CTOT-11

Overview

Status: Recruiting
Keywords: Heart Transplant , Heart Failure , Rituximab , Transplant
IRB Number: 00049937
Specialty: Cardiology, Cardiology, Cardiology
Sub Specialties: Heart Failure, Heart Transplant

Brief Summary

Primary Objective:
 
To determine the cumulative impact of rituximab on the development of coronary allograft vasculopathy (CAV) in heart transplant recipients in the first year post transplant. Using intravascular ultrasound a volumetric measure of CAV will be obtained and quantified by a core lab to compare CAV development in patients treated with rituximab and placebo.
 

 
Primary Endpoint:
 
The primary endpoint will be the nominal change from baseline to 1 year in percent atheroma volume (PAV) measured by IVUS in a target coronary artery.
 

 
Secondary Objectives:
 
To determine whether rituximab treatment is associated with measurable changes in the phenotype of T cells (effector/memory and Tregs), T cell alloreactivity, humoral alloimmunity, phenotypic differentiation of T and B cells, as well as molecular mediators of acute and chronic allograft dysfunction in cardiac transplant recipients; this insight will facilitate the understanding of the mechanism of rituximab to reduce the development of coronary artery vasculopathy and facilitate the development of novel biomarkers to predict short and long term clinical outcomes.
 

 
Secondary Endpoints - Clinical
 
The following secondary clinical endpoints will be assessed:
 

 
(1) Post-transplant outcomes at 6 and 12 months including;
 
a. Death,
 
b. Re-transplantation or re-listed for transplantation,
 
c. Number of episodes of biopsy proven acute rejection (BPAR) of any grade per subject,
 
d. Incidence of BPAR (any grade),
 
e. Incidence of AMR,
 
f. Incidence of Cellular Rejection,
 
g. Incidence of any treated rejection,
 
h. Episodes of rejection associated with hemodynamic compromise (HDC).
 

 
(2) Development of angiographically evident cardiac allograft vasculopathy at 1 year;
 

 
(3) Post-transplant safety outcomes including;
 
a. Serious infections requiring intravenous antimicrobial therapy,
 
b. Incidence of PTLD,
 
c. Safety and tolerability of Rituximab.
 

 
Secondary Endpoints - Mechanistic
 
The following secondary mechanistic endpoints will be assessed:
 
(1) Development of post-transplant anti-HLA antibodies, including DSA (Anti-HLA Ab by Luminex TM );
 
(2) Complement binding antibody (Luminex TM );
 
(3) B cell depletion and recovery profile (Lineage Specific Markers- Intragraft and peripheral B cells);
 
(4) To measure indirect alloreactivity to donor HLA peptides in human heart transplant recipients using both
 
fresh and frozen PBLs (ELISPOT- Indirect);
 
(5) To 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 (Gene Expression- Intragraft and PBLs);
 
(6) Total atheroma volume (TAV), change in average maximal intimal thickness (MIT), percentage of subjects
 
with rapidly progressive CAV (change in maximal intimal thickness) ≥0.5 mm in the first year (IVUS);
 
(7) Histological changes of Antibody Mediated Rejection (Immunohistochemistry).
 

 
Study Design / Treatment Description
 
This is a phase 2, prospective, multi-center, randomized, placebo-controlled clinical trial in which 300 primary heart transplant recipients with a PRA of <10% will be randomized (1:1) to placebo (IV day 0 and 12 post-transplant) plus conventional immunosuppression (tacrolimus, MMF and steroid taper) versus induction therapy
 
with anti-CD20 mAb (1gm IV on day 0 and day 12 post-transplant) plus conventional immunosuppression (tacrolimus, MMF, and steroid taper).
 

Principal Investigator: Josef Stehlik
Department: Cardiology
Co Investigator: Stavros Drakos
Co Investigator: Jose Nativi-Nicolau
Co Investigator: Edward Gilbert

Contact Information

Name:Melissa Whipple
Phone: 801-587-9048
Email: melissa.whipple@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria- Enrollment
Patients who meet all of the following criteria are eligible for enrollment as study subjects:
1 Subject must be able to understand and provide informed consent;
2 Male or Female, 18 to 75 years of age;
3 Candidate for a primary heart transplant (listed as a heart transplant only);
4 Historical PRA less than 30%;
5 Calculated GFR >40mL/minute using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) at time of enrollment;
6 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 - Randomization
Subjects who meet all of the following criteria are eligible for randomization:
1. Negative PRA within 12 weeks prior to transplant (Local HLA Center Testing) using one of the following:
a. One Lambda’s LABScreen® Mixed Class I & II, or
b. Less than 10% by One Lambda’s LABScreen® PRA Class I and II with an MFI of <2000, or
c. cPRA less than 10% by LABScreen® Single Antigen testing. 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 ;
2. Calculated GFR >40mL/minute using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) at time of randomization ;
3. Serum IgG Immunoglobulin level greater than 500mg/dL within 90 days prior to randomization;
4. 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.
5. Female subjects of childbearing potential must have a negative pregnancy test.

Exclusion Criteria

Exclusion Criteria- Enrollment
Patients who meet any of these criteria are not eligible for enrollment as study subjects:
1. Prior history of organ transplantation;
2. Previous treatment with Rituximab (MabThera® / Rituxan ®);
3. Transplant physician intention to use any induction agents;
4. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
5. History of severe reaction to previous therapy with IVIG;
6. Active systemic infection at time of enrollment;
7. Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
8. History of malignancy less than 5 years in 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;
9. Any condition that, in the opinion of the investigator, would interfere with the subject’s ability to comply with study requirements;
10. Use of other investigational drugs within 4 weeks of enrollment;
11. Currently breast-feeding or plans to become pregnant during the timeframe of the study follow-up period.

Exclusion Criteria- Randomization
Subjects who meet any of these criteria are not eligible for randomization:
1. Recipient of multiple solid organ or tissue transplants;
2. Previous treatment with Rituximab (MabThera® / Rituxan ®);
3. Use of any induction agents;
4. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
5. History of severe reaction to previous therapy with IVIG;
6. Lack of IV venous access;
7. Active systemic infection at time of randomization;
8. Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
9. Any condition that, in the opinion of the investigator, would interfere with the subject’s ability to comply with study requirements;
10. Use of other investigational drugs within 4 weeks prior to randomization;
11. Receipt of a live vaccine within 30 days prior to randomization;
12. Currently breast-feeding or plans to become pregnant during the timeframe of the study follow-up period.