Evaluation of Optimal Dosing of Rabbit Anti-Human T-Lymphocyte Immunoglobulin and Mycophenolic Acid in Low Immunological Risk Renal Transplant Recipients

The primary objective of this study is to determine the optimal non-depleting dose of rabbit anti-human T-lymphocyte **immunoglobulin** (Grafalon®) to prevent complications associated with prolonged CD4 T cell lymphopenia in renal transplant recipients with low immunological risk. This is clinically relevant as it aims to minimize the risk of opportunistic infections and other complications that can arise from prolonged lymphopenia, thereby improving patient outcomes post-transplantation.

Secondary objectives include:

• Evaluating the tolerance of Grafalon® at each dose level.
• Assessing the pharmacokinetics of Grafalon® during the treatment period and up to three months post-treatment, and describing the immune profile and immune restoration at each dose level.
• Describing time-to-event clinical endpoints since transplantation at each dose level.
• Describing the rate and number of infections in patients up to one year after transplantation at each dose level.
• Describing the rate of patients experiencing an atherosclerotic event up to one year post-transplantation at each dose level.
• Describing the rate of patients diagnosed with cancer up to one year after transplantation at each dose level.
• Describing renal function at one year post-transplantation at each dose level.

The clinical trial involves participants who are **renal transplant** recipients, specifically those at low immunological risk. The study population includes both male and female subjects aged 18 years and older, who are receiving their first kidney transplantation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' general health status is characterized by their condition as renal transplant recipients, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection criteria focus on age and the status of receiving a first kidney transplant, without additional lifestyle or health status requirements.

The clinical trial is designed to evaluate the optimal non-depleting dose of **rabbit anti-human T-lymphocyte immunoglobulin** (Grafalon®) in patients undergoing a **renal transplant** with low immunological risk. This is a Phase 4, randomized, double-blind, controlled study. The trial aims to prevent complications associated with prolonged CD4 T cell lymphopenia. The study is expected to commence on October 1, 2024, and conclude by September 30, 2026, with a maximum treatment period of 4 days. Participants will be involved in the study for approximately one year, with the primary endpoint being the relative depletion of T cells (CD3+) above 30% compared to baseline at the end of the Grafalon® induction treatment on Day 4.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility, which includes criteria such as being 18 years or older and receiving a first kidney transplantation. Follow-up visits will occur at specified intervals to monitor the incidence and grade of adverse events, pharmacokinetics, and the absolute count and proportion of different immune cell subpopulations. The end-of-study visit will assess long-term outcomes such as renal function, infection rates, atherosclerotic events, and cancer diagnosis up to one year post-transplant.

Participants may be withdrawn from the study early if they experience severe adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for the participant's safety. The trial will utilize intravenous infusion as the route of administration for the investigational product, with a maximum daily dose of 140 mg and a total dose not exceeding 2940 mg. The study will adhere to the guidelines outlined in CTCAE V5.0 for adverse event reporting and will include a comprehensive pharmacokinetic analysis to evaluate the plasmatic clearance and trough levels of Grafalon®.

The clinical trial involves the administration of **mycophenolic acid**, a chemical substance known for its immunosuppressive properties. The experimental medication is formulated as an intravenous infusion under the product name **Antithymocyte Immunoglobulin (Rabbit)**. The pharmaceutical form is designated as PHF00094MIG. The maximum daily dose of mycophenolic acid is 140 mg, with a total maximum dose of 2940 mg over the treatment period. The administration is conducted intravenously, and the treatment duration is limited to a maximum of four weeks. The study aims to determine the optimal non-depleting dose of rabbit anti-human T-lymphocyte immunoglobulin to prevent complications associated with prolonged CD4 T cell lymphopenia in kidney transplant recipients with low immunological risk.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the study protocol. The trial focuses solely on the administration of the experimental medication. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The trial does not involve any pediatric formulations, and the product is not classified as an orphan drug. The study is conducted under strict clinical guidelines to evaluate the efficacy and safety of the experimental treatment in the specified patient population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the dose-limiting toxicity (DLT), defined by a relative depletion of T cells (CD3+) exceeding 30% compared to baseline (Day 0) at the conclusion of the Grafalon® induction treatment on Day 4. This endpoint is critical for determining the optimal non-depleting dose of rabbit anti-human T-lymphocyte immunoglobulin in kidney transplant recipients with low immunological risk.

Secondary endpoints include a comprehensive evaluation of toxicities, such as the incidence and grade of adverse events (AEs), drug-related AEs, and serious adverse events (SAEs) according to CTCAE V5.0. Pharmacokinetic parameters will be assessed by calculating the plasmatic clearance of Grafalon® through the area under the curve (AUC) at Day 0 and Day 4, as well as monitoring trough levels at each visit until month 3. Additionally, the study will measure the absolute count and proportion of various T and B cell subpopulations, NK cells, monocytes, and neutrophils at each time point.

Further secondary endpoints include the time to transplant failure, defined as the duration from transplantation to either graft loss or death with a functioning graft, and the time to kidney allograft acute rejection. The study will also track infections up to one year post-transplant, defined by severe bacterial or opportunistic infections, and assess atherosclerotic events through major adverse cardiovascular events (MACE). Cancer diagnosis up to one year post-transplant will be evaluated, encompassing all types and stages of post-transplant malignancies. Renal function will be assessed at one year post-transplant using the estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI formula.