Clinical trial NCT02457559
Conditions: Relapsed/Refractory B-cell Malignancies
Sponsor: Gilead Sciences
Start date: 2015-09-10; Completion date: 2020-12-30
Enrollment: 29 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to determine the long-term safety and tolerability of tirabrutinib in adults with relapsed/refractory B-cell malignancy who have tolerated and achieved stable disease or improved with tirabrutinib treatment while enrolled in a prior (parent study) tirabrutinib study (NCT01659255). The dosing regimen will be based on the prior dosing regimen from the parent study.

Detailed description:

Arms: arm 1: Participants with relapsed/refractory chronic lymphocytic leukemia (CLL) received tirabrutinib 40 mg once daily for up to 96 months from first dose in the parent study. arm 2: Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily for up to 96 months from first dose in the parent study. arm 3: Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily for up to 96 months from first dose in the parent study. arm 4: Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily for up to 96 months from first dose in the parent study. arm 5: Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily for up to 96 months from first dose in the parent study. arm 6: Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily for up to 96 months from first dose in the parent study. arm 7: Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily for up to 96 months from first dose in the parent study. arm 8: Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily for up to 96 months from first dose in the parent study. arm 9: Participants with relapsed/refractory non-Hodgkin's lymphoma (NHL) received tirabrutinib 160 mg once daily for up to 96 months from first dose in the parent study. arm 10: Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily for up to 96 months from first dose in the parent study. arm 11: Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily for up to 96 months from first dose in the parent study. arm 12: Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily for up to 96 months from first dose in the parent study.
Interventions: intervention 1: Tirabrutinib
Intervention descriptions: intervention 1: Tablets or capsules administered orally

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
An Open-label Study to Assess the Long-term Safety and 
Efficacy of Tirabrutinib (ONO/GS-4059) in Subjects with 
Relapsed/Refractory B-cell malignancies 
Gilead Sciences, Inc. 
This is a non-IND study 
2015-001404-58 
Relapsed/Refractory B-cell malignancies 
GS-US-401-1787 
Naine: 
Telephone: 
Naine: 
Telephone: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
19 May 2015 
24 J aimary 2017 
12 May 2017 
30 November 2017 
23 J aimary 2019 
29 October 2019 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The infonnation is only to be 
used by you in connection with authorized clinical studies of the investigational drug 
described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain 
infonned consent from those persons to whom the drug may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Tirabrutinib ............................................................................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Tirabrutinib Preclinical Pharmacology and Toxicology.......................................................19
1.2.3.
Clinical Trials of Tirabrutinib ..............................................................................................21
1.3.
Rationale for This Study ........................................................................................................................21
1.4.
Compliance ............................................................................................................................................21
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Endpoints ...............................................................................................................................................23
3.2.
Study Design..........................................................................................................................................23
3.3.
Study Treatments ...................................................................................................................................23
3.4.
Duration of Treatment............................................................................................................................23
3.5.
Criteria for Discontinuation of Study Drug............................................................................................23
3.6.
Source Data............................................................................................................................................24
4.
SUBJECT POPULATION..................................................................................................................................25
4.1.
Number of Subjects and Subject Selection ............................................................................................25
4.2.
Inclusion Criteria....................................................................................................................................25
4.3.
Exclusion Criteria...................................................................................................................................25
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................26
5.1.
Enrollment and Treatment Assignment..................................................................................................26
5.2.
Description and Handling of Tirabrutinib..............................................................................................26
5.2.1.
Tirabrutinib ..........................................................................................................................26
5.3.
Dosage and Administration of Tirabrutinib ...........................................................................................27
5.4.
Prior and Concomitant Medications.......................................................................................................28
5.5.
Accountability for Tirabrutinib ..............................................................................................................28
6.
STUDY PROCEDURES ....................................................................................................................................29
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................30
6.2.
Description of Study Procedures............................................................................................................30
6.2.1.
Written Informed Consent....................................................................................................30
6.2.2.
Recording Medical History ..................................................................................................30
6.2.3.
Medication History...............................................................................................................30
6.2.4.
Physical Examination...........................................................................................................30
6.2.5.
Vital Signs............................................................................................................................30
6.2.6.
Electrocardiogram................................................................................................................31
6.2.7.
Laboratory Assessments.......................................................................................................31
6.2.8.
Pharmacokinetic Samples.....................................................................................................32
6.2.9.
Bone Marrow Examination ..................................................................................................32


