Clinical trial NCT03693625
Conditions: Urticaria
Sponsor: Genentech, Inc.
Start date: 2018-09-27; Completion date: 2019-10-23
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase II, multicenter, open-label extension (OLE) study to evaluate the long-term safety and efficacy of fenebrutinib in participants with Chronic Spontaneous Urticaria (CSU) who have completed the treatment period in a fenebrutinib CSU parent study. Participants may enroll in this OLE study at any time after completing the treatment period of the parent study. Participants will receive open-label fenebrutinib at a dose of 200 milligram (mg) orally twice a day. Treatment may continue until the end of the study.

Detailed description:

Arms: arm 1: Participants (who had received 50, 150 and 200mg GDC-0853 in Cohort 2 of the Parent GS39684 Study) received open-label fenebrutinib/GDC-0853 at a dose of 200mg orally twice a day. arm 2: Participants (who had received Placebo in Cohort 2 of the Parent GS39684 Study) received open-label fenebrutinib/GDC-0853 at a dose of 200mg orally twice a day.
Interventions: intervention 1: GDC-0853
Intervention descriptions: intervention 1: Participants were administered GDC-0853 200mg orally, as per the dosing schedules described above.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Phase II Open-Label Extension Study to Evaluate the Long-Term 
Safety and Efficacy of Fenebrutinib in Patients Previously Enrolled in a 
Fenebrutinib Chronic Spontaneous Urticaria Study 
NCT Number: 
NCT03693625 
Document Date: 
Protocol Version 1: 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The information contained in this document, especially any unpublished data, is the property of 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—Genentech, Inc. 
Protocol GS40868, Version 1 
PROTOCOL 
TITLE: 
A PHASE II OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND 
EFFICACY OF FENEBRUTINIB IN PATIENTS 
PREVIOUSLY ENROLLED IN A FENEBRUTINIB 
CHRONIC SPONTANEOUS URTICARIA STUDY 
PROTOCOL NUMBER: GS40868 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2018-002296-17 
IND NUMBER: 
137810 
TEST PRODUCT: 
Fenebrutinib (GDC-0853, RO7010939) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
See electronic date stamp below. 
 
09-Aug-2018 23:39:17
Title
Approver's Name
Date and Time (UTC)


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 8
PROTOCOL SYNOPSIS ...................................................................................... 9
1.
BACKGROUND .......................................................................................... 15
1.1
Background on Chronic Spontaneous Urticaria..................... 15
1.2
Role of Bruton’s Tyrosine Kinase .......................................... 15
1.3
Background on Fenebrutinib.................................................. 16
1.4
Study Rationale and Benefit–Risk Assessment..................... 16
2.
OBJECTIVES AND ENDPOINTS ............................................................... 17
2.1
Safety Objective .................................................................... 17
2.2
Exploratory Efficacy Objective............................................... 17
2.3
Pharmacokinetic Objectives................................................... 17
18
3.
STUDY DESIGN......................................................................................... 18
3.1
Description of the Study......................................................... 18
3.2
End of Study and Length of Study......................................... 19
3.3
Rationale for Study Design.................................................... 20
3.3.1
Rationale for Fenebrutinib Dose and Schedule ..................... 20
20
4.
MATERIALS AND METHODS .................................................................... 20
4.1
Patients.................................................................................. 20
4.1.1
Inclusion Criteria.................................................................... 20
4.1.2
Exclusion Criteria................................................................... 21
4.2
Method of Treatment Assignment and Blinding..................... 22
4.3
Study Treatment.................................................................... 22
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 22
4.3.1.1
Fenebrutinib........................................................................... 22
4.3.1.2
Background Therapy:  Standard-of-Care 
H1-Antihistamines for Chronic Spontaneous 
Urticaria ................................................................................. 22


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4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 22
4.3.2.1
Fenebrutinib........................................................................... 22
4.3.2.2
Background Therapy: Standard-of-Care 
H1-Antihistamines for Chronic Spontaneous 
Urticaria ................................................................................. 23
4.3.3
Investigational Medicinal Product Accountability ................... 23
4.3.4
Continued Access to Fenebrutinib......................................... 24
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 24
4.4.1
Permitted Therapy................................................................. 24
4.4.2
Cautionary Therapy ............................................................... 25
4.4.2.1
Immunosuppressive Agents .................................................. 25
4.4.2.2
Acid-Reducing Agents ........................................................... 25
4.4.2.3
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 25
4.4.2.4
Medications Given with Precaution due to Effects 
Related to Breast Cancer Resistance Protein ....................... 26
4.4.2.5
Dose Adjustments for Statins due to Effects 
Related to Cytochrome P450 Enzymes or Breast 
Cancer Resistance Protein.................................................... 26
4.4.3
Prohibited Therapy ................................................................ 27
4.4.3.1
Live or Attenuated Vaccinations ............................................ 27
4.4.4
Prohibited Food ..................................................................... 27
4.5
Study Assessments ............................................................... 27
4.5.1
Informed Consent Forms and Screening Log........................ 27
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 28
4.5.3
Physical Examinations........................................................... 28
4.5.4
Vital Signs.............................................................................. 28
4.5.5
Laboratory, 
 and Other Biological 
Samples................................................................................. 28
4.5.6
Electrocardiograms................................................................ 29
4.5.7
Patient-Reported and Clinician-Reported 
Outcomes .............................................................................. 30
4.5.7.1
Urticaria Patient Daily Diary................................................... 31


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4.5.7.2
The Urticaria Control Test...................................................... 31
4.5.7.3
Physician’s Global Assessment of Disease 
Control–Likert Scale .............................................................. 32
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 32
4.6.1
Study Treatment Discontinuation........................................... 32
4.6.2
Patient Discontinuation from Study........................................ 32
4.6.3
Study Discontinuation............................................................ 33
4.6.4
Site Discontinuation............................................................... 33
5.
ASSESSMENT OF SAFETY....................................................................... 33
5.1
Safety Plan ............................................................................ 33
5.1.1
Potential Risks Associated with Fenebrutinib ........................ 34
5.1.1.1
Infections ............................................................................... 34
5.1.1.2
Vaccinations .......................................................................... 34
5.1.1.3
Bleeding................................................................................. 35
5.1.1.4
Cytopenias............................................................................. 36
5.1.1.5
Gastrointestinal Effects.......................................................... 36
5.1.1.6
Hepatotoxicity........................................................................ 36
5.1.1.7
Cardiovascular Effects........................................................... 36
5.1.1.8
Vascular Inflammation ........................................................... 37
5.1.1.9
Malignancy ............................................................................ 37
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 37
5.1.2.1
Dose Modifications ................................................................ 37
5.1.2.2
Treatment Interruption ........................................................... 37
5.1.2.3
Management Guidelines........................................................ 38
5.1.2.4
Management of Increases in QT Interval............................... 39
5.2
Safety Parameters and Definitions ........................................ 40
5.2.1
Adverse Events ..................................................................... 40
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 41
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 42


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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 42
5.3.1
Adverse Event Reporting Period ........................................... 42
5.3.2
Eliciting Adverse Event Information....................................... 43
5.3.3
Assessment of Severity of Adverse Events ........................... 43
5.3.4
Assessment of Causality of Adverse Events ......................... 43
5.3.5
Procedures for Recording Adverse Events............................ 44
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 44
5.3.5.2
Adverse Events That are Secondary to Other
Events.................................................................................... 45
5.3.5.3
Persistent or Recurrent Adverse Events................................ 45
5.3.5.4
Abnormal Laboratory Values ................................................. 46
5.3.5.5
Abnormal Vital Sign Values ................................................... 47
5.3.5.6
Abnormal Liver Function Tests.............................................. 47
5.3.5.7
Deaths ................................................................................... 47
5.3.5.8
Preexisting Medical Conditions.............................................. 48
5.3.5.9
Lack of Efficacy or Worsening of Chronic 
Spontaneous Urticaria ........................................................... 48
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 48
5.3.5.11
Patient-Reported Outcome Data ........................................... 49
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 49
5.4.1
Emergency Medical Contacts................................................ 50
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 50
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 50
5.4.2.2
Events That Occur after Study Drug Initiation........................ 50
5.4.3
Reporting Requirements for Pregnancies.............................. 51
5.4.3.1
Pregnancies in Female Patients............................................ 51
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 51
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 52
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 52
5.5
Follow-Up of Patients after Adverse Events .......................... 54


