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

Chronic Spontaneous Urticaria Clinical Trial

— REMIX-2  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05032157
• Other study ID #: CLOU064A2302
• Secondary ID: 2021-000424-35
• Status: Completed
• Phase: Phase 3
• Start date: December 1, 2021
• Est. completion date: January 5, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 456
• Est. completion date: January 5, 2024
• Est. primary completion date: December 7, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Spontaneous Urticaria
• Chronic Urticaria
• Urticaria

Intervention

Drug:
• LOU064 (blinded)
LOU064 (blinded) active treatment
• Placebo
Placebo
• LOU064 (open-label)
LOU064 (open -label) active treatment

Locations

Country	Name	City	State
Austria	Novartis Investigative Site	Linz	Oberoesterreich
Brazil	Novartis Investigative Site	Sao Bernardo do Campo	SP
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Fredericton	New Brunswick
Canada	Novartis Investigative Site	Kingston	Ontario
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Niagara Falls	Ontario
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Verdun	Quebec
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chang Chun	Jilin
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Guangdong	Guangzhou
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanyang
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Wuhan	Hubei
China	Novartis Investigative Site	Wuxi	Jiangsu
China	Novartis Investigative Site	Yi Wu	Zhejiang
Denmark	Novartis Investigative Site	Copenhagen NV
Denmark	Novartis Investigative Site	Hellerup
Germany	Novartis Investigative Site	Bad Bentheim
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bramsche
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Gottingen
Germany	Novartis Investigative Site	Halle
Germany	Novartis Investigative Site	Halle (Saale)
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Langenau
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Luebeck
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Merzig
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Tuebingen
India	Novartis Investigative Site	Ahmedabad	Gujarat
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	DehraDun	Uttarakhand
India	Novartis Investigative Site	Kolkata	West Bengal
India	Novartis Investigative Site	Mysore	Karnataka
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nashik	Maharashtra
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Surat
Malaysia	Novartis Investigative Site	Ipoh	Perak
Malaysia	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan
Malaysia	Novartis Investigative Site	Muar	Johor
Malaysia	Novartis Investigative Site	Penang
Malaysia	Novartis Investigative Site	Wilayah Persekutuan
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Warszawa
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	Stavropol
Slovakia	Novartis Investigative Site	Kezmarok
Slovakia	Novartis Investigative Site	Kosice	Slovak Republic
Slovakia	Novartis Investigative Site	Svidnik
Slovakia	Novartis Investigative Site	Topolcany
South Africa	Novartis Investigative Site	Cape Town	Western Province
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Pretoria	Gauteng
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Zuerich
Switzerland	Novartis Investigative Site	Zuerich
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taoyuan
Thailand	Novartis Investigative Site	Bangkok	Phayathai
Thailand	Novartis Investigative Site	Bangkoknoi	Bangkok
Thailand	Novartis Investigative Site	Chiang Mai
Thailand	Novartis Investigative Site	Khon Kaen	THA
United Kingdom	Novartis Investigative Site	Cardiff
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	Oxford
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boise	Idaho
United States	Novartis Investigative Site	Dublin	Ohio
United States	Novartis Investigative Site	Farmington	Connecticut
United States	Novartis Investigative Site	Glenview	Illinois
United States	Novartis Investigative Site	Greenfield	Wisconsin
United States	Peters Medical Research	High Point	North Carolina
United States	Research Solutions of Arizona .	Litchfield Park	Arizona
United States	Novartis Investigative Site	Little Rock	Arkansas
United States	Novartis Investigative Site	Little Silver	New Jersey
United States	Novartis Investigative Site	Mayfield Heights	Ohio
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Missoula	Montana
United States	Novartis Investigative Site	North Charleston	South Carolina
United States	Novartis Investigative Site	North Miami Beach	Florida
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Allergy and Asthma Specialist P S C Main Center	Owensboro	Kentucky
United States	Novartis Investigative Site	Pembroke Pines	Florida
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	The Indiana Clinical Trials Center	Plainfield	Indiana
United States	Asthma and Allergy Center of Chicago S C	River Forest	Illinois
United States	Novartis Investigative Site	Salt Lake City	Utah
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	Savannah	Georgia
United States	Novartis Investigative Site	Seattle	Washington
United States	TrueBlue Clinical Research .	Tampa	Florida
United States	Revival Research Institute	Troy	Michigan
United States	Novartis Investigative Site	White Marsh	Maryland
Vietnam	Novartis Investigative Site	Hanoi
Vietnam	Novartis Investigative Site	Ho Chi Minh

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Vietnam,  Austria,  Brazil,  Canada,  China,  Denmark,  Germany,  India,  Malaysia,  Poland,  Russian Federation,  Slovakia,  South Africa,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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