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

August 12, 2020 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
362

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Beverly Hills, California, United States, 90211
        • Cedars Sinai Heart Institute
      • Los Angeles, California, United States, 90095
        • Ronald Regan UCLA Medical Center
      • Palo Alto, California, United States, 94304
        • Stanford University/Palo Alto VA
      • San Francisco, California, United States, 94143-0124
        • University of California San Francisco
      • Stanford, California, United States, 94305
        • Stanford University
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern University
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Brigham and Women's Hospital
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota
      • Minneapolis, Minnesota, United States, 55407
        • Minneapolis Heart Institute
    • New York
      • New York, New York, United States, 10029
        • Mount Sinai School of Medicine
      • New York, New York, United States, 10032'
        • Columbia University Medical Center
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Foundation
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19102
        • Drexel University College of Medicine
      • Pittsburgh, Pennsylvania, United States, 15212
        • Allegheny General Hospital
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
    • Texas
      • Dallas, Texas, United States, 75230
        • Medical City Dallas Hospital/CRSTI
      • Houston, Texas, United States, 77030
        • The Methodist Hospital
    • Utah
      • Murray, Utah, United States, 84157
        • Intermountain Medical Center
      • Salt Lake City, Utah, United States, 84132-2401
        • University of Utah
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Baseline, 1 year

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Death
Time Frame: 12 months
Participants who died within 12 months post-transplant
12 months
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.
6 to 12 months
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.
6 to 12 months
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.
6 to 12 months
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.
6 to 12 months
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
6 to 12 months
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.
6 to 12 months
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.
6 to 12 months
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.
1 year
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.
Transplantation through end of study, up to 1 year post transplantation.
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.
Transplantation through end of study, up to 1 year post transplantation.
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.
Transplantation through end of study, up to 1 year post transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Rho Federal Systems Division, Inc.
Clinical Trials in Organ Transplantation

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Mohamed Sayegh, MD, Brigham and Women's Hospital/Harvard
  • Study Chair: Anil Chandraker, MD, Brigham and Women's Hospital/Harvard

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2011

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 1, 2015

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 16, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 16, 2011

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 19, 2011

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 25, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 12, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • DAIT CTOT-11

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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