A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1 Antihistamines (REMIX-1)

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

The purpose of this study was 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.

Study Overview

• Status: Completed
• Conditions: Chronic Spontaneous Urticaria
• Intervention / Treatment: Drug: Placebo; Drug: LOU064 25 mg (b.i.d); Drug: LOU064 25 mg (b.i.d) as a tablet.

Detailed Description

This was a global Phase III multi-centered, randomized,double-blind, parallel-group, placebo-controlled study investigating the safety, tolerability, and efficacy of remibrutinib (25 mg b.i.d.) in adult patients with CSU inadequately controlled by second generation H1-antihistamines (H1-AHs). 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 planned sample size was approximately 450 patients randomized in 2:1 ratio to remibrutinib or placebo arm (300 in the remibrutinib arm and 150 in placebo arm).

• Study Type: Interventional
• Enrollment (Actual): 470
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Bahia Blanca, Argentina, B8000JRB
    • Novartis Investigative Site
  • Capital Federal, Argentina, C1023AAB
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000FIL
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1181ACH
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1414AIF
      • Novartis Investigative Site
    • La Plata, Buenos Aires, Argentina, B1902COS
      • Novartis Investigative Site
  • Nueve De Julio
    • Buenos Aires, Nueve De Julio, Argentina, B6500BWQ
      • Novartis Investigative Site
  • Rosario
    • Santa Fe, Rosario, Argentina, S2000DBS
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000JKR
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • Novartis Investigative Site
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
    • Parkville, Victoria, Australia, 3050
      • Novartis Investigative Site
• Bulgaria
  • Pleven, Bulgaria, 5800
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1431
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1407
    • Novartis Investigative Site
• Colombia
  • Barranquilla, Colombia, 080020
    • Novartis Investigative Site
  • Bogota, Colombia, 110221
    • Novartis Investigative Site
  • Antioquia
    • Medellin, Antioquia, Colombia, 050010
      • Novartis Investigative Site
  • Atlantico
    • Barranquilla, Atlantico, Colombia, 080002
      • Novartis Investigative Site
• Czechia
  • Plzen, Czechia, 305 99
    • Novartis Investigative Site
  • Praha 5, Czechia, 150 06
    • Novartis Investigative Site
  • CZE
    • Olomouc, CZE, Czechia, 779 00
      • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 91
      • Novartis Investigative Site
• France
  • Antony, France, 92160
    • Novartis Investigative Site
  • Bordeaux Cedex, France, 33075
    • Novartis Investigative Site
  • Nice, France, 06000
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
  • Reims, France, 51100
    • Novartis Investigative Site
  • Rouen, France, 76031
    • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Szeged, Hungary, 6720
    • Novartis Investigative Site
  • Hajdu Bihar
    • Debrecen, Hajdu Bihar, Hungary, 4026
      • Novartis Investigative Site
• India
  • Belgavi, India, 590010
    • Novartis Investigative Site
  • Chandigarh, India, 160012
    • Novartis Investigative Site
  • Delhi
    • New Delhi, Delhi, India, 110 060
      • Novartis Investigative Site
  • Maharashtra
    • Nagpur, Maharashtra, India, 440015
      • Novartis Investigative Site
    • Nagpur, Maharashtra, India, 440012
      • Novartis Investigative Site
    • Nashik, Maharashtra, India, 422005
      • Novartis Investigative Site
  • Telangana
    • Hyderabad, Telangana, India, 500004
      • Novartis Investigative Site
  • Uttar Pradesh
    • Varanasi, Uttar Pradesh, India, 221005
      • Novartis Investigative Site
  • West Bengal
    • Kolkata, West Bengal, India, 700054
      • Novartis Investigative Site
• Italy
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10128
      • Novartis Investigative Site
• Japan
  • Fukuoka, Japan, 819 0167
    • Novartis Investigative Site
  • Hiroshima, Japan, 734-8551
    • Novartis Investigative Site
  • Hokkaido
    • Obihiro, Hokkaido, Japan, 080 0013
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 220-6208
      • Novartis Investigative Site
  • Kumamoto
    • Kamimashi-gun, Kumamoto, Japan, 861-3106
      • Novartis Investigative Site
  • Osaka
    • Takatsuki, Osaka, Japan, 569-8686
      • Novartis Investigative Site
  • Tokyo
    • Koto, Tokyo, Japan, 136-0074
      • Novartis Investigative Site
• Korea, Republic of
  • Gwangju, Korea, Republic of, 61469
    • Novartis Investigative Site
  • Incheon, Korea, Republic of, 405 760
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 07441
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 07061
    • Novartis Investigative Site
  • Dalseo Gu
    • Daegu, Dalseo Gu, Korea, Republic of, 42602
      • Novartis Investigative Site
  • Gyeonggi Do
    • Hwaseong si, Gyeonggi Do, Korea, Republic of, 18450
      • Novartis Investigative Site
    • Suwon si, Gyeonggi Do, Korea, Republic of, 16499
      • Novartis Investigative Site
• Mexico
  • Distrito Federal
    • Ciudad de Mexico, Distrito Federal, Mexico, 06700
      • Novartis Investigative Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44130
      • Novartis Investigative Site
  • Tabasco
    • Villahermosa, Tabasco, Mexico, 86035
      • Novartis Investigative Site
• Puerto Rico
  • Carolina, Puerto Rico, 00985
    • Novartis Investigative Site
  • San Juan, Puerto Rico, 00927
    • Novartis Investigative Site
• Russian Federation
  • Izhevsk, Russian Federation, 426061
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 308205
    • Novartis Investigative Site
• Spain
