A Study of GDC-0853 in Participants With Refractory Chronic Spontaneous Urticaria (CSU).

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of GDC-0853 compared with placebo in participants with Refractory Chronic Spontaneous Urticaria (CSU) already treated with anti-histamines. Participants have the option to enter the Open-Label Extension (OLE) study after completing the 8-week treatment period.

Official Title
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A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot and Dose-Ranging Study of GDC-0853 in Patients With Refractory Chronic Spontaneous Urticaria (CSU).

Conditions
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Urticaria

Intervention / Treatment
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* Drug: GDC-0853
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-75 years, inclusive Diagnosis of chronic spontaneous urticaria (CSU) refractory to H1 antihistamines at the time of randomization Willing and able to complete an Urticaria Participant Daily eDiary for the duration of the study No evidence of active or latent or inadequately treated infection with tuberculosis (TB) Partcipants with a history of Bacille Calmette-Guérin (BCG) vaccination should be screened using the QuantiFERON-TB-Gold (QFT) test Only for participants currently receiving proton-pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs): Treatment must be at a stable dose during the 2-week screening period prior to randomization and with a plan to remain at a stable dose for the duration of the study For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 4 weeks after the last dose of study drug. Women must refrain from donating eggs during this same period. Exclusion Criteria: Treatment with omalizumab or other monoclonal antibody therapies used to treat CSU within 4 months prior to screening or primary nonresponse to omalizumab Use of a non-biologic investigational drug or participation in an investigational study with a non-biologic drug within 30 days prior to study drug administration on Day 1 (or within 5 half-lives of the investigational product, whichever is greater) Use of a biologic investigational therapy or participation in an investigational study involving biologic therapy within 90 days or 5 half-lives, whichever is greater, prior to study drug administration on Day 1 Previous treatment with GDC-0853 or other Bruton's tyrosine kinase (BTK) inhibitors Participants whose urticaria is solely due to physical urticaria Other diseases with symptoms of urticaria or angioedema, including urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, or leukemia Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, or other skin disease associated with itch such as psoriasis Routine doses of the following medications within 30 days prior to screening: systemic or cutaneous (topical) corticosteroids (prescription or over the counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide Prior utilization of intravenous (IV) steroids for treatment of laryngeal angioedema Intravenous immunoglobulin G (IV IG) or plasmapheresis within 30 days prior to screening History of anaphylactic shock without clearly identifiable avoidable antigen Hypersensitivity to GDC-0853 or any component of the formulation Major surgery within 8 weeks prior to screening or surgery planned prior to end of study (12 weeks after randomization) Require any prohibited concomitant medications History of live attenuated vaccine within 6 weeks prior to randomization or requirement to receive these vaccinations at any time during study drug treatment Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, or gastrointestinal (GI) disease that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participant participation Current treatment with astemizole, terfenadine, and/or ebastine Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1: Placebo<br>Participants received matching placebo twice daily from Day 1 to 56. | Drug: Placebo<br>* Matching Placebo will be administered orally, as per the dosing schedules described above.<br>|
| Experimental: Cohort 1: GDC-0853 200mg BID<br>Participants received GDC-0853 200mg twice daily from Day 1 to 56. | Drug: GDC-0853<br>* GDC-0853 will be administered orally at dosages of 50, 150 and 200mg to participants, as per the dosing schedules described above.<br>|
| Placebo Comparator: Cohort 2: Placebo<br>Participants received matching placebo up to twice daily from Day 1 to 56. | Drug: Placebo<br>* Matching Placebo will be administered orally, as per the dosing schedules described above.<br>|
| Experimental: Cohort 2: GDC-0853 50mg QD<br>Participants received GDC-0853 50mg once daily from Day 1 to 56. | Drug: GDC-0853<br>* GDC-0853 will be administered orally at dosages of 50, 150 and 200mg to participants, as per the dosing schedules described above.<br>|
| Experimental: Cohort 2: GDC-0853 150mg QD<br>Participants received GDC-0853 150mg once daily from Day 1 to 56. | Drug: GDC-0853<br>* GDC-0853 will be administered orally at dosages of 50, 150 and 200mg to participants, as per the dosing schedules described above.<br>|
| Experimental: Cohort 2: GDC-0853 200mg BID<br>Participants received GDC-0853 200mg twice daily from Day 1 to 56. | Drug: GDC-0853<br>* GDC-0853 will be administered orally at dosages of 50, 150 and 200mg to participants, as per the dosing schedules described above.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (Day 57 score minus Baseline score) indicates improvement. | Baseline and Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. Participants with UAS7 score ≤6 are considered well controlled. | Day 57 | 
| Change From Baseline in the UAS7 at Day 29 | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (Day 29 score minus Baseline score) indicates improvement. | Baseline and Day 29 | 
| Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events. | Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months). | 
| Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Plasma Concentration Data for fenebrutinib (GDC-0853) will be tabulated and summarised by visits. Descriptive summary statistics for Arithmetic Mean and Standard Deviation will be presented. Please note that the Placebo Cohorts were not evaluated for this Outcome Measure. | Days 1, 8 and 57. |