV. Infections, high cholesterol, and rejection also increase the risk of developing CAV. People who develop CAV usually have to receive another transplant. The purpose of this research study is to see if a study drug called Rituximab prevents CAV. Rituximab destroys certain types of white blood cells called B cells. B cells are important cells in the immune system that help the body fight infection by producing substances called antibodies. B cells and the antibodies they produce are also involved in some kinds of rejection after organ transplantation. Rituximab decreases the number of B cells in the blood and other tissues. The goal of this study is to determine if decreasing B cells with Rituximab can prevent injury to the transplanted heart.


Condition Intervention Phase
Cardiac Allograft Vasculopathy
Biological: Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
Drug: Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation (CTOT-11)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Nominal change from baseline to 1 year in percent atheroma volume measured by intravascular ultrasound [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Post-transplant outcomes [ Time Frame: 6 months and 12 months post-transplant ] [ Designated as safety issue: Yes ]
    Outcomes include death, re-transplantation or re-listed for transplantation, number of episodes of biopsy proven acute rejection (BPAR) of any grade per subject, incidence of BPAR (any grade), Incidence of AMR, incidence of cellular rejection, incidence of any treated rejection, episodes of rejection associated with hemodynamic compromise (HDC)

  • Development of angiographically evident cardiac allograft vasculopathy [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
  • Post-transplant safety outcomes [ Time Frame: up to 12 months ] [ Designated as safety issue: Yes ]
    Serious infections requiring intravenous antimicrobial therapy, incidence of post-transplant lymphoproliferative disorder (PTLD), safety and tolerability of Rituximab

  • Development of post-transplant anti-HLA antibodies, including donor specific antibody [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Complement binding antibody [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • B cell depletion and recovery profile [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Measure indirect alloreactivity to donor HLA peptides in human heart transplant recipients using both fresh and frozen PBLs [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Develop a set of surrogate biomarkers of cellular, humoral, and molecular assays to monitor development of or protection from chronic allograft dysfunction, and explore mechanisms of action of novel therapies in humans [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Total atheroma volume change in average maximal intimal thickness, percentage of subjects with rapidly progressive CAV ≥0.5 mm in the first year [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Histological changes of antibody mediated rejection [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 163
Study Start Date: September 2011
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab
Rituximab induction/conventional immunosuppression
Biological: Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
Placebo Comparator: Rituximab Placebo
Rituximab Placebo / conventional immunosuppression
Drug: Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Initial Enrollment:

  • Subject must be able to understand and provide informed consent;
  • Male or Female, 18 to 75 years of age;
  • Candidate for a primary heart transplant;
  • All previous PRA testing <30%LABScreen® PRA Class I and II with an MFI of <2000 or less than 10% by LABScreen® Single Antigen with an MFI <2000 at the time of transplant (Local HLA Center Testing);
  • Calculated GFR >40 mL/minute using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) ;
  • Female and male subjects with reproductive potential, must agree to use FDA approved methods of birth control for the duration of the study

Inclusion Criteria for Randomization / Post-transplant:

  • Negative PRA within 12 weeks prior to transplant (Local HLA Center Testing) using one of the following:

    1. One Lambda's LABScreen® Mixed Class I & II, or
    2. Less than 10% by One Lambda's LABScreen® PRA Class I and II with an MFI of <2000, or
    3. cPRA less than 10% by LABScreen® Single Antigen testing (Anti-HLA-A, B, DR, DQ). The antigens reported will include those with an MFI >2000.

      The Luminex Gen-Probe beads are equivalent to the One Lambda and may be used as an alternative ;

  • Calculated GFR >40mL/minute using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) at time of randomization ;
  • Serum IgG Immunoglobulin level greater than 500mg/dL within 90 days prior to randomization;
  • Negative test for HIV, HBsAg, HBcAb, and HCV Ab within 12 months prior to transplant. If documentation is not present to support that the testing was performed in the past 12 months, then a blood sample will be collected prior to transplant and sent for local testing. Results may be available after randomization. If positive result, the oversight committee will review the case and provide further recommendations.
  • Female subjects of childbearing potential must have a negative pregnancy test.

Exclusion Criteria for Enrollment:

  • Prior history of organ transplantation- Prior history of organ transplantation;
  • Previous treatment with Rituximab (MabThera® / Rituxan ®);
  • Intention to use any induction agents;
  • History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
  • History of severe reaction to previous therapy with IVIG;
  • Lack of IV venous access;
  • Active systemic infection at time of enrollment;
  • Any history of Serologic positivity to HIV, HBsAg, HBcAb, and HCV Ab;
  • History of malignancy except adequately treated in-situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of the skin;
  • Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements;
  • Use of other investigational drugs within 4 weeks of enrollment;
  • Currently breast-feeding or plans to become pregnant during the timeframe of the study follow-up period.

Exclusion Criteria for Randomization/Post-transplant:

  • Recipient of multiple solid organ or tissue transplants;
  • Previous treatment with Rituximab (MabThera® / Rituxan ®);
  • Use of any induction agents;
  • History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
  • History of severe reaction to previous therapy with IVIG;
  • Lack of IV venous access;
  • Active systemic infection at time of randomization;
  • Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
  • Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements;
  • Use of other investigational drugs within 4 weeks prior to randomization;
  • Receipt of a live vaccine within 30 days prior to randomization;
  • Currently breast-feeding or plans to become pregnant during the timeframe of the study follow-up period.
  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: NCT01278745

  Show 26 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Randall Starling, MD The Cleveland Clinic
Principal Investigator: Mohamed Sayegh, MD Brigham and Women's Hospital/Harvard
Study Chair: Anil Chandraker, MD Brigham and Women's Hospital/Harvard
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01278745     History of Changes
Other Study ID Numbers: DAIT CTOT-11
Study First Received: January 16, 2011
Last Updated: August 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Vascular Diseases
Cardiovascular Diseases
Rituximab
Tacrolimus
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014