Evaluation of Belatacept as a Non-Nephrotoxic Immunosuppressive Agent in Cardiac Transplant Recipients at Risk of Chronic Kidney Disease

The primary objective of this study is to observe a significant improvement in **glomerular filtration rate (GFR)**, calculated using the CKD-EPI formula, of 20 ml/min between 3 months (M3) and 12 months (M12) post-heart transplant in patients at risk of chronic kidney disease (CKD). These patients are treated with 9 monthly infusions of belatacept, alongside a progressive reduction in calcineurin inhibitors. This objective is clinically relevant as it aims to address the risk of CKD, a common complication in cardiac transplant patients, by utilizing a non-nephrotoxic immunosuppressive regimen.

Secondary objectives include: - Demonstrating that the risk of rejection greater than grade 2 is less than 30% during the first year post-transplant, aligning with literature benchmarks for non-inferiority. - Quantifying the percentage of patients developing New Onset Diabetes After Transplantation (NODAT) at M3 and M12 post-transplant. - Evaluating mortality specific to M12 post-transplant. - Assessing the use of renal replacement therapy between M3 and M12 post-transplant.

The clinical trial involves **cardiac transplant** patients experiencing early graft dysfunction. The study population includes both male and female participants, all over the age of 18, with no specific vulnerable populations selected. The total number of participants is not provided by the sponsor. Participants were selected based on specific criteria, including having undergone a heart transplant for at least three months, possessing a DFG of less than 30 ml/min or a significant decrease in DFG post-transplant, and being EBV positive. Lifestyle factors such as diet and physical activity are not specified. The trial excludes individuals with DSA at D0 and requires participants to have stable renal function for 15 days prior to inclusion. All participants must have signed informed consent and, if of childbearing potential, must have a negative pregnancy test and agree to use effective contraception during and after the study.

The clinical trial is designed to evaluate the efficacy of **belatacept** as a non-nephrotoxic immunosuppressive treatment in cardiac transplant patients at risk of chronic renal failure. This study is a Phase 4, randomized, double-blind, controlled trial. The trial is expected to span approximately seven years, with an estimated recruitment start date of December 18, 2020, and an estimated end date of November 18, 2027. Participants will be involved in the study for a maximum treatment period of nine months, during which they will receive monthly infusions of belatacept. The primary objective is to observe a significant improvement in the glomerular filtration rate (GFR) of 20 ml/min between three months (M3) and twelve months (M12) post-transplantation, calculated using the CKD-EPI formula.

Study visits are structured to include an initial screening visit, followed by regular follow-up visits, and a final end-of-study visit. The inclusion visit will assess eligibility based on criteria such as being a cardiac transplant patient for three months, over 18 years of age, and having a GFR of less than 30 ml/min or a significant decrease in GFR post-transplantation. Follow-up visits will occur monthly to monitor the primary endpoint, which involves determining plasma creatinine levels and calculating clearance at M3 and M12. Secondary endpoints include myocardial biopsies, anti-HLA antibody testing, fasting blood glucose, HbA1c levels, and the number of dialysis sessions between M3 and M12. The end-of-study visit will conclude the participant's involvement, provided there are no conditions necessitating early termination, such as adverse events or withdrawal of consent.

Participants are expected to adhere to the study protocol, including the use of effective contraception for those of childbearing potential, and must not have any difficulty in understanding or communicating with the study team. Conditions that may lead to early termination from the study include the development of significant adverse effects, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of belatacept in reducing nephrotoxicity in cardiac transplant patients, thereby improving long-term renal outcomes.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The **experimental medication** is **NULOJIX** (belatacept), which is provided as a 250 mg powder for concentrate for solution for infusion. This medication is administered via **intravenous infusion**. The dosing schedule involves a maximum daily dose of 6 mg/kg, with a total maximum dose of 54 mg/kg over a treatment period of 9 months. The primary objective of using belatacept is to serve as a non-nephrotoxic immunosuppressive treatment in cardiac transplant patients at risk of chronic renal failure.

In addition to the experimental treatment, the trial includes the use of **Advagraf** (tacrolimus) 5 mg prolonged-release hard capsules. This medication is administered orally, with a maximum daily dose of 5 mg and a total maximum dose of 877.5 mg over an 11-month period. Advagraf is used as part of the standard immunosuppressive regimen in transplant patients.

Another non-experimental treatment used in the study is **PROGRAF** (tacrolimus) 5 mg capsules, also administered orally. The maximum daily dose for PROGRAF is 10 mg, with a total maximum dose of 1755 mg over the same 11-month period. This medication is part of the standard-of-care therapy for transplant patients.

Additionally, **Neoral** (ciclosporin) 100 mg soft capsules are included in the trial. This medication is administered orally, with a maximum daily dose of 200 mg and a total maximum dose of 36000 mg over 11 months. Neoral is used as a comparator treatment in the study to evaluate the efficacy and safety of the experimental medication.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the impact of belatacept on renal function in cardiac transplant patients, with a focus on improving clearance rates as calculated by the CKD EPI formula.

Efficacy in this clinical trial will be assessed primarily through the determination of plasma creatinine levels and the calculation of **glomerular filtration rate (GFR)** using the CKD EPI formula at months 3 (M3) and 12 (M12) post-heart transplant (HT). This primary endpoint aims to observe a significant improvement in GFR of 20 ml/min between these timepoints in cardiac transplant patients at risk of chronic kidney disease (CKD), treated with belatacept and a progressive decrease in calcineurin inhibitors.

Secondary endpoints include myocardial biopsies conducted between M3 and M12 post-HT, anti-HLA antibody testing according to the standard practices of heart transplant centers, and measurements of fasting blood glucose and HBA1C at M3 and M12 post-HT. Additionally, the trial will monitor the occurrence of death and the number of dialysis sessions required between M3 and M12 post-HT. These assessments will provide a comprehensive evaluation of the treatment's efficacy in improving renal function and overall patient outcomes.