Efficacy and Safety Evaluation of EVO756 Potassium in Adults with Moderate to Severe Chronic Spontaneous Urticaria: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of EVO756 at multiple dose levels compared with placebo in adults with moderate to severe **Chronic Spontaneous Urticaria**. This is clinically relevant as it aims to determine the potential of EVO756 to provide therapeutic benefits in managing symptoms of this condition, which is characterized by persistent and spontaneous hives and itching, significantly impacting patients' quality of life.

Secondary objectives include:

• To evaluate the **safety** of EVO756, ensuring that the treatment does not pose undue risks to patients.
• To explore changes in quality of life, biomarkers, and genetic variations correlated with disease activity and the activity of EVO756, which may provide insights into the biological mechanisms of the drug and its impact on patient well-being.

The clinical trial involves a total of **101 participants** diagnosed with **Moderate to Severe Chronic Spontaneous Urticaria**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their ability to provide written informed consent and their willingness to comply with study requirements. All subjects have a confirmed diagnosis of chronic spontaneous urticaria for at least three months and have shown an inadequate response to H1 antihistamines. Additionally, participants must have an **Urticaria Activity Score (UAS7)** of 16 or higher at Day 1, with completed UAS entries for a minimum of four out of the seven days prior to Day 1. Those taking H1 antihistamines are required to be on a stable regimen for four weeks prior to Day 1 and throughout the study. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse patient groups.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **EVO756 Potassium** in adults with moderate to severe **chronic spontaneous urticaria**. The trial will involve multiple dose levels of EVO756 compared to a placebo, with the primary objective being the assessment of the mean change from baseline in the Urticaria Activity Score (UAS7) at Week 12. Secondary endpoints include percent change from baseline in UAS7 at various intervals, as well as changes in other related scores such as ISS7, HSS7, and AAS7.

The trial is expected to commence recruitment in May 2025 and conclude by April 2026, with a total duration of approximately 12 months for each participant. Participants will be involved in the study for the entire duration unless early termination is warranted due to adverse events, non-compliance with study protocols, or withdrawal of consent. The study will include an initial screening visit to confirm eligibility, followed by regular follow-up visits at Weeks 1, 2, 4, 8, and 12 to monitor progress and collect data on efficacy and safety. The end-of-study visit will occur at Week 12, marking the completion of the participant's involvement in the trial.

Inclusion criteria require participants to be adults aged 18 or older with a confirmed diagnosis of chronic spontaneous urticaria for at least three months and an inadequate response to H1 antihistamines. Participants must also have a UAS7 score of 16 or higher at Day 1 and be on a stable regimen of H1 antihistamines for four weeks prior to the start of the study. The trial will exclude individuals who do not meet these criteria or who have conditions that could interfere with the study's objectives.

The investigational product, EVO756 Potassium, will be administered orally in tablet form, with a maximum daily dose of 1 mg. The placebo will also be administered in tablet form, with no active substance. The study's design ensures that neither the participants nor the investigators will know which treatment the participants are receiving, maintaining the integrity of the double-blind methodology.

The clinical trial involves the administration of **EVO756 Potassium**, a chemically derived active substance, formulated as a tablet. The pharmaceutical form is a tablet, and the medication is administered orally. The maximum daily dose is 1 mg, with a total dose not exceeding 1 mg per day. The treatment period is set for a maximum of 12 weeks. The medication is not a pediatric formulation and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

A **placebo** is used as a comparator in this study. The placebo is also formulated as a tablet and administered orally. It contains no active pharmaceutical ingredients and serves as a control to evaluate the efficacy of EVO756 Potassium. The placebo is administered under the same conditions as the experimental medication, with a maximum treatment period of 12 weeks. The use of a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the assessment of the treatment's efficacy and safety.

The efficacy of EVO756 in the treatment of moderate to severe **Chronic Spontaneous Urticaria** (CSU) will be assessed through a randomized, double-blind, placebo-controlled, dose-ranging study. The primary endpoint for evaluating efficacy is the mean change from baseline in the Urticaria Activity Score over 7 days (UAS7) at Week 12. Secondary endpoints include the percent change from baseline in UAS7 at Week 12, as well as mean and percent changes from baseline in UAS7 at Weeks 1, 2, 4, and 8. Additional secondary endpoints involve mean and percent changes from baseline in the Itch Severity Score over 7 days (ISS7), Hive Severity Score over 7 days (HSS7), and Angioedema Activity Score over 7 days (AAS7) at Weeks 1, 2, 4, 8, and 12. The proportion of subjects achieving UAS7 ≤ 6 and UAS7 = 0 will also be evaluated.

Efficacy parameters will be collected and analyzed at specified timepoints throughout the study, including Weeks 1, 2, 4, 8, and 12. The UAS7, ISS7, HSS7, and AAS7 scores will be utilized as validated scales for measuring symptom severity and treatment response. These assessments will be conducted to determine the therapeutic impact of EVO756 compared to placebo, with the aim of identifying optimal dosing regimens for managing CSU symptoms.