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6.4. 
6.5. 
6.6. 
6.7 
Treatment Response Assessment ......................................................................................... 32 
ECOG Performance Status ................................................................................................... 32 
Tumor Imaging CT ............................................................................................................ 32 
Assessments for Premature Discontinuation from Study ....................................................................... 34 
End of Study ........................................................................................................................................... 34 
Tirabrutinib Dose interruption and adjustment ...................................................................................... 35 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 36 
7. I. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 36 
7.1.1. 
Adverse Events ..................................................................................................................... 36 
7 .1.2. 
Serious Adverse Events ........................................................................................................ 36 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 37 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 38 
7 .2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 38 
7 .2.2. 
Assessment of Severity ........................................................................................................ 38 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 38 
7.4. 
Gilead Reporting Requirements ............................................................................................................. 40 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 40 
7.6. 
Toxicity Management ............................................................................................................................ 40 
7.6.1. 
Warnings and Precautions .................................................................................................... 41 
7.7. 
Special Situations Reports ...................................................................................................................... 41 
7.7.1. 
Definitions of Special Situations .......................................................................................... 41 
7.7.2. 
lnstmctions for Reporting Special Situations ....................................................................... 42 
8. 
STATISTICAL CONSIDERA TIONS ................................................................................................................ 44 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
"O. 
8.11. 
Analysis Objectives and Endpoints ........................................................................................................ 44 
8.1.1. 
Analysis Objectives .............................................................................................................. 44 
8.1.2. 
Primary Endpoint ................................................................................................................. 44 
8.1.3. 
Secondary Endpoint ............................................................................................................. 44 
Analysis Sets .......................................................................................................................................... 44 
8.2.1. 
Rollover Analysis Set ........................................................................................................... 44 
8.2.2. 
Full Analysis Set .................................................................................................................. 45 
8.2.3. 
Pharmacokinetics Anal sis Set.. ........................................................................................... 45 
-
Data Hand mg onventtons ................................................................................................................... 45 
Subject Disposition ................................................................................................................................ 45 
Subject Characteristics ........................................................................................................................... 45 
Efficacy Analysis ................................................................................................................................... 46 
Safety Analysis ....................................................................................................................................... 46 
8.7.1. 
Extent of Exposure and Compliance .................................................................................... 46 
8.7.2. 
Adverse Events ..................................................................................................................... 46 
8.7.3. 
Laboratory Evaluations ........................................................................................................ 47 
Pharmacokinetic Anal sis ...................................................................................................................... 48 
amp e tze ............................................................................................................................................ 4 
Data Monitoring Committee .................................................................................................................. 48 
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9.
RESPONSIBILITIES..........................................................................................................................................49
9.1.
Investigator Responsibilities ..................................................................................................................49
9.1.1.
Good Clinical Practice..........................................................................................................49
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................49
9.1.3.
Informed Consent.................................................................................................................49
9.1.4.
Confidentiality......................................................................................................................50
9.1.5.
Study Files and Retention of Records ..................................................................................50
9.1.6.
Case Report Forms...............................................................................................................51
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................52
9.1.8.
Inspections............................................................................................................................52
9.1.9.
Protocol Compliance............................................................................................................52
9.2.
Sponsor Responsibilities ........................................................................................................................52
9.2.1.
Protocol Modifications.........................................................................................................52
9.2.2.
Study Report and Publications .............................................................................................53
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................53
9.3.1.
Payment Reporting...............................................................................................................53
9.3.2.
Access to Information for Monitoring..................................................................................53
9.3.3.
Access to Information for Auditing or Inspections ..............................................................54
9.3.4.
Study Discontinuation..........................................................................................................54
10.
REFERENCES ...................................................................................................................................................55
11.
APPENDICES ....................................................................................................................................................61
Appendix 1.
Investigator Signature Page....................................................................................................62
Appendix 2.
Study Procedures Table..........................................................................................................63
Appendix 3.
Definitions of Response for Waldenstrom’s Macroglobulinemia ..........................................65
Appendix 4.
Modified International Workshop on Chronic Lymphocytic Lymphoma Leukemia 
(IWCLL) Criteria for Response Assessment..........................................................................66
Appendix 5.
Follicular Lymphoma, Marginal Zone Lymphoma, and Small Lymphocytic 
Lymphoma Response Assessment..........................................................................................73
Appendix 6.
ECOG status...........................................................................................................................79
Appendix 7.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................80
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................81
LIST OF IN-TEXT TABLES
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study ...........................................28
Table 6-1.
Analytes..................................................................................................................................31
LIST OF IN-TEXT FIGURES
Figure 1-1.
Inhibition of the BCR Pathway by Tirabrutinib .....................................................................17
Figure 6-1.
Initial Study Procedures .........................................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
An Open-label Study to Assess the Long-term Safety and Efficacy of 
Tirabrutinib in Subjects with Relapsed/Refractory B-cell 
malignancies
IND Number:
EudraCT Number:
This is a non-IND study
2015-001404-58
Study Centers 
Planned:
Initially, 6 sites in the EU will participate in this study; the number of 
sites and countries will be expanded as additional tirabrutinib studies 
are initiated
Objectives:
The primary objective of this study is:

To determine the long-term safety and tolerability of tirabrutinib
in subjects in a prior tirabrutinib study and whose disease had not 
progressed on the parent study 
The secondary objective of this study is: 

To determine the long term efficacy of tirabrutinib
Study Design:
An open-label study for subjects who have tolerated and achieved 
stable disease or have improved with tirabrutinib treatment while 
enrolled in a prior tirabrutinib study 
Number of 
Subjects Planned:
The number of subjects enrolled will be determined by the number of 
subjects who complete a prior tirabrutinib study without disease 
progression, wish to continue therapy with tirabrutinib and meet the 
study entry criteria
Target Population:
Subjects who complete a prior tirabrutinib study without disease 
progression
Duration of 
Treatment:
Subjects will continue on tirabrutinib for a maximum duration of 
5 years from the start of this study.


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Diagnosis and 
Eligibility 
Criteria:
Inclusion Criteria:
1) Currently enrolled in a prior tirabrutinib Study 
2) Did not discontinue treatment with tirabrutinib for any reason 
other than to enroll in this study
3) Eastern Cooperative Oncology Group (ECOG) performance status 
of 0, 1, or 2 at enrollment in this study
4) Any Grade 3 or 4 non-hematologic toxicity that the investigator 
considers related to previous tirabrutinib use must have resolved, 
reverted to Grade 1, or reverted to the baseline of the prior study 
prior to Day 1 of this study
5) Negative serum and urine pregnancy test is required for female 
subjects (unless surgically sterile or greater than 2 years 
post-menopausal)
6) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in Appendix 8.
7) Lactating females must agree to discontinue nursing before the 
study drug is administered
8) Ability and agreement to attend protocol-specified visits at the 
study site
9) Able to comprehend and willing to sign the informed consent 
form
Exclusion Criteria:
1) Known hypersensitivity to tirabrutinib, its metabolites, or 
formulation excipients
Study Procedures/
Frequency:
Procedures performed at a regular follow-up visit on subject’s 
previous tirabrutinib study may be used to fulfill screening criteria 
and to establish any new medical history on this study.
At Day 1, the starting dose of tirabrutinib capsules/tablets will be 
identical to the dose administered in the prior tirabrutinib study. All 
subjects will self-administer tirabrutinib capsules/tablets.


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The initial study procedures to be conducted for each subject enrolled 
in this study are presented in the following figure:
Initial Study Procedures

Steps 1 through 5 may occur on the same or different days, but 
must occur sequentially 

The maximum amount of time allowed from Step 1 to Step 5 is 
30 days 

Results from laboratory assessments and procedures performed up 
to 30 days prior to Step 5 (eg, results from procedures performed 
during the previous study or as part of the subject’s routine care 
[if documentation is available] may be utilized for determining 
eligibility)
Study visits consisting of clinical, laboratory, and disease assessments 
will be completed every 28 days up to Cycle 22, then every 12 weeks. 
All study required laboratory assessments will be performed by a 
laboratory and ECG assessments will be performed and interpreted by 
local departments. Following treatment, subjects will be followed for 
safety and disease status for a period of 30 days.
Test Product, Dose, 
and Mode of 
Administration:
Tirabrutinib oral capsules are brown, opaque, hard capsules and 
contain 10 mg, 25 mg, or 100 mg of tirabrutinib per capsule. 
Tirabrutinib oral tablets are supplied as either 20 mg blue, 
plain-faced, round, film-coated tablets, 80-mg yellow, plain-faced, 
modified capsule-shaped, film-coated tablets or 100 mg white, 
plain-faced, round, film-coated tablets.
The dosing regimen will be once or twice daily based on the prior 
dosing regimen from the parent study. The capsules/tablets are 
packaged in blister packs; the capsule blister packs are also within an 
aluminum foil pouch. The tirabrutinib tablets are also packaged in 
white, high density polyethylene (HDPE) bottles.
Reference Therapy, 
Dose, and Mode of 
Administration:
n/a
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  


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Criteria for 
Evaluation:
Safety: The primary endpoint for this study is safety. Safety will be 
evaluated by the incidence and severity of adverse events (AEs) and 
clinical laboratory abnormalities.
Efficacy: Efficacy endpoints are considered secondary and will 
include:

Overall response rate (ORR): defined as the proportion of subjects 
who achieve partial response (PR) or complete response (CR)

Duration of response (DOR): defined as the interval from 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Progression-free survival (PFS): defined as the interval from date 
of the first dose of tirabrutinib on the parent study to the earlier of 
the first documentation of definitive disease progression or death 
from any cause

Overall survival (OS): defined as the interval from date of the 
first dose of tirabrutinib on the parent study until death from any 
cause.
Pharmacokinetics: The pharmacokinetic (PK) Analysis Set will 
consist of all enrolled subjects who have at least 1 evaluable PK 
sample.
Statistical Methods:
Analysis Methods
The Rollover Study Analysis Set consists of all subjects who are 
enrolled into this study. This analysis set will be used for the 
summary of subject characteristics, disposition, and study drug 
treatment administration.
The Full Analysis Set (FAS) consists of all subjects who are enrolled 
and treated in the parent study. This analysis set will be used for the 
summary of safety and efficacy endpoints. 
Subject characteristics and disposition will be summarized using 
descriptive statistics. In general, continuous variables will be 
summarized by sample size, mean, standard deviation (StD), median, 
minimum, and maximum and categorical variables by counts and 
percentages. Baseline data are defined as the data collected prior to 
dosing on the parent study. 


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Tumor response will be based on investigator assessment. ORR will 
be estimated and its associated 95% confidence interval will be 
calculated using the exact method. All time-to-event endpoints 
(DOR, PFS, and OS) will be analyzed using the Kaplan-Meier 
method. The medians and associated 95% confidence intervals for 
these endpoints will be provided if the medians can be estimated. 
AEs will be summarized by system organ class, high level term, and 
preferred term and by severity and relationship to study treatment. 
Clinical laboratory tests, vital signs, and their changes from baseline 
will be summarized descriptively.
Sample Size
No formal hypothesis testing is planned for this study. The number of 
subjects enrolled will be determined by the number of subjects who
rollover from prior tirabrutinib studies.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
ADME
absorption, distribution, metabolism, elimination
AE
adverse event
ALT
alanine transaminase
AM
morning
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin
AST
aspartate transaminase
AUC
area under the plasma/serum/peripheral mononuclear cell concentration versus time 
curve 
AUC0-last
area under the concentration verses time curve from time 0 to the last quantifiable 
concentrations
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated 
as AUC0-last + (Clast/λz)
AUCτ
area under the concentration versus time curve over the dosing interval 
BCRP
breast cancer resistance protein
BSC
best supportive care
BSEP
bile salt export pump
BUN
blood urea nitrogen
C1D1
Cycle 1 Day 1
CBC
complete blood count
CEA
carcinoembryonic antigen
CFR
Code of Federal Regulations 
CI
confidence interval
Clast
last observed quantifiable plasma concentration of drug
CLL
chronic lymphocytic leukemia
CL/F
apparent oral clearance after administration of the drug:
CL/F= Dose/AUCinf
where “dose” is the dose of the drug
Cmax
maximum observed serum/plasma concentration of drug
CMH
Cochran-Mantel-Haenszel
Conmed
concomitant medication
CR
complete response
CrCL
creatinine clearance
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CRP
c-reactive protein


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CSR
clinical study report
CT
computed tomography/ computed axial tomography scan
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome P450
DDI
drug-drug interaction
DLT
dose limiting toxicity 
DMC
data monitoring committee
DLBCL
diffuse large B-cell lymphoma
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form(s)
EOT
end of treatment
eSAE
electronic serious adverse event
ET
essential thrombocythemia
EudraCT
European clinical trials database
EU
European Union
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
5-FU
5-fluorouracil
FL
follicular lymphoma
GCP
Good Clinical Practice (Guidelines)
GGT
gamma-glutamyl transpeptidase
GLP
Good Laboratory Practice
GSI
Gilead Sciences, Inc.
H
hour
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
IC50
inhibitory concentration 50
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL
interleukin 
IND
Investigational New Drug
INR
international normalized ratio
IMP
investigational medicinal product
IRB
Institutional Review Board


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ITT
intent-to-treat
IUD
intrauterine device(s)
Kg
kilogram
KM
Kaplan-Meier
KRAS
Kirsten rat sarcoma viral oncogene homolog
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MF
myelofibrosis
µM
micromole
msec
millisecond
MRD
maximum recommended dose
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N
number enrolled
NOAEL
no observed adverse effect level
NHL
non-Hodgkin’s lymphoma
OAT
organic anion transporter
OCT
organic cation transporter
OS
overall survival
ORR
overall response rate
PD
progressive disease
PE
physical exam
PFS
progression-free survival
P-gp
permeability glycoprotein
PK
pharmacokinetic
PP
per-protocol
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
PTT
partial thromboplastin time
PV
polycythemia vera
PVE
Pharmacovigilance and Epidemiology
QTc
corrected QT interval
RAF
rapidly accelerated fibrosarcoma
RBC
red blood cell
RECIST
Response Evaluation Criteria In Solid Tumor
RNA
ribonucleic acid
RP2D
recommended phase 2 dose 
SADR
serious adverse drug reaction(s)