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5.5.1
Investigator Follow-Up........................................................... 54
5.5.2
Sponsor Follow-Up ................................................................ 54
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 54
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 55
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 55
6.1
Determination of Sample Size ............................................... 55
6.2
Summaries of Conduct of Study............................................ 55
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 55
6.4
Safety Analyses..................................................................... 56
6.5
Exploratory Efficacy Analyses ............................................... 56
6.6
Pharmacokinetic Analyses..................................................... 56
56
6.8
Interim Analysis ..................................................................... 56
7.
DATA COLLECTION AND MANAGEMENT ............................................... 56
7.1
Data Quality Assurance......................................................... 56
7.2
Electronic Case Report Forms............................................... 57
7.3
Source Data Documentation.................................................. 57
7.4
Use of Computerized Systems .............................................. 58
7.5
Retention of Records............................................................. 58
8.
ETHICAL CONSIDERATIONS.................................................................... 58
8.1
Compliance with Laws and Regulations ................................ 58
8.2
Informed Consent.................................................................. 59
8.3
Institutional Review Board or Ethics Committee.................... 60
8.4
Confidentiality........................................................................ 60
8.5
Financial Disclosure .............................................................. 61
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 61
9.1
Study Documentation ............................................................ 61
9.2
Protocol Deviations................................................................ 62


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9.3
Site Inspections ..................................................................... 62
9.4
Administrative Structure......................................................... 62
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 62
9.6
Protocol Amendments ........................................................... 63
10. REFERENCES ........................................................................................... 64
LIST OF TABLES
Table 1
Twice-Daily Patient Assessment of CSU Disease Activity 
(UAS Scale) ................................................................................ 31
Table 2
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 38
Table 3
Adverse Event Severity Grading Scale ....................................... 43
Table 4
Causal Attribution Guidance ....................................................... 44
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 19
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 67
Appendix 2
Urticaria Patient Daily Diary ........................................................ 70
Appendix 3
Urticaria Control Test.................................................................. 75
Appendix 4
Physician’s Global Assessment of Disease Control–Likert 
Scale (PhyGA-LS)....................................................................... 76
Appendix 5
Cautionary Therapy:  Concomitant Medications (Including 
Foods and Herbal Products) with Specific Drug-Drug 
Interaction ................................................................................... 77
Appendix 6
Fenebrutinib Bottle and Label Configuration............................... 79


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PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE II OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND EFFICACY 
OF FENEBRUTINIB IN PATIENTS PREVIOUSLY 
ENROLLED IN A FENEBRUTINIB CHRONIC 
SPONTANEOUS URTICARIA STUDY
PROTOCOL NUMBER:
GS40868
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-002296-17
IND NUMBER:
137810
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 retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO.


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II OPEN-LABEL EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF FENEBRUTINIB 
IN PATIENTS PREVIOUSLY ENROLLED IN A FENEBRUTINIB 
CHRONIC SPONTANEOUS URTICARIA STUDY 
PROTOCOL NUMBER: 
GS40868 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2018-002296-17 
IND NUMBER: 
137810 
TEST PRODUCT: 
Fenebrutinib (GDC-0853, RO7010939) 
PHASE: 
Phase II 
INDICATION: 
Chronic Spontaneous Urticaria 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
This open-label extension (OLE) study will evaluate the long-term safety and efficacy of 
fenebrutinib in patients with chronic spontaneous urticaria (CSU).  Specific objectives and 
corresponding endpoints for the study are outlined below. 
Safety Objective 
The primary safety objective for this study is to evaluate the long-term safety of fenebrutinib on 
the basis of the following endpoints: 
• 
Incidence, nature, severity, and timing of adverse events, with severity characterized as 
either mild, moderate, or severe 
• 
Change from parent-study baseline in targeted clinical laboratory test results at Weeks 4, 8, 
and 12 and at specified timepoints thereafter (approximately every 12 weeks)  
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
fenebrutinib on the basis of the following endpoints:  
• 
Change from parent study baseline in Urticaria Activity Score over 7 days (UAS7) at 
Weeks 4, 8, and 12 
• 
Change from parent study baseline in Urticaria Control Test (UCT) score at Weeks 4, 8, 
and 12 and at specified timepoints thereafter (approximately every 12 weeks)  
• 
Withdrawal of standard-of-care H1-antihistamines for CSU (background therapy) 
summarized every 6 months  
• 
Physician’s Global Assessment of Disease Control (PhyGA) summarized at Weeks 4, 8, 
and 12 and at specified timepoints thereafter (approximately every 12 weeks)  




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Target Population 
This study will enroll patients with CSU who have completed the treatment period in a 
fenebrutinib CSU parent study. 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
•
Signed Informed Consent Form
•
Ability to comply with the study protocol, in the investigator's judgment
•
Completion of the treatment period as specified in the parent study
•
Acceptable demonstration of tolerance to study drug during the parent study as determined
by the investigator or Medical Monitor
•
For patients receiving treatment with proton-pump inhibitors (PPIs) or H2-receptor
antagonists (H2RAs), agreement to maintain treatment at a stable dose for the first
12 weeks of the study
•
For women of childbearing potential:  agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for at least 4 weeks after the final dose 
of fenebrutinib.  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).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices. 
Hormonal contraceptive methods containing estrogen must be supplemented by a 
barrier method. 
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 postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
•
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 4 weeks after 
the final dose of fenebrutinib 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 postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
•
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
4 weeks after the final dose of fenebrutinib 
Women of childbearing potential must have a negative urine pregnancy test result prior 
to initiation of the first dose of study drug. 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
BCRP
breast cancer resistance protein
BID
twice a day
BTK
Bruton’s tyrosine kinase
CIU
chronic idiopathic urticaria
ClinRO
clinician-reported outcome
CSU
chronic spontaneous urticaria
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
FcRI
high-affinity IgE receptor
GI
gastrointestinal
H2RA
H2-receptor antagonist
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
MAD
multiple-ascending dose
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NOAEL
no-observed-adverse-effect level
OLE
open-label extension
PD
pharmacodynamic
PhyGA
Physician's Global Assessment of Disease Control
PhyGA-LS
Physician's Global Assessment of Disease Control-Likert 
Scale
PK
pharmacokinetic
PO
orally, by mouth
PPI
proton-pump inhibitor
PRO
patient-reported outcome
Q4W
every 4 weeks
QD
once a day
QTcF
QT interval corrected through use of Fridericia’s formula
TPO
thyroperoxidase


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Abbreviation
Definition
UAS
Urticaria Activity Score
UAS7
Urticaria Activity Score over 7 days
UCT
Urticaria Control Test
ULN
upper limit of normal
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).  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).
The etiology of CSU is not clear.  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).  One hypothesis suggests that IgE antibodies targeted against an 
endogenous antigen 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 those patients have IgE antibodies directed against thyroperoxidase
(TPO) (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).  A common pathway in CSU 
is the abnormal activation of mast cells and basophils in the skin.  Increased numbers of 
mast cells can be found in both affected and unaffected skin (Kay et al. 2014), and mast 
cells from patients with CSU 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). Collective data from 
several studies suggest that basophil signaling and activation are dysregulated in 
patients with CSU (Luquin et al. 2005).
Patients may remain symptomatic despite ongoing H1-antihistamine treatment (up to 
four 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, 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
ROLE OF BRUTON’S TYROSINE KINASE
Bruton's tyrosine kinase (BTK) is essential for the differentiation and activity of B cells 
during immune system ontogeny and normal adaptive immune responses.  BTK is 
important in IgE receptor (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; 


