Efficacy, Safety, and Tolerability of Remibrutinib in Adults with Chronic Inducible Urticaria Unresponsive to H1-Antihistamines: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the efficacy of **remibrutinib** compared to placebo in achieving a complete response in participants with Chronic Inducible Urticaria (CINDU), specifically those with symptomatic dermographism, cold urticaria, and cholinergic urticaria, at Week 12. This objective is clinically relevant as it aims to provide an effective treatment option for patients inadequately controlled by H1-antihistamines, potentially improving their quality of life by reducing urticaria symptoms.

Secondary objectives include demonstrating the superiority of remibrutinib over placebo in various measures across different cohorts and time points:

• Change from baseline in Total Fric Score (TFS), Critical Temperature Threshold (CTT), and itch response to provocation tests at Week 12.
• Physician Global Assessment (PGA) of severity of hives for cholinergic urticaria cohort at Week 12.
• Complete response to provocation tests at Week 24.
• Itch NRS following provocation tests at Week 12.
• Proportion of participants with complete response to FricTest® and TempTest® at Week 2.
• Change from baseline in response to FricTest® and TempTest® at Week 2.
• Itch NRS following provocation tests at Week 2 and PGA of severity of hives at Week 2.
• Change in NRS score for the most bothersome symptom between baseline and Week 12 on the Urticaria Symptom Daily Diary (USDD).
• Achieving DLQI = 0-1 at Week 12.
• Assessing the safety of remibrutinib for the specified urticaria types.

The clinical trial involves a total of **244 participants** diagnosed with **Chronic Inducible Urticaria (CINDU)**, including subtypes such as symptomatic dermographism, cold urticaria, and cholinergic urticaria. The study population comprises both male and female adults aged 18 years and older. Participants were selected based on a confirmed diagnosis of CINDU for at least four months, with inadequate control using H1-antihistamines at locally approved doses. The trial does not include a vulnerable population. Participants' general health status is not specified, and no specific lifestyle considerations such as diet or physical activity are mentioned. The selection criteria required a specific response to provocation tests for each CINDU subtype at the randomization visit. The sponsor has not provided additional information regarding the participants' general health or lifestyle factors.

The clinical trial is designed as a 52-week, multi-center, **randomized**, **double-blind**, placebo-controlled study with an open-label extension. The primary objective is to evaluate the efficacy, safety, and tolerability of **remibrutinib** in adults with **Chronic Inducible Urticaria (CINDU)** who are inadequately controlled by H1-antihistamines. The trial will involve a comparison between remibrutinib and a placebo, with the primary endpoint being the proportion of participants achieving a complete response at Week 12. The study will include several visits, starting with a screening visit to confirm eligibility based on specific inclusion criteria, such as age and confirmed CINDU diagnosis. Participants will be required to demonstrate a response to provocation tests for each subtype of CINDU at the randomization visit.

Following the initial screening, participants will be randomized to receive either remibrutinib or placebo. The trial will include regular follow-up visits to monitor the participants' response to treatment and assess any adverse events. These visits will occur at specified intervals, including key assessments at Weeks 2, 12, and 24, with the primary endpoint evaluation at Week 12. The end-of-study visit will occur at Week 52, marking the completion of the trial. The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. The trial is structured to ensure rigorous assessment of the investigational product's impact on CINDU, with secondary endpoints evaluating changes from baseline in various clinical measures and safety outcomes.

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, identified by the sponsor product code LOU064. The active substance, remibrutinib, is of chemical origin. The medication is administered orally, with a maximum treatment period of 208 weeks. The specific dosage and frequency of administration are not detailed in the provided data.

A **placebo** is used as a comparator in this study. It is designed to match the remibrutinib film-coated tablet in appearance but does not contain the active substance. The placebo is administered orally, and its role is to serve as a control to evaluate the efficacy of remibrutinib in participants with Chronic Inducible Urticaria (CINDU).

Additionally, the study includes the use of **corticosteroids for systemic use, plain**, which are known for their anti-inflammatory effects through influencing multiple signal transduction pathways. The pharmaceutical form is identified as PHF00245MIG, and the administration route is oral. The maximum treatment period for corticosteroids is 24 weeks. The specific dosage and frequency of administration are not provided.

**Antihistamines for systemic use** are also part of the study, functioning by blocking histamine release from histamine-1 receptors. Similar to corticosteroids, the pharmaceutical form is PHF00245MIG, and the administration route is oral. The maximum treatment period is 24 weeks, with no specific dosage or frequency details available.

The efficacy of remibrutinib (LOU064) in the treatment of **Chronic Inducible Urticaria (CINDU)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints include the proportion of participants achieving a complete response at Week 12. For symptomatic dermographism, this is defined as a complete response to the Total Fric Score (TFS) following the FricTest® 4.0. For cold urticaria, it is the proportion of participants with a complete response in the Critical Temperature Threshold (CTT) following the TempTest®. For cholinergic urticaria, the endpoint is the proportion of participants with an itch Numerical Rating Scale (NRS) score of 0 following the pulse-controlled ergometry test.

Secondary endpoints will evaluate changes from baseline at Week 12 and Week 24. These include changes in TFS for symptomatic dermographism, CTT for cold urticaria, and itch NRS for cholinergic urticaria. Additionally, the proportion of participants with a Physician Global Assessment (PGA) of severity of hives equal to 0 for cholinergic urticaria will be assessed. Measurements will be conducted using validated tools such as the FricTest® for symptomatic dermographism, the TempTest® for cold urticaria, and the pulse-controlled ergometry test for cholinergic urticaria. Efficacy assessments are scheduled at multiple timepoints, including Week 2, Week 12, and Week 24, to monitor both immediate and sustained responses to treatment.