Clinical trial NCT01278745: Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation
Official title: Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation (CTOT-11)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cardiac Allograft Vasculopathy
Heart Transplant Recipients
Keywords: cardiac allograft vasculopathy (CAV)
prevention
cardiac transplantation
rituximab
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Clinical Trials in Organ Transplantation
name: Genentech, Inc.
name: Rho Federal Systems Division, Inc.
First posted: 2011-01-19
Enrollment: 362
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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. Infections, high cholesterol, and rejection also increase the risk of developing CAV. People who develop CAV usually have to receive another transplant.

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.

Eligibility 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 (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.

Primary outcomes:
measure: Change in Percent Atheroma Volume (PAV)
timeFrame: Baseline, 1 year
Secondary outcomes:
measure: Death
timeFrame: 12 months
measure: Re-transplantation or Re-listed for Transplantation
timeFrame: 6 to 12 months
measure: Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant
timeFrame: 6 to 12 months
measure: Incidence of BPAR (Any Grade)
timeFrame: 6 to 12 months
measure: Incidence of AMR
timeFrame: 6 to 12 months
measure: Incidence of Cellular Rejection
timeFrame: 6 to 12 months
measure: Incidence of Any Treated Rejection
timeFrame: 6 to 12 months
measure: Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC)
timeFrame: 6 to 12 months
measure: Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy
timeFrame: 1 year
measure: Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy
timeFrame: Transplantation through end of study, up to 1 year post transplantation.
measure: Number of Participants With Post-transplant Incidence of PTLD
timeFrame: Transplantation through end of study, up to 1 year post transplantation.
measure: Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab
timeFrame: Transplantation through end of study, up to 1 year post transplantation
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Cedars Sinai Heart Institute
state: California
city: Los Angeles
country: United States
facility: Ronald Regan UCLA Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford University/Palo Alto VA
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Medical City Dallas Hospital/CRSTI
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: The Cleveland Clinic
name: Randall Starling, MD
role: STUDY_CHAIR
affiliation: Brigham and Women's Hospital/Harvard
name: Mohamed Sayegh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital/Harvard
name: Anil Chandraker, MD
role: STUDY_CHAIR
References:
citation: 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.