Clinical trial NCT03137069
Conditions: Urticaria
Sponsor: Genentech, Inc.
Start date: 2017-05-26; Completion date: 2019-10-25
Enrollment: 134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Participants received matching placebo twice daily from Day 1 to 56. arm 2: Participants received GDC-0853 200mg twice daily from Day 1 to 56. arm 3: Participants received matching placebo up to twice daily from Day 1 to 56. arm 4: Participants received GDC-0853 50mg once daily from Day 1 to 56. arm 5: Participants received GDC-0853 150mg once daily from Day 1 to 56. arm 6: Participants received GDC-0853 200mg twice daily from Day 1 to 56.
Interventions: intervention 1: GDC-0853 intervention 2: Placebo
Intervention descriptions: intervention 1: GDC-0853 will be administered orally at dosages of 50, 150 and 200mg to participants, as per the dosing schedules described above. intervention 2: Matching Placebo will be administered orally, as per the dosing schedules described above.

Protocol documents:
Prot_SAP_000.pdf: 
 
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) 
NCT Number:  NCT03137069 
Document Date: 
Protocol Version 4: 09-August-2018 
 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable 
Ethics Committee or Institutional Review Board.  It is understood that this information will not be 
disclosed to others without written authorization from Genentech except to the extent necessary 
to obtain informed consent from persons to whom the drug may be administered.
Fenebrutinib (GDC-0853)—Genentech, Inc.
Protocol GS39684, Version 4
PROTOCOL
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)
PROTOCOL NUMBER: GS39684
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004624-35
TEST PRODUCT:
Fenebrutinib (GDC-0853, RO7010939)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  13 December 2016
Version 2 (Germany Only): 11 April 2017
Version 3:  19 December 2017
Version 4:  See electronic date stamp below.
 
09-Aug-2018 23:42:38
Title
Approver's Name
Date and Time (UTC)


Fenebrutinib (GDC-0853)—Genentech, Inc.
2/Protocol GS39684, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol GS39684 has been amended to allow patients the option to enter an open-label 
extension (OLE) Study GS40868 after completing the 8-week treatment period. 
Language has been updated throughout the protocol to include the OLE (Sections 3.1, 
3.1.2, and 4.3.2.1 and Appendix 1). 
The following additional changes have been made:

The name of the study drug has been updated from GDC-0853 to fenebrutinib 
throughout the document.

The Medical Monitor has changed.

General enrollment update for subjects who received fenebrutinib or placebo 
(Section 1.2.3).  

Safety data regarding hepatotoxicity has been updated (Section 1.2.3, 1.3.4, and 
5.1.1.6).

Clarification regarding the use of rescue medication (Section 3.1).

Clarification of contradictory language regarding tubal ligation since bilateral tubal 
ligation is an example of a contraceptive method with a failure rate of 1% per year 
(Section 4.1.1).

The inclusion criterion that women must refrain from donating eggs during the 
treatment period and for at least 4 weeks after the last dose of study drug has been 
added (Section 4.1.1)

Clarification of fasting before morning clinic visits (Section 4.3.2.1)

Bilastine dose range has been updated based on daily-recommended dose of 
20 mg (Section 4.3.2.3).

Recommendations have been updated regarding the maximum dose of several 
lipid-lowering agents (statins) that are metabolized by CYP3A (simvastatin, 
lovastatin) and/or transported by BCRP (rosuvastatin, atorvastatin), and thus may 
be affected by drug-drug interaction with fenebrutinib (Section 4.4.2.2 and 
Appendix 5).

Clarification regarding the effect of ethinyl estradiol with fenebrutinib has been 
added (Section 4.4.2.3).

Clarification regarding the use of prohibited therapies and corticosteroids for 
exacerbations has been added (Section 4.4.3).

Eligibility criteria for re-screening have been clarified (Section 4.5.2.2).

Added language to clarify use of samples after withdrawal of patient consent 
(Section 4.5.7).

Contradictory language between Section 4.5.8 and the Schedule of Activities 
regarding electrocardiograms has been corrected.

Clarification of the UAS7 definition (Section 4.5.9.2).


Fenebrutinib (GDC-0853)—Genentech, Inc.
3/Protocol GS39684, Version 4
 
 

Additional information around infections has been added (Section 5.1.1.1).

Additional information around bleeding has been added (Section 5.1.1.3).

Additional information around gastrointestinal effects has been added 
(Section 5.1.1.5).

Language has been revised to account for the fact that some sites may not allow 
follow-up on partner pregnancies (Section 5.4.3.2).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable) 
(Section 7.6).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


 
Fenebrutinib (GDC-0853)—Genentech, Inc. 
4/Protocol GS39684, Version 4 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND .......................................................................................... 25 
1.1 
Background on Chronic Spontaneous Urticaria ..................... 25 
1.2 
Background on Bruton’s Tyrosine Kinase and 
fenebrutinib ............................................................................ 26 
1.2.1 
Bruton’s Tyrosine Kinase ....................................................... 26 
1.2.2 
Nonclinical Experience with Fenebrutinib .............................. 27 
1.2.3 
Clinical Experience with Fenebrutinib .................................... 28 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 30 
1.3.1 
Infections ............................................................................... 31 
1.3.2 
Bleeding ................................................................................. 31 
1.3.3 
Cytopenias ............................................................................. 31 
1.3.4 
Hepatotoxicity ........................................................................ 32 
1.3.5 
Cardiovascular Effects ........................................................... 32 
1.3.6 
Malignancy ............................................................................ 32 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 33 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Description of the Study ......................................................... 34 
3.1.1 
Internal Monitoring Committee ............................................... 37 
3.1.2 
Open-Label Extension Study GS40868 ............................................38 
3.2 
End of Study and Length of Study ......................................... 38 
3.3 
Rationale for Study Design .................................................... 38 
 
 38 
3.3.2 
Rationale for Patient Population ............................................ 39 
3.3.3 
Rationale for Control Group ................................................... 40 
 
40 
3.3.5 
Rationale for Pharmacokinetic Sample Collection   
Schedule ................................................................................ 40 
3.3.6 
Rationale for Efficacy Endpoints ............................................ 40 


 
Fenebrutinib (GDC-0853)—Genentech, Inc. 
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4. 
MATERIALS AND METHODS .................................................................... 41 
4.1 
Patients .................................................................................. 41 
4.1.1 
Inclusion Criteria .................................................................... 41 
4.1.2 
Exclusion Criteria ................................................................... 43 
4.2 
Method of Treatment Assignment and Blinding ..................... 46 
4.2.1 
Randomization and Blinding .................................................. 46 
4.2.2 
Unblinding .............................................................................. 47 
4.3 
Study Treatment .................................................................... 48 
4.3.1 
Formulation, Packaging, and Handling .................................. 48 
4.3.1.1 
Fenebrutinib and Placebo ...................................................... 48 
4.3.1.2 
Background Therapy: Standard-of-Care H1 
Antihistamines for CSU ....................................................................48 
4.3.2 
Dosage, Administration, and Compliance of 
Fenebrutinib and Placebo ...................................................... 48 
4.3.2.1 
Fenebrutinib and Placebo Dose and 
Administration ........................................................................ 48 
4.3.2.2 
Fenebrutinib and Placebo Compliance .................................. 49 
4.3.2.3 
Background Therapy:  Standard-of-Care H1 
Antihistamines for CSU ....................................................................50 
4.3.3 
Investigational Medicinal Product Accountability ................... 50 
4.3.4 
Post-Trial Access to Fenebrutinib .......................................... 51 
4.4 
Concomitant Therapy and Additional Restrictions ................. 51 
4.4.1 
Permitted Therapy ................................................................. 51 
4.4.2 
Cautionary Therapy ..........................................................................51 
4.4.2.1 
Acid-Reducing Agents ........................................................... 51 
4.4.2.2 
Statins ................................................................................................52 
4.4.2.3 
CYP3A and BCRP-Mediated Drug Interactions ..................... 52 
4.4.3 
Prohibited Therapy ................................................................ 54 
4.4.3.1 
Live or Attenuated Vaccinations ............................................ 54 
4.4.4 
Prohibited Food ..................................................................... 54 
4.4.5 
Additional Restrictions ........................................................... 54 
4.5 
Study Assessments ............................................................... 54 
4.5.1 
Informed Consent Forms and Screening Log ........................ 54 
4.5.2 
Eligibility at Screening............................................................ 55 


 
Fenebrutinib (GDC-0853)—Genentech, Inc. 
6/Protocol GS39684, Version 4 
4.5.2.1 
Retesting: Laboratory Inclusion/Exclusion ............................. 55 
4.5.2.2 
Re-screening ......................................................................... 55 
4.5.3 
Medical History and Demographic Data ................................ 55 
4.5.4 
Physical Examinations ........................................................... 55 
4.5.5 
Vital Signs .............................................................................. 56 
4.5.6 
FricTest .................................................................................. 56 
4.5.7 
Laboratory,
, and Other Biological  
Samples ................................................................................. 56 
4.5.8 
Electrocardiograms ................................................................ 58 
4.5.9 
Patient-Reported Outcomes .................................................. 59 
4.5.9.1 
Urticaria Patient Daily eDiary ................................................. 59 
4.5.9.2 
Urticaria Activity Score ........................................................... 60 
 
 60 
 
60 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 61 
4.6.1 
Patient Discontinuation .......................................................... 61 
4.6.2 
Study Treatment Discontinuation ........................................... 62 
4.6.3 
Study and Site Discontinuation .............................................. 62 
5. 
ASSESSMENT OF SAFETY ....................................................................... 63 
5.1 
Safety Plan ............................................................................ 63 
5.1.1 
Safety Plan for Potential Risks Associated with 
Fenebrutinib ........................................................................... 63 
5.1.1.1 
Infections ............................................................................... 63 
5.1.1.2 
Vaccinations .......................................................................... 65 
5.1.1.3 
Bleeding ................................................................................. 65 
5.1.1.4 
Cytopenias ............................................................................. 66 
5.1.1.5 
Gastrointestinal Effects .......................................................... 67 
5.1.1.6 
Hepatotoxicity ........................................................................ 67 
5.1.1.7 
Cardiovascular Effects ........................................................... 68 
5.1.1.8 
Vascular Inflammation ........................................................... 69 
5.1.1.9 
Malignancy ............................................................................ 69 
5.1.2 
Management of Patients Who Experience 
Specific Adverse Events ........................................................ 70 


 
Fenebrutinib (GDC-0853)—Genentech, Inc. 
7/Protocol GS39684, Version 4 
5.1.2.1 
Management of Specific Adverse Events .............................. 70 
5.1.2.2 
Management of Increases in QT Interval ............................... 71 
5.2 
Safety Parameters and Definitions ........................................ 72 
5.2.1 
Adverse Events ..................................................................... 72 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 72 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 73 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 74 
5.3.1 
Adverse Event Reporting Period ........................................... 74 
5.3.2 
Eliciting Adverse Event Information ....................................... 74 
5.3.3 
Assessment of Severity of Adverse Events ........................... 74 
5.3.4 
Assessment of Causality of Adverse Events ......................... 75 
5.3.5 
Procedures for Recording Adverse Events ............................ 76 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 76 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events .................................................................................... 76 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 76 
5.3.5.4 
Abnormal Laboratory Values ................................................. 77 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 78 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 78 
5.3.5.7 
Deaths ................................................................................... 78 
5.3.5.8 
Preexisting Medical Conditions .............................................. 79 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic 
Spontaneous Urticaria ........................................................... 79 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 79 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 80 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 80 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 80 
5.4.1 
Emergency Medical Contacts ................................................ 81 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 81 


 
Fenebrutinib (GDC-0853)—Genentech, Inc. 
8/Protocol GS39684, Version 4 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 81 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 81 
5.4.3 
Reporting Requirements for Pregnancies .............................. 82 
5.4.3.1 
Pregnancies in Female Patients ............................................ 82 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 82 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 83 
5.5 
Follow-Up of Patients after Adverse Events .......................... 83 
5.5.1 
Investigator Follow-Up ........................................................... 83 
5.5.2 
Sponsor Follow-Up ................................................................ 83 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 83 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 84 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 84 
6.1 
Determination of Sample Size ............................................... 84 
6.1.1 
Cohort 1: Pilot Assessment ................................................... 84 
6.1.2 
Cohort 2: Dose-Ranging Assessment ................................... 85 
6.2 
Summaries of Conduct of Study ............................................ 85 
6.3 
Summaries of Treatment Group Comparability ..................... 86 
6.4 
Efficacy Analyses .................................................................. 86 
6.4.1 
Primary Efficacy Endpoint ...................................................... 86 
6.4.2 
Secondary Efficacy Endpoints ............................................... 87 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 87 
6.5 
Safety Analyses ..................................................................... 88 
6.6 
Pharmacokinetic Analyses ..................................................... 88 
 
88 
6.8 
Interim Analysis ..................................................................... 89 
6.8.1 
Cohort 1: Planned Interim Analysis ....................................... 89 
6.8.2 
Cohort 2: Optional Interim Analysis ....................................... 89 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 89 
7.1 
Data Quality Assurance ......................................................... 89 
7.2 
Electronic Case Report Forms ............................................... 90 




Fenebrutinib (GDC-0853)—Genentech, Inc.
10/Protocol GS39684, Version 4
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 37
LIST OF APPENDICES
Appendix 1
Schedule of Activities (Cohorts 1 and 2)................................... 101
Appendix 2
Childbearing Potential, Pregnancy Testing, and 
Contraception............................................................................ 106
Appendix 3
Urticaria Patient Daily eDiary .................................................... 108
113
Appendix 5 
Concomitant Medications (Including Foods and Herbal 
Products)................................................................................... 114


Fenebrutinib (GDC-0853)—Genentech, Inc.
11/Protocol GS39684, Version 4
PROTOCOL ACCEPTANCE FORM
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)
PROTOCOL NUMBER:
GS39684
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004624-35
TEST PRODUCT:
Fenebrutinib (GDC-0853, RO7010939)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name (print)
Principal Investigator's Signature
Date
Please return a copy of the signed form as instructed by the CRO.  Please retain the 
original for your study files.


Fenebrutinib (GDC-0853)—Genentech, Inc.
12/Protocol GS39684, Version 4
PROTOCOL SYNOPSIS
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)
PROTOCOL NUMBER:
GS39684
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004624-35
TEST PRODUCT:
Fenebrutinib (GDC-0853, RO7010939)
PHASE:
Phase II
INDICATION:
Refractory Chronic Spontaneous Urticaria (CSU)
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This pilot and dose-ranging study will evaluate the efficacy, safety, and pharmacokinetics of 
fenebrutinib compared with placebo in patients with chronic spontaneous urticaria (CSU) 
refractory to anti-histamines (up to 4 times the approved dose per local treatment guidelines).  
Specific objectives and corresponding endpoints for the study are outlined below.
Objectives and Corresponding Endpoints
Objectives
Corresponding Endpoints
Efficacy Objective:
To evaluate the efficacy of fenebrutinib
compared with placebo in patients with 
CSU who are refractory to 
anti-histamines 
Primary Endpoint:
Change from baseline in the UAS7 at Day 57 (Week 8)
Secondary Endpoints:
Proportion of patients who are well controlled (UAS7 6) at 
Day 57
Change from baseline in the UAS7 at Day 29 (Week 4)
Exploratory Endpoints:
Change from baseline in the weekly itch score at Day 29
Change from baseline in the weekly itch score at Day 57
Change from baseline in the weekly hives score at Day 57
Proportion of patients who are well controlled (UAS7 6) at 
Day 29
Proportion of patients who achieve complete response 
(UAS7 0) at Day 29
Proportion of patients who achieve complete response 
(UAS7 0) at Day 57
Proportion of patients achieving MID in UAS7 at Day 57 
(reduction from baseline 11 points)
Proportion of patients achieving MID in the weekly itch score at 
Day 57 (reduction from baseline 5 points)




Fenebrutinib (GDC-0853)—Genentech, Inc.
14/Protocol GS39684, Version 4
will enroll approximately 45 patients across multiple sites.  After screening, eligible patients will 
be randomly allocated in a 2:1 ratio to receive fenebrutinib 200 mg orally (PO) twice daily (BID)
or matching placebo for 8 weeks and will maintain stable doses of standard-of-care H1 
antihistamine therapy throughout the study. On the basis of results from an interim analysis of 
Cohort 1, a dose-ranging cohort, Cohort 2, will be opened and approximately 120 patients will 
be randomly allocated in a 1:1:1:1 ratio to receive 50 mg PO daily (QD), 150 mg PO QD, 
200 mg PO BID of fenebrutinib, or placebo, respectively, for 8 weeks and will maintain stable 
doses of standard-of-care H1 antihistamine therapy (background therapy) throughout the study.
Both cohorts will consist of 3 distinct study periods over a time-period of 14 weeks as outlined 
below: 

Screening period:  Day 14 to Day 1

Treatment Period:  Day 1 to Day 57 (Week 0 to Week 8)

Follow-Up Period:  Day 57 to Day 85 (Week 8 to Week 12)
Patients in both cohorts will have a screening period of approximately 2 weeks to establish their 
eligibility for the study and baseline symptom scores.  For the duration of the screening period, 
patients must maintain stable doses of their pre-screening combination therapy with standard-
of-care H1 antihistamines (i.e., up to 4 times the approved dose per local treatment guidelines).  
The screening period will consist of visits at Day 14 and Day 7.  Patients must meet all of the 
following criteria to enter the screening period:

Documented treatment with a regimen that includes standard-of-care H1 antihistamine for 
CSU at Day 14 and for at least the 3 consecutive days immediately prior to Day 14

Willing and able to complete a symptom electronic diary (Urticaria Patient Daily eDiary) 
twice daily throughout the screening period to establish the patient’s Urticaria Activity Score 
over 7 days (UAS7) score.
To be eligible for randomization in both cohorts, for the 7 days prior to randomization, patients 
must meet all of the following:

Seven consecutive days of entries in the Urticaria Patient Daily eDiary, and 

UAS7 symptom score of 16 (range:  0 42)
Only in exceptional circumstances, when information concerning eligibility is outstanding (e.g., 
delayed laboratory results), will a longer screening period be permitted up to 3 business days.  
Upon approval from the Medical Monitor, patients may be re-screened or may be retested 
during the screening period.  Circumstances that may permit re-screening or retesting include, 
but are not limited to, a laboratory test result that does not meet eligibility requirements.
On Day 1, eligible patients in Cohort 1 will be randomly allocated in a 2:1 ratio to receive 
fenebrutinib 200 mg orally (PO) twice daily (BID) or placebo for 8 weeks.  Eligible patients in
Cohort 2 will be will be randomly allocated in a 1:1:1:1 ratio to receive 50 mg PO daily (QD), 150 
mg PO QD, 200 mg PO BID of fenebrutinib, or placebo, respectively, for 8 weeks. The primary 
efficacy endpoint will be at Day 57 (Week 8).  Throughout the treatment period, patients must 
maintain stable doses of their pre-randomization H1 antihistamine therapy.  
After completion of the 8-week treatment period, all patients in both cohorts will either enter a 
4-week safety follow-up period to allow for further characterization of the pharmacokinetics and 
pharmacodynamics of fenebrutinib, and collection of additional efficacy and safety or they will 
have the opportunity to participate in the open-label extension Study GS40868. During
safety follow-up period, no study treatment will be given; patients must maintain stable doses of 
their pre-randomization CSU H1 antihistamine treatment (background therapy).  In the safety 
follow-up period, patients may add up to one additional H1 antihistamine therapy in case of 
worsened symptoms.  The goal of allowing additional H1 antihistamine therapy after the 
treatment period is to reduce patient dropout for improved safety evaluation.
In addition to their daily background therapy, for the duration of the study all patients will be able 
to use a single approved dose of loratadine (10 mg maximum) or cetirizine (10 mg maximum) 
within a 24-hour period as rescue medication if symptoms worsen. If a patient needs rescue 
therapy and is already on background treatment with cetirizine or loratadine, the patient may 
receive 10 mg more of the same drug only if the total daily dose remains below 4 times the 


Fenebrutinib (GDC-0853)—Genentech, Inc.
15/Protocol GS39684, Version 4
approved dose. Otherwise, the alternate rescue medication may be used. Patients should 
record the use of this medication in their eDiary.  Patients receiving proton-pump inhibitors 
(PPIs) or H2 receptor antagonists (H2RAs) should be stabilized on a regimen beginning at least 
2 weeks prior to randomization and continuing throughout the study.
Internal Monitoring Committee
For Cohort 2, periodic safety reviews and any interim analysis will be performed by the 
Sponsor’s internal monitoring committee (IMC) as outlined in the IMC charter.  This committee 
will be unblinded to treatment assignments and will include Sponsor representatives from the 
following functions: Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and 
Analysis.  The IMC members will not have direct contact with investigational staff or site 
monitors.  The IMC may decide to unblind the study team to enable decision-making and 
potential interactions with regulatory bodies. The IMC may invite representatives from other 
functional areas on an ad-hoc basis when additional expertise is required (e.g., Clinical 
Pharmacology, Research, etc.) or additional Sponsor scientists to participate in data analyses 
and review. 
At any time during the study, the Sponsor may choose to inactivate and suspend enrollment 
and further dosing for a given treatment arm (in Cohort 2) or reduce the dose due to safety 
concerns and as guided by the IMC.  In Cohort 2, subsequently enrolled patients will be 
randomly allocated to the remaining active arms. 
Open-Label Extension Study GS40868
After completing the 8-week treatment period (at Day 57), eligible patients from Cohort 1 and 
2 will have the option to enter the OLE Study GS40868 and receive open-label fenebrutinib 
treatment.  Patients who do not enter the OLE after completing the treatment period will 
undergo assessments at 4 weeks after the last dose of study drug (safety follow-up). 
Patients who completed the treatment period and 4-week safety follow-up period may also 
enroll in the OLE study if eligible.
Number of Patients
Approximately 45 patients, aged 18 to 75 years old who have been diagnosed with refractory 
CSU and who remain symptomatic despite standard-of-care H1 antihistamine (i.e., up to 4 times 
the approved dose per local treatment guidelines), will be enrolled in Cohort 1.  On the basis of 
results from an interim analysis of Cohort 1, a dose-ranging cohort, Cohort 2, will be opened 
and approximately 120 patients will be enrolled.
Target Population
Inclusion Criteria
Patients in Cohort 1 and 2 must meet the following criteria for study entry:

Willing to give written informed consent, adhere to the visit schedules, comply with the 
study drug regimen, and meet other study requirements

Aged 18 75 years, inclusive 

Diagnosis of CSU refractory to H1 antihistamines at the time of randomization, as defined 
by all of the following:

The presence of itch and hives for 6 consecutive weeks at any time prior to enrollment 
despite current use of H1 antihistamine, consistent with standard of care (i.e., up to 
4 times the approved dose per local treatment guidelines) during this time period

UAS7 score 16 during the 7 days prior to randomization (Day 1)

Patients must have been on daily stable doses of H1 antihistamine, consistent with 
standard of care (i.e., up to 4 times the approved dose per local treatment guidelines) 
treatment for CSU starting at least 3 consecutive days immediately prior to the 
screening visit through Day 1and must document current use on all visits.

CSU diagnosis for 6 months

Willing and able to complete an Urticaria Patient Daily eDiary for the duration of the study


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
Completion of 7 days of the Urticaria Patient Daily eDiary entries in the 7 days prior to 
randomization (7 of 7 days must be completed [i.e., must complete an entry every day] with 
up to 2 non-consecutive entries missed)

No evidence of active or latent or inadequately treated infection with tuberculosis (TB) as 
defined by the following:

A negative QuantiFERON-TB-Gold(QFT) performed at the screening visit or within 
the 3 months prior to screening (for German sites only: QFT is the preferred test)
If QFT is unavailable, a negative Mantoux purified protein derivative (PPD) skin 
test as defined by the Centers for Disease Control and Prevention guidelines, may 
be performed at the screening visit or within the 3 months prior to 
screening -AND-
Any additional procedures (e.g., chest X-Ray) required per local guidelines to rule 
out latent or active TB
NOTE:  A documented negative screening for TB via the PPD test or a negative QFT 
within 3 months prior to screening (and if required per local standard of care, a chest 
X-ray), is sufficient and no further screening with QFT is required.
Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should be screened 
using the QFT test, only. 

An indeterminate QFT test should be repeated. 

A positive QFT test or two successive indeterminate QFT results should be considered 
a positive diagnostic TB test. 

An indeterminate QFT test followed by a negative QFT test should be considered a 
negative diagnostic TB test.

Only for patients currently receiving PPIs or 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.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, established proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.  Women using estrogen-containing hormonal contraceptives as a method of 
contraception must also use a barrier, such as a male condom, in conjunction with the 
hormonal contraceptives. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 4 weeks
after the last dose of study treatment to avoid exposing the embryo.  Men must refrain 
from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 


 
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(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
 
Exclusion Criteria 
Patients in Cohort 1 and 2 who meet any of the following criteria will be excluded from study 
entry: 
 
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 fenebrutinib or other Bruton’s tyrosine kinase (BTK) inhibitors 
 
Patients 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 (daily or every other day during 5 or more consecutive days) 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 
 
IV immunoglobulin G (IVIG) or plasmapheresis within 30 days prior to screening 
 
History of anaphylactic shock without clearly identifiable avoidable antigen (e.g., due to food 
allergy) 
 
Hypersensitivity to fenebrutinib 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 
Seasonal influenza and H1N1 vaccination is permitted if the inactivated vaccine 
formulation is administered.  
 
Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, hepatic, 
endocrine (including uncontrolled diabetes mellitus), metabolic, or gastrointestinal (GI)  
disease that, in the investigator’s opinion, would compromise the safety of the patient, 
interfere with the interpretation of the study results, or otherwise preclude patient 
participation.   
Any items that are cause for uncertainty must be reviewed with the Medical Monitor. 
 
Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, 
where flares are commonly treated with oral or parenteral corticosteroids 
 
History of vasculitis 
 
Current liver disease  
 
Any known active infection (with the exception of fungal nail infections or oral herpes) 


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
History of recurrent bacterial, viral, mycobacterial or fungal infections (defined as 2 similar 
episodes requiring anti-microbial treatment within the previous 12 months), with the 
exception of recurrent oral or genital herpes (herpes simplex virus 1/herpes simplex virus 2) 
or uncomplicated urinary tract infections in females.

Any history of opportunistic infections that, in the investigator or Sponsor’s judgment, would 
raise safety concerns regarding the patient's participation in the study

Any major episode of infection requiring hospitalization or treatment with IV antimicrobials
within 8 weeks prior to and during screening or treatment with oral antimicrobials within 
2 weeks prior to and during screening
Antimicrobials include antifungal, antibacterial, and antiviral agents.

History of or currently active primary or secondary immunodeficiency, including known 
history of HIV infection

Evidence of chronic and/or active hepatitis B or C
Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless of 
treatment status)
Positive hepatitis B core antibody (HBcAb)

History of cancer, including hematologic malignancy and solid tumors, within 10 years 
before screening
Basal or squamous cell carcinoma of the skin that has been excised and is considered 
cured and in situ carcinoma of the cervix treated with apparent success by curative 
therapy 1 year prior to screening are not exclusionary.

Women who are pregnant, nursing (breastfeeding), or intending to become pregnant during 
the study or within 4 weeks after completion of the study

For women of childbearing potential (including those who have had a tubal ligation):  
positive serum pregnancy test result at screening or on Day 1.
A serum pregnancy test is needed on Day 1 only if the urine pregnancy test is positive.

History of alcohol, drug(e.g., tetrahydrocannabinol [THC], marijuana), or chemical abuse 
within the 12 months prior to screening as determined by the investigator

Need for systemic anti-coagulation with warfarin, other oral or injectable anti-coagulants, or 
anti-platelet agents other than non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and 
other salicylates

History of non-gallstonerelated pancreatitis or chronic pancreatitis

History of hospitalizations or transfusion for a GI bleed

History of cerebrovascular accident (CVA) within 10 years or any history of hemorrhagic 
CVA

History of spontaneous intracranial hemorrhage or history of traumatic intracranial 
hemorrhage within 10 years

Known bleeding diathesis

Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect 
patient safety or interpretation of study results, including
QT interval corrected using Fridericia’s formula (QTcF) 440 ms demonstrated by at 
least two ECGs 30 minutes apart

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as long 
QT syndrome and other genetic risk factors (e.g., Brugada syndrome), structural heart 
disease (e.g., severe left ventricular systolic dysfunction, severe left ventricular hypertrophy), 
coronary heart disease (symptomatic, or with ischemia demonstrated by diagnostic testing, 
prior coronary artery bypass grafting, or coronary lesions 70% diameter stenosis that have 
not been or cannot be re-vascularized), clinically significant electrolyte abnormalities (e.g., 
hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained 
death or cardiac ion channel mutations (e.g., congenital long QT syndrome)


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
Current treatment with medications that are well known to prolong the QT interval (see 
https://crediblemeds.org/index.php/login/dlcheck) at doses that have a clinically meaningful 
effect on QT, as determined by the investigator; the investigator may contact the Sponsor 
for confirmation if needed

Current treatment with astemizole, terfenadine, and/or ebastine

Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically significant
diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass)
Procedures such as gastric banding, that simply divide the stomach into separate 
chambers, are not exclusionary.

Any uncontrolled clinically significant laboratory abnormality that would affect safety, 
interpretation of study data, or the patient’s participation in the study 

For German sites only:  Subjects who live in detention on court order or on regulatory action 
as per local and national law (see §40 subSection 1 sentence 3 no. 4 Arzneimittelgesetz). 
The following exclusion criteria are based on screening laboratory tests.  Laboratory tests may 
be repeated once during the screening period unless otherwise indicated:

Creatinine 1.5 times the upper limit of normal (ULN; may be repeated if 1.52 ULN)

Creatinine clearance 70 mL/min (may be repeated if 6069 mL/min) as estimated by the 
Cockcroft-Gault Equation

ALT or AST 1.5 times ULN (may be repeated if 1.53 ULN)

Total bilirubin ULN (may be repeated if 13 ULN)

Hemoglobin 11 g/dL (may be repeated if 1010.9 g/dL)

ANC 1.5 109/L (may be repeated if 1.21.5 109/L)

Platelet count 100 109/L (may be repeated if 80100 109/L)

IgG 500 mg/dL (should not be repeated)

Abnormalities in hepatic synthetic function tests (e.g., PT, INR, PTT, albumin) judged by the 
investigator to be clinically significant
End of Study
The end of this study is defined as the date when all patients have completed the study 
completion visit or early termination visit or have otherwise been discontinued from the study.  
Length of Study
The total duration of this study for each subject is approximately 14 weeks, including screening, 
treatment, and safety follow-up periods.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 19 months.
Investigational Medicinal Products
The investigational medicinal product for this study is fenebrutinib.  For Cohort 1, patients will 
receive fenebrutinib 200 mg PO BID or placebo for 8 weeks.  For Cohort 2, will receive 
fenebrutinib 50 mg QD, 150 mg QD, 200 mg BID, or placebo for 8 weeks.
Non-Investigational Medicinal Products
Throughout the treatment period, patients must maintain stable doses of their pre-randomization 
H1 antihistamine therapy.  In addition to their daily background therapy, for the duration of the 
study all patients will be able to use a single approved dose of loratadine (10 mg maximum) or 
cetirizine (10 mg maximum) within a 24-hour period as rescue medication if symptoms worsen.
If a patient needs rescue therapy and is already on background treatment with cetirizine or 
loratadine, the patient may receive 10 mg more of the same drug only if the total daily dose 
remains below 4 times the approved dose. Otherwise, the alternate rescue medication may be 
used.


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Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in the UAS7 at Day 57 (Week 8).  
The Urticaria Activity Score (UAS) is to be recorded twice daily (i.e., morning and evening) 
using an eDiary that will be provided to each patient.  Scores ranging from 0 (none) to 3 
(severe) will be entered for each of the two UAS domains consisting of number of wheals 
(hives) and intensity of pruritis (itch) resulting in a total possible score of 0 to 6.  The daily UAS 
is calculated as the average of the morning and evening scores.  When either the morning or 
evening score is missing, the non-missing UAS for that day (morning or evening) will be used as 
the daily UAS, and when both the morning and evening UAS are missing, the daily UAS will be 
deemed missing.  The UAS7 is the sum of the daily UAS over the 7 days prior to the time point 
of interest.  The baseline UAS7 will be calculated as the sum of daily UAS values over the week 
(7 days) prior to Day 1.  
When one or more daily UAS values is missing, over the week prior to a timepoint of interest, 
rules for deriving UAS7 will be as follows: 

If a patient has at least 4 completed daily scores on the UAS (both domains) over the 
7 days prior to the time point of interest, the UAS7 will be defined as the average of the 
available daily scores, multiplied by 7.

If a patient has fewer than 4 completed daily scores on the UAS over the 7 days prior to the 
time point of interest, then the UAS7 will be considered missing for that time point.
The primary endpoint will be analyzed using a mixed model for repeated measures model.  
Additional model covariates will include baseline UAS7 and its interaction with visit.  Missing 
data will be handled by the model under the missing-at-random assumption without need for 
imputation.  As a sensitivity analysis, an analysis of covariance (ANCOVA) model adjusted for 
country and baseline UAS7 will be fit, and missing Day 57 data will be imputed by last 
observation carried forward.
Determination of Sample Size  
Cohort 1: Pilot Assessment
The purpose of this cohort is to evaluate the efficacy of fenebrutinib compared with placebo in 
improving the UAS7.  Point and interval estimates of the change from baseline of the UAS7
within each treatment group as well as of the difference in change from baseline of the UAS7 
between treatment groups will be presented.
The cohort will enroll approximately 45 patients.  Patients will be randomized in a 2:1 ratio to 
receive treatment with either fenebrutinib or placebo.  The sample size of approximately 
30 patients in the fenebrutinib arm and 15 patients in the placebo arm provides approximately 
80% power to detect an 11-point difference in the UAS7 change from baseline at Day 57 
between treatment groups under the following assumptions:

The absolute change from baseline at Day 57 is normally distributed with a standard 
deviation of 13.

Two-sided alpha is 0.10.

Drop out at Day 57 is 10%, leading to a 10% loss of information.
Cohort 2: Dose-Ranging Assessment
The purpose of this cohort is estimation and hypothesis generation regarding the dose-ranging 
effects of fenebrutinib compared with placebo in improving the UAS7.  Point and interval 
estimates of the change from baseline of the UAS7 within each treatment group as well as of 
the difference in change from baseline of the UAS7 between treatment groups vs placebo will 
be presented.
The cohort will enroll approximately 120 patients.  Patients will be randomly allocated in a 
1:1:1:1 ratio to receive treatment with one of three dose levels of fenebrutinib or placebo.  The 
sample size of approximately 30 in each arm provides approximately 90% power to detect an 
11-point difference in the UAS7 change from baseline at Day 57 between treatment groups, 
under the following assumptions:


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
The absolute change from baseline at Day 57 is normally distributed with a standard 
deviation of 13

Two-sided alpha is 0.10

Dropout rate at Day 57 is 10%, leading to a 10% loss of information.
The overall sample size may be adjusted depending on the outcome of a planned interim 
analysis for Cohort 1, which will include an evaluation of these assumptions.
Interim Analysis
Cohort 1: Planned Interim Analysis
An interim analysis will be performed after approximately 33 patients have completed their 
8week treatment period.  The purpose of this analysis is to assess the efficacy of the 200mg 
fenebrutinib BID daily arm compared with the placebo, to guide internal decision-making around 
issues such as ungating of Cohort 2, adequacy of sample sizes for safety and/or efficacy 
analyses in Cohort 2, or to inform further development decisions.  Summaries of safety and 
efficacy data by treatment groups will be prepared and reviewed by Sponsor personnel who do 
not have direct contact with investigational staff, monitors, and patients.  Further details of the 
interim analysis will be specified in the data analysis plan (DAP) prior to the conduct of the 
interim analysis.  Access to treatment assignment information will follow the Sponsor’s standard 
procedures.
Cohort 2: Optional Interim Analysis
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct up to 
two interim efficacy analyses.  The decision to conduct an optional interim analysis and the 
timing of the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis.  The interim analysis will be performed and interpreted by members of the 
IMC.  Access to treatment assignment information will follow the Sponsor’s standard procedures.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC0-t
area under the concentration-time curve from time 0 to time t
BCG
Bacille Calmette-Guérin
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BID
twice a day
BTK
Bruton’s tyrosine kinase
Cmax
maximum observed concentration
Ctrough
steady-state concentration at the end of a dosing interval
CIU
chronic idiopathic urticaria
CL/F
apparent clearance
CRP
C-reactive protein
CSR
clinical study report
CSU
chronic spontaneous urticaria
CTCAE
Common Terminology Criteria for Adverse Events
CVA
cerebrovascular accident
DAP
data analysis plan
DLAE
dose-limiting adverse events
DLT
dose-limiting toxicity
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
FcRI
high affinity IgE receptor
FDA
Food and Drug Administration
GI
gastrointestinal
H2RA
H2 receptor antagonist
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
ICH
International Conference on Harmonisation


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Abbreviation
Definition
IL-1
interleukin 1
IL-6
interleukin 6
IMC
Internal monitoring committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IV
intravenous
IVIG
intravenous immunoglobulin G
IxRS
interactive voice or web-based response system
LTRA
leukotriene receptor antagonist
MAD
multiple-ascending dose
MID
minimally important difference
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures
NCI
National Cancer Institute
NOAEL
no observed adverse effect level
NSAID
non-steroidal anti-inflammatory drug
PD
pharmacodynamic
PK
pharmacokinetic
PO
by mouth, orally
PPD
Purified Protein Derivative
PPI
proton-pump inhibitor
PRO
patient-reported outcome
QD
once a day
QFT
QuantiFERON-TB-Gold
QTcF
QT interval corrected using Fridericia’s formula
RA
rheumatoid arthritis
SAD
single-ascending dose
SLE
systemic lupus erythematosus
t1/2 
half-life
tmax
time to maximum concentration
TB
tuberculosis
THC
tetrahydrocannabinol
TNF-
tumor necrosis factor alpha
UAS
Urticaria Activity Score
UAS7
Urticaria Activity Score over 7 days


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Abbreviation
Definition
XLA
X-linked agammaglobulinemia


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1.
BACKGROUND
1.1
BACKGROUND ON CHRONIC SPONTANEOUS URTICARIA
Chronic spontaneous urticaria (CSU, also referred to as chronic idiopathic urticaria 
[CIU]) is defined by the presence of wheals (hives), angioedema, or both for at least 
6 weeks without an obvious cause (Greaves 2003).  Previous estimates of the 
prevalence of CSU were approximately 0.1%, which persists in 20% of CSU patients 
2 decades after diagnosis (Greaves 2000; Saini 2014).  More recent evidence indicates 
that the point prevalence of the disease is approximately 1% (Maurer et al. 2011).  
Affected patients experience frequent pruritic hives with associated erythema and/or 
episodes of angioedema.  CSU is reported to be associated with angioedema in 
approximately 50% of cases (McGirt et al. 2006).  The classic urticaria description is a 
wheal and flare with a pale elevated lesion and surrounding erythema, ranging in size 
from a few millimeters to a few centimeters across, usually occurring in groups and often 
coalescing to form large confluent lesions.  
The etiology of CSU is not clear.  There are several theories including one proposing an 
infectious origin and another related to an autoimmune origin (Kaplan 2002).  Some 
studies have found that approximately 30%60% of patients with CSU have an 
autoimmune component as evidenced by the presence of a positive autologous serum 
skin test (Fiebiger et al. 1995; Tong et al. 1997; Zweiman et al. 1998).  Another 
hypothesis regarding the etiology of CSU is that of a specific IgE antibody targeted to an 
endogenous antigen (Altrichter et al. 2011).  Crosslinking of this IgE antibody docked in 
the high affinity IgE receptor (FcRI) could result in the activation of skin mast cells and 
release of chemical mediators, such as histamine, that lead to the wheal and flare 
formation of a hive.  In fact, recent findings in a study of more than 450 patients with 
CSU indicate that greater than 50% of CSU patients have IgE antibodies directed 
against thyroperoxidase (Altrichter et al. 2011).  While an autoimmune etiology can be 
found in a large percentage of patients, many patients do not have an identified 
autoimmune etiology despite having a similar disease presentation (Ferrer 2015).  
The final common pathway in CSU is the abnormal activation of mast cells and 
basophils in the skin.  In patients with CSU, increased numbers of mast cells can be 
found in both affected and unaffected skin (Kay et al. 2014).  Furthermore, mast cells 
from CSU patients are more sensitive, have lower thresholds for activation, and respond 
more robustly by releasing more histamine and other inflammatory mediators.  Similarly, 
increased numbers of basophils have been seen in the lesional and non-lesional skin of 
patients with CSU (Ying et al. 2002).  In patients with CSU, there is a paradoxical 
basopenia thought to be due to increased recruitment of basophils to diseased skin.  
The peripheral basopenia is inversely correlated with severity of disease activity.  In 
comparison with healthy controls, studies have shown that blood basophils of CSU 
patients have a reduced capacity to release histamine following IgE stimulation.  This 
paradoxical reduction is attributed to prior in vivo activation in the skin (Kern and 
Lichtenstein 1976).  However, when basophils from CSU patients are incubated with 


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serum from other CSU patients or even normal sera, they release more histamine than 
basophils from healthy donors.  Collectively, these data suggest that basophil signaling 
and activation are dysregulated in patients with CSU (Luquin et al. 2005).
Roughly half of patients with CSU achieve symptomatic control with H1 antihistamine 
therapy at approved doses.  In some cases, the dose of antihistamine is increased (up to 
4 times the approved dose per local treatment guidelines) and additional therapies, such 
as leukotriene receptor antagonists (LTRAs), are used although increased doses of 
antihistamines and LTRAs are not approved for the treatment of CSU.  CSU can be a 
debilitating condition because of a lack of clinical response as well as the unpredictable 
course of the disease, both of which can have a profound negative influence on the 
patient’s quality of life (Tilles 2005). 
Patients may remain symptomatic despite ongoing H1 antihistamine treatment (up to 
4 times the approved dose per local treatment guidelines; Powell et al. 2015), and for 
this group of patients, therapies such as immunosuppressants (including cyclosporine, 
corticosteroids, intravenous immunoglobulin G [IVIG], and methotrexate) and 
plasmapheresis have been used (Kozel and Sabroe 2004).  These agents have variable 
success and may be associated with severe adverse effects.  More recently, 
omalizumab was approved for treatment of refractory CSU/CIU.  
1.2
BACKGROUND ON BRUTON’S TYROSINE KINASE AND 
FENEBRUTINIB
1.2.1
Bruton’s Tyrosine Kinase
Discovery of the genetic basis for primary immunodeficiencies has been the source 
of new therapeutic targets in immunomodulatory therapies (Puri et al. 2013; 
Bugatti et al. 2014; Whang and Chang 2014).  In humans, mutations in the gene for 
Bruton’s tyrosine kinase (BTK), which is located on the X chromosome, can result in the 
development of an immunodeficiency state characterized by a significant absence of 
circulating B cells (Bruton 1952; Tsukada et al. 1993; Vetrie et al. 1993; Conley et al. 
2005) and very low immunoglobulin levels due to a defect in B-cell differentiation at the 
proto preB cell stage that precludes assembly of the B-cell receptor (BCR) complex 
and immunoglobulin gene expression (Reth and Nielsen 2014).  Affected male patients 
have a primary immune deficiency, X-linked agammaglobulinemia (XLA), and are 
susceptible to recurrent infections starting shortly after birth.  Patients with XLA can live 
relatively normal lives on a standard therapy of intravenous (IV) immunoglobulin, which 
suggests that BTK can be safely inhibited, especially in people with established immune 
systems.  IV immunoglobulin replacement therapy lowers the rate of infection, reduces 
hospitalization rates for patients with XLA, and has greatly improved the long-term 
prognosis of these patients.
BTK is essential for the differentiation and activity of B cells during immune system 
ontogeny and normal adaptive immune responses.  BTK is activated by 
phosphatidylinositol 3-kinasedependent plasma membrane recruitment and 


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phosphorylation on tyrosine Y551 by the Src-family kinase Lyn.  Autophosphorylation 
and activation also occurs on tyrosine Y223 in a BTK-specific manner.  Once activated, 
BTK induces PLC2- and Ca2-dependent signaling, which leads to the activation of 
NF-κBand NFAT-dependent pathways leading to cellular activation and differentiation 
(Niiro and Clark 2002).  In addition, BTK is important in FcRI signaling in both basophils 
and mast cells, the key cell types in the pathogenesis of CSU.  BTK null mice have 
impaired FcRI signaling resulting in decreased histamine and inflammatory cytokine 
release (Hata et al. 1998; Iyer et al. 2011).
1.2.2
Nonclinical Experience with Fenebrutinib
Fenebrutinib (also referred to as GDC-0853 or RO7010939) is a highly selective, orally
administered, reversible inhibitor of BTK that is being developed by Genentech, Inc. as a
potential therapeutic for autoimmune diseases, including CSU.  Fenebrutinib has
undergone extensive investigation in nonclinical in vitro and in vivo studies to 
characterize its pharmacological, metabolic, and toxicological properties (see the 
Fenebrutinib Investigator’s Brochure for further details).
In vitro cell-based experiments suggest that antagonism of BTK leads to inhibition of 
BCR-dependent B-cell proliferation and a reduction of inflammatory cytokine production 
from myeloid cells (including tumor necrosis factor alpha [TNF-, interleukin 1 [IL-1], and
interleukin 6 [IL-6]) by preventing signaling through the FcRIII receptor (Di Paolo et al.
2011; Liu et al. 2011).  Fenebrutinib effectively blocks BCR- and CD40-mediated 
activation and proliferation of B cells. BTK in B cells also plays a role in TLR4-mediated 
B-cell proliferation and class switching.  In monocytes, fenebrutinib inhibits TLR4- and
immune complex-mediated inflammatory cytokine production, including TNF-, which 
contributes to disease pathogenesis in rheumatoid arthritis (RA). 
As described above, the pathophysiology of CSU is not completely understood.  A key 
step is FcRI-activation and release of histamine and inflammatory cytokines from mast 
cells and basophils, leading to the wheal and flare formation of a hive as well as 
angioedema.  In support of the importance of BTK in FcRI signaling and the 
pathogenesis of CSU, BTK null mice have impaired FcRI signaling, resulting in 
decreased histamine and inflammatory cytokine release (Hata et al. 1998; Iyer et al. 
2011).  
Consistent with these findings, in vitro experiments with human mast cell lines 
demonstrated that fenebrutinib could effectively inhibit the release of histamine induced
by cross-linking of IgE bound to FcRI on the surface of mast cells.  In addition, in a 
Phase Ib study in healthy volunteers, oral administration of fenebrutinib inhibited ex vivo 
basophil activation as measured by diminished cell surface expression of CD63 after 
cross-linking of IgE.  As such, fenebrutinib inhibits the activity of two specific cell types 
that play key roles in disease pathology in CSU.  


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The fenebrutinib safety profile has been assessed in repeat-dose, general toxicology 
studies (once a day [QD] oral dosing) ranging from 1 week to 9 months in rats and dogs; 
in vitro and in vivo genetic toxicology studies; in vitro phototoxicity evaluation; in vitro 
and in vivo safety pharmacology studies of the central nervous, respiratory, and 
cardiovascular systems; and embryo-fetal development (Seg II) studies in rats and 
rabbits.  Overall, fenebrutinib was well tolerated for up to 6 months in rats (up to 
104 M hr) and up to 9 months in dogs (up to 36 M hr).  Notable findings identified in 
nonclinical toxicology studies include vascular inflammation (56 M hr) in dogs, 
hepatotoxicity (180 M hr) in dogs and rats, and a minimal increase in corrected QT 
interval (QTc; 7 ms or 3%; extrapolated unbound maximum observed concentration 
[Cmax] of 3.17 M) in dogs.  Fetal malformations in rats (at 627 M hr) and rabbits 
(10.6 M hr) warrant the continued use of highly effective contraception in clinical 
trials.  On the basis of the nonclinical and clinical safety data to date, fenebrutinib is 
expected to be well tolerated at the doses and duration administered in the current study.  
1.2.3
Clinical Experience with Fenebrutinib
As of 12 March 2018, fenebrutinib or placebo has been administered to 1099 subjects 
(i.e., 333 healthy subjects, 24 patients with hematological malignancies, 576 patients 
with rheumatoid arthritis, 129 patients with systemic lupus erythematosus, and 
37 patients with chronic spontaneous urticaria) at doses with a range of 0.5600 mg 
and has been generally well tolerated with no safety concerns that have led to a change 
in the conduct of the studies.
Study GO29089 is a Phase I, open-label study in which fenebrutinib has been evaluated 
in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma or chronic 
lymphocytic leukemia.  In order to focus on the autoimmune indications, Genentech 
elected to stop development of fenebrutinib in oncology, and the Phase I study is 
continuing without further patient enrollment. Enrollment was stopped after completion 
of the 400-mg dose level at which time 24 patients had been enrolled in 3 cohorts:  
100 mg, 200 mg, and 400 mg fenebrutinib daily. Seven patients remain in the study, 
and all have undergone intrapatient dose escalation to 400 mg QD fenebrutinib. The 
mean duration of daily dosing for these 7 patients has been 21 months (range of 1823 
months).  Fenebrutinib was well tolerated with no dose-limiting toxicities (DLTs), 
maximum tolerated dose was not reached, and adverse events have been generally 
non-serious National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0) Grade 1 or Grade 2 events that have been clinically 
manageable.  The adverse events regardless of causality reported in 15% of patients 
include fatigue, nausea, diarrhea, headache, abdominal pain, dizziness, cough, and 
thrombocytopenia.  As of August 2016, 11 serious adverse events had been reported in 
5 patients, of whom 2 had a fatal outcome (i.e., complications of H1N1 influenza and 
influenza pneumonia).  


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Study GP29318 was a two-part, single-ascending dose (SAD) study to assess the safety, 
tolerability, and pharmacokinetics of fenebrutinib administered to 93 healthy subjects.  In 
Part 1, the single-doseescalation portion, 71 subjects were randomized to panels of 
8 subjects (6:2 active:placebo ratio) per dose group (0.5600 mg), with 53 subjects 
receiving active fenebrutinib.  In Part 2, 100 mg fenebrutinib was administered to 
40 subjects in the open-label food and pilot rabeprazole effect study.  There were no 
serious adverse events and no withdrawals due to adverse events during the conduct of 
Study GP29318.  In Part 1 of the study, there were no dose-limiting adverse events 
(DLAEs) at single doses up to 600 mg fenebrutinib.  All adverse events were mild in 
intensity (Grade 1; Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) and transient.  No adverse events 
increased in intensity or frequency with dose escalation.  There were two 
treatment-emergent adverse events of mild self-limited headache reported as related to 
fenebrutinib administration.  There were no trends in safety laboratory findings, vital sign 
changes, physical examination findings, or ECG changes.  There were no trends in 
hepatic laboratory changes following single doses of fenebrutinib in healthy subjects.  
Administration of fenebrutinib inhibited ex vivo basophil activation as demonstrated by 
diminished CD63 cell surface expression after cross-linking of IgE. Refer to the 
Fenebrutinib Investigator’s Brochure for further information on Study GP29318, including 
pharmacokinetics.
Study GA29347 was a multiple-ascending dose (MAD) study to assess the safety, 
tolerability, and pharmacokinetics of multiple doses of fenebrutinib administered to 
30 healthy subjects for 14 days.  Forty subjects were randomized to panels of 8 subjects 
(6:2 active:placebo) per dose group, at doses of 20 mg twice a day (BID), 60 mg BID, 
150 mg BID, 250 mg BID, or 500 mg QD for 14 days, with 30 subjects receiving active 
fenebrutinib.  The study drug was well tolerated.  There were no serious adverse events 
and no withdrawals due to adverse events during the conduct of the study.  All adverse 
events were mild in intensity (Grade 1) and transient, with no relationship to dose.  
Adverse events included skin reactions (i.e., rash, contact dermatitis, and skin irritation 
from ECG leads), nausea, headache, insomnia, toothache, tinnitus, and asymptomatic 
bacteriuria.  There were no trends in safety laboratory, vital sign, physical examination, 
or ECG findings. Similar to the SAD study, dose-dependent inhibition of CD63 
expression was observed following fenebrutinib administration, with sustained inhibition 
over the duration of dosing.
Study GP29832 was a relative bioavailability study designed to evaluate the effects of 
formulation, food, and proton-pump inhibitor (PPI) or methotrexate co-administration on 
the pharmacokinetics of fenebrutinib in healthy subjects.  Fenebrutinib was well tolerated 
when administered to 48 healthy subjects at the 200-mg dose level.  
Study GA29350 is a multicenter Phase II dose ranging study comparing the efficacy and 
safety of fenebrutinib versus placebo and adalimumab in patients with RA who have had 
an inadequate response to previous methotrexate therapy and versus placebo in 


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patients with an inadequate response to previous tumor necrosis factor therapy.  The 
study began enrollment in September 2016, and the total planned enrollment is 
approximately 580 patients.  
Study GA30044 is the first study investigating fenebrutinib in systemic lupus 
erythematosus (SLE).  This is a multicenter, Phase II, randomized, double-blind, 
placebo-controlled, parallel-group, dose-ranging study designed to evaluate the efficacy 
and safety of fenebrutinib in patients with moderate-to-severe active SLE in combination 
with standard-of-care therapy.  
The drug-drug interaction Study GP39616 has recently concluded.  While final results 
are not yet available, preliminary data suggests:

Fenebrutinib is a Breast Cancer Resistance Protein (BCRP) inhibitor. 
Consequently, fenebrutinib may alter transport of BCRP substrates and result in 
increased plasma concentrations of BCRP substrates.
The study also confirmed the following: 

Fenebrutinib is a mild inhibitor of CYP3A at clinically relevant doses.  
Consequently, fenebrutinib may alter metabolism of CYP3A substrates and result 
in increased plasma concentrations of CYP3A substrates.

Fenebrutinib is a moderately sensitive substrate of CYP3A at clinically relevant 
doses.  There is a moderate potential for levels of fenebrutinib to increase in 
patients taking concomitant medications that inhibit CYP3A and decrease in 
patients taking medications that induce CYP3A.
Refer to the Fenebrutinib Investigator’s Brochure for detailed background information on 
fenebrutinib as well as for additional details on nonclinical and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Omalizumab, an anti-IgE monoclonal antibody, has demonstrated efficacy in treating 
patients with CSU, highlighting the key role of IgE in CSU pathogenesis. Inhibition of 
IgE-mediated FcRI signaling by BTK inhibition offers a promising mechanism for the 
treatment of CSU. In preclinical in vitro studies, BTK inhibition was able to prevent the 
release of histamine and inflammatory cytokines from mast cells after FcRI
engagement and cross-linking. In addition, in the healthy volunteer SAD and MAD 
studies, oral administration of fenebrutinib was able to inhibit ex vivo basophil activation 
as demonstrated by diminished CD63 cell surface expression.  As such, fenebrutinib
inhibits two key pathogenic cell types in CSU.  The aim of this study is to determine if 
fenebrutinib can effectively treat patients with CSU, as measured by reduction in disease 
activity.
Humans with XLA lack functional BTK but can live relatively normal lives on a standard 
therapy of IV immunoglobulin (Kaveri et al. 2011), suggesting that BTK can be safely 
inhibited in patients with CSU who have functional immune systems.  Clinical experience 


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with fenebrutinib to date has not generated safety concerns that would preclude further 
evaluation in patients with CSU.  In the SAD (Study GP29318), MAD (Study GA29347), 
relative bioavailability (Study GP29832), and oncology (Study GO29089) studies, 
fenebrutinib was well tolerated with no DLAEs or DLTs.  In the oncology study, there 
were 2 deaths due to complications of confirmed influenza (i.e., H1N1 influenza and 
influenza pneumonia).  
Several measures will be taken to ensure the safety of patients participating in this study 
based on the potential risks for fenebrutinib based on nonclinical and clinical studies and 
published literature (see Section 5.1.1).  Eligibility criteria have been designed to exclude 
patients at higher risk for potential toxicities.  In addition, the sites selected for this study 
will be specialty dermatology and immunology clinics with experience in treating CSU. 
1.3.1
Infections
Fenebrutinib is a targeted immunomodulator; however, as a reversible inhibitor, the 
degree to which fenebrutinib antagonism of BTK signaling may suppress immune activity 
is unknown.  Patients participating in this study may be at risk for infections, including 
opportunistic infections.  Therefore, patients at high risk for infection will be excluded 
(see Section 5.1.1.1).  Patients will be carefully monitored throughout the study for 
infections.  Fenebrutinib will be discontinued in any patient who develops a serious 
infection, opportunistic infection, or any infection requiring treatment with an IV 
antimicrobial agent.
1.3.2
Bleeding
BTK is expressed in platelets and is involved in platelet function via GPVI/collagen 
receptor signaling and GP1b receptor signaling.  Platelets from patients with XLA 
demonstrate decreased activation in response to submaximal collagen stimulation but 
normal response to thrombin; clinically, there is no reported bleeding propensity in 
patients with XLA.  In the fenebrutinib clinical study involving oncology patients 
(GO29089), 2 patients experienced Grade 3 gastrointestinal (GI) bleeding.  These 
events were not dose related and occurred in patients on non-steroidal anti-inflammatory 
drugs (NSAIDs)/acetylsalicylic acid with a history of gastroesophageal or peptic ulcer 
disease.
It is unknown whether fenebrutinib will increase the risk of bleeding in patients with CSU 
who receive antiplatelet or anticoagulant therapies.  Therefore, the eligibility criteria 
exclude patients at high risk for bleeding complications.  
1.3.3
Cytopenias
Neutropenia, anemia, and thrombocytopenia have been observed in patients with 
hematologic malignancies who received fenebrutinib.  No clinically significant changes in 
cell counts were observed in the healthy volunteer studies.  Events have been 


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monitorable and clinically manageable.  Cell counts will be monitored regularly 
throughout the study.
1.3.4
Hepatotoxicity
Evidence of hepatobiliary injury was observed in animals administered relatively high 
doses of fenebrutinib in repeat-dose toxicity studies.  In clinical studies to date, in 
autoimmune indications, enrolling over 800 patients, multiple cases of treatment 
emergent Grade 3 (or severe) elevations of ALT, some of which were considered serious 
adverse events, have been observed in the randomized clinical studies, which remain 
blinded to the Sponsor in terms of treatment assignment, as well as in open label 
extensions of fenebrutinib. These cases have been seen in blinded studies in CSU. None 
of the cases of transaminase elevations resulted in clinical jaundice or bilirubin 
2 ULN (Hy’s Law).  All transaminase elevations have been reversible when dosing 
of blinded study medication/placebo was withheld. These findings have not been seen in
single dose and multiple dosing for 14 days in healthy subjects and QD dosing in 
patients with hematological malignancies. To minimize this risk, exclusion criteria have 
been defined for abnormal liver enzyme and function tests and current liver disease (see 
Section 4.1.2).  For further information on nonclinical and clinical findings of 
hepatotoxicity, please see the Fenebrutinib Investigator’s Brochure.
1.3.5
Cardiovascular Effects
Fenebrutinib is considered to have a low potential to cause QT interval prolongation or to 
directly affect other cardiovascular parameters at therapeutic exposures.  A minimal 
increase in corrected QT (QTc; 7 ms or 3%) interval was noted at 45 mg/kg in the 
single-dose cardiovascular safety pharmacology study in telemetry-instrumented dogs.  
Cardiac safety will be evaluated in all patients at baseline and throughout the study, with 
routine monitoring of vital signs, including heart rate and blood pressure, collection of 
ECGs, and reporting of cardiac adverse events.
1.3.6
Malignancy
The impact of BTK inhibition on the development of malignancies is not known; however, 
malignancies are considered a potential concern for all immunomodulatory agents.  
Patients with a history of cancer within 10 years of screening will be excluded from study 
participation, except for basal or squamous cell carcinoma of the skin that has been 
excised and is considered cured and in situ carcinoma of the cervix treated with 
apparent success by curative therapy more than 1 year prior to screening.  
Overall, fenebrutinib has been well tolerated in Phase I healthy subjects and an 
oncology study.  On the basis of the compelling mechanism for BTK inhibition in CSU, 
the benefit-risk ratio for this study is deemed acceptable.  The safety profile of 
fenebrutinib will be further characterized in this Phase II study.  A robust safety 
monitoring plan that describes the potential risks for fenebrutinib and the risk-mitigation 
strategies to minimize risks for the patients in this trial is provided in Section 5.  






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therapy for the treatment of adult patients 1875 years old who have been diagnosed 
with CSU and who remain symptomatic despite treatment with H1 antihistamines 
(including doses up to 4 times the approved dose per local treatment guidelines).  The 
study will consist of two cohorts. Cohort 1 will enroll approximately 45 patients across 
multiple sites.  After screening, eligible patients will be randomly allocated in a 2:1 ratio 
to receive fenebrutinib 200 mg orally (PO) twice daily (BID) or matching placebo for 
8 weeks and will maintain stable doses of standard-of-care H1 antihistamine therapy 
throughout the study. On the basis of results from an interim analysis of Cohort 1, a 
dose-ranging cohort, Cohort 2, will be opened and approximately 120 patients will be 
randomly allocated in a 1:1:1:1 ratio to receive 50 mg PO daily (QD), 150 mg PO QD, 
200 mg PO BID of fenebrutinib, or placebo, respectively, for 8 weeks and will maintain 
stable doses of standard-of-care H1 antihistamine therapy (background therapy)
throughout the study.
Both cohorts will consist of 3 distinct study periods over a time-period of 14 weeks as 
outlined below (see Figure 1): 

Screening period:  Day 14 to Day 1

Treatment Period:  Day 1 to Day 57 (Week 0 to Week 8)

Follow-Up Period:  Day 57 to Day 85 (Week 8 to Week 12)
Patients in both cohorts will have a screening period of approximately 2 weeks to 
establish their eligibility for the study and baseline symptom scores.  For the duration of 
the screening period, patients must maintain stable doses of their pre-screening 
combination therapy with standard-of-care H1 antihistamines (i.e., up to 4 times the 
approved dose per local treatment guidelines).  The screening period will consist of visits 
at Day 14 and Day 7.  Patients must meet all of the following criteria to enter the 
screening period:

Documented treatment with a regimen that includes standard-of-care H1 
antihistamine for CSU at Day 14 and for at least the 3 consecutive days 
immediately prior to Day 14 (see Section 4.4.1 for list of H1 antihistamines available 
for use in this study)

Willing and able to complete a symptom electronic diary (Urticaria Patient Daily 
eDiary) twice daily throughout the screening period to establish the patient’s Urticaria 
Activity Score over 7 days (UAS7) score.
To be eligible for randomization in both cohorts, for the 7 days prior to randomization, 
patients must meet all of the following:

Seven consecutive days of entries in the Urticaria Patient Daily eDiary, and 

UAS7 symptom score of 16 (range:  042)
Only in exceptional circumstances, when information concerning eligibility is outstanding 
(e.g., delayed laboratory results), will a longer screening period be permitted up to 


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3 business days.  Upon approval from the Medical Monitor, patients may be re-screened 
or maybe retested during the screening period (see Section 4.5.2.2 and Section 4.5.2.1,
respectively).  Circumstances that may permit re-screening or retesting include, but are 
not limited to, a laboratory test result that does not meet eligibility requirements.
The primary efficacy endpoint will be at Day 57 (Week 8).  Throughout the treatment 
period, patients must maintain stable doses of their pre-randomization H1 antihistamine 
therapy.  
After completion of the 8-week treatment period, all patients in both cohorts will either 
enter a 4-week safety follow-up period to allow for further characterization of the 
pharmacokinetics and pharmacodynamics of fenebrutinib and collection of additional 
efficacy and safety data or they will have the opportunity to participate in the OLE
Study GS40868 (see Section 3.1.2). During safety follow-up period, no study treatment 
will be given; patients must maintain stable doses of their pre-randomization CSU H1 
antihistamine treatment (background therapy).  In the safety follow-up period, patients 
may add up to one additional H1 antihistamine therapy in case of worsened symptoms 
(see Section 4.4.3).  The goal of allowing additional H1 antihistamine therapy after the 
treatment period is to reduce patient dropout for improved safety evaluation.
In addition to their daily background therapy, for the duration of the study, all patients will 
be able to use a single approved dose of loratadine (10 mg maximum) or cetirizine 
(10 mg maximum) within a 24-hour period as rescue medication if symptoms worsen. If
a patient needs rescue therapy and is already on background treatment with cetirizine 
or loratadine, the patient may receive 10 mg more of the same drug only if the total 
daily dose remains below 4 times the approved dose. Otherwise, the alternate rescue 
medication may be used. Patients should record the use of this medication in their 
eDiary.  Patients receiving PPIs or H2 receptor antagonists (H2RAs) should be stabilized 
on a regimen beginning at least 2 weeks prior to randomization and continuing 
throughout the study (see Section 4.4.2.1).


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Figure 1
Study Schema
BIDtwice daily; PO = orally; QD = daily.
a Last blinded dosep.m. before Day 57 visit
3.1.1
Internal Monitoring Committee
For Cohort 2, periodic safety reviews and any interim analysis will be performed by the 
Sponsor’s internal monitoring committee (IMC) as outlined in the IMC charter. This 
committee will be unblinded to treatment assignments and will include Sponsor 
representatives from the following functions: Clinical Science, Drug Safety, Biostatistics, 
and Statistical Programming and Analysis. The IMC members will not have direct 
contact with investigational staff or site monitors. The IMC may decide to unblind the 
study team to enable decision-making and potential interactions with regulatory bodies. 
The IMC may invite representatives from other functional areas on an ad-hoc basis 
when additional expertise is required (e.g., Clinical Pharmacology, Research, etc.) or 
additional Sponsor scientists to participate in data analyses and review. 
At any time during the study, the Sponsor may choose to inactivate and suspend 
enrollment and further dosing for a given treatment arm (in Cohort 2) or reduce the dose 
due to safety concerns and as guided by the IMC. In Cohort 2, subsequently enrolled 
patients will be randomly allocated to the remaining active arms. 






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score of 16 during the 7 days prior to randomization despite current use of combination 
therapy.  
While H1 antihistamines are the mainstay of therapy for CSU, some patients do not 
respond or respond only partially to these therapies, and these patients tend to 
experience more severe disease.  This patient population was selected for this study 
because of the unmet medical need for more effective oral treatments. 
3.3.3
Rationale for Control Group
A placebo-treated control group is required for this study in order to achieve its efficacy 
and safety objectives given the inherent variability in symptoms and the different rates of 
improvement in the placebo arms of prior studies.  Patients in the placebo arm will 
continue to receive stable standard-of-care anti-H1 therapy throughout the study.  In 
addition, the study will allow for rescue medications for persistent symptoms.
 
 
  
3.3.5
Rationale for Pharmacokinetic Sample Collection Schedule
The sampling schedule is designed to assess multiple pre-dose (prior to study drug 
administration in clinic) plasma fenebrutinib concentrations, which will enable the 
estimation of systemic fenebrutinib exposures and subsequent exposure-response 
analyses, both of which may be reported separately.  Results will be used to inform 
dosing regimens for future studies of fenebrutinib.  
3.3.6
Rationale for Efficacy Endpoints
The change in the UAS7 (see Table 2 for daily assessment of Urticaria Activity Score 
[UAS]) has been chosen as the primary efficacy endpoint as it has been used in pivotal 
trials in CSU to measure reduction in CSU disease severity. The UAS7 is a summation 
of the average daily (a.m./p.m.) scores on the UAS (range: 06), which is a composite 
diary score with numeric severity intensity ratings on a scale of 03 (0none to 
3intense/severe) for two domains:  the intensity of the itch and the number of 
wheals/hives (see Table 2).  The UAS will be recorded by the patient twice daily 
(morning and evening) in the patient Urticaria Patient Daily eDiary.  UAS7 scores range 
from 042 and the minimally important difference (MID) is considered to be a reduction 
from baseline of 9.5 to 10.5 points (Mathias et al. 2012).  The baseline UAS7 is the 
sum of the daily scores on the UAS over the 7 days prior to randomization (Day 1 visit
for both cohorts), and the UAS7 at Day 57 is the sum of daily scores on the UAS over 
the 7 days prior to the Day 57 visit (for both cohorts).  The same principles of calculating 
baseline and Day 57 weekly scores will be applied to the other weekly outcomes unless 
otherwise stated.  


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The kinetics of response to fenebrutinib will also be carefully evaluated throughout the 
course of the study at regular intervals (at least every 12 weeks for a period of 
8 weeks).  In addition, disease recurrence or duration of treatment benefit after study 
drug is withdrawn during the safety follow-up period will be measured during this study.  
This will provide initial guidance for the duration of therapy in future studies.
Table 2
Twice Daily Patient Assessment of CSU Disease Activity (UAS 
Scale)
Score
Wheals (Hives)
Pruritus (Itch)
0
None
None
1
Mild (16 hives/12 hour)
Mild
2
Moderate (712 hives/12 hour)
Moderate
3
Intense (12 hives/12 hour)
Severe
CSU chronic spontaneous urticaria; UAS Urticaria Activity Score.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 45 patients in Cohort 1 and approximately 120 patients in Cohort 2, aged 
18 to 75 years old who have been diagnosed with refractory CSU and who remain 
symptomatic despite standard-of-care H1 antihistamine therapy (i.e., up to 4 times the 
approved dose per local treatment guidelines), will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients in Cohort 1 and 2 must meet the following criteria for study entry:

Willing to give written informed consent, adhere to the visit schedules, comply with 
the study drug regimen, and meet other study requirements

Aged 1875 years, inclusive 

Diagnosis of CSU refractory to H1 antihistamines at the time of randomization, as 
defined by all of the following:
–
The presence of itch and hives for 6 consecutive weeks at any time prior to 
enrollment despite current use of H1 antihistamines, consistent with standard of 
care (i.e., up to 4 times the approved dose per local treatment guidelines) during 
this time period
–
UAS7 score 16 during the 7 days prior to randomization (Day 1)
–
Patients must have been on daily stable doses of H1 antihistamines, consistent 
with standard-of-care therapy (i.e., up to 4 times the approved dose per local 
treatment guidelines) for CSU starting at least 3 consecutive days immediately 
prior to the screening visit through Day 1 and must document current use on all 
visits.
–
CSU diagnosis for 6 months


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
Willing and able to complete an Urticaria Patient Daily eDiary for the duration of the 
study

Completion of 7 days of the Urticaria Patient Daily eDiary entries in the 7 days prior 
to randomization (7 of 7 days must be completed [i.e., must complete an entry every 
day] with up to 2 non-consecutive entries missed)

No evidence of active or latent or inadequately treated infection with tuberculosis 
(TB) as defined by the following:
–
A negative QuantiFERON-TB-Gold(QFT) performed (for German sites only: 
QFT is the preferred test) at the screening visit or within the 3 months prior to 
screening 
If QFT is unavailable, a negative Mantoux purified protein derivative (PPD) 
skin test as defined by the Centers for Disease Control and Prevention 
guidelines, may be performed at the screening visit or within the 3 months 
prior to screening -AND-
Any additional procedures (e.g., chest X-Ray) only if required per local 
guidelines/standard of care to rule out latent or active TB
NOTE: A documented negative screening for TB via the PPD test or a negative 
QFT within 3 months prior to screening and if required per local standard of 
care, a chest X-ray, is sufficient and no further screening with QFT is required.
Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should be 
screened using the QFT test, only. 
–
An indeterminate QFT test should be repeated. 
–
A positive QFT test or two successive indeterminate QFT results should be 
considered a positive diagnostic TB test. 
–
An indeterminate QFT test followed by a negative QFT test should be 
considered a negative diagnostic TB test.

Only for patients currently receiving PPIs or 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 (see Section 5.4.3.1). Women must refrain from donating eggs during 
this same period.

A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
has not undergone surgical sterilization (removal of ovaries and/or uterus).


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
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices.  Women using estrogen-containing 
hormonal contraceptives as a method of contraception must also use a 
barrier, such as a male condom, in conjunction with the hormonal 
contraceptives.

The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below (also see Section 5.4.3.2):

With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom during the treatment period and 
for at least 4 weeks after the last dose of study treatment to avoid exposing 
the embryo.  Men must refrain from donating sperm during this same period.

The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception.
4.1.2
Exclusion Criteria
Patients in Cohort 1 and 2 who meet any of the following criteria will be excluded from 
study entry:

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 fenebrutinib or other BTK inhibitors

Patients 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


 
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 
Routine (daily or every other day during 5 or more consecutive days) 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 IV steroids for treatment of laryngeal angioedema 
 
IVIG or plasmapheresis within 30 days prior to screening 
 
History of anaphylactic shock without clearly identifiable avoidable antigen (e.g., due 
to food allergy) 
 
Hypersensitivity to fenebrutinib 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 (see Section 4.4.3) 
 
History of live attenuated vaccine within 6 weeks prior to randomization or 
requirement to receive these vaccinations at any time during study drug treatment 
 
Seasonal influenza and H1N1 vaccination is permitted if the inactivated 
vaccine formulation is administered.  
 
Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, 
hepatic, endocrine (including uncontrolled diabetes mellitus), metabolic, or GI 
disease that, in the investigator’s opinion, would compromise the safety of the patient, 
interfere with the interpretation of the study results or otherwise preclude patient 
participation  
 
Any items that are cause for uncertainty must be reviewed with the Medical 
Monitor. 
 
Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel 
disease, where flares are commonly treated with oral or parenteral corticosteroids 
 
History of vasculitis 
 
Current liver disease  
 
Any known active infection (with the exception of fungal nail infections or oral herpes) 
 
History of recurrent bacterial, viral, mycobacterial or fungal infections (defined as 
 2 similar episodes requiring anti-microbial treatment within the previous 
12 months), with the exception of recurrent oral or genital herpes (herpes simplex 
virus 1/herpes simplex virus 2) or uncomplicated urinary tract infections in females. 
 
Any history of opportunistic infections that, in the investigator or Sponsor’s judgment, 
would raise safety concerns regarding the patient's participation in the study 
 
Any major episode of infection requiring hospitalization or treatment with IV 
antimicrobials within 8 weeks prior to and during screening or treatment with oral 
antimicrobials within 2 weeks prior to and during screening 
 
Antimicrobials include antifungal, antibacterial, and antiviral agents. 
 
History of or currently active primary or secondary immunodeficiency, including 
known history of HIV infection 


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
Evidence of chronic and/or active hepatitis B or C

Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology 
(regardless of treatment status)

Positive hepatitis B core antibody (HBcAb)

History of cancer, including hematologic malignancy and solid tumors, within 
10 years before screening

Basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured and in situ carcinoma of the cervix treated with apparent 
success by curative therapy 1 year prior to screening are not exclusionary.

Women who are pregnant, nursing (breastfeeding), or intending to become pregnant 
during the study or within 4 weeks after completion of the study

For women of childbearing potential (including those who have had a tubal ligation):  
positive serum pregnancy test result at screening or on Day 1.

A serum pregnancy test is needed on Day 1 only if the urine pregnancy test is 
positive (see Section 4.1.1 for definition of “childbearing potential”).

History of alcohol, drug (e.g., tetrahydrocannabinol [THC], marijuana), or chemical 
abuse within the 12 months prior to screening as determined by the investigator

Need for systemic anti-coagulation with warfarin, other oral or injectable 
anti-coagulants, or anti-platelet agents other than NSAIDs, aspirin, and other 
salicylates

History of non-gallstonerelated pancreatitis or chronic pancreatitis

History of hospitalizations or transfusion for a GI bleed

History of cerebrovascular accident (CVA) within 10 years or any history of 
hemorrhagic CVA

History of spontaneous intracranial hemorrhage or history of traumatic intracranial 
hemorrhage within 10 years

Known bleeding diathesis

Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect patient safety or interpretation of study results, including
–
QT interval corrected using Fridericia’s formula (QTcF) 440 ms
demonstrated by at least two ECGs 30 minutes apart

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome), 
structural heart disease (e.g., severe left ventricular systolic dysfunction, severe left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing, prior coronary artery bypass grafting, or 
coronary lesions 70% diameter stenosis that have not been or cannot be 
re-vascularized), clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or 
cardiac ion channel mutations (e.g., congenital long QT syndrome)


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
Current treatment with medications that are well known to prolong the QT interval 
(see https://crediblemeds.org/index.php/login/dlcheck) at doses that have a clinically 
meaningful effect on QT, as determined by the investigator; the investigator may 
contact the Sponsor for confirmation if needed

Current treatment with astemizole, terfenadine, and/or ebastine

Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically 
significant diabetic gastroenteropathy, or certain types of bariatric surgery such as 
gastric bypass)

Procedures such as gastric banding, that simply divide the stomach into 
separate chambers, are not exclusionary.

Any uncontrolled clinically significant laboratory abnormality that would affect safety, 
interpretation of study data, or the patient’s participation in the study 

For German sites only:  Subjects who live in detention on court order or on regulatory 
action as per local and national law (see §40 subSection 1 sentence 3 no. 4 
Arzneimittelgesetz; Medicinal Products Act). 
The following exclusion criteria are based on screening laboratory tests.  Laboratory 
tests may be repeated once during the screening period unless otherwise indicated (see 
Section 4.5.2.1):

Creatinine 1.5 times the upper limit of normal (ULN; may be repeated if 1.52ULN)

Creatinine clearance 70 mL/min (may be repeated if 6069 mL/min) as estimated 
by the Cockcroft-Gault Equation

ALT or AST 1.5 times ULN (may be repeated if 1.53ULN)

Total bilirubin ULN (may be repeated if 13ULN)

Hemoglobin 11 g/dL (may be repeated if 1010.9 g/dL)

ANC 1.5109/L (may be repeated if 1.21.5109/L)

Platelet count 100109/L (may be repeated if 80100109/L)

IgG 500 mg/dL (should not be repeated)

Abnormalities in hepatic synthetic function tests (e.g., PT, INR, PTT, albumin) 
judged by the investigator to be clinically significant
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Randomization and Blinding
This study is randomized, double-blinded, and placebo-controlled to minimize potential 
bias in treatment assignment, patient monitoring, and efficacy assessments. Random 
allocation will be conducted via an interactive voice or web-based response system 
(IxRS) and the Sponsor will provide the specifications of the randomization algorithm to 
the IxRS vendor. Patients in Cohort 1 will be randomly allocated to 200 mg PO BID 
fenebrutinib or placebo at an approximately 2:1 ratio using a stratified permuted blocks 
randomization scheme with stratification by country. Patients in Cohort 2 will be 


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randomly allocated to each of the four treatment arms at an approximately 1:1:1:1 ratio, 
using a stratified permuted blocks randomization scheme with stratification by country.
Patients and study site personnel will be blinded to the individual treatment assignments 
throughout the study.  Only standard and safety laboratory data results from the local 
laboratory (such as CBC, chemistries, and pregnancy testing) will be available to sites.  
Results of other assessments performed after randomization that might unblind 
investigators to the treatment patients received will not be provided to sites or to the 
Sponsor’s staff directly involved in study conduct.  
 
 
 
Although PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  Sponsor 
personnel or a designee responsible for performing PK assays will be unblinded to 
patients’ treatment assignments to identify appropriate PK samples to be analyzed.  
Samples from patients assigned to the placebo arm will not be analyzed except by 
request (e.g., to evaluate a possible error in dosing).
Patient and study site personnel will be blinded to treatment assignments throughout the 
study.  During trial conduct, the Sponsor will monitor blinded clinical and safety data on 
safety and study conduct on an ongoing basis.  For Cohort 1, if required for safety 
evaluations, Sponsor team personnel, but not the sites, not directly involved in the 
conduct of the study will have access to unblinded data.  These Sponsor team personnel 
may include individuals with clinical and medical experience, biostatisticians, and 
individuals responsible for analyzing and interpreting the pharmacodynamics and 
pharmacokinetics of the study drug. For information on Cohort 2, see Section 3.1.1.
4.2.2
Unblinding
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly.  The investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event).  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected, suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug.


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4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is fenebrutinib.
4.3.1
Formulation, Packaging, and Handling 
4.3.1.1
Fenebrutinib and Placebo
Fenebrutinib will be provided by the Sponsor as 50-mg dose strength tablets with 
corresponding matching placebo tablets, which will be indistinguishable in appearance.  
Study drug (fenebrutinib or placebo) will be dispensed at the Day 1 and 29 visits for both 
cohorts. 
Tablets will be supplied in bottles (Cohort 1) and blister wallets (Cohort 2) for the 
treatment arm to which the patient is randomly allocated.  Each bottle and blister wallet 
will be labeled per local regulatory requirements.  Fenebrutinib and placebo tablets 
should be stored between 2C and 8C.  Please refer to the pharmacy manual 
for detailed instructions on study drug storage and preparation.
For information on the formulation and handling of fenebrutinib, see the Fenebrutinib 
Investigator’s Brochure.
4.3.1.2
Background Therapy: Standard-of-Care H1 Antihistamines
for CSU
For information on the formulation, packaging, and administration of standard-of-care 
H1 antihistamines for CSU, see local prescribing information.
4.3.2
Dosage, Administration, and Compliance of Fenebrutinib and 
Placebo
4.3.2.1
Fenebrutinib and Placebo Dose and Administration
For Cohort 1, the fenebrutinib dose level is 200 mg (4 tablets) BID (total of 8 tablets each 
day) with matching placebo (see Section 3.1). For Cohort 2, the fenebrutinib dose levels 
are 50 mg QD, 150 mg QD, and 200 mg BID, with matching placebos (see Table 3).
Patients in both cohorts will take fenebrutinib/placebo on Day 1 and ending on the Day 
56 visit.  Although the Day 57 visit is the last day of the study treatment period, no study 
drug for Study GS39684 will be given on the Day 57 visit. If eligible, patients may 
enroll into the OLE Study GS40868 to receive their first open-label dose of fenebrutinib 
on Day 1 of the OLE or they will proceed and return for the safety follow-up visit 4 
weeks after the last dose of study drug. For patients enrolling into the OLE, Day 1 of 
Study GS40868 may be the same day as the Day 57 visit in Study GS39684.
For mandatory morning clinic visits (see Appendix 1 and Section 4.4.5), patients should 
be instructed that the morning dose of study drug will be taken in the clinic.  On other 
clinic visit days, if the visit occurs in the morning, the patient should be instructed that the 
morning dose of study drug will be taken in the clinic. 


 
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Table 3 
Fenebrutinib Dosing Regimen by Treatment Arm (Cohort 2) 
Fenebrutinib Dose Arm 
Number of Tablets 
Fenebrutinib 
(a.m./p.m.) 
Placebo 
(a.m./p.m.) 
50 mg QD 
1/0 
3/4 
150 mg QD 
3/0 
1/4 
200 mg BID 
4/4 
0/0 
Placebo 
0/0 
4/4 
BIDtwice daily; QDonce daily. 
Fenebrutinib or placebo may be taken orally with or without food, except on certain days 
(see Appendix 1), when the morning dose of oral study drug will be administered at the 
morning (mandatory) clinic visit while fasting.  The dates and times of the most recent 
prior meal, last dose of oral study drug (prior to clinic visit), and timing of oral study drug 
administration in clinic should be recorded at each clinic visit.  Patients should be 
instructed that a missed dose should not be taken with the next scheduled dose.  
In addition, any antacids (e.g., Pepto-Bismol, Rolaids) should be recorded as 
concomitant medications, including date and time of last administration.  Administration 
of study drug should be staggered with antacid use (i.e., study drug should be taken 
2 hours before or 2 hours after the antacid). 
At the Day 1 and 29 visits, sufficient study medication tablets will be dispensed to 
complete dosing until the end of the study.  When study medication is administered at 
the site, it will be administered under supervision of study personnel, and the amount of 
study medication dispensed must be recorded. 
4.3.2.2 
Fenebrutinib and Placebo Compliance 
The following measures will be taken to assess patient compliance with study drug.  For 
Cohort 1, patients will be directed to bring the study drug bottle to each visit after 
randomization.  In addition, sites will be responsible for prepopulating the dates on the 
dosing label (affixed to the bottle) for when patients are scheduled to take study drug.  
The patients will record the times (a.m. or p.m.) that they take each dose in their eDiary.  
The number of tablets issued minus the number of tablets returned will be used to 
calculate the number of tablets taken and compliance.   
For Cohort 2, sites will be responsible for prepopulating the dates on the blister wallets 
for when patients are scheduled to take study drug.  The patients will record the times 
(a.m. or p.m.) that they take each dose in their eDiary.  Patients will be instructed to 
return all blister wallets (used and unused) at each study visit for assessment of 
compliance and for medication disposal. 
Compliance will be documented on the source record.  Any overdose or incorrect 
administration of study drug should be noted on the Study Drug Administration electronic 


 
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Case Report Form (eCRF).  Adverse events associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If 
compliance is  80%, the investigator or designee is to counsel the patient and ensure 
steps are taken to improve compliance.   
4.3.2.3 
Background Therapy:  Standard-of-Care H1 Antihistamines 
for CSU 
The following H1 antihistamine medications are allowed: 
 
Cetirizine 1040 mg QD 
 
Levocetirizine 520 mg QD 
 
Fexofenadine 180720 mg QD 
 
Loratadine 1040 mg QD 
 
Desloratadine 520 mg QD 
 
Rupatadine 1040 mg QD 
 
Bilastine 2080 mg QD 
 
All patients will be allowed to take study-defined, second-generation, H1 antihistamine 
medications consistent with standard-of-care (i.e., up to 4 times the approved dose per 
local treatment guidelines) during the screening, treatment, and follow-up periods.  
Patients should remain on a stable H1 antihistamine regimen throughout the study 
period.  Loratadine (10 mg) or cetirizine (10 mg) will be provided and used on an 
as-needed basis (maximum 1 per day) during screening, treatment, and follow-up 
periods).  Therapies used for the treatment of CSU prior to enrollment will be collected 
as part of the patient’s medical history. 
Patients taking either LTRAs or H2 blockers for diseases other than CSU (e.g., asthma 
or gastroesophageal reflux disease, respectively) at screening will be permitted to 
continue their use at a stable dose during the study.  These diseases must be recorded as 
part of the medical history collected during the screening period.  Inhaled asthma 
controllers, including inhaled corticosteroids, are permitted during the study. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (fenebrutinib and placebo) will be provided 
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.   
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 


 
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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Fenebrutinib 
Patients may be eligible to receive fenebrutinib as part of open-label extension study 
(GS40868) offered by the Sponsor (Genentech, a member of the Roche Group), as 
described in Section 3.1.2.  The Roche Global Policy on Continued Access to 
Investigational Medicinal Product is available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 14 days prior to initiation of study drug to the study completion/ 
discontinuation visit.  All such medications (including standard-of-care H1 
antihistamines for CSU) should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.   
4.4.1 
Permitted Therapy  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  All concomitant medications should be 
reported to the investigator and recorded on the appropriate eCRF.  Patients will be 
encouraged to use the minimal dose required to control their symptoms.   
For the purposes of this study, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties. 
Vitamins, minerals, and purified food substances are allowed in amounts not known to 
be associated with adverse effects (e.g., hypervitaminosis).  Herbals with 
pharmaceutical properties are allowed only if there is acceptable evidence of no CYP3A 
inhibition or induction (refer to Section 4.4.3 for a list of prohibited concomitant 
medications, including herbal products).  Otherwise, herbals with pharmaceutical 
properties must be discontinued for at least 4 weeks prior to the first dose of study 
medication, unless there are sufficient data available regarding the duration of an 
herbal medication’s PK and PD effects to allow a shorter washout to be specified (e.g., 
5 half-lives).  Please direct any questions to the Medical Monitor. 
4.4.2 
Cautionary Therapy 
4.4.2.1 
Acid-Reducing Agents 
Patients who use antacids (e.g., Pepto-Bismol®, Rolaids®) for symptomatic relief of 
heartburn should take fenebrutinib or matching placebo at least 2 hours before or 
2 hours after antacid administration because gastric acid improves fenebrutinib 
absorption.   


 
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Patients may be treated with PPIs or H2RAs at up to the maximum recommended dose 
according to local labeling.  The dose should remain stable for at least the 2 weeks 
before randomization and throughout the study.   
At visits with scheduled PK assessments (see Appendix 1), any use of PPIs, H2RAs, 
and/or other antacids (e.g., Pepto-Bismol, Rolaids) should be recorded as concomitant 
medications, including the date and time of last administration. 
4.4.2.2 
Statins 
Several lipid-lowering agents (statins) are metabolized by CYP3A (simvastatin, 
lovastatin) and/or transported by BCRP (rosuvastatin, atorvastatin), and thus may be 
affected by drug-drug interaction with fenebrutinib, therefore, dose adjustments of 
these medications should be considered (Kellick et al. 2014).  
 
Simvastatin: recommended maximum dose of 10 mg/day 
 
Lovastatin: recommended maximum dose of 20 mg/day 
 
Rosuvastatin: recommended maximum dose of 10 mg/day 
 
Atorvastatin: recommended maximum dose of 20 mg/day 
 
The use of statins has been associated with myopathy, which can manifest as weakness, 
tenderness or muscle pain with elevations of creatine kinase (CK) above ten times the 
ULN. In severe cases, myopathy can cause rhabdomyolysis with or without acute 
kidney injury secondary to myoglobinuria, and rare fatalities due to rhabdomyolysis 
have occurred. The risk of myopathy is increased by elevated plasma levels of statins. 
Predisposing factors for myopathy include advanced age ( 65 years), female gender, 
uncontrolled hypothyroidism, renal impairment, or the use of concomitant medications 
that increase the plasma levels of the statin. 
4.4.2.3 
CYP3A and BCRP-Mediated Drug Interactions 
Preliminary data from a clinical drug-drug interaction study (Study GP39616) suggest 
that fenebrutinib can be classified as a mild inhibitor of CYP3A at clinically relevant 
doses.  It is possible that fenebrutinib inhibition of CYP3A may alter the metabolism of 
CYP3A substrates and result in increased plasma concentrations of CYP3A substrates.  
Therefore, medications in the following categories (listed in detail in Appendix 5) should 
be used with caution in consultation with the Medical Monitor (or delegate) as necessary 
unless otherwise specified in Appendix 5: 
 
Sensitive CYP3A substrates 
 
CYP3A substrates with a narrow therapeutic window 
The use of hormone-replacement therapy or hormonal contraceptives containing the 
CYP3A substrate ethinylestradiol (with the concomitant use of a barrier method) is 
permitted; however, these agents should be used with caution, and patients should be 
counseled regarding the potential risks and benefit of these medications per the local 
prescribing information.  Ethinyl estradiol is metabolized by CYP3A so plasma 


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concentrations of ethinyl estradiol are expected to increase in the presence of 
fenebrutinib (Zhang et al. 2007, Wang et al. 2004). Ethinyl estradiol is not a sensitive 
substrate of CYP3A (Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers, www.fda.gov). Therefore, the magnitude of increase in ethinyl 
estradiol plasma concentrations is expected to be less than the increase observed in 
midazolam concentrations (i.e., less than 2-fold) in Study GP39616, a drug-drug 
interaction study evaluating the effect of fenebrutinib on the PK of the sensitive CYP3A 
substrate midazolam. Minor increases in ethinyl estradiol concentrations are not 
generally associated with adverse events (e.g., Ortho Tri-Cyclen® USPI). Ethinyl 
estradiol efficacy is expected to be maintained, and ethinyl estradiol continues to be 
considered a reliable and effective form of contraception in combination with 
fenebrutinib.
Preliminary data from Study GP39616 also suggest that fenebrutinib can be classified as 
a moderately sensitive substrate of CYP3A at clinically relevant doses.  There is a 
moderate potential for a drug-drug interaction with any medication that strongly inhibits 
or induces this enzyme.  Therefore, medications in the following categories (listed in 
detail in Appendix 5) should be avoided for 7 days or 5 half-lives, whichever is longer, 
prior to the first dose of study drug and until the last dose of study drug.  If use of one of 
these medications is necessary, the risks and benefits should be discussed with the 
Medical Monitor (or delegate) prior to concomitant administration with study drug:

Strong CYP3A inhibitors

Moderate or strong CYP3A inducers 
Lastly, preliminary data from Study GP39616 suggest that fenebrutinib is a moderate 
inhibitor of the breast cancer resistance protein (BCRP) (also known as ABCG2) 
transporter protein at clinically relevant doses.  There is a potential for increased plasma 
concentrations of drugs that are known to be substrates of the BCRP transporter.  
Plasma concentrations of the medications in the following category (listed in detail in 
Appendix 5) may increase; therefore, they should be used with caution in consultation 
with the Medical Monitor (or delegate) as necessary unless otherwise specified in 
Section 4.4.1.
The medications listed above and in Section 4.4.1 are not necessarily comprehensive.  
Thus, the investigator should consult the prescribing information for any concomitant 
medication as well as the Internet references provided below when determining whether 
a certain medication is metabolized by or strongly inhibits or induces CYP3A.  The 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above.  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm (Tables 3-1, 3-2, 3-3, and 5-1)
http://medicine.iupui.edu/clinpharm/ddis/table.aspx


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4.4.3
Prohibited Therapy
Prior to the screening visit (Day 14 for both cohorts) as specified below, and during 
the study (not including the safety follow-up period if patient failed additional H1 
antihistamine for worsened symptoms; see Section 3.1) the following medications and 
treatments will be restricted.  Patients who receive these medications as therapy for 
CSU will be discontinued from the study treatment but will be followed for safety 
evaluation:

Systemic or topical corticosteroids (prescription or over the counter), 
hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide within 
30 days prior to screening if used routinely (daily or every other day during 5 or more 
consecutive days) – The use of corticosteroids may be used for exacerbations 

Doxepin within 30 days prior to screening

Omalizumab or other monoclonal antibody therapies used to treat CSU within 
4 months prior to screening

IVIG within 30 days prior to screening

Plasmapheresis within 30 days prior to screening

LTRAs within 1 day prior to screening

Astemizole, terfenadine, and ebastine within 1 day prior to screening
4.4.3.1
Live or Attenuated Vaccinations
Immunization with a live or attenuated vaccine is prohibited within 6 weeks prior to study 
drug administration on Day 1 and for the duration of study participation, including the 
4-week safety follow-up period after the administration of the last dose.  See Section 5
for further details and precautions around vaccinations.
4.4.4
Prohibited Food
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment:  furanocoumarin derivatives as found in grapefruit, Seville 
orange, pomegranate, or star fruit juice or products.  Please refer to Appendix 5 for 
additional information.
4.4.5
Additional Restrictions
Patients in both cohorts should be fasting overnight for 8 hours prior to the PK draw 
and/or fasting lipid panel on Days 1, 8, 29, 57, and 85 (see Appendix 1).
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of activities to be performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.


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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Eligibility at Screening
At screening, patients who fail to meet any laboratory inclusion/exclusion criteria or other 
eligibility criteria may be retested or re-screened as per the instructions in 
Section 4.5.2.1 and Section 4.5.2.2, respectively.
4.5.2.1
Retesting: Laboratory Inclusion/Exclusion
If a patient does not meet certain laboratory inclusion/exclusion criteria at screening, the 
investigator may repeat the tests once within the screening period (see Section 4.1.2 for 
laboratory tests and levels that can be retested). If the patient meets the laboratory 
eligibility criteria on the second assessment, he or she will be permitted to enter the 
study. It will not be considered a retesting if blood samples have to be redrawn because 
of sample handling problems, breakage, sample integrity, or laboratory error.
4.5.2.2
Re-screening
Re-screening refers to repeating the entire screening process. Re-screening is required 
if a patient has not met eligibility criteria within the original screening visit. (Note: 
patients who have failed two laboratory testing attempts as described in Section 4.1.2
cannot be re-screened). Patients are allowed to be re-screened only once per cohort.
Each patient must be re-consented before re-screening occurs. It will not be considered 
a re-screening if blood samples have to be redrawn because of sample handling 
problems, breakage, sample integrity, or laboratory error.
4.5.3
Medical History and Demographic Data
Comprehensive medical and surgical history, including a comprehensive review of the 
patient’s CSU medical history, will be collected at the Day 14 visit for both cohorts.  
This review will include onset of symptoms, date of diagnosis, and therapies received for 
CSU.  In addition, history of omalizumab (Xolair) use and reason for discontinuation will
be collected. 
Concomitant medical usage will be collected at all visits, including unscheduled visits.  
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.4
Physical Examinations
A complete physical examination should be performed at the Day 14 visit for both 
cohorts and should include an evaluation of the head, eyes, ears, nose, and throat, and 
the cardiovascular, dermatological, musculoskeletal, respiratory, GI, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.


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Subsequent examinations may be limited to detect changes in symptoms of CSU as well 
as directed by patient complaints regarding adverse events.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
4.5.5
Vital Signs
Vital signs will include measurements of heart rate, systolic and diastolic blood pressure 
while the patient is in a seated position, and temperature.  Vital signs will be assessed 
as outlined in the Schedule of Activities in Appendix 1 and during other unscheduled 
study visits when clinically indicated.  The patients’ height and weight will be measured 
once during the screening visit for both cohorts.
4.5.6
FricTest
For subjects who have a history of dermographism, a FricTest® will be performed at 
screening (Day14), baseline (Day 1), and Days 57 and 85 for both cohorts.  The 
FricTest® is a flat, plastic comb with four round-ended plastic pins, 3 mm in diameter and 
of different lengths.  The FricTest® defines provocation thresholds and severity of 
dermographism (i.e., 4 pins inducing wheals defines severe dermographism).
4.5.7
Laboratory, 
 and Other Biological Samples
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis as per the Schedule of Activities in Appendix 1.  Laboratory 
tests prior to randomization and dosing may be performed locally on Day 0, if central 
laboratory tests are not available due to sampling handling problems, breakage, or lab 
error.

Hematology:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent and absolute differential counts (neutrophils, bands, lymphocytes, 
monocytes, eosinophils, basophils, other cells) 

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, 
BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, 
total protein, albumin, ALT, AST, LDH, alkaline phosphatase, 
creatine phosphokinase, CRP, lipase, and uric acid 

Urinalysis including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria) 

Coagulation:  INR, activated PTT, PT, fibrinogen 

Fasting lipid panel

Viral serology

Hepatitis B:  HBsAg, total HBcAb, and hepatitis B surface antibody

Hepatitis C antibody


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
The following samples will be sent to the Sponsor or a designee for analysis:
 

Plasma samples for PK analysis

See the Schedule of Activities provided in Appendix 1 for specific timepoints.  

Samples for the following laboratory tests will be sent to the study site's local 
laboratory for analysis:

Pregnancy test
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test result 
is positive, it must be confirmed by a serum pregnancy test.  Should a positive 
result be recorded at any time, the procedures detailed in Section 5.4.3 should 
be followed. If a local urine pregnancy test shows a positive result, then study 
drug will not be administered that day.  Other study procedures should also be 
postponed and the result must be confirmed by a serum pregnancy test prior to 
proceeding.

QFT or PPD (if QFT not available) and additional procedures (e.g., chest X-ray) to 
rule out latent or active TB per local guidelines
See the Schedule of Activities provided in Appendix 1 for specific timepoints.  
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


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Biological samples will be destroyed when the final clinical study report (CSR) has been 
completed, with the following exceptions:

Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final CSR has been completed.

Blood, urine, and serum samples collected 
 will be destroyed 
no later than 15 years after the final CSR has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.8
Electrocardiograms
A single ECG recording, without artifacts, must be obtained at specified timepoints, as 
indicated in Appendix 1.  The ECG intervals (e.g., PR, QRS, QT, QTcF, and RR) and 
heart rate from this ECG will be entered into the eCRF.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECGs for each patient should be 
obtained from the same machine whenever possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes 
prior to beginning the ECG recording.  All ECGs can be performed without specific 
restrictions (e.g., can be performed at any time of day, before or after dosing, fasting or 
fed) but are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws). Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Circumstances 
that may induce changes in heart rate, including environmental distractions (e.g., 
television, radio, conversation) should be avoided during the pre-ECG resting period and 
during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  If considered appropriate by the Sponsor, ECGs may be analyzed 
retrospectively at a central laboratory.
If at a particular post-dose timepoint the mean QTcF is 500 ms or 60 ms longer than 
the baseline value, another ECG must be recorded, ideally within the next 5 minutes, 
and ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  


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The Medical Monitor should be notified as soon as possible within 24 hours.  Standard-
of-care treatment may be instituted per the discretion of the investigator.  If a PK sample 
is not scheduled for that timepoint, an unscheduled PK sample should be obtained.  A 
decision on study drug discontinuation should be made, as described in Section 4.6.2.  
The investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia).
4.5.9
Patient-Reported Outcomes 
Data from two patient reported outcomes (PRO) tools will be collected via questionnaires 
to document the treatment benefit of fenebrutinib:  the Urticaria Patient Daily eDiary, 
 
. The eDiary and 
, translated into the local language 
as required, will be completed in their entirety at specified timepoints during the study.  
 
 
 
Patients will use an electronic device to capture the Urticaria Patient Daily eDiary (see 
Appendix 3).  The electronic device and/or instructions for completing the questionnaires 
electronically will be provided by the investigator staff.  The data will be transmitted to a 
centralized database maintained by the electronic device vendor.  The data will be 
available for access by appropriate study personnel.
 
 
 
4.5.9.1
Urticaria Patient Daily eDiary
The Urticaria Patient Daily eDiary includes the UAS, which will be used to calculate the 
UAS7.  The eDiary comprises questions regarding largest hive size, sleep interference 
score, activity interference question, rescue medication use, angioedema episodes, 
number of calls to doctor or nurse practitioner, and study medication compliance.
The eDiary is to be completed twice per day (a.m./p.m.) by the patient for the duration of 
the study.  The eDiary will be given to the patient at the Day 14 visit for both cohorts.


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4.5.9.2
Urticaria Activity Score 
During the week prior to Day 1 (i.e., Week 1), UAS7 will be recorded twice daily for the 
purposes of enrollment eligibility for both cohorts.  Subsequently, the UAS will be 
recorded twice daily using the Urticaria Patient Daily eDiary.
The UAS is a composite, eDiary-recorded score with numeric severity intensity ratings 
(0 none to 3intense/severe) for a) the number of wheals (hives) and b) the intensity of 
the pruritus (itch) over the past 12 hours (twice daily; see Section 3.3.6). The daily UAS 
is calculated as the average of the morning and evening scores. The UAS7 will be 
calculated and 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; the 
intensity of the itch/pruritus and the number of wheals/hives are graded in Table 2.
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  


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4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator must withdraw a patient from the study for the following, but 
not limited to, reasons:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

The investigator may withdraw a patient from the study at any time due to patient 
non-compliance (e.g., drug compliance 80%, missed visits, missing Urticaria 
Patient Daily eDiary entries) 
For patients who withdraw from the study, every effort should be made to complete an 
early termination visit including the assessments on the Schedule of Activities (see 
Appendix 1).  The primary reason for withdrawal from the study should be documented 


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on the appropriate eCRF.  However, patients will not be followed for any reason after 
consent has been withdrawn.  Patients who withdraw from the study will not be replaced. 
If the patient discontinues the study prior to Day 85 visit, the patient will be asked to 
return to the clinic for a safety followup visit 4 weeks after the last dose of study drug.
Patients who refuse to complete the safety followup period should undergo an early 
termination visit.  Patients who discontinue during the safety follow-up period prior to 
completion of the 4-week safety follow-up will be asked to complete an early termination 
visit (see Appendix 1).
If a patient withdraws for reasons related to a serious adverse event, every attempt 
should be made to follow the patient until resolution of the event.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Pregnancy

Malignancy 

Any serious infection or infection requiring treatment with an IV antimicrobial agent

Any prohibited medication as defined in Section 4.4.3
Patients who discontinue study treatment prematurely (prior to Day 85 visit), including 
but not limited to the reasons listed above, will be asked to return to the clinic for a safety 
follow-up visit 4 weeks after the last dose of study drug. Patients who refuse to 
complete the safety follow up period should return to the clinic for an early termination 
visit.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study include, but are not limited to, the following:

The Sponsor must terminate the study if the Sponsor believes that the incidence or 
severity of adverse events in this or other studies indicates a potential health hazard 
to patients.

The Sponsor may terminate the study if patient enrollment or completion of the 
study unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

The Sponsor must close a site if corrective actions to improve site performance in 
the following areas do not yield significant improvement:
–
Excessively slow recruitment
–
Poor protocol adherence
–
Inaccurate or incomplete data recording
–
Non-compliance with the International Council on Harmonisation (ICH) 
guideline for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled).
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on nonclinical and clinical experience 
with fenebrutinib in completed and ongoing studies, as well as published literature, on 
other BTK inhibitors and BTK biology.  The important potential safety risks for 
fenebrutinib are outlined below.  Please refer to the Fenebrutinib Investigator’s Brochure
for a complete summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for potential 
toxicities.  Patients will undergo safety monitoring during the study, including monitoring 
of vital signs, physical examination, ECGs, and routine laboratory safety assessments 
(hematology, chemistry, and urinalysis) and assessment of the nature, frequency, and 
severity of adverse events.  In addition, guidelines for managing potential adverse
events, including criteria for treatment interruption or discontinuation, and enhanced 
safety reporting are provided below.
In addition, an unblinded IMC will monitor patient safety throughout the study for 
Cohort 2 (see Section 3.1.1).
5.1.1
Safety Plan for Potential Risks Associated with Fenebrutinib
5.1.1.1
Infections
Fenebrutinib is a reversible inhibitor of BTK, and the degree to which fenebrutinib
antagonism of BTK signaling may suppress immune activity is unknown.  On the basis 
of patients with XLA, a primary immunodeficiency caused by mutations in the BTK gene, 
it is anticipated that inhibitors of BTK may raise the risk for certain bacterial infections 
(Lederman and Winkelstein 1985; Broides et al. 2006), enteroviral infections 
(Misbah et al. 1992; Ziegner et al. 2002), intestinal infections with giardia and 
Campylobacter species (Winkelstein et al. 2006; van den Bruele et al. 2010), or other 
opportunistic infections, which are cleared primarily by B-cell adaptive immune 


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responses.  This risk is likely independent of sex for patients exogenously administered 
fenebrutinib.  
Effects on lymphocytes and immunoglobulins in rats and dogs were reversible and 
considered to be related to pharmacological activity involving BTK inhibition.  See 
Section 1.2.2 for related primary nonclinical toxicity findings and the Fenebrutinib 
Investigator’s Brochure for further details.
To date, no immune-challenge experiments (e.g., T-dependent antigen response test) 
have been conducted in animals.  It is not known whether these effects on B cells and 
IgG concentrations in animals will translate to humans or whether such changes would 
have functional or deleterious impact on immune function.
Infections, including pneumonia and fatal influenza, have occurred in patients with B-cell 
malignancies treated with fenebrutinib.  In studies with healthy subjects with single 
doses and with dosing for 14 days, self-limited Grade 1 events of nasopharyngitis were 
reported but did not lead to any change in study drug dosing.  One healthy subject had 
asymptomatic bacteriuria, which resolved while study drug dosing continued. In blinded 
and open-label studies in autoimmune indications, serious, severe, and opportunistic 
infections have been reported, including one case of pulmonary tuberculosis as well as 
cases of pneumonia, bronchitis, cellulitis, enterobacter infection, herpes zoster, acute 
pyelonephritis, necrotizing soft tissue infection, colitis, periorbital cellulitis, and 
sinusitis.  As a safety precaution, the study protocol contains exclusion criteria for 
infections and potential infection risk and guidelines for study drug management in the 
event of infection.  Study subjects and patients should be monitored for fever and 
potential infectious complications, including opportunistic infections, and evaluated 
promptly.
Patients will be excluded from the study if they have a history of hospitalization due to an 
infection in the 8 weeks before screening, evidence of active or latent or inadequately 
treated infection with Mycobacterium TB, known active infection (current) or history of 
recurrent infection, or any known immunodeficiency including IgG 500 mg/dL.
  All 
patients in the study should be monitored for fever and potential infectious complications, 
including opportunistic infections and TB, and should be evaluated promptly.  Physicians 
or a health care provider should give patients advice to prevent potential transmission of 
and exposure to endemic infections according to local or Centers for Disease Control 
and Prevention guidelines.  Patients should be advised to seek immediate medical 
attention if they develop signs and symptoms suggestive of an infection.  All infections 
occurring during the study, including but not limited to respiratory infections, cutaneous 
infections, urinary tract infections, systemic viral infections, and episodes of suspicious 
or febrile diarrhea, should be evaluated using serology or polymerase chain reaction, if 
available, and cultured, if feasible, and any identified organisms noted in the eCRF.  Any 
serious infection, infection requiring IV antimicrobials, or any opportunistic infection is 


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considered an adverse event of special interest and should be reported to the Sponsor 
as outlined in Section 5.4.2.
Guidelines for management of study treatment in the event that infections are observed 
in patients are provided in Section 5.1.2.
Please refer to the Fenebrutinib Investigator’s Brochure for further details.
5.1.1.2
Vaccinations
The effect of fenebrutinib upon the efficacy of vaccinations is unknown.  It is 
recommended that appropriate vaccinations per local guidelines be up to date before 
study participation.  Patients will be excluded from study participation and will not be 
dosed with fenebrutinib if they have been vaccinated with live, attenuated vaccines (e.g., 
the intranasal live attenuated influenza vaccines, BCG, varicella) within 6 weeks before 
planned dosing.  In addition, immunization with a live or attenuated vaccine is prohibited 
for the duration of study participation, including the 4-week safety follow-up period after 
the administration of the last dose.  
In addition, current routine household contact with children or others who have been 
vaccinated with live vaccine components may pose a risk to the patient during study 
treatment with fenebrutinib.  Some of these vaccines include varicella (“chickenpox”) 
vaccine, oral polio vaccine, and the inhaled flu vaccine.  Following vaccination with live 
component vaccines, the virus may be shed in bodily fluids, including stool, and there is 
a potential risk that the virus may be transmitted to the patient.  
General guidelines for immunosuppressed patients suggest that exposure to vaccinated 
individuals should be avoided following vaccination with these vaccines for the stated 
time periods:

Varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination

Oral polio vaccination for 6 weeks following vaccination

Attenuated rotavirus vaccine for 10 days following vaccination

FluMist(inhaled flu vaccine) for 1 week following vaccination
Please refer to the Fenebrutinib Investigator’s Brochure for further details.
5.1.1.3
Bleeding
No decrease in platelets, changes in coagulation parameters, or bleeding events were 
observed in nonclinical studies with fenebrutinib.  Bleeding events, including non-serious 
NCI CTCAE v4.0 Grade 1 bruising and serious Grade 3 GI bleeding, have been 
reported in patients with hematological malignancies treated with fenebrutinib in Study 
GO29089.  The GI bleeding events have not been dose related, and the events occurred 
in patients who were taking concomitant NSAIDs and who had a history of 
gastroesophageal or peptic ulcer disease.  The impact of BTK inhibition as a potential 
risk factor for bleeding is unknown.  BTK is expressed in platelets and is involved in 


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platelet function via GPVI/collagen receptor signaling and GP1b receptor signaling.  
Platelets from patients with XLA, a genetic deficiency of BTK, demonstrate decreased 
activation in response to submaximal collagen stimulation but normal response to 
thrombin; clinically, there is no reported bleeding propensity of patients with XLA.
Bruising or bleeding events related to fenebrutinib have not been reported in healthy 
subjects. Grade 2 bleeding events have been reported in blinded and open-label studies 
of fenebrutinib in autoimmune indications, including hematuria, purpura, hematoma, 
and uterine and vaginal bleeding.
It is unknown whether fenebrutinib will increase the risk of bleeding in patients, 
especially in those receiving anti-platelet or anticoagulant therapies.  As a precautionary 
safety measure, patients will be excluded from study participation if they have a need for 
systemic anticoagulation with warfarin or other oral or injectable anticoagulants or 
anti-platelet agents (other than NSAIDs, aspirin, and other salicylates), any history of 
hospitalizations or transfusion for a GI bleed, any history of a hemorrhagic CVA, any 
history of spontaneous intracranial hemorrhage, traumatic intracranial hemorrhage within 
10 years prior to the study, or a known bleeding diathesis.  Patients should be advised to 
seek immediate medical attention if they develop signs and symptoms suggestive of 
clinically significant bleeding.  
Bleeding events of moderate or greater severity are considered adverse events of 
special interest and should be reported to the Sponsor in an expedited manner as 
outlined in Section 5.4.2.
Guidelines for management of study treatment in the event that bleeding is observed in 
patients are provided in Section 5.1.2.  Please refer to the Fenebrutinib Investigator’s 
Brochure for further details.
5.1.1.4
Cytopenias
Cytopenias have been observed in patients with hematological malignancies who 
received fenebrutinib as well as in the ongoing, blinded Phase II studies and OLEs in 
autoimmune diseases. Cytopenias have included neutropenia, anemia, and 
thrombocytopenia; events have been monitorable and clinically manageable (see the 
Fenebrutinib Investigator’s Brochure for further details).  
Patients should be monitored regularly with hematology laboratory evaluations as 
outlined in the schedule of activities (see Appendix 1) and should receive appropriate 
supportive care as clinically indicated.  Patients should be advised to seek immediate 
medical attention if they develop signs and symptoms suggestive of cytopenias (e.g., 
persistent fever, bruising, bleeding, pallor).  Cytopenias should be managed according to 
local clinical guidelines.


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Guidelines for managing study treatment in the event that cytopenia is observed are 
provided in Section 5.1.2.  Please refer to the Fenebrutinib Investigator’s Brochure for 
further details.
5.1.1.5
Gastrointestinal Effects
Body weight gain and food consumption changes have been observed in animals, 
including nonsignificant increases in male Wistar-Han rats administered 2 mg/kg/day 
(4.3 M hr) for 6 months, and significant reductions in rats administered 100 mg/kg/day 
(1438 M hr) and dogs administered 25 mg/kg (180 M hr) for 4 weeks.  These effects 
on body weight gain and food consumption were reversible following discontinuation of 
fenebrutinib dosing.
NCI CTCAE v4.0 Grade 1 diarrhea, nausea, and abdominal pain have been reported in 
patients with B-cell malignancies; however, the events have resolved and have not led to 
study drug discontinuation.  Healthy subjects in the MAD Study GA29347 reported 
events of mild self-limited nausea.  Across studies with immune indications receiving 
blinded or open-label treatment, approximately 5% of enrolled patients have reported 
nausea, vomiting, diarrhea, or other gastrointestinal symptoms.
Throughout the study, patients will be monitored for GI side effects.  
Guidelines for management of study treatment in the event of GI side effects in patients 
are provided in Section 5.1.1.5.  Please refer to the Fenebrutinib Investigator’s Brochure
for further details.
5.1.1.6
Hepatotoxicity
Evidence of hepatobiliary injury was observed in animals administered relatively high 
doses of fenebrutinib in repeat-dose toxicity studies.  Dose-dependent increases in ALT, 
AST, and/or bilirubin have been observed in rats administered 6 mg/kg/day 
(17 M hr) and dogs administered 10 mg/kg/day (36 M hr), with corresponding 
microscopic changes in the liver of dogs administered 25 mg/kg/day (180 M hr).  The 
hepatotoxicity findings in dogs were associated with moribundity in two high-dose 
animals.  The NOAEL for these findings was considered to be 10 mg/kg (36 M hr) in 
dogs, the most sensitive species, given the absence of fenebrutinibrelated 
hepatotoxicity at this dose when administered for 9 months.  
The hepatotoxicity findings were fully reversible and considered 
monitorable by changes in plasma transaminases and bilirubin that occurred at doses 
lower than those producing histopathology findings (see the Fenebrutinib Investigator’s 
Brochure for further details).  
In clinical studies in autoimmune indications, including in patients with CSU, cases of 
Grade 3 (or severe) transaminase elevations, including cases that were considered 
serious by the investigator have been reported.  These transaminase elevations have 
occurred in both the randomized clinical studies, which remain blinded to the Sponsor 


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in terms of treatment assignment, and the open-label extension.  The transaminase 
levels returned to normal after discontinuation of the study treatment.  There have been 
no observed AEs of liver enzyme elevation in clinical studies to date in healthy subjects 
or patients with hematological malignancies. To date, no cases of transaminase 
elevations have led to clinical jaundice or bilirubin 2 ULN (Hy’s Law).  All 
transaminase elevations have been reversible when dosing of blinded study 
medication/placebo was withheld.
As a safety risk-mitigation measure, to be eligible for the study, AST and/or ALT levels 
should be no more than 1.5ULN, and total bilirubin levels should be normal at 
screening.  Safety monitoring for potential hepatotoxicity includes baseline and routine 
evaluations of AST/ALT and total bilirubin levels throughout the study as outlined in the 
schedule of activities (see Appendix 1).
Laboratory results of either an AST or ALT 5ULN or an AST or ALT 3ULN in 
combination with a total bilirubin 2ULN, of which at least 35% is direct bilirubin or 
there is clinical jaundice, are considered adverse events of special interest and should 
be reported to the Sponsor in an expedited manner as outlined in Section 5.4.2.  
Guidelines for the management of study treatment in the event of hepatotoxicity in 
patients are provided in Section 5.1.2.  Please refer to the Fenebrutinib Investigator’s 
Brochure for further details.
5.1.1.7
Cardiovascular Effects
Fenebrutinib is considered to have a low potential to cause QT interval prolongation or to 
directly affect other cardiovascular parameters, at therapeutic exposures.  A minimal 
increase in QTc (7 ms or 3%) interval was noted at 45 mg/kg in the single-dose 
cardiovascular safety pharmacology study in telemetry-instrumented dogs.  
 
 
 There 
have been no fenebrutinibrelated changes in ECG parameters in the 4-week or 
9-month dog toxicity studies. 
Analysis of ECG data from the SAD and MAD studies in healthy subjects did not 
demonstrate any significant increase in either QRS interval or QTcF intervals.  However, 
cardiac safety will be evaluated in all patients at baseline and throughout this study, with 
routine monitoring of vital signs (including heart rate and blood pressure), routine safety 
ECGs, and collection of adverse events (see Section 5.1.1.7 and Section 5.2.1).
Management of patients with sustained QTcF prolongation (QTcF that is 500 ms or 
60 ms longer than the baseline value) should include recording another ECG, ideally 
within the next 5 minutes, and ECG monitoring should continue until QTcF has stabilized 
on two successive ECGs.  The Medical Monitor should be notified as soon as possible 
within 24 hours.  Standard-of-care treatment may be instituted per the discretion of the 




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Guidelines for management of study treatment in the event of malignancies in patients 
are provided in Section 5.1.2. Please refer to the Fenebrutinib Investigator’s Brochure
for further details.
5.1.2
Management of Patients Who Experience Specific Adverse 
Events
5.1.2.1
Management of Specific Adverse Events
Guidelines for management of specific adverse events are outlined in Table 5.
Table 5
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to be Taken a
Infection b
Serious infection, opportunistic infection, 
or any infection requiring treatment with 
an IV antimicrobial agent
Discontinue study treatment and report event as an 
adverse event of special interest.  
Self-limited infections that require 
treatment
Withhold study treatment during antimicrobial therapy.  
Study treatment may resume after consultation with the 
Medical Monitor.
Bleeding
Bleeding events of moderate or greater severity are 
considered adverse events of special interest and 
should be reported to the Sponsor in an expedited 
manner.
For serious bleeding events or bleeding events 
requiring transfusion, radiologic endoscopic, or elective 
operative intervention, withhold study treatment and 
consult with the Medical Monitor.
Gastrointestinal effects
Nausea, vomiting, and/or diarrhea
Manage according to site institutional guidelines.
Consider administration of study treatment with food as 
a possible mitigation strategy.
Malignancy
Any malignancy 
Discontinue study treatment, with the exception of 
non-serious local and resectable basal or squamous 
cell carcinoma of the skin.  Report event as an adverse 
event of special interest to the Sponsor in an expedited 
manner.
Hepatotoxicity
AST or ALT 3.05.0 ULN
Withhold study treatment and consult with the Medical 
Monitor.
AST or ALT 3 ULN in combination 
with a total bilirubin 2 ULN, of which 
at least 35% is direct bilirubin, or clinical 
jaundice 
Discontinue study treatment.  Report event(s) as 
adverse event of special interest (Hy’s law) to the 
Sponsor in an expedited manner.


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Table 5
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to be Taken a
AST or ALT 5 ULN
Discontinue study treatment.  Any elevation of an AST 
or ALT 5 ULN should be reported as an adverse 
event of special interest to the Sponsor in an expedited 
manner. 
Cardiovascular effects 
Sustained (at least two ECG 
measurements 30 minutes apart) 
QTcF that is 500 ms or 60 ms longer 
than the baseline value
Unless there is a clear alternative cause other than 
study drug, discontinue study treatment. c
Sustained absolute QTcF that is 
515 ms
Unless there is a clear alternative cause other than 
study drug, discontinue study treatment. c
An episode of torsades de pointes or a 
new ECG finding of clinical concern
Unless there is a clear alternative cause other than 
study drug, discontinue study treatment. c
Vascular inflammation
Vasculitis
Discontinue study treatment and consult with the 
Medical Monitor.
IV intravenous; QTcF QT interval corrected using Fridericia’s formula; ULN upper limit of normal.
Note:  “Study treatment” includes study drug (fenebrutinib or placebo).  
a
Any patient who discontinues study treatment should enter safety follow-up, if possible.
b
Appropriate laboratory investigations, including but not limited to cultures, should be performed to establish 
the etiology of any serious infection.  
c
In rare circumstances, it may be acceptable to resume study drug, provided that any ECG abnormalities 
have resolved and that the patient is appropriately monitored.  Clinical judgment should be applied.
5.1.2.2
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms or 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms 

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias, such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation, in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  In 
such a situation, saving all available ECG data is highly suggested.


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Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended to help 
in the management of such patients.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)


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
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
o
This does not include any adverse event that had it occurred in a more 
severe form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe; see Section 5.3.3); the event 
itself may be of relatively minor medical significance (such as severe headache without 
any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Any serious infection, any infections requiring IV antimicrobials and any opportunistic 
infections

Bleeding events of moderate or greater severity

All malignancies

Adverse events of special interest for general drug development

A laboratory result of AST or ALT 5ULN

Cases of potential drug-induced liver injury that include an ALT or AST 3ULN 
in combination with a total bilirubin 2ULN, of which at least 35% is direct 
bilirubin or there is clinical jaundice, as defined by Hy’s law (see Section 5.1.1.6)


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
Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this Section and in Section 5.4Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsy sample collection, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 4 weeks after the 
last dose of study drug the patients receives.  After this period, the investigator should 
report any serious adverse events that are believed to be related to prior study drug 
treatment (see Section 5.4.2).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
Table 6 provides the adverse event grading scale for severity.


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Table 6
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  Refer to 
definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 7):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatmentrelated factors that are known to be associated with the 
occurrence of the event
Table 7
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.


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5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should be recorded only once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 


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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).


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5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of chronic spontaneous urticaria.


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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to angioedema of CSU, "chronic spontaneous urticaria
angioedema" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Chronic Spontaneous 
Urticaria
Medical occurrences or symptoms of deterioration that are anticipated as part of CSU 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature compared to 
baseline at any time during the study.  When recording an unanticipated worsening of 
CSU on the Adverse Event eCRF, it is important to convey the concept that the condition 
has changed by including applicable descriptors (e.g., "accelerated CSU").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care


 
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 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours.  For this scenario, record the 
underlying medical condition which resulted in hospitalization on the Adverse Event 
eCRF. 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
No safety data related to overdosing of GDC-0853 are available. 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (see Section 5.4.2 for further details) 


 
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 
Adverse events of special interest (see Section 5.4.2 for further details) 
 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board or Ethics Committee 
(IRB/EC). 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Medical Monitor contact information: 
Medical Monitor: 
, M.D. 
Telephone Nos.: 
Mobile: 
 
  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 4 weeks after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system. 


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In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur 4 weeks after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 4 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
4 weeks after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug. When permitted by 
the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  If 
the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.


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5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
4 weeks after the last dose of study drug; see Section 5.3.1), if the event is believed to 
be related to prior study drug treatment.  These events should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Fenebrutinib Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary and secondary efficacy analyses will be based on a modified intent-to-treat 
(mITT) approach.  All patients who received at least one dose of study drug will be 
included in the mITT population, with patients grouped according to the treatment 
assigned at randomization.  Safety analyses will be conducted on the safety-evaluable 
population, defined as all patients who received at least one dose of study drug, with 
patients grouped according to the actual treatment received.
For each cohort, the final analysis of data from the 8-week, placebo-controlled period will 
be performed when the following two criteria have been met:  1) All patients in the cohort 
have either completed the Day 57 visit or discontinued from the placebo-controlled 
period prematurely and 2) all data from the placebo-controlled period in the cohort are in 
the database and have been cleaned and verified.  Patients and study site personnel will 
remain blinded to the individual treatment assignment until after the study is completed 
(i.e., after all patients in both cohorts have either completed the safety follow-up period 
or discontinued early from the study), the database is locked, and the study analyses are 
final for both cohorts.
The focus of the trial is estimation and generation of hypotheses to be confirmed in 
future trials; therefore, Type I error control is not addressed.
6.1
DETERMINATION OF SAMPLE SIZE
6.1.1
Cohort 1: Pilot Assessment
The purpose of this cohort is to evaluate the efficacy of fenebrutinib at 200 mg PO BID
compared with placebo in improving the UAS7.  Point and interval estimates of the 


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change from baseline of the UAS7 within each treatment group as well as of the 
difference in change from baseline of the UAS7 between treatment groups will be 
presented.
The cohort will enroll approximately 45 patients.  Patients will be randomized in a 
2:1 ratio to receive treatment with either fenebrutinib or placebo.  The sample size of 
approximately 30 patients in the fenebrutinib arm and 15 patients in the placebo arm 
provides approximately 80% power to detect an 11-point difference in the UAS7 change 
from baseline at Day 57 between treatment groups under the following assumptions:

The absolute change from baseline at Day 57 is normally distributed with a standard 
deviation of 13.

Two-sided alpha is 0.10.

Dropout rate at Day 57 is 10%, leading to a 10% loss of information. 
6.1.2
Cohort 2: Dose-Ranging Assessment
The purpose of this cohort is estimation and hypothesis generation regarding the dose-
ranging effects of fenebrutinib compared with placebo in improving the UAS7.  Point and 
interval estimates of the change from baseline of the UAS7 within each treatment group 
as well as of the difference in change from baseline of the UAS7 between treatment 
groups vs placebo will be presented.
The cohort will enroll approximately 120 patients.  Patients will be randomly allocated in 
a 1:1:1:1 ratio to receive treatment with one of three dose levels of fenebrutinib or 
placebo.  The sample size of approximately 30 in each arm provides approximately 90% 
power to detect an 11-point difference in the UAS7 change from baseline at Day 57 
between treatment groups, under the following assumptions:

The absolute change from baseline at Day 57 is normally distributed with a standard 
deviation of 13

Two-sided alpha is 0.10

Dropout rate at Day 57 is 10%, leading to a 10% loss of information.
The overall sample size may be adjusted depending on the outcome of a planned 
interim analysis for Cohort 1 (see Section 6.8), which will include an evaluation of these 
assumptions.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.


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6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Baseline demographics, disease characteristics, and exposure to study drug will be 
summarized by treatment group using descriptive statistics.  For categorical endpoints, 
the descriptive statistics will include counts and proportions.  For continuous endpoints, 
the descriptive statistics will include the number of observations, mean, standard 
deviation, median, minimum, and maximum.
6.4
EFFICACY ANALYSES
Statistical analysis will be conducted for each cohort separately. Statistical testing will 
be performed as a two-sided test with a statistical significance level of 0.10.  No 
multiplicity adjustments will be performed to control overall Type I error, and positive 
tests will be viewed as hypothesis generating rather than confirmatory.
Continuous longitudinal efficacy endpoints will be analyzed using a mixed model for 
repeated measures (MMRM) and descriptive statistics as appropriate.  An unstructured 
covariance pattern will be specified to model the within-subject errors.  Parameters will 
be estimated with the use of restricted maximum likelihood, and the Kenward-Roger
method will be used for calculating the denominator degrees of freedom.  The MMRM 
method assumes that data are missing at random.  That is, MMRM assumes that given 
the statistical model and given the observed values of the endpoint, missing data are 
independent of the unobserved values (O’Kelly and Ratitch 2014).  High correlation 
between successive observations on a subject allows data from subjects who dropped 
out to make a contribution to estimation of the effects at the final timepoint.
All MMRM models will include country, treatment group, visit, and visit by treatment 
group interaction as covariates. 
Time-to-event endpoints will be analyzed using a Cox proportional hazards model.  
Categorical endpoints will be analyzed using an appropriate statistical method, such as 
Cochran-Mantel-Haenszel test or Fisher’s exact test.  
Details of all statistical methods will be provided in the Data Analysis Plans (DAP).
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in the UAS7 at Day 57 
(Week 8).  
The UAS is to be recorded twice daily (i.e., morning and evening) using an eDiary that 
will be provided to each patient.  Scores ranging from 0 (none) to 3 (severe) will be 
entered for each of the two UAS domains consisting of number of wheals (hives) and 
intensity of pruritis (itch) resulting in a total possible score of 0 to 6 (see Table 2).  The 
daily UAS is calculated as the average of the morning and evening scores.  When either 
the morning or evening score is missing, the non-missing UAS for that day (morning or 
evening) will be used as the daily UAS, and when both the morning and evening UAS 


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are missing, the daily UAS will be deemed missing.  The UAS7 is the sum of the daily 
UAS over the 7 days prior to the timepoint of interest.  The baseline UAS7 will be 
calculated as the sum of daily UAS values over the week (7 days) prior to Day 1.  
When one or more daily UAS values is missing, over the week prior to a timepoint of 
interest, rules for deriving UAS7 will be as follows: 

If a patient has at least 4 completed daily scores on the UAS (both domains) over the 
7 days prior to the timepoint of interest, the UAS7 will be defined as the average of 
the available daily scores, multiplied by 7.

If a patient has fewer than 4 completed daily scores on the UAS over the 7 days prior 
to the timepoint of interest, then the UAS7 will be considered missing for that 
timepoint.
The primary endpoint will be analyzed using a MMRM model as specified in Section 6.4.  
Additional model covariates will include baseline UAS7 and its interaction with visit.  
Missing data will be handled by the model under the missing-at-random assumption 
without need for imputation.
As a sensitivity analysis, an analysis-of-covariance (ANCOVA) model adjusted for 
country and baseline UAS7 will be fit.  Missing Day 57 data will be imputed by last 
observation carried forward.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows: 

Proportion of patients who are well controlled (UAS7 6) at Day 57

Change from baseline in the UAS7 at Day 29 (Week 4)
These endpoints will be analyzed as specified in Section 6.4.  
6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints include the following: 

Change from baseline in the weekly itch score at Day 29

Change from baseline in the weekly itch score at Day 57

Change from baseline in the weekly hives score at Day 57

Proportion of patients who are well controlled (UAS7 6) at Day 29

Proportion of patients who achieve complete response (UAS7 0) at Day 29

Proportion of patients who achieve complete response (UAS7 0) at Day 57

Proportion of patients achieving MID in UAS7 at Day 57 (reduction from baseline 
11 points)

Proportion of patients achieving MID in the weekly itch score at Day 57 (reduction 
from baseline 5 points)


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
Time to achieving MID in UAS7 (reduction from baseline 11 points) 
Further details on the analysis of exploratory endpoints will be included in the DAP.  
6.5
SAFETY ANALYSES
Adverse events will be graded according to the adverse event severity grading scale 
described in Section 5.3.3.  Summaries of adverse events, serious adverse events, 
deaths, adverse events of special interest, adverse events that lead to discontinuation, 
ECG findings, laboratory test results, and vital sign measurements will be presented.  
6.6
PHARMACOKINETIC ANALYSES
The PK endpoints are as follows:

Plasma concentration data for fenebrutinib will be tabulated and summarized by 
visits. Descriptive summary statistics will include the arithmetic mean, median, range, 
SD, and coefficient of variation, as appropriate
 
 
The PK analyses will include patients with sufficient data to enable estimation of key 
parameters (e.g., AUC, tmax, Cmax, t1/2), with patients grouped according to treatment 
received. 
Additional PK analyses will be conducted as appropriate.
 


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6.8
INTERIM ANALYSIS
6.8.1
Cohort 1: Planned Interim Analysis
An interim analysis will be performed after approximately 33 patients have completed 
their 8week treatment period.  The purpose of this analysis is to assess the efficacy of 
the 200mg fenebrutinib BID daily arm compared with the placebo, to guide internal 
decision-making around issues such as ungating of Cohort 2, adequacy of sample sizes 
for safety and/or efficacy analyses in Cohort 2, or to inform further development 
decisions.  Summaries of safety and efficacy data by treatment groups will be prepared 
and reviewed by Sponsor personnel who do not have direct contact with investigational 
staff, monitors, and patients. Further details of the interim analysis will be specified in 
the DAP prior to the conduct of the interim analysis. Access to treatment assignment 
information will follow the Sponsor’s standard procedures.
6.8.2
Cohort 2: Optional Interim Analysis
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two interim efficacy analyses. The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis. The interim analysis will be performed 
and interpreted by members of the IMC. Access to treatment assignment information 
will follow the Sponsor’s standard procedures.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.


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PRO data will be collected through the use of an electronic device provided by a vendor.  
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11).  The electronic data are available for view access 
only via secure access to a web server method.  Only identified and trained users may 
view the data, and their actions become part of the audit trail.  The Sponsor will have 
view access only.  System backups for data stored by the Sponsor and records retention 
for the study data will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patients will use an electronic device to capture PRO data.  The data will be transmitted 
via wireless or web automatically after entry or uploaded by site staff at the appropriate 
frequency to a centralized database maintained by the electronic device vendor.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 


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and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.


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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate Sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 


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Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of the analyses, data derived from 
 will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


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be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last 
visit).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
This trial is sponsored by Genentech.  This pilot study will be conducted at study sites 
experienced in conducting clinical trials in CSU.  Data will be recorded via an EDC 
system from Medidata Solutions (New York, NY) using eCRFs (see Section 7.2).  The 
contract research organization will be responsible for submission to IRB/ECs for 
approval of the study protocol, patient recruitment, data collection, and reporting.  An 
IxRS will be used to assign patients to treatment groups and to manage ongoing 
investigational product requests and shipments. 
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities (Cohorts 1 and 2)
Screening a
Treatment Period
Safety 
Follow Up
b
Early 
Term.
Unscheduled 
Visit
Week
0
1
2
4
6 c
8
12
Day (days)
14
(4/2)
7
1b, d
8 d
(1)
15
(1)
29d
(2)
43
(2)
57d,e
(2)
85 d
(2)
Informed consent
x
Demographic data
x
General medical history and baseline conditions
x
Inclusion/exclusion criteria
x
x
x
Randomization
x
Train patient to complete Urticaria Patient Daily 
eDiary (including UAS) f
x
x
Distribute eDiary to patient g
x
Urticaria Patient Daily eDiary g
x
x
x
x
x
x
x
x
x
Concomitant medicationsi
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
Vital signsj
x
x
x
x
x
x
x
x
x
xk
Height
x
Weight
x
x
x
x
x
x
xk
Complete physical examination l
x
x
Limited physical examinationm
x
x
x
x
x
x
x
xk
ECG n
x
x
x
x
x
xk
Hepatitis Screeningo
x
QFT (PPD if QFT not available)
x


Appendix 1
Schedule of Activities (Cohorts 1 and 2) (cont.)
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Screening a
Treatment Period
Safety 
Follow Up
b
Early 
Term.
Unscheduled 
Visit
Week
0
1
2
4
6 c
8
12
Day (days)
14
(4/2)
7
1b, d
8 d
(1)
15
(1)
29d
(2)
43
(2)
57d,e
(2)
85 d
(2)
Chest X-ray p
x
Fenebrutinib/placebo administration in clinicq, r
x
x
x
x
Drug Dispensing
x
x
Hematologys
x
x
x
x
x
x
x
x
x
xk
Chemistryt
x
x
x
x
x
x
x
x
x
xk
Fasting Lipid Panel
x
x
x
x
Coagulation studies u
x
x
xk
Pregnancy testv
x
x
x
x
x
x
x
x
Urinalysisw
x
x
x
x
x
FricTest (for patients with dermographism only)
x
x
x
x
x
Plasma PK assessmenty
x
x
x
x
xk
Phone call bb
x




Appendix 1
Schedule of Activities (Cohorts 1 and 2) (cont.)
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l
A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Patients should be screened for dermographism.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Condition eCRF.
m Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
n Interpretable digital ECG recording (e.g., without artifacts) will be obtained.  The ECG intervals (e.g., PR, QRS, QT, QTcF, and RR) and heart 
rate from the ECGs will be entered into the eCRF; ECGs for each patient should be obtained from the same machine whenever possible.  ECGs 
can be performed without specific restrictions (e.g., can be any time of day, before or after dosing, fasting or fed) but are to be obtained prior to
other procedures scheduled at that same time (e.g., vital sign measurements, blood draws).  ECGs must be performed after the patient has been 
resting in a supine position for at least 10 minutes prior to beginning the ECG recording.  Environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG recording.
o HBsAg, HBsAb, HBcAb, and HCV Ab.
p Performed only if required by local guidelines to rule out active TB infection.
q On mandatory morning clinic visit days during the treatment period (Days 1, 8, 29, and 57), patients should be instructed that the morning dose of 
study drug will be taken in the clinic.  On other clinic visit days, if the visit occurs in the morning, the patient should be instructed that the morning 
dose of study drug will be taken in the clinic.  The morning dose should be taken after all pre-dose assessments are complete (i.e., ECG, 
questionnaires, and PK and 
 sample collection).  
e Patients will take fenebrutinib/placebo BID approximately every 12 hours starting on Day 1 and ending on Day 56 (pm) or the day before (pm)
the Day 57 visit if it does not occur on Day 57.  One dose (a total of 4 tablets) of fenebrutinib/placebo should be taken with water by mouth BID 
(a total of 8 tablets each day).  The dates and times of the most recent prior meal, last dose of oral study drug (prior to clinic visit), and timing of 
study drug administration in clinic should be recorded at each clinic visit. 
s Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and WBC differential (i.e., neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells if present).
t
Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct 
bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH, CRP, and lipase.
u Includes PT, PTT, INR, and fibrinogen.
v All women of childbearing potential, including those who have had a tubal ligation, will have a serum pregnancy test at screening. Urine 
pregnancy tests will be performed locally at specified subsequent visits.  If a urine pregnancy test result is positive, it must be confirmed by a 
serum pregnancy test (performed locally).
w Includes dipstick, including pH, specific gravity, glucose, protein, ketones, blood, and microscopic examination (e.g., sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria if present).




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Appendix 2
Childbearing Potential, Pregnancy Testing, and Contraception
For Women
All women of childbearing potential (including those who have had a tubal ligation) will
have a serum pregnancy test at screening and a urine pregnancy test on Study Day 1 
prior to administration of study drug and monthly at appropriate clinic visits.  If a urine 
pregnancy test result is positive, study drug will not be administered until pregnancy is 
ruled out.  The result must be confirmed by a serum pregnancy test (conducted by the 
local laboratory). Refer to Section 5.4.3 of the protocol for management of a patient with 
a confirmed pregnancy.
All female patients are considered to be of childbearing potential unless they meet one of
the following criteria:

The patient has been postmenopausal (non−therapy-induced amenorrhea) for at
least 12 continuous months with no other identified cause.

The patient had a surgical bilateral oophorectomy (with or without hysterectomy)
more than 6 weeks prior to enrollment.

The patient had a hysterectomy.
Female patients of reproductive or childbearing potential who are unwilling to use a
method of contraception that results in a failure rate of 1 % per year or remain abstinent 
(refrain from heterosexual intercourse), and refrain from donating eggs during the
treatment period and for at least 4 weeks after the last dose of study drug will be
excluded from study participation.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year include the
following:

Sterilization, bilateral surgical tubal ligation

Intrauterine device

Combined oral contraceptive pill 1

Contraceptive transdermal patch (estrogen and progestin containing)1

Hormonal vaginal device

Progestogen-only hormonal contraception associated with inhibition of ovulation

Implants for contraception

Injections for contraception (with prolonged release)


Appendix 2
Childbearing Potential, Pregnancy Testing, and Contraception
(cont.)
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
Sole sexual partner consisting of surgically sterilized male partner with appropriate
postsurgical verification of the absence of spermatozoa in the ejaculate.  Patients
may provide verbal confirmation that the partner completed appropriate follow-up
after vasectomy. Sites are not required to obtain partner medical records.
1
Women using estrogen-containing hormonal contraceptives as a method of 
contraception must also use a barrier such as a male condom in conjunction with the 
hormonal contraceptives.

For Men:  

All men must agree to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:

With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at least 
4 weeks after the last dose of fenebrutinib to avoid exposing the embryo.  Men must 
refrain from donating sperm during this same period.
For Men and Women
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, and post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.


Fenebrutinib (GDC-0853)—Genentech, Inc.
108/Protocol GS39684, Version 4
Appendix 3
Urticaria Patient Daily eDiary
General Instructions
Please answer each question to the best of your ability.
There are no right or wrong answers. 
For each question, please choose the response that describes your experience. 
Please pay close attention to the timeframe of interest.  Some questions ask 
about the past 12 hours, while others ask about the past 24 hours. 
Instructions for Counting the Number of Hives
and Measuring the Size of the Largest Hive
Count each hive separately even if you have more than one hive grouped 
together with other hives. 
Please use the ruler that you have been given to measure the size of your largest 
hive.  If you need help, please have someone else take this measurement for 
you.  Please do not measure a group of hives as one hive.


Appendix 3
Urticaria Patient Daily eDiary (cont.)
Fenebrutinib (GDC-0853)—Genentech, Inc.
109/Protocol GS39684, Version 4
Today’s Date
-
-
Day              Month                     Year
Please complete this Section every morning throughout the duration of the 
study.  (Please circle only one response.) 
1. Thinking about the past 12 hours, please record the severity of itch and the 
number of hives you may have had associated with your skin condition.  
Please count each hive separately even if you have more than one hive 
grouped together with other hives. 
Itch (severity) 
Hives (number)
0none
1mild
2moderate
3severe
0none
1between 1 and 6 hives
2between 7 and 12 hives
3greater than 12 hives
This next question asks you to estimate the size of your largest hive in 
centimeters (cm).  Please use the ruler that you have been provided with to make 
this measurement.  If your largest hive is located on your back or in a place that 
is hard to reach, please have someone else take this measurement for you.  
When measuring the largest hive size, please do not measure a group of 
hives as one hive.
Largest Hive (size)
0none
1less than 1.25 centimeter (cm) 
2between 1.25 centimeter (cm) and 2.5 centimeters (cm) 
3greater than 2.5 centimeters (cm) 


Appendix 3
Urticaria Patient Daily eDiary (cont.)
Fenebrutinib (GDC-0853)—Genentech, Inc.
110/Protocol GS39684, Version 4
Today’s Date
-
-
Day              Month                     Year
Please complete this Section every evening throughout the duration of the 
study.  (Please circle only one response.) 
2. Thinking about the past 12 hours, please record the severity of itch and the 
number of hives you may have had associated with your skin condition. 
Please count each hive separately even if you have more one than one 
hive grouped together with other hives.
Itch (severity) 
Hives (number)
0none
1mild
2moderate
3severe
0none
1between 1 and 6 hives
2between 7 and 12 hives
3greater than 12 hives
This next question asks you to estimate the size of your largest hive in 
centimeters (cm).  Please use the ruler that you have been provided with to make 
this measurement.  If your largest hive is located on your back or in a place that 
is hard to reach, please have someone else take this measurement for you.  
When measuring the largest hive size, please do not measure a group of 
hives as one hive.
Largest Hive (size)
0none
1less than 1.25 centimeter (cm) 
2between 1.25 centimeter (cm) and 2.5 centimeters (cm) 
3greater than 2.5 centimeters (cm) 


Appendix 3
Urticaria Patient Daily eDiary (cont.)
Fenebrutinib (GDC-0853)—Genentech, Inc.
111/Protocol GS39684, Version 4
Today’s Date
  Day                Month                     Year
Please complete this Section twice each day (a.m. and p.m.) throughout the 
duration of the study (preferably at the same time each day).
(Please circle only one response.)
3. Please rate how much your hives or itch interfered with your sleep during the 
past 24 hours. 
0
No interference
1
Mild, little interference with sleep
2
Moderate, awoke occasionally, some interference with sleep
3
Substantial, woke up often, severe interference with sleep
4. Please rate how much your hives or itch interfered with your daily activities 
during the past 24 hours.  This could include work, school, sports, hobbies, 
and activities with friends and family.
0
No interference
1
Mild, little interference with daily activities
2
Moderate, some interference with daily activities
3
Substantial, severe interference with daily activities 


Appendix 3
Urticaria Patient Daily eDiary (cont.)
Fenebrutinib (GDC-0853)—Genentech, Inc.
112/Protocol GS39684, Version 4
These next questions are about your symptoms and how you managed 
them during the past 24 hours. 
5. During the past 24 hours, did you use loratadine or cetirizine in order to 
control symptoms of your skin condition such as itch or hives? 
0No
1Yes
6a.During the past 24 hours, did you have any rapid swelling on your face, 
(especially your eyelids or lips), inside your mouth (including your throat or 
tongue), or elsewhere on your body?  This rapid swelling, also called 
angioedema, is at a deeper level under your skin than hives. 
0No (GO TO Question 7)
1Yes
6b.If Yes, how did you treat this rapid swelling?  (Circle all that apply.)
0
Did nothing (GO TO Question 7)
1
Took some prescription or non-prescription medication 
2
Called my doctor, nurse or nurse practitioner
3
Went to see my doctor, nurse, or nurse practitioner
4
Went to the emergency room at the hospital
5
Was hospitalized
7. During the past 24 hours, did you or someone else call your doctor, nurse or 
nurse practitioner because of your skin condition?
0No
1Yes 


Fenebrutinib (GDC-0853)—Genentech, Inc.
113/Protocol GS39684, Version 4


 
Fenebrutinib (GDC-0853)—Genentech, Inc. 
114/Protocol GS39684, Version 4 
Appendix 5 
Concomitant Medications (Including Foods and Herbal Products) 
Class 
Expected Interaction 
Recommendation 
Examples of Drugs in this Class a 
Antacids 
Decreased 
fenebrutinib 
absorption due to 
increased gastric pH 
Take fenebrutinib 
2 hours before or 
2 hours after antacid 
 Pepto-Bismol, Rolaids 
Moderate 
or strong 
CYP3A 
inhibitors  
Increased 
fenebrutinib plasma 
concentrations due 
to inhibition of 
metabolism 
Avoid for 7 days or 5 
half-lives (whichever is 
longer) prior to first 
dose of study drug and 
during the treatment 
period 
 Antimicrobials (clarithromycin, 
erythromycin, itraconazole, 
ketoconazole, telithromycin, 
troleandamycin, voriconazole, 
posaconazole) 
 Antidepressants (nefazodone) 
 Antihypertensive/cardiac 
(verapamil, diltiazem) 
 Other (grapefruit juice, Seville 
orange juice, pomegranate, star 
fruit) 
CYP3A 
inducers  
Decreased 
fenebrutinib plasma 
concentrations due 
to increased 
metabolism 
Avoid for 7 days or 5 
half-lives (whichever is 
longer) prior to first 
dose of study drug and 
during the treatment 
period 
 Antimicrobials (rifampin, 
rifapentine, rifabutin) 
 Antidepressants (St. John’s wort, 
hyperforin) 
 Antiepileptics (carbamazepine, 
phenytoin, phenobarbital, 
hyperforin) 
 Diabetes (pioglitazone, 
troglitazone) 
 Other (modafinil, bosentan) 


Appendix 5
Concomitant Medications (Including Foods and Herbal Products)
(cont.)
Fenebrutinib (GDC-0853)—Genentech, Inc.
115/Protocol GS39684, Version 4
Class
Expected Interaction
Recommendation
Examples of Drugs in this Class a
Sensitive 
and narrow 
therapeutic 
window 
CYP3A 
substrates
Potential for 
increased plasma 
concentrations of 
CYP3A substrates 
due to inhibition of 
metabolism by 
fenebrutinib
Use with caution and 
monitor for adverse 
events related to 
CYP3A substrates as 
directed by product 
labeling; consult with 
the Medical Monitor as 
needed
Antiemetic/prokinetic (aprepitant, 
cisapride)
Antihistamine (astemizole, 
terfenadine)
Antihypertensive/cardiac 
(dronedarone, eplerenone, 
felodipine, nisoldipine, quinidine, 
ticagrelor, vardenafil)
Benzodiazepines (alprazolam, 
diazepam, midazolam)
Lipid-lowering (simvastatin 
[recommended maximum dose: 10 
mg/day], lovastatin [recommended 
maximum dose: 20 mg/day])
Migraine (eletriptan, ergotamine)
Steroids (budesonide, fluticasone)
Other (alfentanil, buspirone, 
conivaptan, darifenacin, dasatinib, 
dihydroergotamine, fentanyl, 
lurasidone, pimozide, quetiapine, 
sildenafil, tolvaptan, triazolam)
BCRP 
substrates 
with a 
narrow 
therapeutic 
index
Potential for 
increased plasma 
concentrations of 
BCRP substrates 
due to inhibition of 
transport by 
fenebrutinib
Use with caution and 
monitor for adverse 
events related to 
BCRP substrates as 
directed by product 
labeling; consult with 
the Medical Monitor as 
needed
Antihypertensive (prazosin)
Anti-inflammatory (sulfasalazine)
Lipid-lowering (rosuvastatin 
[recommended maximum dose: 10 
mg/day], atorvastatin 
[recommended maximum dose: 20 
mg/day]
Muscle relaxants (dantrolene)
Steroids (estrone-3-sulfate)
a The following list is not comprehensive.  Please refer to the following websites for additional 
information and consult the Medical Monitor if necessary:
U.S. FDA Table of Substrates, Inhibitors, and Inducers (Tables 3-1, 3-2, 3-3, and 5-1) 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteract
ionsLabeling/ucm093664.htm)
Indiana University Department of Medicine P450 Interaction Table 
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table)