Efficacy and Safety of Barzolvolimab in Patients with Chronic Spontaneous Urticaria Symptomatic Despite H1 Antihistamine Treatment: A Phase 3 Randomized, Placebo-Controlled Study

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 their quality of life and reducing disease burden.

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 effect of barzolvolimab in participants refractory to omalizumab treatment at Week 12.
• Evaluating the effect of barzolvolimab in reducing urticaria activity at Weeks 4, 24, and 52.
• Assessing the effect in participants refractory to omalizumab treatment at Weeks 4, 24, and 52.
• Evaluating the impact of barzolvolimab on health-related quality of life at Weeks 12, 24, and 52.

The clinical trial investigating the effects of barzolvolimab on **Chronic Spontaneous Urticaria** involves a total of 682 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 and their condition being refractory to a stable dose of a second-generation H1 antihistamine. The trial includes individuals who are willing and able to comply with study requirements, such as maintaining a daily symptom diary. The population is characterized by a diverse age range and includes a vulnerable population. Participants' general health status is not specified, but they are required to have a UAS7 score of 16 or higher and an ISS7 score of 8 or higher during the week prior to randomization. Lifestyle considerations such as diet and physical activity are not detailed in the available data.

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 compared to placebo in reducing urticaria activity, as measured by the weekly urticaria activity score (UAS7) at Week 12. The study is expected to commence recruitment on November 12, 2024, and conclude by April 21, 2027.

Participants will be involved in the study for a maximum treatment period of 45 weeks. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and collect data, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be 18 years or older, have a diagnosis of chronic spontaneous urticaria for at least six months, and be refractory to a stable dose of second-generation H1 antihistamines. Participants must also be willing to comply with all study requirements, including maintaining a daily symptom diary.

Study visits will be structured to ensure comprehensive data collection and participant safety. The screening visit will involve a thorough assessment to confirm the diagnosis and eligibility criteria. Follow-up visits will occur at regular intervals to monitor the efficacy and safety of the treatment, with specific attention to changes in UAS7 scores. The end-of-study visit will provide a final evaluation of the treatment's impact and any adverse events experienced by participants.

Participant involvement may be terminated early if they experience significant adverse effects, fail to comply with study protocols, or withdraw consent. The primary endpoint of the study is the mean change from baseline in UAS7 at Week 12, with secondary endpoints including changes in other symptom scores and the proportion of participants achieving specific UAS7 thresholds. The trial will utilize a placebo group to ensure the reliability of the results, with placebo prefilled syringes identical in appearance to those containing barzolvolimab but containing only inactive ingredients.

The clinical trial involves the administration of **epinephrine**, marketed under the name FASTJEKT, which is provided as a **solution for injection** in a prefilled pen. The pharmaceutical form is an injection solution, and the active substance is chemically derived. The maximum daily dose is 600 micrograms, with a total maximum dose of 600 micrograms over a treatment period of one day. The route of administration is subcutaneous. The product is manufactured by Viatris Healthcare GmbH and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

The experimental medication **barzolvolimab** is provided as a **concentrate for solution for infusion**. It is a humanized IgG1k monoclonal antibody against KIT, also known by the sponsor product code CDX-0159. The maximum daily dose is 450 milligrams, with a total maximum dose of 2400 milligrams over a treatment period of 45 days. The route of administration is subcutaneous. The product is developed by Celldex Therapeutics, Inc. and is not intended for pediatric use. Compliance with the dosing schedule will be closely monitored to ensure adherence to the protocol.

The study also includes a **placebo** control, which consists of prefilled syringes identical in appearance to those containing barzolvolimab. These syringes contain only the inactive ingredients, serving as a vehicle without any active barzolvolimab. The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased assessment of the experimental treatment's efficacy and safety. The placebo administration will follow the same schedule and route as the barzolvolimab to ensure consistency in the trial design.

The efficacy of the investigational product, **barzolvolimab**, in the treatment of Chronic Spontaneous Urticaria (CSU) will be assessed through a series of predefined endpoints. The primary endpoint 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 involve 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 assessments will be conducted using validated scales, with UAS7 being a composite score ranging from 0 to 42, ISS7 ranging from 0 to 21, and HSS7 also ranging from 0 to 21. These scores will be collected at specified timepoints, including baseline, Week 4, Week 12, and Week 24. The data will be analyzed to determine the change from baseline, providing insights into the clinical effect of barzolvolimab compared to placebo. The trial is designed as a Phase 3, randomized, double-blind, placebo-controlled study, ensuring rigorous evaluation of the treatment's efficacy in the target population.