Phase 3 Study of Ravulizumab in Thrombotic Microangiopathy Post-Hematopoietic Stem Cell Transplant in Adults and Adolescents

The primary objective of this study is to assess the **efficacy** of ravulizumab compared to placebo in the treatment of adult and adolescent participants with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). This is clinically relevant as HSCT-TMA is a serious complication that can occur after hematopoietic stem cell transplantation, and effective treatment options are crucial for improving patient outcomes.

Secondary objectives include:

• To assess overall survival (OS).
• To assess non-relapse mortality.
• To characterize thrombotic microangiopathy (TMA) response after treatment with ravulizumab.
• To assess improvement in organ dysfunction.

The clinical trial involves a total of **83 participants** diagnosed with **hematopoietic stem cell transplant-associated thrombotic microangiopathy** (HSCT-TMA). The study population includes both male and female subjects, aged **12 years and older**, who have undergone HSCT within the past 12 months. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of TMA and a body weight of at least 30 kg. The trial population is characterized by individuals who are part of a vulnerable group due to their recent transplant history. Participants are required to have been vaccinated against meningococcal infections, with additional vaccinations for those under 18, as per institutional guidelines. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants are capable of providing informed consent and adhere to contraceptive use regulations as applicable.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy of **ravulizumab** in adult and adolescent participants with **hematopoietic stem cell transplant-associated thrombotic microangiopathy** (HSCT-TMA). The trial aims to compare the effects of ravulizumab against a placebo in this patient population. The study is expected to run from October 2020 to June 2026, with a maximum treatment period of 26 weeks for each participant.

Participants will be randomly assigned to receive either ravulizumab or a placebo, administered via **intravenous use**. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes. The primary endpoint is event-free survival during the 26-week treatment period, defined as the time from randomization until death or clinical worsening. Secondary endpoints include overall survival by Day 100 and Week 26, non-relapse mortality, number of TMA response criteria met, hematologic response, and change from baseline in eGFR at Week 26.

Participants are expected to be involved in the study for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is conducted in accordance with ethical guidelines, and participants must provide informed consent prior to enrollment. Eligibility criteria include being 12 years of age or older, having received HSCT within the past 12 months, and meeting specific diagnostic criteria for TMA. Participants must also adhere to vaccination and prophylactic antibiotic guidelines as per institutional standards.

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 300 mg/30 mL and is administered via **intravenous use**. The maximum daily dose is 3600 mg, with a total maximum dose of 26400 mg over the course of the treatment period, which spans up to 26 weeks. Ravulizumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AA43. The pharmaceutical form is a solution for infusion, and the medication is produced by Alexion Europe SAS. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group, which receives the Anti C5 Complement mAb Placebo. This placebo is used as a comparator treatment to evaluate the efficacy of ravulizumab. The placebo is designed to mimic the administration route and form of the experimental drug, although specific details regarding its pharmaceutical form and active substances are not applicable. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial.

The efficacy of **ravulizumab** in the treatment of Thrombotic Microangiopathy (TMA) following Hematopoietic Stem Cell Transplant (HSCT) will be assessed in a Phase 3, randomized, double-blind, placebo-controlled, multicenter study. The primary endpoint for evaluating efficacy is event-free survival during the 26-week treatment period, defined as the time from randomization until the occurrence of either death or clinical worsening. Secondary endpoints include overall survival by Day 100 and Week 26, non-relapse mortality during the 26-week treatment period, the number of TMA response criteria met during the 26-week treatment period, hematologic response during the 26-week treatment period, and change from baseline in estimated glomerular filtration rate (eGFR) at Week 26.