A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1- Antihistamines

Study Overview
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Brief Summary
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The purpose of this study is to establish the efficacy, safety, and tolerability of remibrutinib (LOU064) in adult participants suffering from chronic spontaneous urticaria (CSU) inadequately controlled by H1-antihistamines in comparison to placebo.

Detailed Description
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This is a global, multicenter, randomized, double-blind, parallel-group, placebo-controlled Phase 3 study investigating the safety, tolerability, and efficacy of remibrutinib in adult participants with CSU inadequately controlled by second generation H1-antihistamines. Inadequate control of CSU by H1-antihistamines is defined as: The presence of itch and hives for ≥ 6 consecutive weeks prior to screening despite the use of second generation H1-antihistamines 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) The study consists of four periods, the total study duration is up to 60 weeks: screening period of up to 4 weeks, double-blind placebo controlled treatment period of 24 weeks, open-label treatment with remibrutinib period of 28 weeks, treatment free follow-up period of 4 weeks. Eligible participants will be randomly assigned to the treatment arms in a 2:1 ratio. The study population will consist of approximately 450 female and male adult participants (300 in the active arm and 150 in the placebo arm) with CSU inadequately controlled by second generation H1-antihistamines at least at locally label approved dose.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of Remibrutinib (LOU064) to Investigate the Efficacy, Safety and Tolerability for 52 Weeks in Adult Chronic Spontaneous Urticaria (CSU) Patients Inadequately Controlled by H1-antihistamines

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: LOU064 (blinded)
* Drug: Placebo
* Drug: LOU064 (open-label)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Male and female adult participants ≥18 years of age at the time of screening. CSU duration for ≥ 6 months prior to screening (defined as the onset of CSU determined by the investigator based on all available supporting documentation). Diagnosis of CSU inadequately controlled by second generation H1-antihistamines 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-antihistamines 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 (either at screening and/or at randomization; or documented in the participants medical history). 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: Participants having a clearly defined predominant or sole trigger of their chronic urticaria (CU) (chronic inducible urticaria (CINDU)) including urticaria factitia (symptomatic dermographism), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic-, or contact-urticaria Other diseases with symptoms of urticaria or angioedema, including but not limited to urticaria vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary urticaria, or drug-induced urticaria Any other skin disease associated with chronic itching that might influence in the investigator's opinion the study evaluations and results, e.g. atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus or psoriasis Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, New York heart association (NYHA) Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 12 months prior to Visit 1), 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 Significant bleeding risk or coagulation disorders History of gastrointestinal bleeding, e.g. in association with use of nonsteroidal anti-inflammatory drugs (NSAID), that was clinically relevant (e.g. requiring hospitalization or blood transfusion) Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100 mg/d or clopidogrel. The use of dual anti-platelet therapy (e.g. acetylsalicylic acid + clopidogrel) is prohibited. Requirement for anticoagulant medication (for example, warfarin or Novel Oral Anti-Coagulants (NOAC)) History or current hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) or International Normalized Ratio (INR) of more than 1.5 at screening