 
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Iyer et al. 2011).  IgE-mediated activation of mast cells and basophils via their surface 
FcεRI receptors results in the release of histamine and other inflammatory molecules.   
1.3 
BACKGROUND ON FENEBRUTINIB 
Fenebrutinib (GDC-0853) is a highly selective, orally administered, reversible inhibitor of 
BTK that is being developed 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.   
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 CSU) at doses ranging from 0.5 to 600 mg.  Fenebrutinib has been 
generally well tolerated, with no concerns leading to a change in the conduct of the 
studies.  
Refer to the Fenebrutinib Investigator’s Brochure for details on nonclinical and clinical 
studies. 
1.4 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
This open-label extension (OLE) study GS40868 is designed to assess the long-term 
safety and efficacy of fenebrutinib in patients with CSU.  The study will enroll patients 
previously enrolled in Study GS39684 (parent study).   
Parent study GS39684 is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study of the efficacy and safety of fenebrutinib as add-on therapy for the 
treatment of adult patients with CSU aged 18−75 years who remain symptomatic despite 
treatment with H1-antihistamines.  The pilot cohort (Cohort 1) of Study GS39684 has 
been completed.  On the basis of data from Cohort 1, a dose-ranging cohort (Cohort 2), 
has been opened.  The dose regimen of fenebrutinib selected for this OLE study, 
200 mg orally (PO) twice a day (BID), is the highest dose with an acceptable safety 
profile in Study GS39684. 
Section 5.1 outlines the safety plan for potential risks associated with fenebrutinib.  Refer 
to the Fenebrutinib Investigator's Brochure for a complete summary of safety information. 


 
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2. 
OBJECTIVES AND ENDPOINTS 
This OLE study will evaluate the long-term safety and efficacy of fenebrutinib in patients 
with CSU.  Specific objectives and corresponding endpoints for the study are outlined 
below. 
2.1 
SAFETY OBJECTIVE 
The primary safety objective for this study is to evaluate the long-term safety of 
fenebrutinib on the basis of the following endpoints: 
• 
Incidence, nature, severity, and timing of adverse events, with severity 
characterized as either mild, moderate, or severe 
• 
Change from parent-study baseline in targeted clinical laboratory test results at 
Weeks 4, 8, and 12 and at specified timepoints thereafter (approximately every 
12 weeks)   
 
2.2 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
fenebrutinib on the basis of the following endpoints:  
• 
Change from parent study baseline in Urticaria Activity Score over 7 days (UAS7) 
at Weeks 4, 8, and 12 
• 
Change from parent study baseline in Urticaria Control Test (UCT) score at 
Weeks 4, 8, and 12 and at specified timepoints thereafter (approximately every 
12 weeks)  
• 
Withdrawal of standard-of-care H1-antihistamines for CSU (background therapy) 
summarized every 6 months  
• 
Physician’s Global Assessment of Disease Control (PhyGA) summarized at 
Weeks 4, 8, and 12 and at specified timepoints thereafter (approximately every 
12 weeks)  
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective for this study is to characterize the fenebrutinib PK 
profile on the basis of the following endpoint: 
• 
 Plasma concentrations of fenebrutinib at specified timepoints 
 
 
 
 
 
 
 
 
 
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase II, multicenter, OLE study to evaluate the long-term safety and efficacy 
of fenebrutinib in patients with CSU who have completed the treatment period in a 
fenebrutinib CSU parent study.  Patients may enroll in this OLE study at any time after 
completing the treatment period of the parent study. Up to 165 patients from parent 
study GS39684 are expected to be enrolled globally. 
Patients will receive open-label fenebrutinib at a dose of 200 mg PO BID.  Treatment 
may continue until the end of the study (see Section 3.2). 
Because some patients enrolling in this study may be receiving fenebrutinib for the first 
time (i.e., those patients randomly assigned to placebo in the parent study), all patients 
will be monitored at Weeks 4, 8, and 12.  Thereafter, patients will be monitored 
approximately every 12 weeks (see Appendix 1). 
Patients should maintain a stable dose of standard-of-care H1-antihistamines 
(background therapy) for the first 12 weeks of the study.  Discontinuation or reduction in 
the dose of standard-of-care H1-antihistamines may be attempted at any time after the 
first 12 weeks, at the investigator's discretion (see Sections 4.3.2.2 and 4.4 for details on 
background and concomitant therapies). 
Monitoring for safety and tolerability will continue throughout the study, including 
evaluation of clinical laboratory results and assessment of adverse events.  Patients with 


 
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disease worsening, as determined by the investigator, should return to the clinic as soon 
as possible for an unscheduled visit.  The investigator may also conduct an unscheduled 
visit to assess the patient's disease condition.   
Patients who discontinue study treatment (see Sections 4.6.1 and 5.1.2.2) will be asked 
to return to the clinic for a safety follow-up visit approximately 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 treatment discontinuation visit.   
Details regarding assessments at the safety follow-up, treatment discontinuation, and 
unscheduled visits are provided in Appendix 1. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 
Figure 1 Study Schema 
 
BID  twice a day; BL  baseline; PO  by mouth. 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of the study is expected 
to occur 12 months after the last patient from the parent study is enrolled in this study.  
The Sponsor may decide to terminate the study at any time or amend the study to 
extend its duration.  Patients enrolled in this study may be eligible to enroll into a 
separate extension study, if opened.  


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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Fenebrutinib Dose and Schedule 
The dose regimen of fenebrutinib 200 mg PO BID was the only dose tested in Cohort 1 
of parent study GS39684.   
 
 
  
 
 
 
 
 
 
 
 
  
4.
MATERIALS AND METHODS
4.1 
PATIENTS 
This study will enroll patients with CSU who have completed the treatment period in a 
fenebrutinib CSU parent study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
•
Signed Informed Consent Form
•
Ability to comply with the study protocol, in the investigator's judgment
•
Completion of the treatment period as specified in the parent study
•
Acceptable demonstration of tolerance to study drug during the parent study as
determined by the investigator or Medical Monitor
•
For patients receiving treatment with proton-pump inhibitors (PPIs) or H2-receptor
antagonists (H2RAs), agreement to maintain treatment at a stable dose for the first
12 weeks of the study
•
For women of childbearing potential:  agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive measures, and agreement to refrain
from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure 
rate of < 1% per year during the treatment period and for at least 4 weeks after 
the final dose of fenebrutinib.  Women must refrain from donating eggs during 
this same period. 


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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).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices. 
Hormonal contraceptive methods containing estrogen must be supplemented 
by a barrier method. 
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 postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
•
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, 
men must remain abstinent or use a condom during the treatment period and 
for 4 weeks after the final dose of fenebrutinib 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 postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
•
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 4 weeks after the final dose of fenebrutinib 
Women of childbearing potential must have a negative urine pregnancy test 
result prior to initiation of the first dose of study drug. 
•
Treatment with any investigational agent or live/attenuated vaccine in the preceding
6 weeks
Seasonal influenza vaccination is permitted if the inactivated vaccine 
formulation is administered. 
•
Any signs or symptoms of infection judged by the investigator to be clinically
significant since completing the treatment period of the parent study
•
Any significant changes (e.g., events, changes in medication) occurring after
completion of participation in the parent study that, in the investigator's judgment,
would increase the risk of adverse events in this OLE study


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
All patients in this study will have the opportunity to receive treatment with fenebrutinib at 
a dose of 200 mg PO BID.  All patients, study site personnel, Sponsor agents, and 
Sponsor personnel will be unblinded to the treatment assignment of this study; however, 
the treatment assignment from the parent study will remain blinded until the parent study 
is unblinded.
4.3
STUDY TREATMENT
The investigational medicinal product (IMP) for this study is fenebrutinib.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Fenebrutinib
Fenebrutinib will be supplied by the Sponsor as 50-mg tablets. Tablets will be supplied 
in bottles appropriately labeled for this study. Fenebrutinib tablets should be stored at 
room temperature.  For information on the formulation and handling of fenebrutinib, see 
the pharmacy manual and the Fenebrutinib Investigator's Brochure.
4.3.1.2
Background Therapy: Standard-of-Care H1-Antihistamines for 
Chronic Spontaneous Urticaria
Patients should maintain a stable dose of standard-of-care H1-antihistamines for the first 
12 weeks of the study (see Section 4.3.2.2 for details).  Refer to the local prescribing 
information for the formulation, packaging, and handling of these medications.
4.3.2
Study Treatment Dosage, Administration, and Compliance
4.3.2.1
Fenebrutinib
The treatment regimen is summarized in Section 3.1.  Patients will receive the first dose
of fenebrutinib at the Day 1 study visit.  Thereafter, fenebrutinib will be self-administered.
Each dose, administered approximately every 12 hours (i.e., twice a day, morning and 
evening), will consist of four 50-mg tablets (i.e. eight tablets per day).  Fenebrutinib may 
be taken with or without food. Patients should be instructed that a missed dose should 
not be taken with the next scheduled dose. 
Fenebrutinib tablets will be dispensed on site every 4 weeks. For periods in which study 
site visits (for assessments) are scheduled 4 weeks apart, patients will be expected to 
visit the site to receive allotment of study drug.  
Sites will be responsible for pre-populating the bottle label with the dates when patients 
are scheduled to take study drug during that time period. Under the corresponding 
dates listed on the affixed label, patients will record the time (morning and evening) each 
dose is taken. Refer to Appendix 6 for bottle and label configuration.


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To assess patient compliance with study drug administration, patients will be directed to 
bring all empty and partially-filled bottles to each study visit.  The number of tablets 
issued minus the number of tablets returned will be used to calculate the number of 
tablets taken.  Dosing compliance will be documented in the source documents.  If 
compliance is 80%, the investigator or designee should counsel the patient and ensure 
steps are taken to improve compliance.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in
Section 5.4.4.
Guidelines for dosage modification and treatment interruption or discontinuation for
patients who experience adverse events are provided in Section 5.1.2.
4.3.2.2
Background Therapy: Standard-of-Care H1-Antihistamines for 
Chronic Spontaneous Urticaria
All patients will be permitted to take H1-antihistamine medications consistent with 
standard of care during the study. Standard-of-care H1-antihistamines should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
Patients should maintain a stable dose of standard-of-care H1-antihistamines for the first 
12 weeks of the study. Discontinuation or reduction in the dose of standard-of-care
H1-antihistamines may be attempted at any time after the first 12 weeks, at the 
investigator's discretion.  If an attempt is unsuccessful, the medication may be returned 
to an effective dose at the discretion of the investigator.  In addition, standard-of-care
H1-antihistamines may be added at any time during the study, at the investigator's 
discretion.  Exacerbations of urticaria may be treated with standard-of-care medications
(e.g., short course of systemic corticosteroids for up to 10 days) (Zuberbier et al. 2018).  
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local health authority regulations.  The study site will acknowledge receipt of
IMPs using an interactive voice or web-based response system to confirm the shipment 
condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied 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
Continued Access to Fenebrutinib
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP (fenebrutinib) or any other study treatments or 
interventions to patients who have completed or discontinued from the study.  The 
Sponsor may evaluate whether to continue providing fenebrutinib in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from entry into the extension 
study to the study completion/discontinuation visit of the extension study.  All such 
medications, including standard-of-care H1-antihistamines for CSU, should be reported 
to the investigator and recorded on the Concomitant Medications eCRF. The 
investigator should consult the prescribing information and contact the Medical Monitor 
(or delegate) if questions arise regarding concomitant medications not listed in the 
protocol.  
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Hormone-replacement therapy or oral contraceptives
Hormone-replacement therapy or hormone contraceptives containing the 
CYP3A substrate ethinyl estradiol (with the concomitant use of a barrier method) 
is permitted.  However, these agents should be used with caution as outlined in
Section 4.4.2.3.

Dietary supplements, defined as vitamins, minerals, purified food substances, and 
herbal therapies with pharmaceutical properties
Vitamins, minerals, and purified food substances are permitted in amounts 
lower than that known to be associated with adverse effects 
(e.g., hypervitaminosis). Herbal therapies with pharmaceutical properties are 
permitted only if there is acceptable evidence of no CYP3A inhibition or 
induction. 


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
Leukotriene receptor antagonists or H2RAs for diseases other than CSU 
(e.g., asthma or gastroesophageal reflux disease, respectively) at a stable dose

PPIs or H2RAs at a stable dose, up to the maximum recommended dose according 
to the local prescribing information

Inhaled asthma controllers, including inhaled corticosteroids
4.4.2
Cautionary Therapy
Categories of medications that are to be avoided or used with caution when combined 
with fenebrutinib are described below, and Appendix 5 lists examples of medications
within these categories.  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 fenebrutinib.
4.4.2.1
Immunosuppressive Agents
Caution is advised if adding an immunosuppressive agent (e.g., methotrexate, 
mycophenolate mofetil, cyclophosphamide, rituximab, tacrolimus) to ongoing treatment 
with fenebrutinib.
4.4.2.2
Acid-Reducing Agents
Patients who use antacids for symptomatic relief of heartburn (e.g., Pepto-Bismol,
Rolaids) should take fenebrutinib at least 2 hours before or 2 hours after antacid 
administration because gastric acid improves fenebrutinib absorption.
4.4.2.3
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
Preliminary data from the clinical drugdrug interaction study (GP39616), evaluating the 
effect of fenebrutinib on the pharmacokinetics of the sensitive CYP3A substrate 
midazolam, 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 should be used 
with caution and in consultation with the Medical Monitor (or delegate) as needed:

Sensitive CYP3A substrates

CYP3A substrates with a narrow therapeutic window
The use of hormone-replacement therapy or hormone contraceptives containing the 
CYP3A substrate ethinyl estradiol (with the concomitant use of a barrier method) is 
permitted.  Ethinyl estradiol is metabolized by CYP3A (Wang et al. 2004; Zhang et al. 
2007) so plasma concentrations of ethinyl estradiol are expected to increase in the 
presence of fenebrutinib. Ethinyl estradiol is not a sensitive substrate of CYP3A 
(FDA 2016). 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. Minor increases in ethinyl 


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estradiol concentrations are not generally associated with adverse events (e.g., Ortho 
Tri-CyclenU.S. Package Insert). 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 should be 
avoided for 7 days or 5 drug-elimination half-lives, whichever is longer, prior to the first 
dose of fenebrutinib and during the treatment period (i.e., until the final dose of 
fenebrutinib):

Strong CYP3A inhibitors

Moderate or strong CYP3A inducers
4.4.2.4
Medications Given with Precaution due to Effects Related to 
Breast Cancer Resistance Protein
Preliminary data from Study GP39616 suggest that fenebrutinib is a moderate inhibitor 
of the breast cancer resistance protein (BCRP) (also known as ABCG2) at clinically 
relevant doses.  Consequently, fenebrutinib may alter transport of BCRP substrates and 
result in increased plasma concentrations of BCRP substrates.  Therefore, BCRP 
substrates with a narrow therapeutic window should be used with caution and in 
consultation with the Medical Monitor (or delegate) as needed:
4.4.2.5
Dose Adjustments for Statins due to Effects Related to 
Cytochrome P450 Enzymes or Breast Cancer Resistance 
Protein
Because 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, dose adjustments of these 
medications should be considered (Kellick et al. 2014), as outlined below:

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


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The use of statins has been associated with myopathy, which can manifest as weakness, 
tenderness, or muscle pain, with elevations of creatine kinase above 10upper limit of 
normal (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 sex, uncontrolled hypothyroidism, renal impairment, or use of concomitant 
medications that increase the plasma levels of the statin.
4.4.3
Prohibited Therapy
4.4.3.1
Live or Attenuated Vaccinations
Immunization with a live or attenuated vaccine is prohibited within 6 weeks prior to the 
first dose of fenebrutinib and during the treatment period. 
Seasonal influenza vaccination is permitted if the inactivated vaccine formulation is 
administered.
4.4.4
Prohibited Food
Use of furanocoumarin derivatives, as found in grapefruit, Seville orange, pomegranate, 
or star fruit juice or products, is prohibited within 7 days prior to the first dose of
fenebrutinib and during the treatment period (i.e., until the final dose of fenebrutinib).
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient. 
All assessments on Day 1 are conducted prior to study drug administration unless 
otherwise specified.  Assessments that were performed at the final visit of the parent 
study, if within 3 months prior to Day 1, should not be repeated.
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.
All screening (Day 1) evaluations must be completed and reviewed to confirm that 
patients meet all eligibility criteria before enrollment and receiving the first open-label 
dose in this study.  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.


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4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and reproductive status, will be 
recorded at baseline in the parent study.  In addition, all medications (e.g., prescription 
drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient from the time the patient completed the treatment 
period of the parent study will be recorded.  Past resolved adverse events will be 
recorded in the medical history if clinically significant.  Refer to Section 5.3.5.3 for 
information on recording adverse events that had not resolved at the end of the parent 
study.  At the time of each follow-up physical examination, an interval medical history 
should be obtained and any changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
Limited, symptom-directed physical examinations should be performed at specified visits 
and as clinically indicated.  Changes in parent study 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.
4.5.4
Vital Signs
Vital signs will include measurement of pulse rate and systolic and diastolic blood 
pressure while the patient is in a seated position for at least 5 minutes.
4.5.5
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:

Hematology: hemoglobin, hematocrit, platelet count, RBC count, WBC count, and 
percent and absolute differential counts (neutrophils, bands, lymphocytes, 
monocytes, eosinophils, basophils, other cells)

Serum chemistry: bicarbonate or total carbon dioxide (if considered standard of 
care for the region), sodium, potassium, chloride, glucose, BUN or urea, creatinine, 
calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, 
ALT, AST, lactate dehydrogenase, ALP, creatine phosphokinase, C-reactive protein, 
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, aPTT, PT, and fibrinogen

Lipid panel

Plasma samples for PK analysis


 
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The following laboratory tests will be sent to the site’s local laboratory for analysis: 
• 
Pregnancy test 
For women of childbearing potential:  Urine pregnancy tests will be performed 
at specified visits.  The patient will be requested to conduct monthly urine 
pregnancy tests at the site between in-clinic study visits.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. 
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research, biological samples will be destroyed when the final 
Clinical Study Report has been completed, with the following exceptions: 
• 
Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final Clinical Study Report 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. 
Given the complexity 
, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.6 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  


 
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Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
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).  
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.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected through use of Fridericia’s formula (QTcF) based on the machine readings of 
the individual ECG tracings.  Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF.  If considered appropriate by the 
Sponsor, ECGs may be analyzed retrospectively at a central laboratory. 
If at a particular postdose 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.  
In such a scenario, the Medical Monitor should be notified.  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 5.1.2.4.  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). 
4.5.7 
Patient-Reported and Clinician-Reported Outcomes 
The Urticaria Patient Daily Diary and the Urticaria Control Test (UCT) will be collected to 
document the treatment benefit of fenebrutinib.  The Physician’s Global Assessment of 
Disease Control−Likert Scale (PhyGA-LS) will be collected to record the physician’s 
assessment of disease control.  The Urticaria Patient Daily Diary, UCT, and PhyGA-LS 
will be translated into the local language as required and will be completed in their 
entirety at specified timepoints during the study.  To ensure instrument validity and that 
data standards meet health authority requirements, the UCT will be self-administered 
before the patient receives any information on disease status, prior to the performance 
of non−patient-reported outcome (non-PRO) assessments, and prior to the 
administration of study treatment, unless otherwise specified. 


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Patients will be instructed to complete a paper Urticaria Patient Daily Diary. The diary 
will be returned to the clinic, and the data will be sent for transcribing into the central 
database. 
Patients will be given paper questionnaires to capture the UCT (see Appendix 3) at 
specified visits. Instructions for completing the questionnaires will be provided by the 
investigator staff. Paper forms will be transcribed into the central database.
4.5.7.1
Urticaria Patient Daily Diary
The Urticaria Patient Daily Diary includes questions regarding number of hives, largest 
hive size, sleep interference, activity interference, rescue medication use, angioedema 
episodes, and number of calls to the doctor, nurse, or nurse practitioner (see
Appendix 2).  Urticaria Activity Score (UAS) is derived from patient entries in the daily 
dairy and is used to calculate the UAS7 (see below).
The diary is to be completed by the patient twice daily (morning and evening) for the first 
12 weeks of the study. The last diary entry may occur the day prior to the Week 12 visit.
Weekly Urticaria Activity Score
The UAS is a composite score with numeric severity intensity ratings (0none to 
3intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) 
over the past 12 hours as shown in Table 1 below. The UAS7 is sum of the average 
daily itch and hive score over 7 days and has a maximum value of 42.
Table 1
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
4.5.7.2
The Urticaria Control Test
The UCT is a 4-item questionnaire to assess disease activity (see Appendix 3). The 
recall period is 4 weeks; the score range is 016 with a minimally important difference of 
2.8 (Kulthanan et al. 2016). See Appendix 1 for UCT assessment timepoints.


 
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4.5.7.3 
Physician’s Global Assessment of Disease Control–Likert 
Scale 
The PhyGA-LS is a 5-point scale that reflects the investigator’s assessment of the 
treatment over the previous 4 weeks.  It has the following categories:  no control, little 
control, moderate control, good control, and complete control (see Appendix 4). 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
Pregnancy 
 
Patients who discontinue study treatment either permanently or due to treatment 
interruption (see Section 5.1.2.2) will be asked to return to the clinic for a safety 
follow-up visit approximately 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 a treatment 
discontinuation visit. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.   
4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced. 


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may 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 is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
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:
–
Poor protocol adherence
–
Inaccurate or incomplete data recording
–
Non-compliance with the International Council for Harmonisation (ICH) guideline for
Good Clinical Practice

No study activity (i.e., no patients remain in the OLE and all obligations have been
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Fenebrutinib is not approved, and clinical development is ongoing.  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 anticipated important 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 toxicities.  
Patients will undergo safety monitoring during the study, including monitoring of vital 
signs, 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 adverse events, including criteria for treatment 
interruption or discontinuation, are provided below.


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5.1.1
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 X-linked agammaglobulinemia (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 
responses.
Infections, including pneumonia, fatal influenza, nasopharyngitis, and asymptomatic 
bacteriuria, have occurred in patients treated with fenebrutinib.
The parent study protocol contains exclusion criteria for infections and potential infection 
risk, and patients with any clinically significant signs or symptoms of infection or 
infections requiring treatment with IV antibiotics since enrolling in the parent study will be 
excluded from the OLE study (see Section 4.1.2).  All patients in the study should be 
monitored for fever and potential infectious complications, including opportunistic 
infections and tuberculosis, 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 considered an adverse event of special interest and 
should be reported to the Sponsor as outlined in Section 5.2.3.
Guidelines for management of patients who develop infections are provided in Table 2.
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 if they have been 
vaccinated with live, attenuated vaccines (e.g., the intranasal live attenuated influenza 
vaccines, bacille Calmette-Guérin, varicella) within 6 weeks prior to the first dose of 
study drug. Immunization with a live or attenuated vaccine is prohibited for the duration 
of study participation. 


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Household contact with children or others who have been vaccinated with live vaccine 
components may pose a risk to the patients receiving fenebrutinib. 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.  Thus, patients should avoid exposure to vaccinated individuals during defined 
periods for specified vaccines, as outlined below:

Varicella or attenuated typhoid fever vaccination: 4 weeks following vaccination

Oral polio vaccination: 6 weeks following vaccination

Attenuated rotavirus vaccine: 10 days following vaccination

FluMist(inhaled flu vaccine): 1 week following vaccination
5.1.1.3
Bleeding
Bleeding events, including bruising and bleeding, have been reported in patients with 
hematological malignancies treated with fenebrutinib. The gastrointestinal (GI) bleeding 
events have not been dose related, and the events occurred in patients who were taking 
concomitant non-steroidal anti-inflammatory drugs 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 
platelet function via glycoprotein VI collagen receptor signaling and glycoprotein Ib 
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 of patients with XLA. 
Bruising or bleeding events related to fenebrutinib have not been reported in healthy 
subjects. Grade 2 bleeding events, including hematuria, purpura, hematoma, and 
uterine and vaginal bleeding, have been reported in blinded and open-label studies of 
fenebrutinib in autoimmune indications. 
It is unknown whether fenebrutinib will increase the risk of bleeding in patients, 
especially in those receiving anti-platelet or anti-coagulant therapies. As a precautionary 
safety measure, the parent study protocol has exclusion criteria regarding anti-coagulant 
medications and other risk factors for serious bleeding events. 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 5.2.3.
Guidelines for management of patients who experience bleeding events are provided in
Table 2. 


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5.1.1.4
Cytopenias
Cytopenias, including neutropenia, anemia, and thrombocytopenia, have been observed 
in patients with hematological malignancies who received fenebrutinib.  Events have 
been monitorable and clinically manageable.
Patients should be monitored 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 cytopenia (e.g., persistent fever, 
bruising, bleeding, pallor). Cytopenias should be managed according to local clinical 
guidelines.
5.1.1.5
Gastrointestinal Effects
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 multiple-ascending dose (MAD) Study GA29347 
reported events of mild self-limited nausea.
Throughout the study, patients will be monitored for GI side effects.
Guidelines for management of patients who experience GI events are provided in
Table 2. 
5.1.1.6
Hepatotoxicity
In clinical studies to date in autoimmune indications enrolling over 800 patients, multiple 
cases of treatment emergent Grade 3 (severe) elevations of ALT, some of which were 
considered serious adverse events, have been observed.  Cases have also been 
observed 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 study treatment was withheld.  In addition, there 
have been no observed adverse events of liver enzyme elevation in clinical studies to 
date in healthy subjects or patients with hematological malignancies.  To minimize this 
risk, patients with abnormal liver enzyme and function tests and current liver disease 
were excluded from the parent study. 
Guidelines for the management of patients who develop ALT or AST elevations are 
provided in Table 2.
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. Analysis of 
ECG data from the single-ascending dose 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 throughout this study, with routine 


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monitoring of vital signs (including pulse rate and blood pressure), and routine safety 
ECGs as outlined in the schedule of activities (see Appendix 1).
Guidelines for management of patients who experience cardiovascular events are 
provided in Table 2 and Section 5.1.2.4. 
5.1.1.8
Vascular Inflammation
Drug-induced vasculitis typically involves the skin, but the lung and kidneys may be 
sites of involvement (Radić et al. 2012).  Signs and symptoms associated with 
drug-induced vasculitis can be non-specific and include arthralgia, myalgia, fever, and 
rash (Banks and Freeman 2006; Sharma et al. 2011).  All patients and subjects will be 
monitored during the study for adverse events suggestive of vasculitis as part of routine 
monitoring as outlined in the schedule of activities (see Appendix 1). 
Guidelines for management of patients who develop vasculitis are provided in Table 2. 
5.1.1.9
Malignancy
The impact of BTK inhibition on the development of malignancies is not known; however, 
malignancies have been identified as a potential concern for immunomodulatory agents. 
Malignancies have been reported in patients with XLA, including lymphoreticular
malignancies, gastric and colorectal adenocarcinoma, and squamous cell carcinoma of 
the lung. 
Patients with the history of cancer, including hematologic malignancy and solid tumors, 
were excluded in the parent study. 
All malignancies are adverse events of special interest and should be reported to the 
Sponsor in an expedited manner as outlined in Section 5.2.3.
Guidelines for management patients who develop malignancies are provided in Table 2.
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications
There will be no dose modifications for fenebrutinib in this study.
5.1.2.2
Treatment Interruption
Fenebrutinib treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study drug.  If fenebrutinib has been withheld for 
4 weeks because of toxicity, the patient should be discontinued from the study 
(see Section 4.6.1), unless resumption of treatment is approved following investigator 
discussion with the Medical Monitor.  Fenebrutinib treatment may be suspended for 
reasons other than toxicity (e.g., surgical procedures).  The investigator and the Medical 
Monitor will determine the acceptable length of treatment interruption.


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5.1.2.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 2.  
Additional guidelines are provided in the subsections below.
Table 2
Guidelines for Management of Patients Who Experience Adverse 
Events
Event
Action to Be Taken a
Infection b
Self-limited infections that require 
treatment
Withhold fenebrutinib during antimicrobial therapy
Resume fenebrutinib after consultation with the 
Medical Monitor
Serious infection, opportunistic infection, 
or any infection requiring treatment with 
an IV antimicrobial agent
Permanently discontinue fenebrutinib 
Report event as an adverse event of special interest 
to Sponsor in an expedited manner
Bleeding
Bleeding of moderate 
or greater severity 
Withhold fenebrutinib 
Report event as an adverse event of special interest 
to Sponsor in an expedited manner
Resume fenebrutinib after consultation with the 
Medical Monitor
Serious bleeding or bleeding events 
requiring transfusion, radiologic 
endoscopic, or elective operative 
intervention
Withhold fenebrutinib 
Resume fenebrutinib after consultation with the 
Medical Monitor
Gastrointestinal events
Nausea, vomiting, and/or diarrhea
Continue fenebrutinib
Initiate symptomatic treatment and manage
according to site institutional guidelines.
Consider administration of fenebrutinib with food as 
a possible mitigation strategy.
Malignancy
Non-serious local and resectable basal 
or squamous cell carcinoma of the skin
Continue fenebrutinib
Report event as an adverse event of special interest 
to Sponsor in an expedited manner
Other malignancy
Permanently discontinue fenebrutinib
Report event as an adverse event of special interest 
to Sponsor in an expedited manner
QDonce a day; QTcFQT interval corrected through use of Fridericia’s formula; ULNupper 
limit of normal. 
a Any patient who permanently discontinues fenebrutinib should be followed for safety for 
4 weeks after the last dose of fenebrutinib, if possible.
b Appropriate laboratory investigations, including, but not limited to, cultures should be 
performed to establish the etiology of any serious infection.


 
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Table 2 
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.) 
 
Hepatotoxicity 
AST or ALT 3.0–5.0 × ULN 
• Withhold fenebrutinib  
• Resume fenebrutinib after consultation 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 
• Permanently discontinue fenebrutinib  
• Report event as an adverse event of special interest 
to Sponsor in an expedited manner 
AST or ALT > 5 × ULN 
• Permanently discontinue fenebrutinib  
• Report event as an adverse event of special interest 
to Sponsor in an expedited manner 
Cardiovascular events (for additional information, see Section 5.1.2.4 ) 
Sustained (at least two ECG 
measurements > 30 minutes apart) 
QTcF that is > 500 ms or > 60 ms longer 
than the parent study baseline value 
• Permanently discontinue fenebrutinib unless there is 
a clear alternative cause other than fenebrutinib c 
 
Episode of torsades de pointes or new 
ECG finding of clinical concern 
• Permanently discontinue fenebrutinib unless there is 
a clear alternative cause other than fenebrutinib c 
Vascular inflammation 
Vasculitis 
• Permanently discontinue fenebrutinib 
QD  once a day; QTcF  QT interval corrected through use of Fridericia’s formula; ULN  upper 
limit of normal.  
a Any patient who permanently discontinues fenebrutinib should be followed for safety for 
4 weeks after the last dose of fenebrutinib, 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  fenebrutinib, provided that any ECG 
abnormalities have resolved and the patient is appropriately monitored.  Clinical judgment 
should be applied. 
 
5.1.2.4 
Management of Increases in QT Interval 
Patients who develop any of the following should have study drug discontinued unless a 
clear alternative cause other than fenebrutinib can be identified: 
• 
Sustained (at least two ECG measurements > 30 minutes apart) QTcF that is 
> 500 ms or > 60 ms longer than the parent study baseline value 
• 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 


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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.  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 any arrhythmia.  In 
such a situation, saving all available ECG data is highly suggested.
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.
In rare circumstances, it may be acceptable to resume study drug, provided that any 
ECG abnormalities have resolved and the patient is appropriately monitored.  Clinical 
judgment should be applied.
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) (see Sections 5.3.5.8
and 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline


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
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)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
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 5.3.5.10)

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).


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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 are as follows:

Any serious infection, any infections requiring IV antimicrobials, and any 
opportunistic infections

Bleeding events of moderate or greater severity

Any malignancies

Adverse events of special interest for general drug development
–
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 clinical jaundice, as defined by Hy’s Law (see Section 5.3.5.6)

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 Sections 5.4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 for seriousness criteria), 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.


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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 biopsies, 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 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
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 3 provides guidance for assessing adverse event severity.
Table 3
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 4):

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


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
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 4
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.
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.


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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
Persistent Adverse Events First Reported in Study GS40868
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded 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 
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.
Persistent Adverse Events First Reported in the Parent Study
An adverse event that is ongoing at the end of the parent study will be marked as not 
resolved in the eCRF for that study and will be reopened in this study with the same start 
date, adverse event term, and severity recorded in the parent study. The severity should 
be evaluated by the investigator at the start of this study and updated in the Adverse 
Event Intensity or Grade Changes eCRF if applicable. 


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Recurrent 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., ALP 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 5.3.5.1) 
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 CSU.




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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

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
5.3.5.11
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.  Sites are not expected to review the 
PRO data for adverse events.
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 (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for 
details on reporting requirements)


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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 
Genentech Medical Monitor contact information:
Medical Monitor:
, M.D. (Primary)
Mobile Telephone No.:
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 paper Clinical Trial 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 final 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.
In the event that the EDC system is unavailable, the paper Clinical Trial 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 


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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 final 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 final 
dose of study drug.  A paper 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 final dose of study drug.  A paper 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).
5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately 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).  For 
fenebrutinib, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with fenebrutinib, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.


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
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require two
entries on Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
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 final dose of study drug), 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 paper Clinical Trial 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
6.1
DETERMINATION OF SAMPLE SIZE
No formal sample size calculations were performed for this OLE study.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for 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.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, and self-reported 
race/ethnicity) will be summarized using means, standard deviations, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.


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6.4
SAFETY ANALYSES
The safety analysis population will consist of all patients who received at least one dose 
of study drug. 
Safety will be assessed through descriptive summaries of adverse events and laboratory 
test results.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded.
6.5
EXPLORATORY EFFICACY ANALYSES
The analysis population for the efficacy analyses will consist of all patients enrolled in
this OLE study. Because of the non-comparative nature of the study, no statistical tests 
are planned. Efficacy parameters will be summarized descriptively.  Details will be 
provided in the data analysis plan.
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients with at least one quantifiable plasma 
fenebrutinib concentration.  Individual and mean plasma fenebrutinib concentration data 
will be tabulated and plotted by visit and/or dose level as applicable.  Descriptive 
summary statistics will include the arithmetic mean, median, range, standard deviation, 
and coefficient of variation, as appropriate. 
Additional PK analyses will be conducted as appropriate.
 
 
  
6.8
INTERIM ANALYSIS
No formal interim analysis is planned. Data cuts may be performed at appropriate 
timepoints for inclusion in the submission with the parent study to support evaluation of 
the safety profile.
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.


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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data and other 
additional non-eCRF 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.
PRO and clinician-reported outcome (ClinRO) data will be collected on paper 
questionnaires.  The data from the questionnaires will be entered into the EDC system 
by site staff.
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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review 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, PROs, ClinROs , evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate 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 
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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 7.5.
To facilitate source data verification and review, 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.
7.4
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.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO and ClinRO data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for 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.
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 


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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration 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 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 
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.


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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.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
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.


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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 
, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
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.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.
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 (see definition of end of 
study in Section 3.2).
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.


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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, patients' 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.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored Genentech and will be conducted globally.  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.
9.5
DISSEMINATION 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, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
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 


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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.
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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uginteractionslabeling/ucm093664.htm.
Ferrer M. Immunological events in chronic spontaneous urticaria. Clin Transl Allergy 
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Fiebiger E, Maurer D, Holub H, et al. Serum IgG autoantibodies directed against the 
chain of FcRI: a selective marker and pathogenetic factor for a distinct subset of 
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Hata D, Kawakami Y, Inagaki N, et al. Involvement of Bruton’s tyrosine kinase in 
FcεRI-dependent mast cell degranulation and cytokine production. J Exp Med 
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Iyer AS, Morales JL, Huang W, et al. Absence of Tec family kinases interleukin-2 
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FcεRI-dependent mast cell responses. J Bio Chem 2011;286:950313.
Kay AB, Ying S, Ardelean E, et al. Elevations in vascular markers and eosinophils in 
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Force. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol 
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Kozel MM, Sabroe RA. Chronic urticaria: aetiology, management and current future 
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Luquin E, Kaplan AP, Ferrer M. Increased responsiveness of basophils of patients with 
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Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO guideline for the 
definition, classification, diagnosis and management of urticaria. Allergy 
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Appendix 1  
Schedule of Activities 
Week 
Study Site Visits a Year 1 
Study Site Visits a 
Year 2−End of Study 
UV 
TD c 
SC/ 
4-Week 
SFU d 
1 b
4 
8 
12 
24 
36 
52 
12 
24 
36 
52 
Day 
(Window) 
1 
28 
(± 7) 
56 
(± 7) 
84 
(± 7) 
168 
(± 14) 
252 
(± 14) 
365 
(± 14) 
84 
(± 14) 
168 
(± 14) 
252 
(± 14) 
365 
(± 14) 
(± 14) 
Informed consent 
x 
Inclusion/exclusion criteria 
x 
Concomitant medications e
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs g 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
Weight 
x 
Limited physical examination h 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
ECG i
x 
x 
x 
(x) 
x 
x 
Hematology j
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
Chemistry k
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
Lipid panel 
x 
x 
x 
x 
(x) 
x 
x 
Coagulation l
x 
x 
x 
(x) 
Pregnancy test (urine) women m
x 
Q4W 
(x) 
x 
x 
Urinalysis n 
x 
x 
x 
x 
(x) 
x 
x 
UCT o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
PhyGA-LS p
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
Urticaria Patient Daily Diary q 
x 
x 
x 
x 
Plasma PK sample r 
x 
x 
x 
x 
x 
x 
(x) 
x 
x 
Fenebrutinib administration s
x 
BID 
Fenebrutinib dispensing a 
x 
Q4W 


Appendix 1: Schedule of Activities (Cont.)
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BID  twice a day; CRP  C-reactive protein; CSU  chronic spontaneous urticaria; eCRF  electronic case report form; LDH  lactate dehydrogenase; 
OLE  open-label extension; PK  pharmacokinetics; PRO  patient-reported outcome; PhyGA-LS  Physician's Global Assessment of Disease 
Control-Likert Scale; Q4W  every 4 weeks; SC  study completion; SFU  safety follow-up; TD  treatment discontinuation; UAS  Urticaria Activity 
Score;UAS7  Urticaria Activity Score over 7 days; UCT  Urticaria Control Test; UV  unscheduled visit. 
Note:  (x)  optional/as clinically indicated. 
a Fenebrutinib tablets will be dispensed on site every 4 weeks.  For periods in which study site visits (for assessments) are scheduled > 4 weeks 
apart, patients will be expected to visit site to receive allotment of study drug. 
b All assessments on Day 1 are conducted prior to study drug administration unless otherwise specified.  Activities that were performed at final visit 
of the parent study, if within 3 months prior to Day 1, should not be repeated. 
c Patients who refuse to complete the safety follow-up period should return to the clinic for a treatment discontinuation visit. 
d Patients who discontinue study treatment will be asked to return to the clinic for a safety follow-up visit approximately 4 weeks after the last dose 
of study drug (see Section 4.6.1). 
e Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated treatment from entry into the extension study to the final visit of the 
extension study.  All such medications, including standard-of-care H1-antihistamines for CSU, should be reported to the investigator and recorded 
on the Concomitant Medications eCRF. 
f 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.  After initiation of study drug, all adverse events will be reported until 4 weeks after the final dose of study drug. 
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study drug treatment (see Section 5.6). 
g Includes measurement of pulse rate and systolic and diastolic blood pressure while the patient is in a seated position for at least 5 minutes 
h Limited, symptom-directed physical examination should be performed on Day 1 and as clinically indicated.  Changes in parent study baseline 
abnormalities should be recorded in patient notes.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
i 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).  ECG recordings must be performed 
after the patient has been resting in a supine position for at least 10 minutes.  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.
j Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent and absolute differential counts (neutrophils, bands, 
lymphocytes, monocytes, eosinophils, basophils, other cells). 
k Includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, ALT, AST, LDH, ALP, creatine phosphokinase, CRP, 
lipase, and uric acid.
l Includes INR, aPTT, PT, and fibrinogen. 


Appendix 1: Schedule of Activities (Cont.)
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m For women of childbearing potential:  urine pregnancy tests will be performed locally at specified visits.  The patient will be requested to conduct 
monthly urine pregnancy tests at the site between in-clinic study visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test (performed locally).  . 
n Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
o UCT to be self-administered before the patient receives any information on disease status, prior to the performance of non-PRO assessments,
and prior to study drug administration, unless otherwise specified.
p The PhyGA-LS reflects the investigator’s assessment of the treatment over the previous 4 weeks.  It has the following categories:  no control, little 
control, moderate control, good control, and complete control (see Appendix 4). 
q Patient is to complete the Urticaria Patient Daily Diary twice a day, approximately every 12 hours (morning/evening) through Week 12.  The UAS 
is derived from patient entries in the daily dairy and is used to calculate the UAS7.  The last diary entry may occur the day prior to the Week 12 
visit.
 
 
s Patients will receive the first dose of fenebrutinib at the Day 1 study visit.  Thereafter, fenebrutinib will be self-administered.  Fenebrutinib may be 
taken with or without food.  Patients should be instructed that a missed dose should not be taken with the next scheduled dose. 


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Appendix 2
Urticaria Patient Daily Diary
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 2: Urticaria Patient Daily Diary (Cont.)
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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 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 2: Urticaria Patient Daily Diary (Cont.)
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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 2: Urticaria Patient Daily Diary (Cont.)
Fenebrutinib—Genentech, Inc.
73/Protocol GS40868, Version 1
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 2: Urticaria Patient Daily Diary (Cont.)
Fenebrutinib—Genentech, Inc.
74/Protocol GS40868, Version 1
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—Genentech, Inc.
75/Protocol GS40868, Version 1
Appendix 3
Urticaria Control Test
Patient name: 
Date: (dd mm yyyy): 
Date of birth (dd mm yyyy): 
Instructions:  You have urticaria.  The following questions should help us
understand your current health situation. Please read through each question
carefully and choose an answer from the five options that best fits your situation. 
Please limit yourself to the last 4 weeks.  Please do not think about the questions for a
long time, and do remember to answer all questions and to provide only one answer to
each question.
1. How much have you suffered from the physical symptoms of the urticaria
(itch, hives (welts) and/or swelling) in the last 4 weeks?
O very much       O much           O somewhat           O a little        O not at all
2. How much was your quality of life affected by the urticaria in the last 4 weeks?
O very much       O much           O somewhat           O a little         O not at all
3. How often was the treatment for your urticaria in the last 4 weeks not enough
to control your urticaria symptoms?
O very often        O often             O sometimes          O seldom      O not at all
4. Overall, how well have you had your urticaria under control in the last 4 weeks?
O not at all          O a little           O somewhat           O well            O very well


Fenebrutinib—Genentech, Inc.
76/Protocol GS40868, Version 1
Appendix 4
Physician’s Global Assessment of Disease Control–Likert Scale
(PhyGA-LS)
How would you rate the control of the patient's symptoms within the previous 
4 weeks?
☐no control
☐little control
☐moderate control
☐good control
☐complete control


Fenebrutinib—Genentech, Inc.
77/Protocol GS40868, Version 1
Appendix 5
Cautionary Therapy:  Concomitant Medications (Including Foods and Herbal Products) with 
Specific Drug-Drug Interaction
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
Strong CYP3A 
inhibitors 
Increased fenebrutinib
plasma concentrations 
due to inhibition of 
metabolism
Avoid for 7 days or 
5 drug-elimination half-lives 
(whichever is longer) prior to 
first dose of fenebrutinib and 
during the treatment period
(i.e., until the final dose of 
fenebrutinib)
Antimicrobials (clarithromycin, erythromycin, itraconazole, 
ketoconazole, telithromycin, troleandomycin, voriconazole, 
posaconazole)
Antidepressants (nefazodone)
Antihypertensive/cardiac (verapamil, diltiazem)
Other (grapefruit juice, Seville orange juice, pomegranate, 
star fruit)
Moderate or strong 
CYP3A inducers 
Decreased fenebrutinib
plasma concentrations 
due to increased 
metabolism
Avoid for 7 days or 
5 drug-elimination half-lives 
(whichever is longer) prior to 
first dose of fenebrutinib and 
during the treatment period
(i.e., until the final dose of 
fenebrutinib)
Antimicrobials (rifampin, rifapentine, rifabutin)
Antidepressants (St. John’s wort, hyperforin)
Antiepileptics (carbamazepine, phenytoin, phenobarbital, 
hyperforin)
Diabetes (pioglitazone, troglitazone)
Other (modafinil, bosentan)
a Note that the medications listed below are not necessarily comprehensive.  Consult the prescribing information and refer to the following 
websites for additional information:

U.S. Food and Drug Administration Table of Substrates, Inhibitors, and Inducers (Tables 3-1, 3-2, 3-3, and 5-1):
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm)

Indiana University Department of Medicine P450 Interaction Table:
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table)


Appendix 5: Cautionary Therapy: Concomitant Medications (Including Foods and Herbal Products) (Cont.)
Fenebrutinib—Genentech, Inc.
78/Protocol GS40868, Version 1
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 Note that the medications listed below are not necessarily comprehensive.  Consult the prescribing information and refer to the following 
websites for additional information:

U.S. Food and Drug Administration Table of Substrates, Inhibitors, and Inducers (Tables 3-1, 3-2, 3-3, and 5-1):
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm)

Indiana University Department of Medicine P450 Interaction Table:
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table)


Fenebrutinib—Genentech, Inc.
79/Protocol GS40868, Version 1
Appendix 6
Fenebrutinib Bottle and Label Configuration 
Label to be affixed on the study drug bottle displays morning (sun) and evening (moon)
doses. 
Site will be responsible for prepopulating the dates on the label and affixing the label to 
the bottle.
Patients should record on the label the time in military (24-hour) time of each dose
taken.