24 Weeks Double-blind Randomized Placebo-controlled Trial to Evaluate Efficacy, PK, Safety of LOU064 in Adolescents (12 - <18) With CSU and Inadequate Response to H1-antihistamine Followed by Optional 3 Years Open-label Extension and an Optional 3 Years Safety Long-term Treatment-free Follow-up

Study Overview
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Brief Summary
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The purpose of this trial is: to assess the efficacy, pharmacokinetics, and safety of remibrutinib vs. placebo in adolescents from 12 to < 18 years of age suffering from chronic spontaneous urticaria inadequately controlled by H1-antihistamines to collect long-term efficacy, safety and tolerability data on remibrutinib in adolescents after having completed 24 weeks of treatment to collect safety data in this population for up to three years after the last dose of treatment

Detailed Description
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This trial consists of 3 different periods: 1/ the core period, which is randomized and double-blind, during which 2/3 participants will receive remibrutinib and 1/3 will receive placebo for 12 weeks. After 12 weeks, all participants will receive remibrutinib for an additional 12 weeks. Total duration: approximately 34 weeks (10 site visits). 2/ an optional open-label extension period proposed to all participants who received remibrutinib for at least 4 months in the core period. Depending on their CSU symptoms (as assessed by the doctor), participants will either receive remibrutinib for 24 weeks, or enter an observational treatment-free period for 1 year. If the CSU symptoms return during the observational period, the participants can switch to the treatment period at any time (decided by the doctor). At the end of the 24-week treatment period, if CSU is controlled, participants will enter the 1-year observational period, otherwise, they can continue with another cycle of 24-week remibrutinib treatment. The number of remibrutinib treatment or observational cycles will be limited to 3 times each. Total duration: from 1 year to approximately 3 years, and number of visits: from 3 to 10 (depending on the CSU symptoms). 3/ an optional long-term treatment-free follow-up period proposed to all participants who completed at least 4 months treatment in the core period. No treatment will be given. Duration: 3 years with 1 site visit and up to 5 phone call follow-up visits. The primary clinical question of interest is what is the effect of remibrutinib treatment versus placebo on the change from baseline in UAS7, ISS7 and HSS7 scores after 12 weeks of treatment

Official Title
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A Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy, Pharmacokinetics and Safety of Remibrutinib (LOU064) for 24 Weeks in Adolescents From 12 to Less Than 18 Years of Age With Chronic Spontaneous Urticaria Inadequately Controlled by H1-antihistamines Followed by an Optional Open-label Extension for up to Another 3 Years and an Optional Safety Long-term Treatment-free Follow-up Period for up to an Additional 3 Years

