Efficacy and Safety Evaluation of Crovalimab Versus Eculizumab in Complement Inhibitor-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria

The primary objective of this study is to evaluate the **efficacy** of crovalimab compared to eculizumab in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who have not been previously treated with complement inhibitors. This assessment is based on the non-inferiority evaluation of specific co-primary endpoints. The clinical relevance of this objective lies in determining whether crovalimab can provide a comparable therapeutic benefit to eculizumab, potentially offering an alternative treatment option for PNH, a rare and life-threatening blood disorder.

Secondary objectives include:

• Evaluating the efficacy of crovalimab compared to eculizumab based on the non-inferiority assessment of secondary and exploratory efficacy endpoints.
• Assessing the overall safety and tolerability of crovalimab compared to eculizumab.
• Evaluating the pharmacokinetics of crovalimab and eculizumab.
• Assessing the immune response to crovalimab.
• Identifying and/or evaluating biomarkers that can potentially provide evidence of crovalimab and eculizumab activity.

The clinical trial involves a total of **167 participants** diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The study population includes both male and female subjects, with an age range that encompasses adolescents, adults, and the elderly. Participants were selected based on specific criteria, including a body weight of at least 40 kg and a documented diagnosis of PNH confirmed by high sensitivity flow cytometry evaluation of white blood cells. The trial also considers lifestyle factors such as the requirement for female patients of childbearing potential to agree to remain abstinent or use contraception. The health status of participants is characterized by a lactate dehydrogenase (LDH) level of at least two times the upper limit of normal at screening, a platelet count of at least 30,000/mm³ without transfusion support within seven days of lab testing, and an absolute neutrophil count greater than 500/micro L at screening. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the efficacy of crovalimab compared to eculizumab.

The clinical trial is a Phase III, randomized, open-label, active-controlled, multicenter study designed to evaluate the efficacy and safety of **crovalimab** compared to **eculizumab** in patients with **paroxysmal nocturnal hemoglobinuria (PNH)** who have not been previously treated with complement inhibitors. The trial aims to assess the non-inferiority of crovalimab based on co-primary endpoints, including the proportion of patients achieving transfusion avoidance and those with hemolysis control, as measured by lactate dehydrogenase (LDH) levels. Secondary endpoints include the incidence of breakthrough hemolysis, stabilization of hemoglobin, changes in fatigue, and the incidence and severity of adverse events.

The trial is expected to run from August 31, 2020, to June 30, 2028, with a maximum treatment period of 284 days for crovalimab and 24 days for eculizumab. Participants will be randomly assigned to receive either crovalimab or eculizumab, with crovalimab administered intravenously or subcutaneously and eculizumab administered intravenously. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as body weight, PNH diagnosis, and laboratory values; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess overall outcomes and collect final data.

Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including the occurrence of severe adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding of treatment options for PNH.

The clinical trial involves the administration of **Crovalimab**, an experimental medication, which is provided in the form of a **solution for injection/infusion**. The pharmaceutical form allows for administration either **intravenously (IV)** or **subcutaneously (SC)**. The maximum daily dose of Crovalimab is 1500 mg, with a total maximum dose of 74260 mg over a treatment period of up to 284 days. The active substance in Crovalimab is a protein of other origin, specifically designed for this study. The medication is not a pediatric formulation and is not classified as an orphan drug. The sponsor product codes for Crovalimab are RO 711-2689/F03-10 and RO 711-2689/F03-01, indicating different formulations or batches used in the trial.

The comparator treatment in this study is **Eculizumab**, which is provided as a **concentrate for solution for infusion**. Eculizumab is administered exclusively via the **intravenous route**. The maximum daily dose for Eculizumab is 900 mg, with a total maximum dose of 11400 mg over a treatment period of up to 24 days. Like Crovalimab, Eculizumab is a protein of other origin and is not a pediatric formulation. It serves as the active control in this trial, allowing for a comparative assessment of efficacy and safety against Crovalimab.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of Crovalimab compared to Eculizumab in patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** who have not been previously treated with complement inhibitors. The study is designed as a Phase III, randomized, open-label, active-controlled, multicenter trial, focusing on the non-inferiority of Crovalimab in relation to Eculizumab based on co-primary endpoints.

The efficacy of the investigational drug **Crovalimab** will be assessed in a Phase III, randomized, open-label, active-controlled, multicenter study. The trial aims to evaluate the efficacy and safety of Crovalimab compared to Eculizumab in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who have not been previously treated with complement inhibitors. The primary efficacy endpoints include the proportion of patients who achieve transfusion avoidance and the proportion of patients with hemolysis control, as measured by lactate dehydrogenase (LDH) levels ≤1.5 times the upper limit of normal (ULN).

Secondary efficacy endpoints encompass a range of clinical outcomes, including the proportion of patients experiencing breakthrough hemolysis, stabilization of hemoglobin levels, and mean change in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. Additional secondary endpoints include the incidence and severity of adverse events, changes from baseline in vital signs and clinical laboratory test results, and the incidence of injection-site reactions and other hypersensitivity reactions. The study will also monitor the serum concentration of Crovalimab and Eculizumab, the prevalence and incidence of anti-drug antibodies (ADAs) to Crovalimab, and changes over time in pharmacodynamic biomarkers and free C5 concentration in Crovalimab-treated patients.