A Study to Evaluate Efficacy of Remibrutinib Compared to Dupilumab at Early Timepoints in Adults With Chronic Spontaneous Urticaria Inadequately Controlled by Second Generation H1-antihistamines

Phase 3

Not yet recruiting

• Conditions: Chronic Spontaneous Urticaria (CSU)
• Interventions: Drug: Remibrutinib; Drug: Remibrutinib matching placebo; Drug: Placebo solution for injection; Drug: Dupilumab

• Registration Number: NCT06868212
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

This is a US, multi-center, randomized, double-blind, double-dummy, Phase 3b study to evaluate efficacy of remibrutinib (25 mg twice daily \[b.i.d.\] by mouth \[p.o.\]) compared to dupilumab (600 mg loading dose administered subcutaneously (s.c.) followed by 300 mg every 2 weeks s.c.) at early timepoints (4 weeks and earlier), when administered as an add-on treatment to second generation H1-antihistamines (sgH1-AH) (standard label dose as background therapy) in adult US participants with moderate to severe chronic spontaneous urticaria (CSU) inadequately controlled by sgH1-AHs.

Detailed Description

This study consists of a screening period (up to 4 weeks), a core treatment period (12 weeks double-blind, double-dummy), an optional open-label extension \[OLE\] period, and safety follow-up period.

Screening period: participants will have a screening period of a minimum of 7 days up to a maximum of 28 days to establish eligibility for the study. Participants meeting all the inclusion criteria and none of the exclusion criteria will be eligible to participate in the study.

Core treatment period (double-blind, double-dummy): approximately, 400 participants diagnosed with CSU inadequately controlled by sgH1-AH will be randomized in this study. Participants will be stratified based on prior exposure to anti-IgE biologics.

Eligible participants will be randomized in a 1:1 ratio to receive remibrutinib and placebo solution for injection or dupilumab and remibrutinib matching placebo, both as an add-on treatment to once daily standard label dose of sgH1-AH background therapy, until the Week 12 visit.

Additionally, all participants will be on a stable, standard label dose of a sgH1-AH ("background therapy") throughout the entire core treatment period (starting a minimum of 7 days prior to randomization until the end of Week 12). To treat unbearable symptoms of CSU, participants will be allowed to add more of the same sgH1-AH on an as-needed basis ("rescue therapy"). The total maximum daily dose of sgH1-AH (background plus rescue) should not exceed 4 tablets/day (4-fold the standard label dose).

Optional open-label extension \[OLE\] period: At the end of the 12-week double-blind treatment period, and in case remibrutinib is not commercially available, participants from both arms will be given the choice to roll over into an optional OLE safety period and receive remibrutinib (25 mg b.i.d. p.o.) for 12 weeks (up to Week 24).

Safety follow-up period:

* For participants who do not enter the OLE period: there will be a safety follow-up for 12 weeks with safety follow-up phone calls at Week 16 and Week 24 (Week 24 will be end of study).

* For participants who enter the OLE period: there will be 2 options at the end of Week 24:

* If remibrutinib is commercially available: participants will discontinue study treatment, perform their EOT visit and receive a safety follow-up phone call 4 weeks after the last dose of remibrutinib (this will be the EOS).

* If remibrutinib is not commercially available, participants may continue on remibrutinib 25 mg b.i.d. until its commercial availability and return for site visits for safety follow up and treatment dispensation every 3 months. When remibrutinib becomes commercially available, the participant will be contacted for a site visit to complete the EOT visit and will receive a safety follow-up phone call 4 weeks after the last dose of remibrutinib (this will be the EOS).

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-06
• Study First Submitted QC: 2025-03-06
• Last Update Submitted: 2025-03-06
• Study First Posted: 2025-03-10
• Last Update Posted: 2025-03-10
• Study Start: 2025-07-25
• Primary Completion: 2027-03-22
• Study Completion: 2027-08-23

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

• Adults ≥ 18 years of age at the time of signing the informed consent
• 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 sgH1-AH at the time of randomization, defined as:
• The presence of itch and hives for ≥ 6 consecutive weeks prior to screening despite the use of sgH1-AH during the 7 days prior to randomization (Day 1):
• UAS7 score (range, 0-42) ≥ 16, and
• ISS7 score (range, 0-21) ≥ 6, and
• HSS7 score (range, 0-21) ≥ 6
• Documentation of hives within 3 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