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SAE
serious adverse event(s)
SAP
statistical analysis plan
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvate transaminase
SOP
standard operating procedure
STAT
Signal Transducer and Activator of Transcription
StD
standard deviation
SUSAR
suspected unexpected serious adverse reaction(s)
T1/2
an estimate of the terminal elimination half-life of the drug in serum/plasma, calculated 
by dividing the natural log of 2 by the terminal elimination rate constant (z)
Tlast
the time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
TBK1
TANK-binding kinase 1
TTR
time to response
TYK2
tyrosine kinase 2
ULN
upper limit of normal 
WBC
white blood cell
WM
Waldenstrom’s macroglobulinemia
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the serum, plasma concentration of drug versus time curve


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1.
INTRODUCTION
1.1.
Background
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies arising from 
lymphoid tissue, with varied clinical and biological features. In 2008, there were an estimated 
356,000 new cases of NHL and 192,000 deaths from NHL worldwide {Ferlay 2010}. NHL is the 
eighth most commonly diagnosed cancer in men and the 11th in women. Diffuse large B-cell 
lymphoma (DLBCL) is the most common type of NHL accounting for approximately 30% to 
40% of all new patients {Sweetenham 2007}, whereas follicular lymphoma (FL) and mantle cell 
lymphoma (MCL) account for approximately 20% to25% and 6% to10% of new lymphomas, 
respectively {Dreyling 2007}. B-cell chronic lymphocytic leukemia (CLL) is the most common 
of the chronic leukemias in adults with approximately 8500 new cases per year in the 
European Union and the United States (US) {Kristinsson 2009}. Approximately 90% of 
lymphomas are NHL and nearly 95% of NHLs are of B-cell origin; > 90% of CLL is of B-cell 
origin {Morton 2006}. 
B-cell NHL and CLL arise from the accumulation of monoclonal B lymphocytes in lymph nodes 
and often in organs such as blood, bone marrow, spleen, and liver. This group includes 
histopathologic varieties such as FL, MZL, MCL, CLL, small lymphocytic lymphoma (SLL), 
Waldenstrom’s macroglobulinemia (WM), and DLBCL. These disorders are characterized by 
lymphadenopathy, cytopenias, and sometimes induce life-threatening organ dysfunction. Patients 
may also have constitutional symptoms (fevers, night sweats, and/or weight loss) and fatigue 
{Diehl 2004, Dighiero 2008, Salles 2007, Williams 2010}.
Few patients with B-cell malignancies are cured with available therapies. The 3-year 
progression-free survival (PFS) is only 40% with activated B-cell (ABC) DLBCL compared to 
74% with GCB-DLBLC. For patients who are refractory to primary therapy or progress and are 
not transplant candidates, few therapeutic options exist {Roschewski 2014}. For patients with 
the indolent B-cell malignancies, such as iNHL (FL and MZL), MCL, CLL, SLL, and WM, the 
goal of first and subsequent line therapies is to induce tumor regression and delay tumor 
progression in order to control disease-related complications and potentially extend life. Patients 
who require treatment are commonly given chemotherapeutic and/or immunotherapeutic agents 
{Eichhorst 2010, Friedberg 2011, Gribben 2011, Hoppe 2008, Jost 2007, Zelenetz 2011}. 
Although patients with iNHL and CLL can achieve durable remissions with front-line 
combination therapies, most patients will eventually experience disease relapse {Hallek 2010, 
Lenz 2005, Recher 2011, Santoro 1987, Schulz 2007}. Despite use of agents with differing 
mechanisms of action, progressive resistance to treatment develops. {Di Bella 2010, Friedberg 
2011, Goy 2009, Hess 2009, Keating 2002, Moskowitz 2009, Wierda 2010}.


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1.2.
Tirabrutinib
1.2.1.
General Information
Tirabrutinib (also known as GS-4059, ONO/GS-4059, ONO-4059HCL, ONO-1973, and 
ONO-WG-307) is a potent small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is 
being jointly developed by Gilead Sciences, Inc. (Gilead) and Ono Pharmaceutical Co, Ltd. 
(ONO) for oral administration in the treatment of B-cell malignancies. 
BTK was originally identified in 1993 as a non-receptor intracellular protein tyrosine kinase that 
is defective in the inherited immunodeficiency disease X-linked agammaglobulinaemia (XLA) 
{Tsukada 1993, Vetrie 1993}. XLA is characterized by low levels of immunoglobulin 
production and the absence of peripheral B cells, indicating a specific role for BTK in B-cell 
development and function. BTK is a member of the TEC family of tyrosine protein kinases. BTK 
is primarily expressed in hematopoietic cells, particularly in B cells, but not in plasma cells or 
T cells {de Weers 1993, Genevier 1994, Smith 1994}. BTK is also found in specific cells of the 
myeloid lineage, including monocytes, macrophages, neutrophils, and mast cells, where its 
biological role remains to be fully explored. 
BTK plays a crucial role in the development and activation of B cells through its activation via 
the B-cell receptor (BCR) {Aoki 1994, Hendriks 2014, Honigberg 2010}. Signaling through the 
BCR regulates cellular proliferation and activation and promotes survival, differentiation, and 
clonal expansion of B cells (Figure 1-1) {Rickert 2013}. In addition to BCR signaling, BTK is 
activated by Toll-like receptors (TLR) which contribute to B-cell activation {Jefferies 2003}. 
BTK also plays a critical role in signaling pathways triggered by the C-X-C chemokine receptor 
type 4 and type 5 (CXCR4 and CXCR5) which mediate homing of B cells to lymph nodes and 
bone marrow and control integrin-mediated adhesion and B-cell survival to vascular adhesion 
molecule 1 (VCAM1) and fibronectin {de Rooij 2012, Hendriks 2014}.
Signaling through the BCR has been established as a key oncogenic driver in many B-cell 
malignancies, including (CLL, SLL, ABC-DLBCL, MCL, and WM). A first in class BTK 
inhibitor, ibrutinib (Imbruvica®), has demonstrated clinical benefit to patients with CLL, MCL 
and WM {Pharmacyclics Inc. 2015}. Additionally, transient clinical responses were observed in 
a pilot study of relapsed DLBCL, primarily in the non-GCB subtype {Wilson 2012}. 
Tirabrutinib is an orally administered, potent and selective inhibitor of BTK initially evaluated in 
a Phase 1 single agent dose escalation study, ONO-4059POE001, conducted in the United 
Kingdom (UK) and France. This study is completed and has enrolled and treated 90 subjects 
with relapsed CLL, non-GCB DLBCL, MCL, SLL, and other indolent non-Hodgkin’s 
lymphomas (iNHLs). Tolerability and efficacy were demonstrated in subjects with CLL at doses 
ranging from 40 to 600 mg once daily with no maximum tolerated dose (MTD) identified. 
Responses were observed in subjects in the NHL cohort at doses from 40 to 480 mg. Dose 
limiting toxicities (DLTs) of rash and non-immune reaction were observed at 600 mg once daily 
in the NHL cohort.


