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.
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.
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;
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 400 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).