• Previous use of remibrutinib or other bruton's tyrosine kinase (BTK) inhibitors
• Previous use of dupilumab
• Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 12 months prior to Visit 1), neurological, psychiatric, pulmonary, renal, hepatic (past history or current), endocrine or metabolic disorder, 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.
• Evidence of hematological disorders (including coagulation disorders or significant bleeding risk)
• History or evidence of gastrointestinal disease (including gastrointestinal bleeding, e.g., in association with use of nonsteroidal anti-inflammatory drugs (NSAID), that was clinically relevant (e.g., where 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 [NOAC])
• History or current hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or hepatic parameters at screening: Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) levels more than 1.5x ULN or International Normalized Ratio (INR) > 1.5 at screening

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment group 1: Remibrutinib + Placebo	Remibrutinib	Remibrutinib tablet (25 mg b.i.d. p.o.) + placebo solution for injection in pre-filled syringe (2 s.c. injections at baseline and then 1 s.c. injection every other week \[Weeks 2-10\])
Treatment group 1: Remibrutinib + Placebo	Placebo solution for injection	Remibrutinib tablet (25 mg b.i.d. p.o.) + placebo solution for injection in pre-filled syringe (2 s.c. injections at baseline and then 1 s.c. injection every other week \[Weeks 2-10\])
Treatment group 2: Dupilumab + remibrutinib matching placebo	Remibrutinib matching placebo	Dupilumab pre-filled syringe (600 mg loading dose \[2 x 300 mg dupilumab s.c. injection\] at baseline visit followed by dupilumab 300 mg s.c. injection every other week \[Weeks 2-10\]) + remibrutinib matching placebo tablet (1 tablet b.i.d. p.o.)
Treatment group 2: Dupilumab + remibrutinib matching placebo	Dupilumab	Dupilumab pre-filled syringe (600 mg loading dose \[2 x 300 mg dupilumab s.c. injection\] at baseline visit followed by dupilumab 300 mg s.c. injection every other week \[Weeks 2-10\]) + remibrutinib matching placebo tablet (1 tablet b.i.d. p.o.)

Primary Outcome Measures

Name	Time	Method
Absolute change from baseline in Weekly Urticaria Activity Score (UAS7) at Week 4	Baseline, Week 4	The UAS7 is the sum of the Weekly Hives Severity (HSS7) score and the Weekly Itch Severity (ISS7) score, and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 days preceding the visit.

Secondary Outcome Measures

Name	Time	Method
Improvement of severity of hives, assessed as absolute change from baseline in HSS7 score at Week 4	Baseline, Week 4	The hives (wheals) severity score, defined by number of hives, will be recorded by the participant twice daily in their eCOA device, on a scale of 0 (none) to 3. A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 0 - 21.
Improvement of severity of itch, assessed as absolute change from baseline in ISS7 score at Week 4	Baseline, Week 4	The severity of the itch will be recorded by the participant twice daily in their eCOA device, on a scale of 0 (none) to 3 (severe). A weekly score (ISS7) is derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 0 - 21.
Improvement of UAS7, assessed as absolute change from baseline in UAS7 score at Week 1	Baseline, Week 1	The UAS7 is the sum of the Weekly Hives Severity (HSS7) score and the Weekly Itch Severity (ISS7) score, and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 days preceding the visit.
Percentage of participants with UAS7 ≤ 6 at Week 4	Week 4	Percentage of participants who achieved UAS7 ≤ 6 at Week 4. The UAS7 is the sum of the Weekly Hives Severity (HSS7) score and the Weekly Itch Severity (ISS7) score, and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 days preceding the visit.
Percentage of participants with UAS7=0 at Week 4	Week 4	Percentage of participants who achieved UAS7 = 0 at Week 4. The UAS7 is the sum of the Weekly Hives Severity (HSS7) score and the Weekly Itch Severity (ISS7) score, and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 days preceding the visit.
Percentage of participants with UAS7 ≤ 6 at Week 2	Week 2	Percentage of participants who achieved UAS7 ≤ 6 at Week 2. The UAS7 is the sum of the Weekly Hives Severity (HSS7) score and the Weekly Itch Severity (ISS7) score, and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 days preceding the visit.