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Additional adverse events (AEs) have been observed during Study ONO-4059POE001, 
including: hematological disorders such as neutropenia, anemia, and thrombocytopenia; bleeding 
disorders such as petechiae, purpura, and hemorrhage; pyrexia and concomitant infections; 
gastrointestinal disturbances such as nausea, diarrhea, and abdominal pain; rash and irritation 
such as acne, urticarial, petechial or purpuric rash, dry skin, pruritus, and eye pruritus; asthenia; 
and fatigue. The most commonly reported serious adverse events (SAEs) were infections. Please 
refer to the current edition of the tirabrutinib Investigator’s Brochure (IB) for additional safety
information.
Another BTK inhibitor, ibrutinib, which is approved in the US for CLL, MCL, and WM, has 
identified warnings and precautions for hemorrhagic events, infections, cytopenias, atrial 
fibrillation, second primary malignancies including skin cancers and other carcinomas, tumor 
lysis syndrome, and embryo-fetal toxicity. The most common AEs observed with ibrutinib in 
patients with B-cell malignancies were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, 
musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. As these 
reported events may be related to target BTK inhibition, clinical trial subjects will be monitored 
for these events


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Figure 1-1.
Inhibition of the BCR Pathway by Tirabrutinib
Adapted from Herrera and Jacobsen (2014) {Herrera 2014}
Chronic Lymphocytic Leukemia
Signaling through BTK plays a key role in the maintenance of CLL as demonstrated by the 
efficacy achieved in CLL by ibrutinib, a first in class BTK inhibitor {Byrd 2014}. In a Phase 3 
trial in relapsed or refractory CLL or SLL, ibrutinib-treated patients experienced a rapid and 
sustained decrease in lymphadenopathy accompanied by lymphocytosis, suggesting that CLL 
cells are mobilized from lymphoid tissue to blood. CLL cells from the blood, bone marrow, and 
lymph nodes of patients treated with ibrutinib show reduced proliferation and expression of 
NF-κB regulated genes and surface activation markers such as CD69 and CD86 {Herman 2014}. 
Ibrutinib (Imbruvica®) is approved in the US for the treatment of CLL in patients who have 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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received at least one prior therapy and for patients with 17p deletion based on an overall 
response rate (ORR) of 42.6% and improved PFS and overall survival (OS) compared to 
ofatumumab {Pharmacyclics Inc. 2015}. In Study ONO-4059POE001, with a median follow-up 
of 26.4 months, tirabrutinib demonstrated an ORR of 85.7% (n  28); 7 subjects (25.0%) had a 
complete response (CR), and 17 subjects (60.7%) had a partial response (PR). The Kaplan Meier 
(KM) estimate of median duration of response (DOR), median progression-free survival (PFS) 
and median overall survival (OS) was not reached.
Diffuse Large B-Cell Lymphoma
At present there are no approved drugs for relapsed refractory DLBCL in patients who are 
not candidates for high dose combination chemotherapy and stem cell transplant. 
National Comprehensive Cancer Network (NCCN) Guidelines recommend either a clinical trial, 
palliative radiation therapy or 1 of the following options with or without rituximab:
bendamustine, CEPP (cyclophosphamide, etoposide, procarbazine, prednisone), CEOP 
(cyclophosphamide, etoposide, vincristine, prednisone), DA-EPOCH (dose adjusted etoposide, 
prednisone, vincristine, cyclophosphamide, doxorubicin), GDP (gemcitabine, dexamethasone, 
cisplatin), Gem-Ox (gemcitabine, oxaliplatin), or lenalidomide {National Comprehensive Cancer 
Network (NCCN) 2015}. ORRs with these regimens in this patient population range from 28%
to 63%, with median PFS of 3 to 7 months. The activated B-cell (ABC) -DLBCL subtype, 
identified by gene expression profiling has been identified retrospectively as a poor prognostic 
indicator for PFS and OS for patients treated with first line rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone (R-CHOP) chemotherapy, although not at the time of 
relapse, when all patients have a poor prognosis {Lenz 2008}. 
ABC-DLBCL cells are dependent on NF-κB signaling for survival and proliferation {Davis 
2010}. The sensitivity of ABC-DLBCL to NF-κB inhibition can be explained by the chronic 
activation of BCR and/or TLR signaling mediated in 50% of cases by activating mutations in 
components of the BCR such as CD79B (18% of ABC-DLBCL) or myeloid differentiation 
primary response 88 (MYD88) (29% of ABC-DLBCL) and caspase recruitment domain family, 
member 11 (CARD11) (10% of ABC-DLBCL). Inhibition of BTK inhibits proliferation and 
induces apoptosis in a subset of ABC-DLBCL; tirabrutinib and ibrutinib have demonstrated 
evidence of short-term efficacy in the relapsed setting in the non-GCB DLBCL subgroup 
(41% ORR [12/29] with ibrutinib and ORR 41% [7/17] with tirabrutinib). Median PFS was short 
with both inhibitors, at approximately 4 months. 
Mantle Cell Lymphoma
MCL is a rare type of B-cell non-Hodgkin’s lymphoma (approximately 6% of NHL) which, at 
presentation, can be indolent or aggressive. Cure is uncommon and there is no standard front-line 
regimen, although common therapies are rituximab, cyclophosphamide, doxorubicin, vincristine, 
dexamethasone (R-HyperCVAD), variations on R-CHOP, rituximab-bendamustine, and the 
Nordic regimen {Geisler 2008}. Consolidation with autologous transplant in first remission may 
prolong PFS. If and when patients relapse, the goal of therapy is similar to the other relapsed 
B cell malignancies; to induce tumor regression and delay tumor progression in order to control 
disease-related complications and potentially extend life. Options at relapse include ibrutinib, 


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bortezomib, rituximab-bendamustine, and lenalidomide. Similar to CLL, a large proportion of 
cells from patients with MCL, harbor a stereotypic BCR repertoire, indicating a crucial role for 
BCR stimulation in this disease {Hadzidimitriou 2011}. In addition, constitutive activation of 
NF-κB and the PI3K pathways is observed in MCL, reflecting chronic activation of BCR, TLR, 
and/or tumor necrosis factor receptors (TNFR) in this disease {Colomer 2014, Jares 2012}. 
Ibrutinib is approved for use in patients with MCL who have received at least 1 prior therapy, 
based on an ORR of 65.8% (complete responses [CR] 17.1%) and median PFS of 13.9 months 
{Wang 2013}. In Study ONO-4059POE001, tirabrutinib demonstrated a similar ORR in a small 
number of subjects; (60% [6/10]). 
Waldenstrom’s Macroglobulinemia
In WM, activating mutations in MYD88 are prevalent (67% to 100% of cases), leading to 
constitutive activation of BTK and NF-κB downstream of TLR {Treon 2012, Yang 2013}. In 
WM cell lines and primary cells, ibrutinib, reduced NF-κB activation and triggered apoptosis. 
Ibrutinib is approved for use in WM with a reported ORR of 61.9% (39/63) without any CRs, 
and duration of response (DOR) ranging from 2.8 to 18.8 months {Pharmacyclics Inc. 2015}. In 
Study ONO-4059POE001, 1 of 2 subjects with WM responded to tirabrutinib.
For further information on tirabrutinib, refer to the current edition of the tirabrutinib IB.
1.2.2.
Tirabrutinib Preclinical Pharmacology and Toxicology
1.2.2.1.
Nonclinical Pharmacology
Primary pharmacology studies in enzyme-based and cell-based systems indicate that tirabrutinib
is a potent inhibitor of BTK. BTK inhibition by tirabrutinib resulted in inhibition of proliferation 
and survival in ABC-DLBCL and MCL-derived cell lines, and in primary cells from CLL 
subjects. 
Tirabrutinib is a potent and selective inhibitor of BTK relative to 3 other non-receptor tyrosine 
kinases which function in B-cell and T-cell activation: human FYN, LCK, and LYNa. The IC50
values of tirabrutinib against recombinant human BTK, FYN, LCK, and LYNa were 2.10, 2220, 
788, and 3490 nM, respectively, demonstrating tirabrutinib to be 1060-, 375-, and 1660-fold 
more selective for BTK relative to FYN, LCK, and LYNa, respectively. Selectivity was also 
demonstrated by evaluating the binding affinity (Kd) of tirabrutinib for BTK, BLK, BMX, CSK, 
ERBB2, HUNK, LCK, MAP2K5, RIPK2, TEC, and TXK. tirabrutinib was demonstrated to be
21- to > 3500-fold more selective for BTK than for other kinases that are structurally or 
functionally related, with the exception of similar binding affinity to the tyrosine-protein kinase 
TEC.
Tirabrutinib demonstrated in vitro cellular activity on BTK autophosphorylation in human 
B lymphocytes from peripheral blood monocyte cells and whole blood in ABC-DLBCL-derived 
cell lines. The maximum inhibitory activity and potency of tirabrutinib increased with length of 
exposure and decreased after 24 hours following washout of tirabrutinib from the media. The 
in vitro inhibitory activity of tirabrutinib on 2 ABC-DLBCL lymphoma cell lines, TMD-8 and 
U-2932 demonstrated inhibition of P-BTK in a dose dependent manner.


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These data collectively demonstrate that tirabrutinib is a potent inhibitor of BTK tyrosine kinase 
activity in primary human B lymphocytes from peripheral blood mononuclear cells and in 
ABC-DLBCL-derived cell lines.
For further information on tirabrutinib, refer to the current edition of the IB.
1.2.2.2.
Absorption, Distribution, Metabolism and Elimination (ADME)
The bioavailability of tirabrutinib was 15.5% following a single oral administration of 
tirabrutinib at 5 mg/kg to fasted male rats. Following repeated oral daily administration of 
tirabrutinib for 28 days to non-fasted male rats, the maximum observed concentration (Cmax) and 
area under the concentration-time curve from time 0 to 24 h (AUC24h) increased proportionally 
with doses ranging from 3 to 100 mg/kg/day. There was no obvious accumulation of tirabrutinib
after 28 days repeated dosing. 
Following a single oral administration of [14C]-ONO-4059HCL at 5 mg/kg to fasted male rats, 
the radioactivity concentrations in several tissues were 2.1 to 26 fold that found in plasma at 
0.5 h post-dose with radioactivity concentrations decreasing in all tissues to 7.0% of Cmax or 
lower by 168 h post-dose. The elimination half-life (t1/2) of the radioactivity in the eyeball in 
pigmented rats (130 h) was longer than that in albino rats (79 h), suggesting that tirabrutinib or 
its metabolites binds to melanin. The primary binding protein of tirabrutinib in human serum is 
albumin; protein binding of [14C]-ONO-4059HCL at 0.5μg/mL in rat, monkey, and human serum 
was 98.2%, 90.7%, and 92.3%, respectively. 
Species differences were observed in the main metabolites in in vitro metabolism analysis; 
however, all metabolite peaks detected in cultured human hepatocytes were also detected in 
cultured hepatocytes of rat or monkey. The primary cytochrome P450 (CYP) iso-form 
responsible for tirabrutinib metabolism is CYP3A4/5, but CYP2D6 also metabolizes tirabrutinib
though to a lesser degree. Tirabrutinib is not a CYP inducer. Tirabrutinib inhibited CYP2C8, 
2C9 and 2C19, the respective inhibition constant (Ki) values were 7.02, 8.31, and 14.4μmol/L. 
Tirabrutinib resulted in mechanism based inhibition of CYP3A4/5 at 10μmol/L. Tirabrutinib is a 
P-glycoprotein (P-gp) substrate, whereas tirabrutinib inhibited human P-gp with an IC50 value of 
26.8μmol/L. In addition, tirabrutinib showed inhibitory potential for several other transporters 
including OAT3, OATP1B1, MATE1, OCT1, and OCT2.
Refer to the tirabrutinib IB for additional information.
1.2.2.3.
Nonclinical Toxicology
In the single dose toxicity studies in rats and monkeys, doses of tirabrutinib ranged from 1 to 
2000 mg/kg and 1 to 1000 mg/kg, respectively. The lethal dose was 2000 mg/kg in rats and 
1000 mg/kg in monkeys. In the 4-week repeated oral dose toxicity studies, 8/44 mortalities at
1000 mg/kg/day were observed in rats. These 8 rats showed spontaneous activity decrease along 
with bradypnea, stool volume decrease, lacrimation and a severe body weight decrease. At 
100 mg/kg/day in monkey, one animal was moribund. This single monkey exhibited 
somnolence, ataxia and prone position before showing moribund condition. The primary target 
organs of tirabrutinib were pancreas islets at doses of 10 mg/kg/day or higher in rats and CNS 