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: LOU064 (blinded)<br>LOU064A (blinded) taken orally b.i.d. for 24 weeks, followed by LOU064 (open-label) taken orally open label for 28 weeks. Randomised in 2:1 ratio (active vs placebo) | Drug: LOU064 (blinded)<br>* LOU064 (blinded) active treatment<br>* Other names: remibrutinib;Drug: LOU064 (open-label)<br>* LOU064 (open -label) active treatment<br>* Other names: remibrutinib;|
| Placebo Comparator: Arm 2: LOU064 placebo (blinded)<br>LOU064A placebo (blinded) taken orally for 24 weeks, followed by LOU064 (open-label) taken orally open label for 28 weeks. Randomised in 2:1 ratio (active vs placebo) | Drug: Placebo<br>* Placebo<br>Drug: LOU064 (open-label)<br>* LOU064 (open -label) active treatment<br>* Other names: remibrutinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in UAS7 (Scenario 1 with UAS7 as primary efficacy endpoint) | To demonstrate that remibrutinib is superior to placebo in CSU with respect to change from baseline in UAS7 at Week 12 by assessing absolute change from baseline in UAS7 at Week 12. To demonstrate that remibrutinib is superior to placebo in CSU with respect to change from baseline in UAS7 at Week 12 by assessing absolute change from baseline in weekly Urticaria Activity Score (UAS7) at week 12. The UAS7 is a simple scoring system to evaluate urticaria signs and symptoms. It is based on scoring wheals (hive severity score) and itch (itch severity score) separately on a scale of 0 (no signs/symptoms) to 3 (intense signs/symptoms) over 7 days. The final score is calculated by adding together the daily scores, which can range from 0 to 6, for 7 days. This results in a maximum total score of 42, and a minimum possible score of 0 | 12 weeks | 
| Absolute change in ISS7 an absolute change in HSS7 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints) | To demonstrate that remibrutinib is superior to placebo in CSU with respect to change from baseline in ISS7 and HSS7 at Week 12 by assessing absolute change from baseline in weekly Itch Severity Score (ISS7) and weekly Hive Severity Score (HSS7) at week 12. The ISS7 and HSS7 combined together make up the UAS7 scoring system to evaluate urticaria signs and symptoms. The HSS7 score is the wheal/hives severity score for 7 days and the ISS7 is the itch severity score for 7 days, both these scores range from 0 to 21. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in UAS7 (only in scenario 2) | To demonstrate that remibrutinib is superior to placebo in CSU with respect to change from baseline in UAS7 at Week 12 by assessing absolute change in baseline in UAS7 at week 12. | 12 weeks | 
| Disease activity control (UAS7 ≤ 6) | To demonstrate that a greater proportion of participants achieve disease activity control (UAS7 ≤ 6) at Week 12 who are treated with remibrutinib compared to placebo-treated participants by achievement of UAS7 ≤ 6 at Week 12 | 12 weeks | 
| Complete absence of hives and itch (UAS7 = 0) | To demonstrate that a greater proportion of participants achieve complete absence of hives and itch (UAS7 = 0) at Week 12 who are treated with remibrutinib compared to placebo-treated participants by achievement of UAS7 = 0 at week 12 | 12 weeks | 
| Reduction in weekly ISS score (only in scenario 1) | To demonstrate the superiority of remibrutinib treated participants with respect to a reduction from baseline in the weekly itch severity score at Week 12 compared to placebo-treated participants by assessing the absolute change from baseline in ISS7 score at week 12. | 12 weeks | 
| Reduction of weekly HSS score (only in scenario 1) | To demonstrate the superiority of remibrutinib treated participants with respect to a reduction from baseline in the weekly hive severity score at Week 12 compared to placebo-treated participants assessed by the absolute change from baseline in HSS7 score at Week 12 | 12 weeks | 
| Early onset of disease activity control | To demonstrate that a greater proportion of participants achieve UAS7 ≤ 6 at Week 2 who are treated with remibrutinib compared to placebo-treated participants by assessing achievement of UAS7 ≤ 6 at Week 2 | 2 weeks | 
| Achievement of DLQI = 0-1 | To demonstrate that a greater proportion of participants who are treated with remibrutinib achieve DLQI = 0-1 at Week 12 compared to placebo-treated participants by assessing achievement of DLQI = 0-1 at Week 12 | 12 weeks | 
| Sustained disease activity control (UAS7 ≤ 6) | To demonstrate that remibrutinib treated participants maintain disease activity control (defined as UAS7 ≤ 6) for more weeks compared to placebo treated participants over 12 weeks by assessing cumulative number of weeks with an UAS7 ≤ 6 response between baseline and Week 12 | 12 weeks | 
| Number of weeks without angiodema (AAS7 = 0) | To demonstrate that remibrutinib treated participants have more angioedema occurrence-free weeks over 12 weeks compared with placebo-treated participants by assessing the cumulative number of weeks with an AAS7 = 0 response between baseline and Week 12 | 12 weeks | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability of remibrutinib] | To demonstrate the safety and tolerability of remibrutinib by assessing occurrence of treatment emergent adverse events and serious adverse events during the study. | 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CSU, BTK inhibitor, Chronic spontaneous urticaria, Urticaria activity score, Hives severity score, Itch severity score