BELASBRIDGE : Belatacept as a replacement for CNIs 3 to 12 months post-transplantation in patients with early graft dysfunction

The primary objective of this study is to evaluate the **feasibility** of transiently replacing calcineurin inhibitors (CNIs) with **belatacept** for a period of 9 months, specifically from 3 to 12 months post-transplantation, in renal transplant patients experiencing early graft dysfunction. This objective is clinically relevant as it explores a potential therapeutic strategy to improve graft function and patient outcomes by reducing the nephrotoxic effects associated with long-term CNI use.

Secondary objectives include:

• Assessing the efficacy of belatacept treatment on renal function and the prevention of rejection episodes.
• Evaluating the tolerance of treatments, specifically belatacept during phase 1 and CNIs during phase 2.
• Estimating the cost of management from a societal perspective over a 15-month period and comparing it with theoretical arms receiving continuous belatacept or CNIs.
• Evaluating the evolution of quality of life during the 15 months of follow-up and comparing it to theoretical arms receiving continuous belatacept or CNIs.
• Assessing the differential impact of CNIs and belatacept on immune system cell populations.
• Assessing the differential impact of CNIs and belatacept on the anti-cytomegalovirus (CMV) cellular immune response.

The clinical trial involves participants who have undergone a **kidney transplant** and are experiencing early graft dysfunction. The study population includes both male and female adults over the age of 18, with no specific vulnerable populations selected. Participants are required to have a renal function estimated by CKD-EPI creatinine clearance of less than 30 ml/min/1.73m². The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants must have received a kidney from a deceased or living donor with ABO compatibility and must not have any contraindications to a graft biopsy at 10 weeks post-transplant. They are required to be on maintenance treatment with CNI/MPA with or without prednisone. Key lifestyle considerations include the requirement for participants to be EBV seropositive and, for those of childbearing potential, to have a negative pregnancy test and agree to use effective contraception throughout the study. The trial population was selected based on these criteria, ensuring that participants can understand and communicate effectively with the investigators and are affiliated with the French social security system or are beneficiaries of such a system.

The clinical trial is designed to evaluate the feasibility of replacing calcineurin inhibitors (CNIs) with **belatacept** in patients who have undergone a kidney transplant and exhibit early graft dysfunction. This is a Phase 4, randomized, double-blind, controlled trial with an estimated duration of 15 months, including a 9-month treatment period with belatacept. The trial will commence with a screening visit to assess eligibility based on specific inclusion criteria, such as age over 18, renal function, and seropositivity for Epstein-Barr virus (EBV). Participants must also provide informed consent and meet other health-related criteria.

Following the screening, eligible participants will be randomized to receive either the investigational product, **NULOJIX** 250 mg powder for concentrate for solution for infusion, or continue with their current CNI regimen. The primary endpoint is the feasibility of reintroducing CNIs, assessed by preserved renal function and good tolerance at 6 months post-reintroduction. Secondary endpoints include monitoring renal function, recording rejection events, and evaluating quality of life over the 15-month follow-up period.

Study visits are scheduled at baseline, and then at 3, 6, 9, and 15 months to collect data on renal function, adverse events, and quality of life. The end-of-study visit will occur at 15 months, marking the conclusion of participant involvement. Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide insights into the potential benefits and risks of using belatacept as a CNI replacement in this patient population.

The clinical trial involves the administration of **NULOJIX**, a pharmaceutical product containing the active substance **belatacept**. NULOJIX is formulated as a **powder for concentrate for solution for infusion** and is intended for intravenous infusion. The product is manufactured by Bristol-Myers Squibb Pharma EEIG. The active substance, belatacept, is a protein of non-human origin, classified under the ATC code L04AA28. The maximum daily dose of belatacept is 5 mg/kg, with a total maximum dose of 55 mg/kg over the treatment period. The treatment duration is set for a maximum of 9 months, specifically from 3 to 12 months post-transplantation, targeting patients with early graft dysfunction. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In this study, belatacept is used as a replacement for calcineurin inhibitors (CNIs) in renal transplant patients. The trial aims to evaluate the feasibility of this replacement therapy. No additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The focus is on assessing the effects of belatacept as a standalone intervention within the defined treatment window. Compliance with the administration protocol is critical to the study's success, and measures are in place to monitor and ensure participant adherence to the prescribed dosing schedule.

Efficacy in the clinical trial titled "BELASBRIDGE: Belatacept as a replacement for CNIs 3 to 12 months post-transplantation in patients with early graft dysfunction" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the feasibility of reintroducing calcineurin inhibitors (CNIs) by evaluating preserved renal function and good tolerance at 6 months post-reintroduction, which corresponds to a 15-month follow-up period. Renal function will be considered preserved if the creatinine clearance, as measured by the CKD-EPI formula, does not decrease by more than 25% after discontinuation of **belatacept**. Good tolerance is defined by the absence of complications that necessitate discontinuation of the treatment.

Secondary endpoints include longitudinal monitoring of renal function at months 0, 3, 6, and 9, and the collection of rejection events. Additionally, the trial will collect data on infectious episodes and neoplasia, as well as the number of care resources consumed, including drugs, hospitalizations, transport, consultations, biological procedures, medical procedures, and possible home help, along with associated costs over the 15-month follow-up. Quality of life scores will be measured using the generic EQ-5D scale every 3 months for 15 months, and quality of life data from the literature will be collected for comparison. Furthermore, differential analysis of cell populations and the anti-CMV cellular immune response will be conducted before and after belatacept discontinuation using standardized flow cytometry combined with unbiased analysis.