A Safety and Efficacy Study of Remibrutinib in the Treatment of CSU in Japanese Adults Inadequately Controlled by H1-antihistamines (BISCUIT)

A Multicenter, Open-label Phase 3 Study of Remibrutinib (LOU064) to Investigate the Safety, Tolerability and Efficacy for 52 Weeks in Adult Japanese Chronic Spontaneous Urticaria Patients Inadequately Controlled by H1-antihistamines

The purpose of this study was to evaluate the safety, tolerability and efficacy of remibrutinib (LOU064) in adult Japanese patients chronic spontaneous urticaria (CSU), who remain symptomatic despite treatment by H1-antihistamine (H1-AH) at locally label approved doses, for a duration of 52 weeks of treatment with remibrutinib and a post-treatment follow-up period of up to 4 weeks.

Study Overview

• Status: Completed
• Conditions: Chronic Spontaneous Urticaria
• Intervention / Treatment: Drug: LOU064

Detailed Description

The study consisted of three periods, the total study duration is up to 60 weeks: screening period of up to 4 weeks, open-label treatment period of 52 weeks (remibrutinib 25 mg b.i.d.), and a treatment free follow-up period of 4 weeks.

It was planned to include approximately 70 patients in the study; 71 patients were enrolled and included in the analyses.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 811-1302
    • Novartis Investigative Site
  • Osaka, Japan, 558-0003
    • Novartis Investigative Site
  • Osaka, Japan, 554 0014
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 454-0012
      • Novartis Investigative Site
  • Chiba
    • Urayasu, Chiba, Japan, 279-0011
      • Novartis Investigative Site
  • Osaka
    • Izumiotsu, Osaka, Japan, 595-0025
      • Novartis Investigative Site
    • Neyagawa, Osaka, Japan, 572-0838
      • Novartis Investigative Site
    • Sakai, Osaka, Japan, 593-8324
      • Novartis Investigative Site
    • Takatsuki, Osaka, Japan, 569-0824
      • Novartis Investigative Site
  • Shimane
    • Izumo-city, Shimane, Japan, 693 8501
      • Novartis Investigative Site
  • Tokyo
    • Itabashi-ku, Tokyo, Japan, 173-8610
      • Novartis Investigative Site
    • Minato, Tokyo, Japan, 108-0014
      • Novartis Investigative Site
    • Ota-ku, Tokyo, Japan, 143-0023
      • 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 was required to be obtained prior to participation in the study.
• Male and female patients >= 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-AHs at the time of baseline (Day 1) defined as:

  • The presence of itch and hives for >= 6 consecutive weeks prior to screening despite the use of second generation H1-AHs 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 baseline (Day 1)
• Documentation of hives within three months before baseline (either at screening and/or at baseline; or documented in the patients' medical history)
• Willing and able to complete an UPDD for the duration of the study and adhere to the study protocol
• Patients were required to not have more than one missing UPDD entry (either morning or evening) in the 7 days prior to baseline (Day 1)

Exclusion criteria:

• Patients 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 angioedema, 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 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 patient, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the patient
• Significant bleeding risk or coagulation disorders
• History of gastrointestinal bleeding, e.g., in association with use of nonsteroidal anti-inflammatory drugs, that was clinically relevant (e.g., for which intervention was indicated or requiring hospitalization or blood transfusion)
• Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100 mg/d or clopidogrel up to 75 mg/d. 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)
• History or current hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or AST/ALT levels of more than 1.5 × 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LOU064 25 mg b.i.d.; Patients were treated with remibrutinib 25 mg bis in die/twice a day (b.i.d.). LOU064 open-label treatment taken orally for 52 weeks.	Drug: LOU064; Each patient took one film-coated tablet in the morning and one film-coated tablet in the evening (except the morning dose at the PK sampling visits, which were to be taken on site during the visit).; Other Names: remibrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 30 days after the last study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment.	Baseline up to 30 days after last dose of study medication, assessed up to approximately 56 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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).	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).	Week 2
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).	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).	Up to Week 12
Mean Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12	Change from Baseline in Weekly Urticaria Activity Score (UAS7) was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The Weekly Urticaria Activity Score (UAS7) is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the weekly UAS7 score is 0 - 42 (highest hives and itch severity).	Baseline, Week 12
Change From Baseline in Weekly Itch Severity Score (ISS7) at Week 12	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).	Baseline, Week 12
Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12	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).	Baseline, Week 12
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 as follows: 0-1 (No effect on patient's life), 2-5 (Small effect on patient's life), 6-10 (Moderate effect on patient's life), 11-20 (Very large effect on patient's life), 21-30 (Extremely large effect on patient's life).	Week 12

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): January 15, 2022
• Primary Completion (Actual): December 8, 2023
• Study Completion (Actual): December 9, 2023

Study Registration Dates

• First Submitted: September 8, 2021
• First Submitted That Met QC Criteria: September 8, 2021
• First Posted (Actual): September 17, 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: Bruton Tyrosine Kinase (BTK) inhibitor; Dermatology Life Quality Index (DLQI); 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)
• 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: CLOU064A1301

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