Clinical trial NCT05032157: A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1-antihistamines
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Spontaneous Urticaria
Keywords: Bruton Tyrosine Kinase (BTK) inhibitor
Chronic Spontaneous Urticaria (CSU)
Urticaria Activity Score (UAS)
Weekly Urticaria Activity Score (UAS7)
Hives Severity Score (HSS)
Weekly Hives Severity Score (HSS7)
Itch Severity Score (ISS)
Weekly Itch Severity Score (ISS7)
Angioedema Activity Score (AAS)
Weekly Angioedema Activity Score (AAS7)
Dermatology Life Quality Index (DLQI)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-09-02
Enrollment: 455
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12 (Scenario 1 With UAS7 as Primary Efficacy Endpoint)
timeFrame: Baseline, Week 12
measure: Mean Change From Baseline in Weekly Itch Severity Score (ISS7) at Week 12 (Scenario 2 With ISS7 and HSS7 as Co-primary Efficacy Endpoints)
timeFrame: Baseline, Week 12
measure: Mean Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12 (Scenario 2 With ISS7 and HSS7 as Co-primary Efficacy Endpoints)
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Number of Participants Who Achieved Disease Activity Control (UAS7 =< 6) at Week 12
timeFrame: Week 12
measure: Number of Participants Who Achieved Complete Absence of Hives and Itch (UAS7 = 0) at Week 12
timeFrame: Week 12
measure: Number of Participants Who Achieved Early Onset of Disease Activity Control (UAS7 =< 6) at Week 2
timeFrame: Week 2
measure: Number of Participants Who Achieved Dermatology Life Quality Index (DLQI) = 0-1 at Week 12
timeFrame: Week 12
measure: Mean Cumulative Number of Weeks With Disease Activity Control (UAS7 =< 6) up to Week 12
timeFrame: Up to Week 12
measure: Mean Cumulative Number of Angioedema Occurrence-free Weeks (AAS7 = 0 Response) up to Week 12
timeFrame: Up to Week 12
measure: Number of Participants With Treatment Emergent Adverse Events
timeFrame: Baseline up to 28 days after last dose of study medication, assessed up to approximately 56 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Cahaba Derm and skin hlth ctr 27
state: Alabama
city: Litchfield Park
country: United States
facility: Research Solutions of Arizona
state: Arizona
city: Little Rock
country: United States
facility: Little Rock Allergy and Asthma Clnc
state: Arkansas
city: San Diego
country: United States
facility: Allergy and Asthma Medical Group and Research Center
state: California
city: Farmington
country: United States
facility: UCONN Health Dermatology
state: Connecticut
city: Miami
country: United States
facility: Miami Dade Medical Research
state: Florida
city: North Miami Beach
country: United States
facility: Ziaderm Research LLC
state: Florida
city: Pembroke Pines
country: United States
facility: Riverchase Dermatology
state: Florida
city: Tampa
country: United States
facility: TrueBlue Clinical Research
state: Florida
city: Savannah
country: United States
facility: AeroAllergy Research Laboratories of Savannah Inc
state: Georgia
city: Boise
country: United States
facility: Treasure Valley Medical Research
state: Idaho
city: Glenview
country: United States
facility: Northshore University Health System
state: Illinois
city: River Forest
country: United States
facility: Asthma and Allergy Center of Chicago S C
state: Illinois
city: Plainfield
country: United States
facility: The Indiana Clinical Trials Center
state: Indiana
city: Owensboro
country: United States
facility: Allergy and Asthma Specialist P S C
state: Kentucky
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: White Marsh
country: United States
facility: Chesapeake Clinical Research
state: Maryland
city: Troy
country: United States
facility: Revival Research Institute
state: Michigan
city: Missoula
country: United States
facility: Montana Medical Research
state: Montana
city: Little Silver
country: United States
facility: Allergy Asthma Assoc Monmouth
state: New Jersey
city: High Point
country: United States
facility: Peters Medical Research
state: North Carolina
city: Dublin
country: United States
facility: CR Services Acquisition US
state: Ohio
city: Mayfield Heights
country: United States
facility: Ohio Clinical Research Associates
state: Ohio
city: Oklahoma City
country: United States
facility: Allergy Asthma and Clinical Research
state: Oklahoma
city: Pittsburgh
country: United States
facility: Allergy and Clinical Immunology Associates
state: Pennsylvania
city: North Charleston
country: United States
facility: National Allergy and Asthma Research LLS
state: South Carolina
city: San Antonio
country: United States
facility: STAAMP Research LLC
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain Clinical Research
state: Utah
city: Seattle
country: United States
facility: Seattle Allergy and Asthma Rsch
state: Washington
city: Greenfield
country: United States
facility: Allergy Asthma and amp Sinus Ctr S C
state: Wisconsin
city: Linz
country: Austria
facility: Novartis Investigative Site
state: Oberoesterreich
city: Sao Bernardo do Campo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Fredericton
country: Canada
facility: Novartis Investigative Site
state: New Brunswick
city: Kingston
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Niagara Falls
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Verdun
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Guangdong
country: China
facility: Novartis Investigative Site
state: Guangzhou
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Wuxi
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Chang Chun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Shenyang
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Yi Wu
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Copenhagen NV
country: Denmark
facility: Novartis Investigative Site
city: Hellerup
country: Denmark
facility: Novartis Investigative Site
city: Bad Bentheim
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bramsche
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Gottingen
country: Germany
facility: Novartis Investigative Site
city: Halle Saale
country: Germany
facility: Novartis Investigative Site
city: Halle S
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Langenau
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Luebeck
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Merzig
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ahmedabad
country: India
facility: Novartis Investigative Site
state: Gujarat
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Mysore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Nashik
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Dehradun
country: India
facility: Novartis Investigative Site
state: Uttarakhand
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Surat
country: India
facility: Novartis Investigative Site
city: Muar
country: Malaysia
facility: Novartis Investigative Site
state: Johor
city: Ipoh
country: Malaysia
facility: Novartis Investigative Site
state: Perak
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
state: Wilayah Persekutuan
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Wilayah Persekutuan
country: Malaysia
facility: Novartis Investigative Site
city: Bialystok
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Stavropol
country: Russian Federation
facility: Novartis Investigative Site
city: Kezmarok
country: Slovakia
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Svidnik
country: Slovakia
facility: Novartis Investigative Site
city: Topolcany
country: Slovakia
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
state: Gauteng
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
state: Western Province
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Bangkoknoi
country: Thailand
facility: Novartis Investigative Site
state: Bangkok
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
state: West Yorkshire
city: Cardiff
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: