Long-term Efficacy, Safety, and Tolerability of Remibrutinib in Chronic Spontaneous Urticaria: An Extension Study for Phase 3 Completers

The primary objective of this study is to evaluate the **efficacy** of remibrutinib in patients with **Chronic Spontaneous Urticaria** (CSU) who have achieved a UAS7 score of less than 16 at Week 52 in a prior core study. The assessment focuses on the time to the first occurrence of one of three events: relapse, discontinuation of study treatment due to lack of efficacy, or the intake of strongly confounding prohibited medication, up to Week 24, compared to placebo. This objective is clinically relevant as it aims to determine the sustained efficacy of remibrutinib in maintaining symptom control in CSU patients, which is crucial for long-term management of the condition.

Secondary objectives include assessing the long-term **safety** and **tolerability** of remibrutinib. These objectives are important to ensure that the treatment remains safe and well-tolerated over extended periods, providing comprehensive data on its risk-benefit profile for chronic use in CSU patients.

The clinical trial involves a total of **496 participants** diagnosed with **Chronic Spontaneous Urticaria**. The study population comprises both male and female adults aged 18 years and older. Participants were selected based on their successful completion of preceding core studies, specifically CLOU064A2301, CLOU064A2302, CLOU064A1301, or CLOU064A2305, according to the respective protocols. The trial does not include a vulnerable population. Participants are required to have provided written informed consent and demonstrate willingness and ability to adhere to the study protocol and visit schedule. 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 designed to evaluate the **efficacy**, safety, and tolerability of **remibrutinib** in adult patients with **chronic spontaneous urticaria** who have completed prior Phase 3 studies. This is a multicenter, double-blind, placebo-controlled, randomized withdrawal study followed by an open-label extension and long-term open-label treatment cycles. The trial is expected to conclude by April 2027, with recruitment having commenced in January 2023.

Participants will be randomly assigned to receive either remibrutinib or a placebo during the initial withdrawal period. The primary endpoint is the time to the first composite event, which includes relapse, study treatment discontinuation due to lack of efficacy, or intake of strongly confounding prohibited medication. Secondary endpoints focus on the safety profile, including the occurrence of treatment-emergent adverse events.

The study involves several key visits: an inclusion (screening) visit to confirm eligibility, regular follow-up visits to monitor efficacy and safety, and an end-of-study visit to assess overall outcomes. Participants are expected to be involved in the study for a maximum treatment period of 160 weeks, depending on their response and adherence to the protocol. Conditions that may lead to early termination include non-compliance with the study protocol, adverse events, or withdrawal of consent.

Inclusion criteria require participants to be adults aged 18 years or older who have successfully completed specific preceding studies. Written informed consent is mandatory before any study-related procedures. The trial is not categorized as low intervention, and it is conducted under strict adherence to regulatory standards to ensure the integrity and reliability of the data collected.

The clinical trial involves the administration of **remibrutinib** (LOU064), a low molecular weight compound that covalently binds and inhibits Bruton’s tyrosine kinase. This experimental medication is provided in the form of a film-coated tablet. The route of administration is oral, and the treatment period extends up to 160 days. The dosage form is specified in milligrams, although the exact daily and total dose amounts are not provided. Remibrutinib is developed by Novartis Pharma AG and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

A **placebo** to remibrutinib is also utilized in this study. It is a 25 mg film-coated tablet designed to match the experimental medication in appearance and administration route. The placebo serves as a comparator treatment to evaluate the efficacy of remibrutinib. The placebo is administered orally, and its use is integral to maintaining the double-blind nature of the trial.

Additionally, the trial includes the use of **corticosteroids** for systemic use, which are known for their anti-inflammatory effects through influencing multiple signal transduction pathways. These are administered orally, and the treatment period is limited to 50 days. The pharmaceutical form is indicated as PHF00245MIG, and the product is relabeled in countries where local market regulations require it. The corticosteroids are not a pediatric formulation and are used as auxiliary treatment in the study.

**Antihistamines** for systemic use are also part of the auxiliary treatments in the trial. These medications block histamine release from histamine-1 receptors and are administered orally. The treatment period for antihistamines extends up to 160 days, and the pharmaceutical form is also indicated as PHF00245MIG. Similar to corticosteroids, these are relabeled according to local market requirements and are not pediatric formulations.

The efficacy of remibrutinib in the treatment of chronic spontaneous urticaria will be assessed during a multicenter, double-blind, placebo-controlled, randomized withdrawal and open-label extension study. The primary endpoint for evaluating efficacy is the time to the first composite event during the randomized withdrawal period. This composite event includes **relapse** (defined as UAS7 ≥16), study treatment discontinuation due to lack of efficacy, or the intake of strongly confounding prohibited medication. The assessment will occur up to Week 24, comparing remibrutinib to placebo.

Participants eligible for this study are those who have successfully completed preceding core studies and have a UAS7 score of less than 16 at Week 52 in the prior core study. The efficacy parameters will be collected and analyzed at specified timepoints, with the primary focus on the randomized withdrawal period. The study will also monitor safety endpoints, including the occurrence of treatment-emergent adverse events during the extension study. The trial is designed to ensure rigorous evaluation of remibrutinib's efficacy in managing chronic spontaneous urticaria, with a structured approach to data collection and analysis.