Efficacy of Belatacept Versus Tacrolimus in Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients with De Novo Donor-Specific Antibodies

The primary objective of this study is to evaluate the **efficacy** of belatacept combined with standard of care, compared to tacrolimus combined with standard of care, in kidney transplant recipients with active subclinical antibody-mediated rejection (sABMR) detected on initial biopsy. This is clinically relevant as it aims to improve outcomes in patients with subclinical de novo donor-specific antibodies (dnDSA), potentially enhancing graft survival and patient health post-transplantation.

Secondary objectives include comparing both randomized arms in terms of:

• The Banff 2019 classification criteria on 12-month biopsy
• The estimated glomerular filtration rate (eGFR) at 12 and 36 months
• The proteinuria/creatinuria ratio at 12 and 36 months
• The bad features on 12-month biopsy (cg>1)
• The rate of T cell mediated rejection during the first year of treatment
• The evolution of mean fluorescence intensity (MFI) of de novo DSA at 12 and 36 months
• The tolerance to treatment
• The graft and patient survival at 12 and 36 months
• Comparing patient groups formed at the initial biopsy with respect to eGFR and proteinuria/creatinuria ratio at 36 months
• Comparing patient groups formed at the initial biopsy with respect to graft and patient survival at 12 and 36 months
• Estimation of sABMR incidence at 12 months among patients without sABMR on the initial biopsy (group 1)

The clinical trial involves participants who are **kidney transplant** recipients, specifically adults with active subclinical antibody mediated rejection (sABMR) detected on initial biopsy. The study population includes both male and female subjects, with an age range encompassing young adults to older adults. Participants were selected based on the presence of de novo donor specific antibodies (dnDSA) absent at the time of kidney transplantation and no clinical graft dysfunction at the time of DSA detection. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **belatacept** in combination with standard care compared to **tacrolimus** combined with standard care in kidney transplant recipients with active subclinical antibody-mediated rejection (sABMR). This is a randomized, double-blind, controlled trial with an estimated duration of 12 months for each participant. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as being an adult kidney transplant recipient with de novo donor-specific antibodies (dnDSA) absent at the time of transplantation. Participants will be randomized if they meet the inclusion criteria, including having active sABMR according to the Banff 2019 classification.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor their health status and treatment efficacy. These visits will include assessments such as serum creatinine levels, eGFR calculations, and proteinuria/creatininuria ratios at 12 and 36 months post-biopsy. The primary endpoint is the proportion of patients in each arm with a decrease in eGFR greater than 20% at 12 months post-biopsy or other adverse outcomes such as graft loss or death. Secondary endpoints include the comparison of Banff 2019 elementary lesions, acute T cell rejection rates, and adverse events such as viral infections and cardiovascular events.

The expected length of participant involvement is up to 12 months, with conditions for early termination including significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide valuable insights into the management of sABMR in kidney transplant recipients, with the potential to improve long-term outcomes for this patient population.

The clinical trial involves the administration of two primary treatments. The first treatment is **Advagraf**, which contains the active substance **tacrolimus**. This medication is provided in the form of **prolonged-release hard capsules**. Each capsule contains 0.5 mg of tacrolimus. The route of administration is **oral**, and the dosage is calculated based on the participant's body weight, with a maximum daily dose of 0.3 mg/kg. The total maximum dose over the treatment period is 109.5 mg/kg. The treatment period for Advagraf is up to 12 months. Tacrolimus is a chemical substance, and its role in the trial is as a comparator to evaluate its efficacy in combination with standard care for kidney transplant recipients.

The second treatment is **NULOJIX**, which contains the active substance **belatacept**. This medication is provided as a **powder for concentrate for solution for infusion**. Each vial contains 250 mg of belatacept. The route of administration is **intravenous injection**, and the dosage is also based on the participant's body weight, with a maximum daily dose of 6 mg/kg. The total maximum dose over the treatment period is 2190 mg/kg. The treatment period for NULOJIX is also up to 12 months. Belatacept is a protein-based substance, and its role in the trial is as the test treatment to assess its efficacy in combination with standard care for the same patient population.

Both treatments are administered in conjunction with standard-of-care therapy, which is not specified in the trial data. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to compare the efficacy of belatacept and tacrolimus in managing subclinical antibody-mediated rejection in kidney transplant recipients.

The efficacy of the clinical trial will be assessed by comparing the outcomes of two treatment arms: belatacept combined with standard care and **tacrolimus** combined with standard care, in kidney transplant recipients with active subclinical antibody-mediated rejection (sABMR). The primary endpoint for efficacy evaluation is the proportion of patients in each arm who, at 12 months post-biopsy, experience a decrease in estimated glomerular filtration rate (eGFR) greater than 20% according to the CKD-EPI formula, exhibit adverse features on the 12-month protocol biopsy (cg > 1), have chronic active antibody-mediated rejection as per the Banff 2019 classification, show less than 50% reduction in mean fluorescence intensity (MFI) of donor-specific antibodies (DSA), or have a proteinuria/creatininuria ratio greater than 0.5 g/g, as well as instances of death or graft loss.

Secondary endpoints include a comprehensive comparison of both treatment arms regarding all Banff 2019 elementary lesions observed in kidney graft biopsies at 12 months post-biopsy, serum creatinine levels, and eGFR calculations at 12 and 36 months post-biopsy, proteinuria/creatininuria ratios at the same time points, and biopsy-proven acute T cell rejection rates. Additionally, the MFI of DSA will be measured using the Luminex single antigen assay at 12 months post-randomization and at 36 months from medical charts. Adverse events, including occurrences of BK virus, CMV, and EBV viremia, cardiovascular events, and hospitalizations, will also be collected. Graft loss and death rates will be monitored at 12 and 36 months post-biopsy. The trial will also compare groups based on initial biopsy results concerning serum creatinine, eGFR, proteinuria/creatininuria ratios, graft loss, and death rates, as well as the number of patients with sABMR according to the Banff 2019 classification on biopsies performed at 12 months or earlier.