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

This study has been terminated.
(Due to inability to meet accrual goals within the funding period)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01278745
First Posted: January 19, 2011
Last Update Posted: April 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Trials in Organ Transplantation
Genentech, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
January 16, 2011
January 19, 2011
December 1, 2016
April 11, 2017
April 11, 2017
September 2011
October 2015   (Final data collection date for primary outcome measure)
Change in Percent Atheroma Volume (PAV) [ Time Frame: Baseline, 1 year ]
Nominal or noticeable change, bad or good, from baseline to 1 year in percent atheroma volume (PAV) which is a measure of the degree of coronary arterial obstruction due to host alloimmune processes measured by intravascular ultrasound (IVUS) in a target coronary artery. Thus a decrease in PAV would be an indicator of less obstruction and a better outcome.
Nominal change from baseline to 1 year in percent atheroma volume measured by intravascular ultrasound [ Time Frame: 1 year ]
Complete list of historical versions of study NCT01278745 on ClinicalTrials.gov Archive Site
  • Death [ Time Frame: 12 months ]
    Participants who died within 12 months post-transplant
  • Re-transplantation or Re-listed for Transplantation [ Time Frame: 6 to 12 months ]
    Re-transplantation is defined as the receipt of a subsequent heart transplant and re-listed for transplantation is being listed back on the heart transplant list to be re-transplanted.
  • Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant [ Time Frame: 6 to 12 months ]
    The number of times a participant experienced biopsy proven acute rejection (BPAR). Biopsy proven acute rejection is when an examination of tissue removed from the transplanted organ indicates that the subject's immune system is trying to reject the graft. BPAR was defined as a biopsy that met the International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory.
  • Incidence of BPAR (Any Grade) [ Time Frame: 6 to 12 months ]
    The number of subjects who experienced any grade of biopsy proven acute rejection (BPAR) within the clinical trial. Biopsy proven acute rejection is when an examination of tissue removed from the transplanted organ indicates that the subject's immune system is trying to reject the graft. BPAR was defined as a biopsy which met The International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory.
  • Incidence of AMR [ Time Frame: 6 to 12 months ]
    The number of participants who experienced antibody- mediated rejection (AMR). Antibody-mediated rejection (AMR) occurs when the subject develops antibodies directed against the transplanted heart. This was assessed based on local pathology biopsy reads.
  • Incidence of Cellular Rejection [ Time Frame: 6 to 12 months ]
    Cellular Rejection refers to the organ recipient's immune system recognizing a transplanted organ as foreign and mounting a response to it via cellular mechanisms. Cellular rejection was defined as a biopsy which met The International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory
  • Incidence of Any Treated Rejection [ Time Frame: 6 to 12 months ]
    The number of participants who were treated by their local physician for any type of rejection including, but not limited to cellular rejection and antibody- mediated rejection (AMR) of the transplanted heart regardless of the presence of a biopsy.
  • Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC) [ Time Frame: 6 to 12 months ]
    The number of participants that experienced at least one episode of rejection associated with hemodynamic compromise (HDC). Rejection associated with HDC is when there is insufficient blood flow to the transplanted heart in association with acute rejection found in a biopsy. Local biopsies were used for this outcome measure.
  • Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy [ Time Frame: 1 year ]
    Cardiac allograft vasculopathy is an aggressive form of atherosclerosis that is characterized by the development of fibrosis affecting cardiac arteries that result in concentric narrowing of the arteries and, ultimately allograft failure. Development of cardiac allograft vasculopathy can be diagnosed via an angiograph which is an X-ray of the cardiac arteries by injecting a radiopaque substance such as iodine.
  • Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy [ Time Frame: Transplantation through end of study, up to 1 year post transplantation. ]
    Number of participants experiencing at least one serious infection requiring intravenous antimicrobial therapy which is used to kill the growth of microorganisms such as bacteria, fungi, or protozoans.
  • Number of Participants With Post-transplant Incidence of PTLD [ Time Frame: Transplantation through end of study, up to 1 year post transplantation. ]
    The number of participants experiencing at least one post-transplant lymphoproliferative disorder (PTLD) occurrence during this trial. Post-transplant lymphoproliferative disorder is an uncontrolled proliferation of B cell lymphocytes latently infected with Epstein-Barr virus.
  • Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab [ Time Frame: Transplantation through end of study, up to 1 year post transplantation ]
    Defined as participants that experienced at least one adverse event that was possibly, probably, or definitely related to the study drug (i.e., Rituximab or Placebo). Serious adverse events were used to evaluate this endpoint and the attribution was based on the DAIT Medical Monitor's assessment.
  • Post-transplant outcomes [ Time Frame: 6 months and 12 months post-transplant ]
    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 ]
  • Post-transplant safety outcomes [ Time Frame: up to 12 months ]
    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 ]
  • Complement binding antibody [ Time Frame: 12 months ]
  • B cell depletion and recovery profile [ Time Frame: 12 months ]
  • Measure indirect alloreactivity to donor HLA peptides in human heart transplant recipients using both fresh and frozen PBLs [ Time Frame: 12 months ]
  • 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 ]
  • 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 ]
  • Histological changes of antibody mediated rejection [ Time Frame: 12 months ]
Not Provided
Not Provided
 
Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation
Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation (CTOT-11)
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 (Rituxan®) 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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Cardiac Allograft Vasculopathy
  • Heart Transplant Recipients
  • Biological: Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
  • Drug: Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
  • Experimental: Rituximab
    Rituximab induction/conventional immunosuppression
    Intervention: Biological: Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
  • Placebo Comparator: Rituximab Placebo
    Rituximab Placebo / conventional immunosuppression
    Intervention: Drug: Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
362
October 2015
October 2015   (Final data collection date for primary outcome measure)

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 (e.g., listed for heart transplant only);
  • Historical panel reactive antibodies (PRA) less than 30%;
  • 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:

  • One Lambda's LABScreen® Mixed Class I & II (presence or absence), or
  • Less than 10% by One Lambda's LABScreen® PRA Class I and II with an MFI of <2000, or
  • Calculated panel reactive antibodies (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 CKD-EPI at time of randomization;
  • Serum immunoglobulin G (IgG) 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;
  • Previous treatment with Rituximab (MabThera® / Rituxan ®);
  • Transplant physician 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;
  • Active systemic infection at time of enrollment;
  • Any history of serologic positivity to HIV, HBsAg, HBcAb, and HCV Ab;
  • History of less than 5 years remission of malignancy. Any history of adequately treated in-situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of the skin will be permitted;
  • 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.
Sexes Eligible for Study: All
18 Years to 75 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01278745
DAIT CTOT-11
Yes
Not Provided
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Clinical Trials in Organ Transplantation
  • Genentech, Inc.
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
National Institute of Allergy and Infectious Diseases (NIAID)
February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP