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

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03137069
• Collaborator: (none)
• Enrollment: 134
• Locations: 27
• Arms: 6
• Actual Duration (Months): 29
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Urticaria	Drug: GDC-0853; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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).
• Actual Study Start Date: May 26, 2017
• Actual Primary Completion Date: Sep 27, 2019
• Actual Study Completion Date: Oct 25, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 [Baseline and 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.

Secondary Outcome Measures

1. Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) [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. Participants with UAS7 score ≤6 are considered well controlled.

2. Change From Baseline in the UAS7 at Day 29 [Baseline and 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.

3. Percentage of Participants With Adverse Events (AEs) [Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).]

   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.

4. Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints [Days 1, 8 and 57.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Research Center of Alabama, LLC	Birmingham	Alabama	United States	35209
2	Allergy & Asthma Immunology Associates	Scottsdale	Arizona	United States	85251
3	Kern Allergy Med Clinic, Inc.	Bakersfield	California	United States	93301
4	Southern California Research Center	Mission Viejo	California	United States	92691
5	Allergy & Asthma Consultants	Redwood City	California	United States	94063
6	Integrated Research Group Inc	Riverside	California	United States	92506
7	Integrated Research of Inland	Upland	California	United States	91786
8	New Horizon Research Center	Miami	Florida	United States	33165
9	Renstar Medical Research	Ocala	Florida	United States	34470
10	Vital Prospects Clinical Research Institute PC - CRN	Tulsa	Oklahoma	United States	74136
11	Asthma, Nasal Disease, and Allergy Research Center of New England	East Providence	Rhode Island	United States	02914
12	Center for Clinical Studies	Cypress	Texas	United States	77433
13	Timber Lane Allergy and Asthma Research, LLC	Burlington	Vermont	United States	05403
14	University of British Columbia	Vancouver	British Columbia	Canada	V6T 1Z4
15	Private Practice - Dr. Jason Ohayon	Hamilton	Ontario	Canada	L8S 1G5
16	Lynde Institute for Dermatology	Markham	Ontario	Canada	L3P 1X2
17	Cheema Research	Mississauga	Ontario	Canada	L5A 3V4
18	Yang Medicine	Ottawa	Ontario	Canada	K1G 6C6
19	Gordon Sussman Clinical Research	Toronto	Ontario	Canada	M4V 1R2
20	Private Practice - Dr. Isabelle Delorme	Drummondville	Quebec	Canada	J2B 5L4
21	Centre de Recherche Applique En Allergie de Quebec	Quebec City	Quebec	Canada	G1V 4M6
22	Licca Clinical Research Institute	Augsburg		Germany	86179
23	Charite Mitte; Klinik fur Dermatologie	Berlin		Germany	10117
24	Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Augenheilkunde	Dresden		Germany	01307
25	Hautarztpraxis Mahlow	Mahlow		Germany	15831
26	Universitätsmedizin Johannes Gutenberg Universität	Mainz		Germany	55131
27	Klinik für Haut- und Geschlechtskrankheiten, Universitätsklinikum Münster	Münster		Germany	48419

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 9, 2018

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT03137069
• Other Study ID Numbers: GS39684; 2016-004624-35
• First Posted: May 2, 2017
• Last Update Posted: Sep 29, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Urticaria; Chronic Urticaria

Study Results

Participant Flow

Recruitment Details	The study was conducted at 21 centers in 3 countries.
Pre-assignment Detail	A total of 134 participants were enrolled at 21 centers.

Arm/Group Title	Cohort 1: Placebo	Cohort 1: GDC-0853 200mg BID	Cohort 2: Placebo	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received matching placebo up to twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Period Title: Overall Study
STARTED	13	28	23	23	24	23
COMPLETED	12	22	20	17	22	21
NOT COMPLETED	1	6	3	6	2	2

Baseline Characteristics

Arm/Group Title	Cohort 1: Placebo	Cohort 1: GDC-0853 200mg BID	Cohort 2: Placebo	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID	Total
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received matching placebo up to twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Total of all reporting groups
Overall Participants	13	28	23	23	24	23	134
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.6 (11.0)	41.3 (15.9)	40.2 (14.7)	45.0 (13.1)	43.3 (16.7)	44.3 (13.0)	42.8 (14.4)
Sex: Female, Male (Count of Participants)
Female	11 84.6%	22 78.6%	17 73.9%	18 78.3%	20 83.3%	16 69.6%	104 77.6%
Male	2 15.4%	6 21.4%	6 26.1%	5 21.7%	4 16.7%	7 30.4%	30 22.4%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	0 0%	1 3.6%	5 21.7%	2 8.7%	5 20.8%	2 8.7%	15 11.2%
Not Hispanic or Latino	13 100%	27 96.4%	16 69.6%	21 91.3%	19 79.2%	20 87%	116 86.6%
Not Stated	0 0%	0 0%	1 4.3%	0 0%	0 0%	1 4.3%	2 1.5%
Unknown	0 0%	0 0%	1 4.3%	0 0%	0 0%	0 0%	1 0.7%
Race/Ethnicity, Customized (Number) [Number]
Asian	0 0%	3 10.7%	4 17.4%	3 13%	1 4.2%	4 17.4%	15 11.2%
Black or African American	1 7.7%	1 3.6%	1 4.3%	1 4.3%	0 0%	2 8.7%	6 4.5%
White	10 76.9%	24 85.7%	18 78.3%	19 82.6%	23 95.8%	16 69.6%	110 82.1%
Multiple	2 15.4%	0 0%	0 0%	0 0%	0 0%	1 4.3%	3 2.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57
Description	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.
Time Frame	Baseline and Day 57

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat (mITT) Population was defined as all participants who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized. Data presented below is only for participants included in the actual analysis.

Arm/Group Title	Cohort 1: Placebo	Cohort 1: GDC-0853 200mg BID	Cohort 2: Placebo	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received matching placebo up to twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Measure Participants	12	22	20	19	22	21
Mean (Standard Deviation) [Score on a Scale]	-19.16 (13.49)	-24.05 (9.74)	-11.25 (10.81)	-15.69 (14.25)	-17.05 (10.19)	-21.80 (14.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Placebo, Cohort 1: GDC-0853 200mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0559
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-7.02
	Confidence Interval	(2-Sided) 90%; -13.01 to -1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 50mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8892
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 90%; -6.60 to 5.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 150mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0717
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-6.43
	Confidence Interval	(2-Sided) 90%; -12.29 to -0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 200mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0097
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-9.53
	Confidence Interval	(2-Sided) 90%; -15.50 to -3.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6)
Description	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.
Time Frame	Day 57

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat (mITT) Population was defined as all participants who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized. Data presented below is only for participants included in the actual analysis.

Arm/Group Title	Cohort 1: Placebo	Cohort 1: GDC-0853 200mg BID	Cohort 2: Placebo	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received matching placebo up to twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Measure Participants	13	28	23	23	24	23
Number [Percentage of Participants]	30.8 236.9%	57.1 203.9%	21.7 94.3%	34.8 151.3%	45.8 190.8%	56.5 245.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Placebo, Cohort 1: GDC-0853 200mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1087
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by region

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 50mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3418
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by region

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 150mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0459
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by region

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 200mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0190
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by region

3. Secondary Outcome

Title	Change From Baseline in the UAS7 at Day 29
Description	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.
Time Frame	Baseline and Day 29

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat (mITT) Population was defined as all participants who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized. Data presented below is only for participants included in the actual analysis.

Arm/Group Title	Cohort 1: Placebo	Cohort 1: GDC-0853 200mg BID	Cohort 2: Placebo	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received matching placebo up to twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Measure Participants	13	24	21	19	23	21
Mean (Standard Deviation) [Score on a Scale]	-9.69 (10.70)	-22.15 (10.33)	-9.05 (9.82)	-16.97 (14.31)	-13.75 (12.93)	-21.69 (16.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Placebo, Cohort 1: GDC-0853 200mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-12.88
	Confidence Interval	(2-Sided) 90%; -18.94 to -6.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 50mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4565
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.83
	Confidence Interval	(2-Sided) 90%; -9.11 to 3.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 150mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1711
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-5.03
	Confidence Interval	(2-Sided) 90%; -11.10 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Placebo, Cohort 2: GDC-0853 200mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0050
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates included were region, treatment group, visit, and visit by treatment group interaction
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-10.76
	Confidence Interval	(2-Sided) 90%; -16.97 to -4.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs)
Description	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.
Time Frame	Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).

Outcome Measure Data

Analysis Population Description

The Safety-evaluable population was defined as all participants who received at least one dose of study drug with participants grouped according to their actual treatment. Due to a data entry error, one participant in the (Cohort 2: Placebo) arm was inadvertently analysed in the (Cohort 2: GDC-0853 200 mg BID) arm.

Arm/Group Title	Cohort 1: Placebo	Cohort 1: GDC-0853 200mg BID	Cohort 2: Placebo	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received matching placebo up to twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Measure Participants	13	28	22	23	24	24
Number [Percentage of Participants]	61.5 473.1%	71.4 255%	54.5 237%	60.9 264.8%	66.7 277.9%	58.3 253.5%

5. Secondary Outcome

Title	Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints
Description	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.
Time Frame	Days 1, 8 and 57.

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as all participants who received at least one dose of fenebrutinib (GDC-0853) and had at least 1 evaluable post-dose PK sample. Participants who received incorrect therapy different from the intended therapy were summarized in the group according to the therapy actually received.

Arm/Group Title	Cohort 1: GDC-0853 200mg BID	Cohort 2: GDC-0853 50mg QD	Cohort 2: GDC-0853 150mg QD	Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received GDC-0853 200mg twice daily from Day 1 to 56.	Participants received GDC-0853 50mg once daily from Day 1 to 56.	Participants received GDC-0853 150mg once daily from Day 1 to 56.	Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Measure Participants	28	23	24	23
Day 1	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 8	378 (389)	38.5 (36.9)	178 (237)	424 (385)
Day 57	283 (315)	19.6 (26.3)	24.7 (17.7)	219 (293)

