Efficacy and Safety of Crizanlizumab in Adolescent and Adult Patients with Sickle Cell Disease Experiencing Vaso-Occlusive Crises: A Phase III Randomized Study

The primary objective of this study is to compare the **efficacy** of two doses of crizanlizumab, 7.5 mg/kg and 5.0 mg/kg, versus placebo on the annualized rate of vaso-occlusive crises (VOCs) leading to healthcare visits in patients with **sickle cell disease**. This evaluation is conducted in addition to the standard of care. The clinical relevance of this objective lies in its potential to reduce the frequency of VOCs, which are acute painful episodes that significantly impact the quality of life and healthcare utilization in sickle cell disease patients.

Secondary objectives include:

• Comparing the efficacy of 7.5 mg/kg and 5.0 mg/kg versus placebo on the annualized rate of all VOCs, including those managed at home and those leading to healthcare visits.
• Assessing the annualized rate of VOCs managed at home in each group.
• Evaluating the time to first and second VOC leading to healthcare visits in each group.
• Assessing the rate of participants free from VOCs leading to healthcare visits in each group.
• Evaluating the duration of VOCs leading to healthcare visits in each group.
• Assessing healthcare resource utilization, including clinic visits, emergency room visits, and hospitalizations in each group.
• Evaluating sickle cell disease-related renal damage in each group.
• Characterizing the pharmacokinetic (PK) profile of crizanlizumab at both doses.
• Characterizing the pharmacodynamic (PD) profile, specifically P-selectin inhibition, of crizanlizumab at both doses.
• Assessing the efficacy, safety, and immunogenicity of crizanlizumab over the study period, considering potential treatment switches after primary analysis.

The clinical trial involves a total of **78 participants** diagnosed with **sickle cell disease**. The study population includes both male and female subjects aged 12 years and older, encompassing adolescents (12 to 17 years) and adults (18 years and above). Participants were selected based on specific criteria, including a confirmed diagnosis of sickle cell disease and a history of at least two vaso-occlusive crises (VOCs) leading to healthcare visits within the 12 months prior to screening. The trial includes individuals who are either on stable doses of hydroxyurea, L-glutamine, or erythropoietin-stimulating agents, or those who have not received these treatments for at least six months prior to screening. Participants must demonstrate insufficient control of acute pain despite treatment. The trial population is characterized by a vulnerable group, with specific laboratory values and performance status requirements ensuring general health stability. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of two doses of **crizanlizumab** compared to placebo in adolescent and adult patients with **sickle cell disease** experiencing vaso-occlusive crises (VOCs). The trial will include participants aged 12 years and older, with a confirmed diagnosis of sickle cell disease, who have experienced at least two VOCs leading to healthcare visits in the 12 months prior to the screening visit. The study will be conducted over an estimated duration from September 2019 to December 2026, with participant involvement expected to last up to one year post-randomization.

Participants will be randomly assigned to receive either 7.5 mg/kg or 5.0 mg/kg of crizanlizumab or a placebo, administered via **intravenous use**. The primary endpoint is the annualized rate of VOC events leading to healthcare visits over the first year post-randomization. Secondary endpoints include the annualized rate of all VOCs, duration of VOCs, and the number and percentage of participants free from VOCs leading to healthcare visits.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, including laboratory values and medical history. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, assess pharmacokinetic and pharmacodynamic parameters, and evaluate any treatment-emergent adverse events. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the impact of crizanlizumab on VOCs in sickle cell disease, contributing to the understanding and management of this condition.

The clinical trial involves the administration of **crizanlizumab**, marketed under the product name SEG101, which is a **concentrate for solution for infusion**. This investigational medication is developed by Novartis Pharma AG and is classified as a humanized monoclonal antibody targeting P-selectin. The pharmaceutical form is specifically designed for **intravenous use**. Participants in the trial will receive crizanlizumab at a dosage of either 7.5 mg/kg or 5.0 mg/kg. The administration is conducted intravenously, with the frequency and specific dosing schedule determined by the study protocol. The maximum treatment period for crizanlizumab is set at 60 days. Compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes a **placebo** group to serve as a comparator. The placebo is administered in a manner identical to the investigational drug, ensuring blinding of both participants and investigators. The trial also allows for the concurrent use of standard-of-care therapy, which may include **hydroxyurea/hydroxycarbamide** therapy, as part of the treatment regimen for sickle cell disease. This approach aims to assess the efficacy and safety of crizanlizumab in combination with or without standard therapy. The study design ensures rigorous monitoring of participant compliance and adverse events to maintain the integrity of the trial data.

The efficacy of the clinical trial will be assessed by evaluating the **annualized rate of vaso-occlusive crises (VOCs)** leading to healthcare visits in patients with sickle cell disease. This primary endpoint will be measured over the first year post-randomization for each treatment group. Secondary endpoints include the annualized rate of all VOCs leading to healthcare visits and those managed at home, the duration of VOCs leading to healthcare visits, and the number and percentage of participants free from VOCs leading to healthcare visits. Additionally, the time to the first and second VOCs, the annualized rate of visits to clinics, emergency rooms, and hospitalizations, both overall and VOC-related, will be analyzed.

Further assessments will include the evolution of albuminuria and albumin-to-creatinine ratio (ACR), pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), time to maximum concentration (Tmax), and half-life after the first and fifth doses. Pharmacodynamic parameters, specifically P-selectin inhibition, will also be evaluated after the first and fifth doses. Safety data, including the number, seriousness, severity, and causality assessments of treatment-emergent adverse events, will be collected. Additional measures include the absolute change from baseline in hemoglobin levels, growth and sexual maturity assessment in adolescents, and immunogenicity through the measurement of anti-drug antibodies to crizanlizumab.