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-1  

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: NCT05030311
• Other study ID #: CLOU064A2301
• Secondary ID: 2021-000471-37
• Status: Completed
• Phase: Phase 3
• Start date: November 30, 2021
• Est. completion date: January 19, 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 treatment period of 24 weeks, open-label treatment period of 28 weeks and 4 weeks of treatment-free follow up.

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: 470
• Est. completion date: January 19, 2024
• Est. primary completion date: December 27, 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.

• 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 (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 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
Argentina	Novartis Investigative Site	Bahia Blanca
Argentina	Novartis Investigative Site	Buenos Aires	Nueve De Julio
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal
Argentina	Novartis Investigative Site	La Plata	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Santa Fe	Rosario
Argentina	Novartis Investigative Site	Santa Fe
Australia	Novartis Investigative Site	East Melbourne	Victoria
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Sydney	New South Wales
Bulgaria	Novartis Investigative Site	Pleven
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Colombia	Novartis Investigative Site	Barranquilla	Atlantico
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Medellin	Antioquia
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Olomouc
Czechia	Novartis Investigative Site	Plzen
Czechia	Novartis Investigative Site	Praha 5
France	Novartis Investigative Site	Antony
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Nice
France	Novartis Investigative Site	Pierre Benite
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Rouen
Hungary	Novartis Investigative Site	Debrecen	Hajdu Bihar
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szeged
India	Novartis Investigative Site	Belagavi	Karnataka
India	Novartis Investigative Site	Chandigarh
India	Novartis Investigative Site	Hyderabad	Telangana
India	Novartis Investigative Site	Kolkata	West Bengal
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nashik	Maharashtra
India	Novartis Investigative Site	New Delhi	Delhi
India	Novartis Investigative Site	Varanasi	Uttar Pradesh
Italy	Novartis Investigative Site	Ancona	AN
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Torino	TO
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Hiroshima
Japan	Novartis Investigative Site	Kamimashi-gun	Kumamoto
Japan	Novartis Investigative Site	Koto	Tokyo
Japan	Novartis Investigative Site	Obihiro	Hokkaido
Japan	Novartis Investigative Site	Takatsuki-city	Osaka
Japan	Novartis Investigative Site	Yokohama	Kanagawa
Korea, Republic of	Novartis Investigative Site	Daegu	Dalseo Gu
Korea, Republic of	Novartis Investigative Site	Gwangju
Korea, Republic of	Novartis Investigative Site	Hwaseong si	Gyeonggi Do
Korea, Republic of	Novartis Investigative Site	Incheon
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Suwon si	Gyeonggi Do
Mexico	Novartis Investigative Site	Ciudad de Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Villahermosa	Tabasco
Puerto Rico	Novartis Investigative Site	Carolina
Puerto Rico	Novartis Investigative Site	San Juan
Russian Federation	Novartis Investigative Site	Izhevsk
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Alicante	Comunidad Valenciana
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Las Palmas de Gran Canaria
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Aydin
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Kayseri
Turkey	Novartis Investigative Site	Sakarya
Turkey	Novartis Investigative Site	Samsun
Turkey	Novartis Investigative Site	Talas / Kayseri
United States	Novartis Investigative Site	Albany	Georgia
United States	Oakview Dermatology	Athens	Ohio
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Aventura	Florida
United States	Kern Research	Bakersfield	California
United States	Bellingham Asthma Allergy and Immunology	Bellingham	Washington
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Institute for Asthma and Allergy PC .	Chevy Chase	Maryland
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	El Paso	Texas
United States	Novartis Investigative Site	Evansville	Indiana
United States	Finlay Medical Research	Greenacres City	Florida
United States	Novartis Investigative Site	Lancaster	California
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Murray	Utah
United States	Arkansas Research Trials	North Little Rock	Arkansas
United States	Novartis Investigative Site	Redwood City	California
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	RFSA Dermatology	San Antonio	Texas
United States	Novartis Investigative Site	Sarasota	Florida
United States	Novartis Investigative Site	Tallahassee	Florida
United States	Novartis Investigative Site	Toledo	Ohio
United States	Vital Prospects Clinical Research Institute	Tulsa	Oklahoma
United States	Novartis Investigative Site	Woodstock	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Bulgaria,  Colombia,  Czechia,  France,  Hungary,  India,  Italy,  Japan,  Korea, Republic of,  Mexico,  Puerto Rico,  Russian Federation,  Singapore,  Spain,  Taiwan,  Turkey, 

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 weekly Urticaria Activity Score (UAS7) at week 12.; The UAS7 is a 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 and 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 from baseline in UAS7 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	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 assessing achievement of UAS7 at week 12.	12 weeks
Secondary	Reduction of 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 absolute change from baseline in ISS7 score.	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 by assessing absolute change from baseline in HSS7 score.	12 weeks
Secondary	Early onset of disease control (UAS7 = 6 at week 2)	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 UAS = 6 at week 2.	2 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 assessing achievement of UA7 = 6 at week 12.	12 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	Number of weeks without angioedema (AAS = 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 AAS = 0 response between baseline and week 12.	12 weeks
Secondary	Number of participants with Adverse Events	To demonstrate the safety and tolerability of remibrutinib by assessing the occurrence of treatment emergent adverse events and serious adverse events during the study.	56 weeks