  • Las Palmas de Gran Canaria, Spain, 35010
    • Novartis Investigative Site
  • Madrid, Spain, 280796
    • Novartis Investigative Site
  • Valencia, Spain, 46026
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08003
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03010
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46015
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
• Turkey
  • Aydin, Turkey, 09100
    • Novartis Investigative Site
  • Istanbul, Turkey, 34662
    • Novartis Investigative Site
  • Izmir, Turkey, 35380
    • Novartis Investigative Site
  • Izmir, Turkey, 35100
    • Novartis Investigative Site
  • Izmir, Turkey, 35620
    • Novartis Investigative Site
  • Kayseri, Turkey, 38070
    • Novartis Investigative Site
  • Sakarya, Turkey, 54290
    • Novartis Investigative Site
  • Samsun, Turkey, 55139
    • Novartis Investigative Site
  • Talas Kayseri, Turkey, 38039
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Novartis Investigative Site
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Novartis Investigative Site
  • California
    • Bakersfield, California, United States, 93301
      • Novartis Investigative Site
    • Lancaster, California, United States, 93534
      • Novartis Investigative Site
    • Los Angeles, California, United States, 90025
      • Novartis Investigative Site
    • Redwood City, California, United States, 94063
      • Novartis Investigative Site
  • Colorado
    • Denver, Colorado, United States, 80230
      • Novartis Investigative Site
  • Florida
    • Aventura, Florida, United States, 33180
      • Novartis Investigative Site
    • Greenacres City, Florida, United States, 33467
      • Finlay Medical Research
    • Sarasota, Florida, United States, 34233
      • Novartis Investigative Site
    • Tallahassee, Florida, United States, 32308
      • Novartis Investigative Site
  • Georgia
    • Albany, Georgia, United States, 31707
      • Novartis Investigative Site
    • Woodstock, Georgia, United States, 30188
      • Novartis Investigative Site
  • Indiana
    • Evansville, Indiana, United States, 47715
      • Novartis Investigative Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Novartis Investigative Site
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Novartis Investigative Site
  • Ohio
    • Athens, Ohio, United States, 45701
      • Novartis Investigative Site
    • Columbus, Ohio, United States, 43235
      • Novartis Investigative Site
    • Toledo, Ohio, United States, 43617
      • Novartis Investigative Site
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Novartis Investigative Site
  • Texas
    • Austin, Texas, United States, 78759
      • Novartis Investigative Site
    • El Paso, Texas, United States, 79924
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78213
      • Novartis Investigative Site
  • Utah
    • Sandy, Utah, United States, 84093
      • Novartis Investigative Site
  • Washington
    • Bellingham, Washington, United States, 98225
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LOU064 25mg b.i.d.; Patients initially randomized to Remibrutinib during the Double-blind treatment period and continued Remibrutinib during the Open-label treatment period (Up to Week 52)	Drug: LOU064 25 mg (b.i.d); LOU064 25 mg was administered by oral route twice a day (b.i.d) as a tablet.; Other Names: remibrutinib; Drug: LOU064 25 mg (b.i.d) as a tablet.; LOU064 25 mg was administered by oral route twice a day (b.i.d) as a tablet in open label phase.; Other Names: remibrutinib
Placebo Comparator: Placebo; Patients initially randomized to Placebo (Up to Week 24)	Drug: Placebo; Placebo; Drug: LOU064 25 mg (b.i.d) as a tablet.; LOU064 25 mg was administered by oral route twice a day (b.i.d) as a tablet in open label phase.; Other Names: remibrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Weekly Urticaria 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).	Baseline, Week 12
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).	Baseline, Week 12
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.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Achieved Disease Activity Control (UAS7 ≤6)	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).	Week 12
Number of Patients Who Achieved Complete Absence of Hives and Itch (UAS7 = 0)	The number 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).	Week 12
Number of Patients With Early Onset of Disease 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).	Week 2
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).	up to Week 12
Number of Patients Who Achieved DLQI = 0 - 1	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.	Week 12
Cumulative Number of Weeks Without Angioedema (AAS7 = 0)	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).	Up to Week 12
Number of Participants With 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.	On-treatment adverse events are reported from first dose of study medication up to 28 days after last dose of study medication, for a timeframe up to approximately 56 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Actual): December 27, 2023
• Study Completion (Actual): January 19, 2024

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: August 31, 2021
• First Posted (Actual): September 1, 2021

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 3, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: BTK inhibitor; Chronic spontaneous urticaria; Urticaria activity score; CSU; Hives severity score; Itch severity score
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Skin Diseases; Skin Diseases, Vascular; Chronic Urticaria; Urticaria; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Remibrutinib
• Other Study ID Numbers: CLOU064A2301; 2022-001034-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No