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: LOU064 (blinded)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female adolescent participants aged ≥ 12 to < 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-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 according to local treatment guidelines 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) Key Exclusion criteria: Previous use of remibrutinib or other BTK inhibitors Significant bleeding risk or coagulation disorders. History of gastrointestinal bleeding. Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100 mg/d or clopidogrel up to 75 mg/d. The use of dual anti-platelet therapy (e.g., acetylsalicylic acid + clopidogrel) is prohibited. 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. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes Participants having a clearly defined predominant or sole trigger of their chronic urticaria (chronic inducible urticaria) 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 angioedema, 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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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>LOU064 (blinded) taken orally b.i.d. for 24 weeks, followed by LOU064 (open-label) taken orally b.i.d. for up to 3 cycles of 24 weeks. | Drug: LOU064 (blinded)<br>* LOU064 (blinded) active treatment<br>* Other names: remibrutinib;|
| Placebo Comparator: Arm 2: LOU064 placebo (blinded)<br>LOU064 placebo (blinded) taken orally b.i.d. for 12 weeks (randomized in a 2:1 ratio arm 1: arm 2), followed by LOU064 (open-label) taken orally b.i.d. for 12 weeks | Drug: placebo<br>* matching active drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in UAS7 | The Urticaria Activity Score (UAS) is sum of the Hive Severity Score (HSS) and the Itch Severity Score (ISS). UAS7 is sum of the HSS7 and the ISS7 scores. Possible range of weekly UAS7 score is 0 to 42. Complete UAS7 response is UAS7 = 0. Negative change from baseline indicates improvement. | Baseline, week 12 | 
| Change fron baseline in ISS7 | Itch Severity Score (ISS) scale is 0 to 3. Score (ISS7) is derived by adding up average daily scores of 7 days preceding visit. Possible range of weekly score is therefore 0 to 21. Itch Severity Score scale: 0 - None 1 - Mild (minimal awareness, easily tolerated) 2 - Moderate (definite awareness, bothersome but tolerable) 3 - Severe (difficult to tolerate). Negative change from baseline indicates improvement. | Baseline, Week 12 | 
| Change from baseline in HSS7 | Hives Severity Score (HSS) scale is 0 to 3. A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days preceding the visit. Possible range of the weekly score is therefore 0 to 21. Hives Severity Score scale: 0 - None 1 - Mild (1-6 hives/12 hours) 2 - Moderate (7-12 hives/12 hours) 3 - Severe (>12 hives/12 hours). Negative change from baseline indicates improvement. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of remibrutinib | The maximum (peak) observed blood drug concentration after single dose administration | At Week 12, before study drug intake, then after 30 min, 1 h, 2h, 3h and 4 h after study drug intake | 
| Tmax of remibrutinib | The time to reach maximum (peak) blood drug concentration after single dose administration | At Week 12, before study drug intake, then after 30 min, 1 h, 2h, 3h and 4 h after study drug intake | 
| AUClast of remibrutinib | The Area Under the Curve (AUC) from pre-dose to the last measurable concentration sampling time | At Week 12, before study drug intake, then after 30 min, 1 h, 2h, 3h and 4 h after study drug intake | 
| Absolute change from baseline in ISS7 | Itch Severity Score (ISS) scale is 0 to 3. Score (ISS7) is derived by adding up average daily scores of 7 days preceding visit. Possible range of weekly score is therefore 0 to 21. Itch Severity Score scale: 0 - None 1 - Mild (minimal awareness, easily tolerated) 2 - Moderate (definite awareness, bothersome but tolerable) 3 - Severe (difficult to tolerate). Negative change from baseline indicates improvement. | Baseline - Week 12 | 
| Absolute change from baseline in HSS7 | Hives Severity Score (HSS) scale is 0 to 3. A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days preceding the visit. Possible range of the weekly score is therefore 0 to 21. Hives Severity Score scale: 0 - None 1 - Mild (1-6 hives/12 hours) 2 - Moderate (7-12 hives/12 hours) 3 - Severe (>12 hives/12 hours). Negative change from baseline indicates improvement. | Baseline - Week 12 | 
| Achievement of UAS7 ≤ 6 (yes/no) | Disease activity control is defined as UAS7 ≤ 6. The Urticaria Activity Score (UAS) is sum of the Hive Severity Score (HSS) and the Itch Severity Score (ISS). UAS7 is sum of the HSS7 and the ISS7 scores. Possible range of weekly UAS7 score is 0 to 42. | Week 12 and over time | 
| Achievement of UAS7 = 0 (yes/no) | Complete absence of hives and itch is defined as UAS7 = 0. The Urticaria Activity Score (UAS) is sum of the Hive Severity Score (HSS) and the Itch Severity Score (ISS). UAS7 is sum of the HSS7 and the ISS7 scores. Possible range of weekly UAS7 score is 0 to 42. | Week 12 and over time | 
| Absolute change from baseline in CDLQI score | The Children Dermatology life Quality Index (CDLQI) score range is 0 to 30, with 0 (meaning no impact of skin disease on quality of life) to 30 (meaning maximum impact on quality of life). | Week 12 | 
| Number of weeks without angioedema, assessed by the cumulative number of weeks with an AAS7 = 0 response | Angioedema Activity Score (AAS7) is a measure of the frequency and intensity of angioedema episodes. The total possible range of scores over 7 days is 0-105 where higher scores indicate increased angioedema activity. | baseline - Week 12 | 
| Occurrence of treatment-emergent adverse events (AE) and serious adverse events (SAE) during the core period | To demonstrate the safety and tolerability of remibrutinib by assessing occurrence of treatment emergent adverse events and serious adverse events during the core period of the study. | 28 weeks | 
| Occurrence of treatment emergent AEs, and SAEs during the Open Label Extension (OLE) period | To demonstrate the safety and tolerability of remibrutinib by assessing occurrence of treatment emergent adverse events and serious adverse events during the OLE period of the study. | 3 years | 

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