Efficacy and Safety Evaluation of Barzolvolimab in Chronic Spontaneous Urticaria Patients Unresponsive to H1 Antihistamines: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the clinical effect of **barzolvolimab**, compared to placebo, in reducing urticaria activity as assessed by the weekly urticaria activity score (UAS7) at Week 12. This is clinically relevant as it aims to provide an effective treatment option for patients with Chronic Spontaneous Urticaria who remain symptomatic despite H1 antihistamine treatment, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the clinical effect of barzolvolimab, compared to placebo, in reducing urticaria activity as assessed by weekly itch severity score (ISS7) and weekly hive severity score (HSS7) at Week 12.
• Assessing the clinical effect of barzolvolimab, compared to placebo, in reducing urticaria activity in participants refractory to omalizumab treatment at Week 12.
• Evaluating the clinical effect of barzolvolimab in reducing urticaria activity at Weeks 4 and 24 (vs placebo) and at Week 52.
• Assessing the clinical effect of barzolvolimab in reducing urticaria activity in participants refractory to omalizumab treatment at Weeks 4 and 24 (vs placebo) and at Week 52.
• Evaluating the clinical effect of barzolvolimab on the health-related quality of life at Weeks 12, 24, and 52.

The clinical trial for **Chronic Spontaneous Urticaria** involves a total of 861 participants. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their diagnosis of chronic spontaneous urticaria for at least six months prior to screening, with a condition refractory to a stable dose of second-generation H1 antihistamines. The trial population is characterized by individuals who have experienced recurrent pruritic wheals with or without angioedema for a minimum of six weeks despite treatment. Participants are required to maintain a stable antihistamine regimen throughout the study. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and compliance with study requirements. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to evaluate the clinical effect of barzolvolimab compared to placebo in reducing urticaria activity, as assessed by the weekly urticaria activity score at Week 12.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **barzolvolimab** in patients with **chronic spontaneous urticaria** who remain symptomatic despite H1 antihistamine treatment. The trial aims to assess the clinical effect of barzolvolimab in reducing urticaria activity, as measured by the weekly urticaria activity score (UAS7) at Week 12. The study will involve the administration of barzolvolimab, a concentrate for solution for infusion, and a placebo, both delivered via subcutaneous injection. The trial is expected to commence recruitment on December 15, 2024, and conclude by July 15, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, duration of chronic spontaneous urticaria, and refractoriness to H1 antihistamine treatment. Following successful screening, participants will be randomized to receive either barzolvolimab or placebo. The study will include follow-up visits at regular intervals to monitor safety, efficacy, and adherence to the study protocol. The primary endpoint is the mean change from baseline in UAS7 at Week 12, with secondary endpoints including changes in other urticaria activity scores and the proportion of participants achieving complete symptom resolution.

The expected duration of participant involvement is approximately 45 weeks, with the possibility of early termination if participants experience significant adverse events, non-compliance with study procedures, or withdrawal of consent. Participants will be required to maintain a stable dose of second-generation H1 antihistamines throughout the study and complete a daily symptom diary. The end-of-study visit will involve a comprehensive assessment of the participant's condition and any potential long-term effects of the treatment. The trial's rigorous design ensures the collection of robust data to evaluate the therapeutic potential of barzolvolimab in this patient population.

The clinical trial involves the administration of **barzolvolimab**, a **concentrate for solution for infusion**. Barzolvolimab is a humanized IgG1k monoclonal antibody targeting the KIT receptor, also known by its sponsor product code CDX-0159. The pharmaceutical form is a concentrate for solution for infusion, and it is administered via the **subcutaneous** route. The maximum daily dose is 450 mg, with a total maximum dose of 2400 mg over a treatment period of up to 45 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

The trial also includes the use of a **placebo** in the form of prefilled syringes, which are identical in appearance to those containing barzolvolimab but contain only the inactive ingredients. The placebo is administered subcutaneously, following the same schedule as the experimental medication, to maintain the double-blind nature of the study.

Additionally, **epinephrine** is available as an auxiliary treatment in the form of a solution for injection, marketed under the name FASTJEKT. Each prefilled pen contains 300 micrograms of epinephrine, and it is administered subcutaneously. The maximum daily dose is 600 micrograms, with a total maximum dose of 600 micrograms over a one-day period. This auxiliary treatment is provided to manage any potential acute allergic reactions during the trial.

The efficacy of barzolvolimab in the treatment of **Chronic Spontaneous Urticaria** will be assessed through a Phase 3 randomized, double-blind, placebo-controlled study. The primary endpoint for evaluating efficacy is the mean change from baseline in the weekly urticaria activity score (UAS7) at Week 12. Secondary endpoints include the mean change from baseline in the itch severity score (ISS7) and hives severity score (HSS7) at Week 12, the percentage of participants achieving a UAS7 score of 0 at Week 12, and the mean change from baseline in UAS7 for participants refractory to omalizumab treatment at Week 12. Additional secondary endpoints include the proportion of participants with UAS7 = 0 in those refractory to omalizumab treatment at Week 12, the percentage of participants with UAS7 ≤ 6 at Week 12, the mean change from baseline in UAS7 at Week 4 and Week 24, and the percentage of participants with UAS7 = 0 at Week 24.

Efficacy parameters will be measured using validated scales, with data collection scheduled at specific timepoints, including Week 4, Week 12, and Week 24. The UAS7, ISS7, and HSS7 scores will be utilized to quantify symptom improvement. The study will involve the use of a daily symptom diary to ensure accurate and consistent data collection throughout the trial. The analysis will focus on comparing the changes in these scores from baseline to the specified timepoints, providing a comprehensive assessment of the treatment's impact on disease activity.