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effects at 100 mg/kg/day in monkeys. In the 4-week repeated oral dose toxicity study in rats, 
fibrosis of the centre/periphery of the pancreatic islets was observed at doses at 10 mg/kg/day or 
higher as well as eosinophilic changes and hypertrophy of the hepatocytes, hypertrophy of the
zona fasciculate and glomerulosa cells accompanied with an increase in lipid in the adrenal at 
doses 100 mg/kg/day or higher.
In the 4-week repeated oral dose toxicity study in monkeys, Berlin blue staining positive
pigment-laden macrophages in the medullary sinus were observed at 3 mg/kg/day or higher as 
well as angiectasis and/or haemorrhage in pancreatic islets and lobules at 10 mg/kg/day or 
higher. Surviving animals at 100 mg/kg/day showed CNS effects which were weaker than that of 
moribund animal. The no observed-adverse-effect-levels (NOAEL) in rats and monkeys are 
estimated to be 3 mg/kg/day and less than 3 mg/kg/day, respectively. The severe toxic dose in 
10% (STD 10) in rats and the highest non-severe toxic dose (HNSTD) in monkeys were 
determined to be 600 mg/kg/day and 30 mg/kg/day, respectively.
A more detailed summary of findings from studies in rats and dogs is available in the IB for 
tirabrutinib.
1.2.3.
Clinical Trials of Tirabrutinib
As of 1 October 2017, 6 clinical studies of tirabrutinib are ongoing.
Updated clinical information regarding completed and ongoing clinical studies may be found in 
the tirabrutinib IB.
1.3.
Rationale for This Study
Based on the analysis of Study ONO-4059POE001, subjects obtained a clinical benefit from 
treatment with tirabrutinib as demonstrated by response rate. As of the completion of the study, 
86% of CLL subjects and 39% of NHL subjects demonstrated an objective response.
Tirabrutinib appears to have been well tolerated overall and with prolonged administration in 
Study ONO-4059POE001. 
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To determine the long-term safety and tolerability of tirabrutinib in subjects in a prior 
tirabrutinib study and whose disease had not progressed on the parent study 
The secondary objective of this study is: 

To determine the long term efficacy of tirabrutinib


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3.
STUDY DESIGN
3.1.
Endpoints
The endpoints of this study are described in Section 8.
3.2.
Study Design
This study is an open-label rollover study for subjects who have tolerated and achieved stable 
disease or improved with tirabrutinib treatment while enrolled in a prior tirabrutinib study.
3.3.
Study Treatments
Subjects who meet eligibility criteria will receive a single dose of tirabrutinib on Study Day 1 
(Cycle 1, Day 1). Each cycle will consist of 28 days of therapy. If there is no evidence of disease
progression by clinical assessment or by CT (or MRI), a subject may continue receiving 
tirabrutinib until disease progression (clinical or radiographic), unacceptable toxicity, withdrawal
of consent, or other reasons specified in Section 3.5.
In subjects who have a tumor flare after the discontinuation of therapy or are at a high risk of 
such an event, treatment may be reinstituted or continued following progression until initiation of 
subsequent therapy.
3.4.
Duration of Treatment
Subjects will continue on tirabrutinib for a maximum duration of 5 years from the start of this 
study. After discontinuation of treatment, subjects will be followed for safety for 30 days.
3.5.
Criteria for Discontinuation of Study Drug
Study medication may be discontinued in the following instances:

Documented progression of malignant disease

Pregnancy

Investigator discretion

Non-compliance with study drug

Initiation of other anti-cancer or experimental therapy

Protocol violation

Withdrawal of consent


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
Lost to follow-up

Study termination by the sponsor

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol 
(Section 7.6), or toxicity that, in the judgment of the investigator, compromises the ability to 
continue study-specific procedures or is considered to not be in the subject’s best interest
3.6.
Source Data
The subject identification numbers assigned by the Sponsor or captured by the interactive 
voice/web response system (IXRS) will be considered source data. 


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
All subjects enrolled in a prior tirabrutinib study who are still alive and have not had disease 
progression may be eligible to participate in this extension study.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Currently enrolled in a prior tirabrutinib study 
2) Did not discontinue treatment with tirabrutinib for any reason other than to enroll in this 
study
3) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at enrollment 
4) Any Grade 3 or 4 non-hematologic toxicity that the investigator considers related to previous 
tirabrutinib use must have resolved, reverted to Grade 1 or reverted to the baseline of the 
prior study prior to Day 1 of this study
5) Negative serum and urine pregnancy test is required for female subjects (unless surgically 
sterile or greater than 2 years post-menopausal)
6) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in
Appendix 8.
7) Lactating females must agree to discontinue nursing before the study drug is administered
8) Ability and agreement to attend protocol-specified visits at the study site
9) Able to comprehend and willing to sign the informed consent form
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Known hypersensitivity to tirabrutinib, the metabolites, or formulation excipient


