A global, multicenter, randomized, double-blind, double-dummy, parallel-group, Phase 3b study to assess the efficacy, safety, and tolerability of remibrutinib 25 mg b.i.d. in comparison to placebo with omalizumab 300 mg every 4 weeks as active control over 52 weeks in adult patients with chronic spontaneous urticaria inadequately controlled by second-generation H1-antihistamines and an open-label 52-week optional extension to assess long-term efficacy, safety and tolerability of remibrutinib 25 mg b.i.d.

The primary objective of this study is to demonstrate that **remibrutinib** (25 mg b.i.d.) is superior to placebo in participants with **Chronic Spontaneous Urticaria** (CSU) with respect to change from baseline in UAS7, ISS7, and HSS7 scores at Week 12. This is clinically relevant as it aims to establish the efficacy of remibrutinib in reducing the severity of symptoms associated with CSU, which is often inadequately controlled by second-generation H1-antihistamines.

Secondary objectives include:

• To demonstrate that remibrutinib (25 mg b.i.d.) is superior to placebo in CSU participants with respect to the proportion of participants achieving complete absence of hives and itch (UAS7 = 0) at Week 12.
• To demonstrate that remibrutinib (25 mg b.i.d.) is superior to placebo in CSU participants with respect to change from baseline in ISS7 score at Week 12.
• To demonstrate that remibrutinib (25 mg b.i.d.) is superior to placebo in CSU participants with respect to change from baseline in HSS7 score at Week 12.
• To demonstrate that remibrutinib (25 mg b.i.d.) is superior to placebo in CSU participants with respect to change from baseline in UAS7 score at Week 12.
• To demonstrate the safety and tolerability of remibrutinib (25 mg b.i.d.).

The clinical trial involves a total of **254 participants** diagnosed with **Chronic Spontaneous Urticaria** (CSU). The study population comprises both male and female adults aged 18 years and older. Participants were selected based on their CSU condition, which has persisted for at least six months prior to screening and is inadequately controlled by second-generation H1-antihistamines. The trial does not include a vulnerable population. Participants are required to have documented hives within three months before randomization and must be willing to complete a Urticaria Patient Daily Diary throughout the study. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is a **randomized**, **double-blind**, **double-dummy**, parallel-group, Phase 3b study designed to evaluate the efficacy, safety, and tolerability of remibrutinib 25 mg twice daily in comparison to placebo, with omalizumab 300 mg every four weeks serving as an active control. The trial targets adult patients with **chronic spontaneous urticaria** inadequately controlled by second-generation H1-antihistamines. The study is structured over a 52-week period, with an optional open-label extension for an additional 52 weeks to assess long-term outcomes.

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 response to prior treatments. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety, with assessments including changes in UAS7, ISS7, and HSS7 scores at Week 12 as primary endpoints. Secondary endpoints include the achievement of UAS7=0 and the occurrence of treatment-emergent adverse events. The end-of-study visit will conclude the trial, evaluating the overall efficacy and safety of the treatment regimen.

The expected duration of participant involvement is up to 104 weeks, including the optional extension phase. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide comprehensive data on the comparative effectiveness of remibrutinib and omalizumab, contributing valuable insights into the management of **chronic spontaneous urticaria**.

The clinical trial involves the administration of **Remibrutinib**, a low molecular weight compound that covalently binds and inhibits Bruton’s tyrosine kinase. The pharmaceutical form of Remibrutinib is a film-coated tablet, with a dosage of 25 mg administered orally twice daily (b.i.d.). The maximum daily dose is 50 mg, and the total dose over the treatment period can reach up to 36,400 mg. The treatment period for Remibrutinib is set at 104 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Omalizumab** is used as an active comparator in the study. It is administered subcutaneously at a dosage of 300 mg every four weeks. The maximum total dose over the treatment period is 3,900 mg, with a treatment duration of 52 weeks. Omalizumab is a protein-based therapeutic agent, specifically an anti-IgE monoclonal antibody, which is used to manage chronic spontaneous urticaria inadequately controlled by second-generation H1-antihistamines.

The trial also includes a placebo group to compare the efficacy and safety of Remibrutinib. The placebo for Remibrutinib is a 25 mg film-coated tablet, administered orally twice daily. Additionally, a placebo for Omalizumab is provided as a 150 mg/ml solution for injection in a pre-filled syringe. This placebo is administered subcutaneously to maintain the double-blind nature of the study.

Furthermore, the study incorporates the use of **antihistamines** as auxiliary treatment. These are administered orally and function by blocking histamine release from histamine-1 receptors. The maximum treatment period for antihistamines is 12 weeks. Compliance with the administration of antihistamines will be monitored to ensure adherence to the study protocol.

Lastly, **corticosteroids** are included as an auxiliary treatment option. These are administered orally and exert anti-inflammatory effects by influencing multiple signal transduction pathways. The maximum treatment period for corticosteroids is 9 weeks. Participant adherence to corticosteroid administration will be closely monitored to ensure protocol compliance.

The efficacy of the clinical trial will be assessed by evaluating the change from baseline in the Urticaria Activity Score over 7 days (UAS7), the Itch Severity Score over 7 days (ISS7), and the Hives Severity Score over 7 days (HSS7) at Week 12. These parameters serve as the primary endpoints for determining the efficacy of the treatment. Secondary endpoints include the achievement of UAS7=0 at Week 12, improvement in the severity of itch and hives as assessed by the absolute change from baseline in ISS7 and HSS7 scores at Week 12, and the occurrence of treatment-emergent adverse events and serious adverse events (SAEs) during the study.

The trial is designed to compare the efficacy of remibrutinib 25 mg b.i.d. against a placebo, with omalizumab 300 mg every 4 weeks serving as an active control. The assessments will be conducted at specified timepoints, with the primary focus on Week 12. The UAS7, ISS7, and HSS7 scores will be collected through patient-reported outcomes, specifically using the Urticaria Patient Daily Diary (UPDD), which participants are required to complete throughout the study. This diary will facilitate the consistent and accurate collection of data necessary for evaluating the efficacy endpoints.