A Phase 3b Study to Assess the Efficacy, Safety, and Tolerability of Remibrutinib in Comparison to Placebo and With Omalizumab as Active Control in CSU Adult Patients.

Study Overview
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Brief Summary
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The purpose of this trial is to assess the efficacy, safety and tolerability of remibrutinib (LOU064) 25 milligrams (mg) twice a day (b.i.d.) over placebo for 24 weeks and in comparison to omalizumab 300 mg every 4 weeks (q4w) for 52 weeks in participants with chronic spontaneous urticaria (CSU) inadequately controlled by H1-antihistamines (H1-AH).

Detailed Description
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The study consists of three periods, and the total study duration is up to 72 weeks. Approximately 468 adult participants with CSU are expected to be randomized in the study. Screening period: A screening period of up to 4 weeks will allow for the assessment of eligibility, determination of baseline disease activity and wash-out of prohibited medications. Treatment period: The treatment period will be double-dummy and double-blind, with placebo injections matching omalizumab 300 mg s.c. given to participants in the remibrutinib arm and placebo tablets matching remibrutinib 25 mg given to participants in the omalizumab arm (double-dummy). At the randomization visit, eligible participants will be randomized to one of four treatment arms. Follow-up period: There will be a 16-week, treatment-free, safety follow-up period (for participants who do not roll-over to the extension study). All participants will be on a stable, local label-approved standard dose of a second-generation H1-AH (background therapy) throughout the entire study (starting a minimum of 7 days prior to randomization until the end of the study). In addition, to treat unbearable symptoms of CSU flare-ups, participants will be allowed to use a different second-generation H1-AH on an as-needed basis (rescue therapy).

Official Title
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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

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: Remibrutinib
* Drug: Placebo to remibrutinib
* Drug: Placebo to omalizumab
* Drug: Omalizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adult participants ≥18 years of age at the time of signing the informed consent. CSU duration for ≥ 6 months prior to screening. Diagnosis of CSU inadequately controlled by second generation H1-AH at the time of randomization, defined as: The presence of itch and hives for ≥6 consecutive weeks prior to screening, despite the use of second-generation H1-AH during this time period. UAS7 score (range 0-42) ≥16, ISS7 score (range 0-21) ≥ 6 and HSS7 score (range 0- 21) ≥ 6 during the 7 days prior to randomization (Day 1). Documentation of hives within three months before randomization. Willing and able to complete an Urticaria Patient Daily Diary (UPDD) for the duration of the study and adhere to the study protocol. Participants must not have had more than one missing UPDD entry (either morning or evening) in the 7 days prior to randomization (Day 1). Exclusion Criteria: Prior exposure to ligelizumab, omalizumab and other biologics with any effect in CSU, including anti-IgE therapies. Significant bleeding risk or coagulation disorders. History of gastrointestinal bleeding. Requirement for anti-platelet or anti-coagulant medication. History or current hepatic disease. Evidence of clinically significant cardiovascular, neurological, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, hematological disorders, gastrointestinal disease or immunodeficiency that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant. Evidence of helminthic parasitic infection as evidenced by stools being positive for a pathogenic organism according to local guidelines. Documented history of anaphylaxis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: At the randomization visit, eligible participants will be randomized to one of four treatment arms in a 2:1:1:2 ratio: Remibrutinib 25 mg b.i.d. arm: participants will receive remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w for 52 weeks Placebo to remibrutinib arm: participants will receive placebo for remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w for 24 weeks. From Week 24 to Week 52 participants will receive remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w. Placebo to omalizumab arm: participants will receive placebo for remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w for 24 weeks. From Week 24 to Week 52 participants will receive omalizumab 300 mg q4w and placebo for remibrutinib b.i.d. Omalizumab 300 mg every 4 weeks arm: participants will receive omalizumab 300 mg q4w and placebo for remibrutinib b.i.d. for 52 weeks.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remibrutinib<br>Participants will receive remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w for 52 weeks. | Drug: Remibrutinib<br>* Active treatment<br>|
| Placebo Comparator: Placebo to remibrutinib<br>Participants will receive placebo for remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w for 24 weeks. From Week 24 to Week 52 participants will receive remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w. | Drug: Placebo to remibrutinib<br>* Placebo followed by active treatment<br>|
| Placebo Comparator: Placebo to omalizumab<br>Participants will receive placebo for remibrutinib 25 mg b.i.d. and placebo for omalizumab q4w for 24 weeks. From Week 24 to Week 52 participants will receive omalizumab 300 mg q4w and placebo for remibrutinib b.i.d. | Drug: Placebo to omalizumab<br>* Placebo followed by active comparator<br>|
| Active Comparator: Omalizumab<br>participants will receive omalizumab 300 mg q4w and placebo for remibrutinib b.i.d. for 52 weeks. | Drug: Omalizumab<br>* Active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in Weekly Urticaria Activity Score (UAS7) | The UAS7 is the sum of the Weekly Hives Severity Score (HSS7 score) and the Weekly Itch Severity Score (ISS7 score). The possible range of the weekly UAS7 score is 0 - 42 (highest activity). | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of UAS7=0 (yes/no) | Complete UAS7 response is UAS7 = 0 | Week 12 | 
| Improvement of severity of itch, assessed as absolute change from baseline in ISS7 score | The severity of the itch will be recorded by the participant twice daily in their eDiary, on a scale of 0 (none) to 3 (severe). A weekly score (ISS7) is derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 0 - 21. | Week 12 | 
| Improvement of severity of hives, assessed as absolute change from baseline in HSS7 score | The hives (wheals) severity score, defined by number of hives, will be recorded by the participant twice daily in their eDiary, on a scale of 0 (none) to 3 (> 12 hives/12 hours). A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 0 - 21. | Week 12 | 
| Occurrence of treatment-emergent adverse events and serious adverse events (SAEs) | To demonstrate the safety and tolerability of remibrutinib (25 mg b.i.d.) | up to 68 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CSU, urticaria, LOU064, omalizumab, remibrutinib