Efficacy and Safety of Intravenous Ravulizumab in Reducing Delayed Graft Function in High-Risk Adult Kidney Transplant Recipients: A Phase 3 Randomized Study

The primary objective of this Phase 3, double-blind, randomized, placebo-controlled, multicenter study is to demonstrate the efficacy of **ravulizumab** versus placebo in reducing the severity of **Delayed Graft Function (DGF)**. This is measured by the time to freedom from dialysis in adult participants who are at high risk of DGF after undergoing a kidney transplant from a deceased donor. The clinical relevance of this objective lies in potentially improving post-transplant outcomes and reducing the need for dialysis, which can significantly impact patient recovery and long-term graft survival.

Secondary objectives include: - Assessing the effect of ravulizumab versus placebo on the incidence of DGF in adult participants at high risk after kidney transplantation from a deceased donor. - Evaluating the impact of ravulizumab versus placebo on dialysis utilization in this high-risk population. - Assessing graft function in renal transplant recipients treated with ravulizumab versus placebo. These secondary objectives aim to provide a comprehensive understanding of the potential benefits of ravulizumab in improving transplant outcomes and reducing the burden of dialysis in this patient population.

The clinical trial involves a total of **263 participants** who are adults aged 18 years and older, diagnosed with dialysis-dependent **End-Stage Kidney Disease (ESKD)**. The study population includes both male and female subjects who are candidates for kidney transplant from either a Donation after Circulatory Death (DCD) donor or a high-risk Donation after Brain Death (DBD) donor. Participants were selected based on their high risk of experiencing Delayed Graft Function (DGF) following a kidney transplant from a deceased donor. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population is considered vulnerable, reflecting the serious nature of their medical condition and the complexity of their treatment needs.

The clinical trial is a **Phase 3**, double-blind, randomized, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **ravulizumab** administered intravenously in adult participants at high risk of **Delayed Graft Function** (DGF) after kidney transplantation. The trial aims to demonstrate the efficacy of ravulizumab versus placebo in reducing the severity of DGF, as measured by the time to freedom from dialysis in adult participants who have undergone a transplant of a deceased donor kidney. The primary endpoint is the time to freedom from dialysis through 90 days post-transplant, while secondary endpoints include DGF incidence, the number of dialysis sessions through 90 days post-transplant, and the time to the first occurrence of estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m² through 90 days post-transplant.

The trial is expected to commence recruitment on August 14, 2025, and is estimated to conclude by November 29, 2028. Participants will be involved in the study for a maximum treatment period of one year. The study visits will include an initial screening visit to confirm eligibility based on criteria such as being 18 years or older, having a diagnosis of dialysis-dependent End-Stage Kidney Disease (ESKD), and being a candidate for kidney transplant from specific donor types. Follow-up visits will be scheduled to monitor the participants' response to the treatment and to assess the primary and secondary endpoints. The end-of-study visit will mark the completion of the participant's involvement in the trial.

Participants may be withdrawn from the study early if they experience adverse events that compromise their safety, if they withdraw consent, or if they fail to comply with the study protocol. The trial will utilize a placebo control, with participants randomly assigned to receive either ravulizumab or a placebo, ensuring the study's double-blind nature. The investigational product, Ultomiris 1,100 mg/11 mL concentrate for solution for infusion, will be administered via intravenous infusion. The study is not classified as a low-intervention trial, and the trial phase is categorized as Phase 3, focusing on a new indication for the authorized product.

The clinical trial involves the administration of **ravulizumab**, marketed under the name Ultomiris, which is a **concentrate for solution for infusion**. This experimental medication is provided in a dosage of 1,100 mg/11 mL and is administered via **intravenous infusion**. The maximum daily dose is 3,600 mg, with a total maximum dose of 3,600 mg over the treatment period. The treatment is designed to be administered over a period of one day. Ravulizumab is a **Fc- and CDR-modified humanised monoclonal antibody against C5**, and it is classified under the ATC code L04AJ02. The pharmaceutical form is a solution for infusion, and the product is manufactured by Alexion Europe SAS. The administration of the drug is monitored to ensure compliance with the dosing schedule.

The study also includes a **placebo** group, which receives the Anti C5 Complement mAb Placebo. The placebo is used as a comparator treatment to evaluate the efficacy and safety of ravulizumab. The placebo is administered in a manner consistent with the experimental drug to maintain the double-blind nature of the trial. The placebo does not contain any active substance and is used to ensure that any observed effects can be attributed to the active treatment. Participant compliance with the administration of the placebo is also monitored throughout the study.

The efficacy of **ravulizumab** in the clinical trial will be assessed by evaluating its impact on reducing the severity of Delayed Graft Function (DGF) in adult participants at high risk after kidney transplantation. The primary endpoint for efficacy assessment is the "Time to freedom from dialysis through 90 days post-transplant." This parameter will be measured to determine the time it takes for participants to become independent of dialysis following the transplant procedure.

Secondary endpoints include the incidence of DGF, defined as the requirement of at least one dialysis session within the first seven days post-transplant, the number of dialysis sessions through 90 days post-transplant, and the time to the first occurrence of estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m² through 90 days post-transplant. These endpoints will provide additional insights into the efficacy of ravulizumab in improving kidney function and reducing the need for dialysis in the post-transplant period.