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

Novartis Pharmaceuticals455 enrolled

Overview

The purpose of this study was to establish the efficacy, safety, and tolerability of Remibrutinib 25 mg b.i.d. in adult patients suffering from chronic spontaneous urticaria (CSU) inadequately controlled by second generation H1-antihistamines (H1-AHs) in comparison to placebo.

The study consisted of four periods, the total study duration was up to 60 weeks: Screening period of up to 4 weeks, Double-blind placebo-controlled treatment period of 24 weeks, Open-label treatment period with Remibrutinib period of 28 weeks, and treatment free follow-up period of 4 weeks. The design of this study was a replicate of another Phase III study, CLOU046A2301 (NCT05030311). The study population consisted of female and male adult patients with CSU inadequately controlled by second generation H1-AHs at least at a locally label approved dose. All patients were on a stable, locally label approved 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). To treat unbearable symptoms of CSU, patients were allowed to use another second generation H1-AH on an as-needed basis (rescue therapy). Eligible patients were randomly assigned to the treatment arms in a 2:1 ratio to remibrutinib or placebo arm (300 in the remibrutinib arm and 150 in placebo arm) and stratified based on prior exposure to anti-IgE biologics for CSU and geographic region. An extension Phase IIIb study, CLOU064A2303B (NCT05513001), was initiated to allow CLOU064A2302 eligible patients to roll over after completion of the open-label treatment period. There were two distinct testing strategies (scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint and scenario 2 with Weekly Itch Severity Score (ISS7) and Weekly Hives Severity Score (HSS7) as the co-primary efficacy endpoints) based on two primary objective scenarios related to regional regulatory precedent and Health Authorities' feedback.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

455

Conditions

Chronic Spontaneous Urticaria

Interventions

LOU064 (blinded)DRUG

LOU064 (blinded) active treatment

PlaceboDRUG

Placebo

LOU064 (open-label)DRUG

LOU064 (open-label) active treatment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

Key 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). Key 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

Locations (122)

Outcomes

Primary Outcomes

Mean Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12 (Scenario 1 With UAS7 as Primary Efficacy Endpoint)

The Weekly Urticaria Activity Score (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 (highest urticaria severity), and a minimum possible score of 0. This endpoint is a secondary endpoint for testing strategy Scenario 2 with Weekly Itch Severity Score (ISS7) and Weekly Hives Severity Score (HSS7) as co-primary efficacy endpoints).

Time frame: Baseline, Week 12

Mean Change From Baseline in Weekly Itch Severity Score (ISS7) at Week 12 (Scenario 2 With ISS7 and HSS7 as Co-primary Efficacy Endpoints)

The severity of the itch was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (severe). A weekly score (ISS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest itch severity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint).

Time frame: Baseline, Week 12

Mean Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12 (Scenario 2 With ISS7 and HSS7 as Co-primary Efficacy Endpoints)

The hives (wheals) severity score, defined by number of hives, was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (\> 12 hives/12 hours). A weekly score (HSS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest hives activity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint).

Time frame: Baseline, Week 12

Secondary Outcomes

Data from ClinicalTrials.gov

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Number of Participants Who Achieved Disease Activity Control (UAS7 =< 6) at Week 12

The percentage of patients achieving disease activity control (UAS7 =\< 6) at Week 12 was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 - 42 (highest hives and itch severity).

Time frame: Week 12

Number of Participants Who Achieved Complete Absence of Hives and Itch (UAS7 = 0) at Week 12

The proportion of patients achieving complete absence of hives and itch (UAS7 = 0) at Week 12 was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 - 42 (highest hives and itch severity).

Time frame: Week 12

Number of Participants Who Achieved Early Onset of Disease Activity Control (UAS7 =< 6) at Week 2

The percentage of patients achieving disease activity control (UAS7 =\< 6) at Week 2 was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 - 42 (highest hives and itch severity).

Time frame: Week 2

Number of Participants Who Achieved Dermatology Life Quality Index (DLQI) = 0-1 at Week 12

The Dermatology Life Quality Index (DLQI) is a 10-item (grouped in 6 domains) dermatology-specific quality of life (QoL) measure. Participants are rating their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives thinking about the previous 7 days. An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-related QoL). Domain scores are calculated for: Symptoms and Feelings (0-6), Daily Activities (0-6), Leisure (0-6), Work and School (0-3), Personal Relationships (0-6), Treatment (0-3). The overall DLQI score range was split into score bands and validated in terms of their meaning/relevance to patients overall DLQI = 0-1 means no effect on patient's life.

Time frame: Week 12

Mean Cumulative Number of Weeks With Disease Activity Control (UAS7 =< 6) up to Week 12

Maintaining disease activity control was assessed as cumulative number of weeks with an UAS7 =\< 6 response between baseline and Week 12. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 - 42 (highest hives and itch severity).

Time frame: Up to Week 12

Mean Cumulative Number of Angioedema Occurrence-free Weeks (AAS7 = 0 Response) up to Week 12

Angioedema occurrence was recorded once daily in the evening in the electronic Diary by the participant. Reporting the occurrence of angioedema was used as opening question for the assessment of the Angioedema Activity Score (AAS). The AAS consists of 5 questions with 4 answer options (scored 0-3) for each item, with a minimum score of 0 and a maximum score of 15 per day. The AAS score over 7 days (AAS7) ranges from 0 (no angioedema episodes) to 105 (highest angioedema severity).

Time frame: Up to Week 12

Number of Participants With Treatment Emergent Adverse Events

An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 28 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 28 days after the last study treatment.

Time frame: Baseline up to 28 days after last dose of study medication, assessed up to approximately 56 weeks