A RANDOMIZED DOUBLE-BLIND PHASE IIA STUDY EVALUATING THE EFFICACY, SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF CROVALIMAB AS ADJUNCT TREATMENT IN PREVENTION OF VASO-OCCLUSIVE EPISODES (VOE) IN SICKLE CELL DISEASE (SCD)

The primary objective of this study is to evaluate the **efficacy** of crovalimab compared with placebo in the prevention of vaso-occlusive episodes in patients with **Sickle Cell Disease**. This is clinically relevant as vaso-occlusive episodes are a significant complication of Sickle Cell Disease, leading to pain and potential organ damage, thus improving management strategies is crucial for patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of crovalimab compared with placebo.
• Assessing the safety and tolerability of crovalimab compared with placebo.
• Investigating the pharmacokinetics of crovalimab.
• Evaluating the immune response to crovalimab.

The clinical trial involves a total of **82 participants** diagnosed with **Sickle Cell Disease**. The study population includes both male and female subjects, with an age range of 12 to 65 years. Participants were selected based on specific criteria, including a confirmed diagnosis of HbSS or HbSβ0 genotypes, a body weight of at least 40 kg, and a history of two to ten documented vaso-occlusive events in the 12 months prior to randomization. The trial population is required to have stable concurrent SCD-directed therapy, if applicable, and must have received vaccinations against N. meningitides, H. influenza type B, and S. pneumonia. Participants are expected to maintain adequate hepatic and renal function throughout the study. The trial includes a vulnerable population, ensuring comprehensive evaluation across diverse demographic groups.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of crovalimab as an adjunct treatment in the prevention of vaso-occlusive episodes (VOE) in patients with **sickle cell disease**. The trial is expected to run from March 8, 2022, to August 17, 2026. Participants will be randomly assigned to receive either crovalimab or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study.

The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as body weight, confirmed diagnosis of sickle cell disease, and stable concurrent therapy, among others. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including the annualized rate of medical facility VOEs and other secondary endpoints such as changes in hematologic measures and patient-reported outcomes. The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment.

Participant involvement is expected to last until the end of the study in 2026, with conditions for early termination including significant adverse events or withdrawal of consent. The primary endpoint is the annualized rate of medical facility VOEs, while secondary endpoints include various clinical and patient-reported outcomes. The trial aims to provide comprehensive data on the potential benefits of crovalimab in managing sickle cell disease, contributing to the understanding of its role in reducing VOEs.

The clinical trial involves the evaluation of **crovalimab**, an investigational medication, as an adjunct treatment for the prevention of vaso-occlusive episodes in patients with sickle cell disease. Crovalimab is a protein-based therapeutic agent developed by F. Hoffmann-La Roche Ltd. The pharmaceutical form, dosage, route, and frequency of administration for crovalimab are not specified in the provided data. The investigational product is not a paediatric formulation and is not classified as an orphan drug. The trial aims to assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of crovalimab.

The study also includes a **placebo** as a comparator treatment. The placebo is used to evaluate the efficacy of crovalimab by providing a control group for comparison. Details regarding the pharmaceutical form, dosage, route, and frequency of administration for the placebo are not provided in the data. The use of a placebo is standard in clinical trials to ensure that the effects observed are due to the investigational medication and not other factors.

The efficacy of crovalimab as an adjunct treatment in the prevention of **vaso-occlusive episodes (VOE)** in sickle cell disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the annualized rate of medical facility VOEs (AVR). Secondary endpoints include the annualized rate of home VOE captured by patient report on a handheld device, the annualized rate of uncomplicated medical facility VOE, the annualized rate of acute chest syndrome (ACS), and the annualized rate of days hospitalized for medical facility VOE. Additional secondary endpoints involve the annualized rate of days hospitalized for treatment of non-VOE complications of sickle cell disease, changes in hematologic measures from baseline to Week 49, and time to first medical facility VOE from randomization.

Further secondary endpoints include changes in urinary albumin-creatinine ratio from baseline to Week 49, changes from baseline to Week 49 in tricuspid regurgitant jet velocity (TRV), and the proportion of patients with TRV greater than 2.5 m/s at Week 49. Additionally, changes from baseline to Week 49 in the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults will be evaluated. These efficacy parameters will be measured and collected at specified timepoints, with the analysis conducted to determine the impact of crovalimab compared to placebo in the study population.