Study to Evaluate the Efficacy, Safety, and Tolerability of Tirabrutinib in Participants With Antihistamine-Resistant Chronic Spontaneous Urticaria

A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Tolerability of Tirabrutinib in Subjects With Antihistamine-Resistant Chronic Spontaneous Urticaria

The primary objective of this study is to evaluate the efficacy of tirabrutinib in reducing disease activity in participants with chronic spontaneous urticaria (CSU) with respect to change from baseline in urticaria activity score over 7 days (UAS7) at Week 8 when added to standard of care.

Study Overview

• Status: Withdrawn
• Conditions: Chronic Spontaneous Urticaria
• Intervention / Treatment: Drug: Placebo; Drug: Tirabrutinib

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Diagnosis of chronic spontaneous urticaria (CSU) (with or without urticarial dermatographism) for ≥ 6 months prior to screening
• Presence of itch and hives for ≥ 6 consecutive weeks prior to screening, refractory to nonsedating H1-antihistamines (according to local treatment guidelines) during that time
• Individuals must be maintained on approved H1-antihistamine doses as per the 2018 European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) guidelines (2018 EAACI/GA2LEN/EDF/WAO; ie, up to 4 times standard dosing) from 7 days prior to randomization.
• Individuals must have active disease defined as UAS7 ≥ 16 and HSS7 ≥ 8 during the 7 consecutive days (with no missing timepoints) prior to randomization (Day -7 to Day -1).

Key Exclusion Criteria:

• Clearly defined underlying etiology for chronic urticaria other than CSU, including:

  • Inducible urticaria as the only manifestation of disease (cold, heat, pressure, delayed pressure, aquagenic, contact, cholinergic, dermatographism)
  • Known underlying genetic cause of urticaria or angioedema such as hereditary angioedema (C1-inhibitor deficiency)
  • Urticarial dermatoses associated with a known diagnosis of an autoinflammatory syndrome or monoclonal gammopathy
  • Diseases with possible urticarial manifestations such as urticarial vasculitis, erythema multiforme, or cutaneous mastocytosis
  • Any other skin disease associated with chronic itching that could confound the study evaluation (eg, atopic dermatitis, psoriasis, bullous pemphigoid, and dermatitis herpetiformis)
• Previous treatment with omalizumab or any other monoclonal antibody used to treat CSU within 16 weeks prior to randomization
• Refractory to omalizumab or biosimilar
• Previous use of a Bruton's tyrosine kinase (BTK) inhibitor
• Any prior history of anaphylaxis
• Use of a nonbiologic investigational drug or participation in an investigational study involving biologic therapy within 90 days or 5 half-lives (whichever is greater) prior to randomization
• Intravenous immunoglobulin (IVIg) or plasmapheresis within 28 days prior to randomization
• Use of cyclosporine A, methotrexate, mycophenolate mofetil (or mycophenolic acid), or azathioprine within 28 days prior to randomization; or use of dupilumab within 16 weeks prior to randomization
• Routine (daily or every other day use for 5 or more consecutive days) of systemic corticosteroids within 28 days of randomization
• Use of intramuscular corticosteroids within 28 days of randomization
• Any clinically unstable disease states that would likely require rescue corticosteroids (eg, severe asthma) that may interfere with data interpretation

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirabrutinib; Participant will receive tirabrutinib twice daily in addition to their standard-of-care therapy for up to 8 weeks.	Drug: Tirabrutinib; Tablets administered orally; Other Names: GS-4059
Placebo Comparator: Placebo; Participants will receive placebo twice daily in addition to their standard-of-care therapy for up to 8 weeks.	Drug: Placebo; Tablets administered orally
Experimental: Tirabrutinib, Open Label Extension; At Week 8, participants who have not discontinued the study drug will receive tirabrutinib twice daily in addition to their standard-of-care therapy for up to 16 weeks.	Drug: Tirabrutinib; Tablets administered orally; Other Names: GS-4059

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Urticaria Activity Score Over 7 Days (UAS7) at Week 8.	The UAS7 is the sum of the Hives Severity Score Over 7 Days (HSS7) and Itch Severity Score Over 7 Days (ISS7). The possible range of the UAS7 is 0 to 42. A well-controlled urticaria response is defined as a UAS7 ≤ 6. Higher scores indicate high disease activity in hives and itch. Hives Severity Score (HSS) is defined as the number of hives recorded twice daily by the participant on a scale from 0 (none) to 3 (severe). HSS7 is derived by adding together the daily average scores over a consecutive 7-day period. The severity of itch will be recorded twice daily by the participant using a scale from 0 (none) to 3 (severe). ISS7 is derived by adding together the daily average scores over a consecutive 7-day period.	Baseline; Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of Hives Severity Score Over 7 Days (HSS7) at Week 8	Hives Severity Score (HSS) is defined as the number of hives recorded twice daily by the participant on a scale from 0 (none) to 3 (severe). HSS7 is derived by adding together the daily average scores over a consecutive 7-day period. The range of weekly scores is 0 to 21. Higher scores indicate increase severity in hives.	Baseline; Week 8
Change from baseline of Itch Severity Score Over 7 Days (ISS7) at Week 8	The severity of itch will be recorded twice daily by the participant using a scale from 0 (none) to 3 (severe). ISS7 is derived by adding together the daily average scores over a consecutive 7-day period. The range of weekly scores is 0 to 21. Higher scores indicate increase severity in itch.	Baseline; Week 8
Proportion of Participants Achieving a Complete Response (UAS7 = 0) at Week 8		Week 8
Proportion of Participants Achieving Well-controlled Urticaria (UAS7 ≤ 6) at Week 8		Week 8
Change from Baseline in Angioedema Activity Score Over 7 Days (AAS7) at Week 8	The Angioedema Activity Score (AAS) assesses the occurrence of episodes of angioedema. The AAS will be recorded by the participant once daily. A weekly score (AAS7) is derived by adding together the daily scores over a consecutive 7-day period. The range of weekly scores is 0 to 105, with a higher score corresponding to greater severity.	Baseline; Week 8
Proportion of Participants Achieving a Complete Angioedema Response (AAS7 = 0) at Week 8		Week 8
Change From Baseline in the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) Measurement at Week 8	The CU-Q2oL is a 23-item questionnaire. Domains in the questionnaire include urticaria- and angioedema-specific symptoms, discomfort, sleep, mood and activities of daily living. Each response is scored from 1 (no symptoms) to 5 (severe symptoms). Individual responses are summed to produce the overall CU-Q2oL score, which is then converted to a 0 to 100-point scale. A higher score indicates greater impairment in quality of life.	Baseline; Week 8

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2021
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: March 30, 2021
• First Submitted That Met QC Criteria: March 30, 2021
• First Posted (Actual): April 1, 2021

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 22, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Chronic Urticaria
• Other Study ID Numbers: GS-US-556-5960; 2020-005394-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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