Adverse Events

Time Frame	Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).
Adverse Event Reporting Description	One participant in Cohort 2 was randomized into the Placebo arm (Cohort 2: Placebo) and received the Placebo treatment in the study. However due to a data entry error, this participant was inadvertently analysed in the (Cohort 2: GDC-0853 200 mg BID) arm in the Safety-evaluable population.
Arm/Group Title	Cohort 1: Placebo		Cohort 1: GDC-0853 200mg BID		Cohort 2: Placebo		Cohort 2: GDC-0853 50mg QD		Cohort 2: GDC-0853 150mg QD		Cohort 2: GDC-0853 200mg BID
Arm/Group Description	Participants received matching placebo twice daily from Day 1 to 56.		Participants received GDC-0853 200mg twice daily from Day 1 to 56.		Participants received matching placebo up to twice daily from Day 1 to 56.		Participants received GDC-0853 50mg once daily from Day 1 to 56.		Participants received GDC-0853 150mg once daily from Day 1 to 56.		Participants received GDC-0853 200mg twice daily from Day 1 to 56.
All Cause Mortality
	Cohort 1: Placebo		Cohort 1: GDC-0853 200mg BID		Cohort 2: Placebo		Cohort 2: GDC-0853 50mg QD		Cohort 2: GDC-0853 150mg QD		Cohort 2: GDC-0853 200mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/28 (0%)		0/22 (0%)		0/23 (0%)		0/24 (0%)		0/24 (0%)
Serious Adverse Events
	Cohort 1: Placebo		Cohort 1: GDC-0853 200mg BID		Cohort 2: Placebo		Cohort 2: GDC-0853 50mg QD		Cohort 2: GDC-0853 150mg QD		Cohort 2: GDC-0853 200mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		3/28 (10.7%)		0/22 (0%)		0/23 (0%)		0/24 (0%)		0/24 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN UPPER	0/13 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Infections and infestations
PERIORBITAL CELLULITIS	0/13 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Investigations
HEPATIC ENZYME INCREASED	0/13 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1: Placebo		Cohort 1: GDC-0853 200mg BID		Cohort 2: Placebo		Cohort 2: GDC-0853 50mg QD		Cohort 2: GDC-0853 150mg QD		Cohort 2: GDC-0853 200mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)		16/28 (57.1%)		7/22 (31.8%)		7/23 (30.4%)		13/24 (54.2%)		12/24 (50%)
Eye disorders
VISION BLURRED	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Gastrointestinal disorders
DIARRHOEA	0/13 (0%)	0	1/28 (3.6%)	1	2/22 (9.1%)	2	0/23 (0%)	0	1/24 (4.2%)	1	0/24 (0%)	0
NAUSEA	0/13 (0%)	0	2/28 (7.1%)	2	0/22 (0%)	0	1/23 (4.3%)	1	2/24 (8.3%)	2	2/24 (8.3%)	2
General disorders
CHILLS	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
FATIGUE	0/13 (0%)	0	1/28 (3.6%)	1	2/22 (9.1%)	2	0/23 (0%)	0	1/24 (4.2%)	1	0/24 (0%)	0
FEELING ABNORMAL	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Infections and infestations
EYE INFECTION	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
NASOPHARYNGITIS	3/13 (23.1%)	3	7/28 (25%)	9	1/22 (4.5%)	1	3/23 (13%)	3	3/24 (12.5%)	4	3/24 (12.5%)	4
TOOTH INFECTION	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
UPPER RESPIRATORY TRACT INFECTION	0/13 (0%)	0	1/28 (3.6%)	1	1/22 (4.5%)	1	0/23 (0%)	0	0/24 (0%)	0	2/24 (8.3%)	2
URINARY TRACT INFECTION	0/13 (0%)	0	0/28 (0%)	0	0/22 (0%)	0	1/23 (4.3%)	1	2/24 (8.3%)	2	1/24 (4.2%)	1
Injury, poisoning and procedural complications
BONE CONTUSION	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
CONTUSION	0/13 (0%)	0	2/28 (7.1%)	2	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1
INJURY	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/13 (0%)	0	2/28 (7.1%)	2	0/22 (0%)	0	0/23 (0%)	0	1/24 (4.2%)	1	3/24 (12.5%)	3
ASPARTATE AMINOTRANSFERASE INCREASED	0/13 (0%)	0	2/28 (7.1%)	2	0/22 (0%)	0	0/23 (0%)	0	1/24 (4.2%)	1	2/24 (8.3%)	2
WEIGHT DECREASED	1/13 (7.7%)	1	0/28 (0%)	0	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	0/24 (0%)	0
Musculoskeletal and connective tissue disorders
BACK PAIN	1/13 (7.7%)	1	0/28 (0%)	0	1/22 (4.5%)	2	1/23 (4.3%)	1	0/24 (0%)	0	0/24 (0%)	0
Nervous system disorders
DIZZINESS	1/13 (7.7%)	1	2/28 (7.1%)	2	0/22 (0%)	0	0/23 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1
HEADACHE	3/13 (23.1%)	3	4/28 (14.3%)	5	2/22 (9.1%)	2	0/23 (0%)	0	1/24 (4.2%)	1	3/24 (12.5%)	3
Skin and subcutaneous tissue disorders
CHRONIC SPONTANEOUS URTICARIA	0/13 (0%)	0	2/28 (7.1%)	3	1/22 (4.5%)	1	1/23 (4.3%)	2	2/24 (8.3%)	3	0/24 (0%)	0
URTICARIA	0/13 (0%)	0	5/28 (17.9%)	5	2/22 (9.1%)	2	3/23 (13%)	3	4/24 (16.7%)	4	5/24 (20.8%)	5

Limitations/Caveats

Recruitment was stopped after an interim analysis of Cohort 2 based on pre-specified internal criteria.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.