Cardiac Allograft VasculopathyPhase 2NCT01278745
Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation
A Phase 2 study testing Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper) in people with Cardiac Allograft Vasculopathy and Heart Transplant Recipients, run by National Institute of Allergy and Infectious Diseases (NIAID) at 24 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Cardiac Allograft Vasculopathy, Heart Transplant Recipients
- What is being tested?
- Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 362 participants
- Where
- 24 sitesUnited States
- Study dates
- Sep 2011to Oct 2015
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- --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.
Who cannot join
- 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;
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- 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.
- 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.
Trial locations and contacts
24 sites in 1 country.
24 sites in 1 country
United States24 sites
University of Maryland
Baltimore, Maryland, 21201
Cedars Sinai Heart Institute
Beverly Hills, California, 90211
Tufts Medical Center
Boston, Massachusetts, 02111
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Medical University of South Carolina
Charleston, South Carolina, 29425
Northwestern University
Chicago, Illinois, 60611
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Medical City Dallas Hospital/CRSTI
Dallas, Texas, 75230
The Methodist Hospital
Houston, Texas, 77030
Ronald Regan UCLA Medical Center
Los Angeles, California, 90095
University of Wisconsin
Madison, Wisconsin, 53792
Minneapolis Heart Institute
Minneapolis, Minnesota, 55407
University of Minnesota
Minneapolis, Minnesota, 55455
Intermountain Medical Center
Murray, Utah, 84157
Mount Sinai School of Medicine
New York, New York, 10029
Columbia University Medical Center
New York, New York, 10032'
Stanford University/Palo Alto VA
Palo Alto, California, 94304
Drexel University College of Medicine
Philadelphia, Pennsylvania, 19102
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Allegheny General Hospital
Pittsburgh, Pennsylvania, 15212
University of Utah
Salt Lake City, Utah, 84132-2401
University of California San Francisco
San Francisco, California, 94143-0124
Stanford University
Stanford, California, 94305
About this study
Official title: 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.
Read the 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.
- Being tested
- Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper), Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
- Keywords
- cardiac allograft vasculopathy (CAV), prevention, cardiac transplantation, rituximab
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)Biological
Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)Drug
| Study group | Role | What they receive |
|---|---|---|
| Rituximab | Experimental | Rituximab induction/conventional immunosuppression Receives: Biological: Rituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper) |
| Rituximab Placebo | Placebo comparator | Rituximab Placebo / conventional immunosuppression Receives: Drug: Rituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Percent Atheroma Volume (PAV)
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.
Measured: Baseline, 1 year
Secondary outcomes (12)
Death
Participants who died within 12 months post-transplant
Measured: 12 months
Re-transplantation or Re-listed for Transplantation
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.
Measured: 6 to 12 months
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant
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.
Measured: 6 to 12 months
Incidence of BPAR (Any Grade)
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.
Measured: 6 to 12 months
Incidence of AMR
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.
Measured: 6 to 12 months
Incidence of Cellular Rejection
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
Measured: 6 to 12 months
Incidence of Any Treated Rejection
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.
Measured: 6 to 12 months
Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC)
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.
Measured: 6 to 12 months
Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy
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.
Measured: 1 year
Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy
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.
Measured: Transplantation through end of study, up to 1 year post transplantation.
Number of Participants With Post-transplant Incidence of PTLD
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.
Measured: Transplantation through end of study, up to 1 year post transplantation.
Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab
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.
Measured: Transplantation through end of study, up to 1 year post transplantation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jan 2011 (estimated)
- Study startSep 2011
- Primary completionOct 2015
- Study completionOct 2015
Why it stopped: Due to inability to meet accrual goals within the funding period
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cardiac Allograft VasculopathyStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 362 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Clinical Trials in Organ Transplantation, Genentech, Inc., Rho Federal Systems Division, Inc.
- Responsible party
- Sponsor
- Investigators
- Randall Starling, MD, Study chair, The Cleveland ClinicMohamed Sayegh, MD, Principal investigator, Brigham and Women's Hospital/HarvardAnil Chandraker, MD, Study chair, Brigham and Women's Hospital/Harvard
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01278745
- Sponsor's protocol ID
- DAIT CTOT-11
- Status last verified
- Sep 2026
- First submitted
- 16 Jan 2011
- Last updated
- 24 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Starling RC, Armstrong B, Bridges ND, Eisen H, Givertz MM, Kfoury AG, Kobashigawa J, Ikle D, Morrison Y, Pinney S, Stehlik J, Tripathi S, Sayegh MH, Chandraker A; CTOT-11 Study Investigators. Accelerated Allograft Vasculopathy With Rituximab After Cardiac Transplantation. J Am Coll Cardiol. 2019 Jul 9;74(1):36-51. doi: 10.1016/j.jacc.2019.04.056.
PubMed 31272550