INduction in Sensitized kidney Transplant recipients without pre-Existing donor-specific AntiboDies: a randomized multicentre trial between a lymphocyte depleting and basiliximab (INSTEAD)

The primary objective of this study is to demonstrate that **rabbit anti-human thymocyte immunoglobulin (rATG)** is more efficient than **basiliximab** in preventing biopsy-proven acute rejection (BPAR) during the first post-transplantation year in sensitized kidney transplant recipients (KTR) without pre-existing donor-specific antibodies (DSAs). This is clinically relevant as preventing BPAR is crucial for improving graft survival and patient outcomes in kidney transplantation.

Secondary objectives include:

• Demonstrating that rATG is more efficient than basiliximab in preventing BPAR at year 3.
• Evaluating the efficiency of rATG over basiliximab for composite criteria including BPAR, death, and graft loss at year 3.
• Comparing the incidence of T cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR) between rATG and basiliximab groups at year 1 and 3.
• Assessing the incidence of de novo donor-specific antibodies (DSA) in both groups at year 1 and 3.
• Comparing the incidence of cytomegalovirus (CMV) and BK virus (BKv) infections in the two groups at year 1 and 3.
• Evaluating graft function and proteinuria in both groups at various time points up to year 3.
• Comparing the incidence of primary and secondary outcomes in subgroups defined by the rank of transplantation.
• Conducting health-economics analyses to determine the cost-utility and cost-effectiveness of rATG compared to basiliximab in terms of cost per Quality Adjusted Life Year (QALY) gained and cost per prevented BPAR at 12 months.

The clinical trial involves participants diagnosed with **kidney transplant** conditions, aiming to evaluate the efficacy of rATG compared to basiliximab in preventing biopsy-proven acute rejection during the first year post-transplantation in sensitized kidney transplant recipients without pre-existing donor-specific antibodies. The study population includes both male and female subjects, aged between 18 and 79 years. Participants are required to have at least one anti-HLA antibody identified by the Luminex Single Antigen test with a mean fluorescence intensity of 2000 or greater, and a graft incompatibility rate of less than 85%. The trial does not involve a vulnerable population. Participants must be capable of understanding the study's nature and objectives and comply with its requirements, with written informed consent obtained. Additionally, participants should be covered by or entitled to social security. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **rabbit anti-human thymocyte immunoglobulin** (rATG) compared to **basiliximab** in preventing biopsy-proven acute rejection (BPAR) in sensitized kidney transplant recipients without pre-existing donor-specific antibodies. This is a randomized, double-blind, controlled, multicenter trial. The trial is expected to last until March 2029, with recruitment starting in September 2023. Participants will be randomly assigned to receive either rATG or basiliximab, both administered via infusion. The maximum treatment period for rATG is 7 days, while for basiliximab, it is 4 days.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will assess eligibility based on criteria such as age (18-79 years), presence of anti-HLA antibodies, and graft incompatibility rate. Participants must provide written informed consent and be covered by social security. Follow-up visits will occur at specified intervals, including day 10, month 1, month 3, month 6, and annually up to year 3. These visits will evaluate primary and secondary endpoints, including the incidence of BPAR, graft loss, and other health outcomes. The end-of-study visit will conclude the participant's involvement, summarizing their health status and study outcomes.

Participant involvement is expected to last up to 3 years, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study protocols. The trial aims to provide robust data on the comparative effectiveness of rATG and basiliximab, contributing to improved management strategies for kidney transplant recipients.

The clinical trial involves the administration of **THYMOGLOBULINE**, a **rabbit anti-human thymocyte immunoglobulin**, which is provided in the form of a powder for solution for infusion. This experimental medication is manufactured by Genzyme Europe B.V. and is authorized under the marketing authorization number 34009 570 281 8 3. The pharmaceutical form is a solution for infusion, and the route of administration is via infusion. The maximum daily dose is 100 mg, with a total maximum dose of 700 mg over a treatment period of up to 7 days. The active substance is derived from a structurally diverse blood-derived source. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Simulect**, which contains the active substance **basiliximab**. This medication is provided as a powder and solvent for solution for injection or infusion, manufactured by Novartis Europharm Limited, and is authorized under the marketing authorization number EU/1/98/084/001. The pharmaceutical form is a solution for injection/infusion, and the route of administration is also via infusion. The maximum daily dose is 20 mg, with a total maximum dose of 40 mg over a treatment period of up to 4 days. Basiliximab is a protein-based substance. Compliance with the administration schedule will be closely monitored to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed by evaluating the incidence of biopsy-proven acute rejection (BPAR) during the first post-transplantation year in sensitized kidney transplant recipients without pre-existing donor-specific antibodies. The primary endpoint is the incidence of BPAR, including treated suspicious T-cell mediated rejection (TCMR) and confirmed TCMR with grade ≥ 1 and antibody-mediated rejection (ABMR), in the groups receiving **rabbit anti-human thymocyte immunoglobulin** (rATG) and basiliximab. This will be determined after blind central reading according to the Banff 2019 classification.

Secondary endpoints include the incidence of BPAR at year 3, incidence of composite criteria including BPAR, death, and graft loss at year 3, and incidence of confirmed TCMR and ABMR at year 1 and 3. Additional secondary endpoints are the incidence of de novo donor-specific antibodies (DSA), cytomegalovirus (CMV) viremia, CMV disease, BK virus (BKv) viremia, and BKv nephropathy at year 1 and 3. The estimated glomerular filtration rate (eGFR) according to the MDRD formula and proteinuria/creatinuria ratio will be measured at day 10, month 1, month 3, month 6, year 1, year 2, and year 3. Health-economics endpoints will also be evaluated, including the Incremental Cost Utility Ratio (ICUR) and Incremental Cost Effectiveness Ratio (ICER) from the French Healthcare Insurance perspective at 12 months.