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible for the study prior to 
enrollment. Subjects will be assigned a unique screening number at the time of consent.
An interactive web response system (IWRS) will be employed to manage the conduct of the trial. 
The IWRS will be used to maintain a central log documenting screening and enrollment, to
manage dose modifications, to assess current inventories of study drug, to initiate any necessary
resupply of study drug, and to document discontinuation of treatment.
Once eligibility is confirmed subjects will be assigned a unique subject number. This is an 
open-label study.
All baseline tests and procedures must be completed prior to the administration of the first dose 
of tirabrutinib on Day 1. Once a subject number is assigned to a subject, it will not be reassigned 
to another subject.
5.2.
Description and Handling of Tirabrutinib
5.2.1.
Tirabrutinib
5.2.1.1.
Formulation
Tirabrutinib capsules are brown, opaque hard HPMC capsules. Each capsule contains the 
equivalent of 10 mg, 25 mg, or 100 mg tirabrutinib as the hydrochloride salt (GS-4059-01). The 
capsules contain the following inactive ingredients: microcrystalline cellulose, and magnesium 
stearate. Each capsule shell contains carrageenan, potassium chloride, titanium dioxide, red iron 
oxide, and hypromellose.
Tirabrutinib film-coated tablets, 20 mg, contain the equivalent of 20 mg tirabrutinib as the
hydrochloride salt (GS-4059-01). The 10% drug load formulation tablet is a blue, plain-faced,
round, film-coated tablet. The tirabrutinib film-coated tablets, 20 mg, contain the following
inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal
silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol,
talc, and FD&C blue #2/indigo carmine aluminum lake.
Tirabrutinib film-coated tablets, 80 mg, contain the equivalent of 80 mg tirabrutinib as the
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is a yellow, plain-faced,
modified capsule-shaped, film-coated tablet. The tirabrutinib film-coated tablets, 80 mg, contain 
the following inactive ingredients: lactose monohydrate, microcrystalline cellulose,
crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide,
polyethylene glycol, talc, and iron oxide yellow.


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Tirabrutinib film-coated tablets, 100 mg, contain the equivalent of 100 mg tirabrutinib as the 
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is a white, plain-faced, 
round, film-coated tablet. The tirabrutinib film-coated tablets, 100 mg, contain the following 
inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal 
silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, 
and talc.
5.2.1.2.
Packaging and Labeling
Tirabrutinib (ONO/GS-4059) capsules, 10 mg, 25 mg, and 100 mg are packaged in polyvinyl 
chloride (PVC) blisters with aluminum foil lidding and placed within an aluminum foil pouch.
Tirabrutinib (ONO/GS-4059) tablets 20 mg and 100 mg are packaged in blister strips made of 
polyvinyl chloride/ polychlorotrifluoroethylene (Aclar) film and have aluminum foil lidding 
materials that are then placed in a blister card. 
Tirabrutinib (GS-4059) tablets 80 mg and 100 mg are also packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets, silica gel desiccant and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant 
polypropylene screw cap with an induction sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products, Feb. 2010), and/or other local regulations.
5.2.1.3.
Storage and Handling
Tirabrutinib packaged drug product should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25C (77F); excursions 
are permitted between 15C and 30C (59F to 86F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling tirabrutinib.
5.3.
Dosage and Administration of Tirabrutinib
Tirabrutinib capsules/tablets will be provided by Gilead and will be taken orally. Initiation of 
treatment with the study drug will take place after enrollment and cohort assignment. Subjects 
will self-administer tirabrutinib capsules 10 mg, 25 mg, or 100 mg capsules or tirabrutinib tablets 
20 mg, 80 mg or 100 mg orally once or twice daily from prior dosing regimen on parent study.
To reduce variability in drug absorption, subjects will be instructed to take tirabrutinib at least
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If the subject misses a dose, he/she should be instructed to take the study drug as soon as he/she 
remembers, unless more than 8 hours has elapsed since the scheduled time of the missed dose. In 
this case, the subject should be instructed to wait and take the next dose at the regularly 
scheduled time. 
5.4.
Prior and Concomitant Medications
In vitro data indicate tirabrutinib is a substrate of CYP3A4. Co-administration of CYP3A4 
inhibitors may increase tirabrutinib exposure. However, preliminary PK data from Study 
GS-US-401-1757 demonstrate that idelalisib, a CYP3A4 inhibitor, does not cause a clinically 
relevant increase in tirabrutinib exposure, indicating tirabrutinib is not a sensitive CYP3A4 
substrate. As such, co-administration of strong CYP3A4 inhibitors is allowed in this study, but 
caution should be exercised. Co-administration of the strong CYP3A4 and P-gp inducer rifampin 
resulted in a significant decrease in tirabrutinib exposure (~70%). As such, potent CYP3A4 and 
P-gp inducers are prohibited while subjects are receiving tirabrutinib and ≥2 weeks prior to 
study drug administration. Examples of strong CYP3A4 and P-gp inducers are provided in the 
Table 5-1. 
In vitro data indicate tirabrutinib has the potential to inhibit several CYPs and transporters. 
Therefore, tirabrutinib may affect the plasma concentrations of their substrates. Caution should 
be exercised when co-administering concomitant medications that are metabolized by CYP3A4/5 
and transported by OAT3, OATP1B1, MATE1, OCT1, OCT2, or P-gp. 
Examples of strong CYP3A4/P-gp inducers are provided in Table 5-1.
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study
Strong
CYP3A4/P-gp Inducer
carbamazepine, phenytoin, rifampin, St. John’s Wort, enzalutamide rifabutin, 
phenobarbital, mitotane, avasimibe
5.5.
Accountability for Tirabrutinib
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Tirabrutinib accountability records will be provided to each study site to:

Record the date received and quantity of tirabrutinib

Record the date, subject number, subject initials, the tirabrutinib blister number dispensed

Record the date, quantity of used and unused tirabrutinib returned, along with the initials of 
the person recording the information.
The methods of tirabrutinib return and destruction are described in Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Procedures performed at a regular follow-up visit on subject’s previous tirabrutinib study may be 
used to fulfill screening criteria and to establish any new medical history on this study.
At Day 1, the starting dose of tirabrutinib capsules/tablets will be identical to the dose 
administered in the prior tirabrutinib study. All subjects will self-administer tirabrutinib
capsules/tablets.
The initial study procedures to be conducted for each subject enrolled in the study are presented
in Figure 6-1.
Figure 6-1.
Initial Study Procedures

Steps 1 through 5 may occur on the same or different days, but must occur sequentially

The maximum amount of time allowed from Step 1 to Step 5 is 30 days 

Results from laboratory assessments and procedures performed up to 30 days prior to Step 5
(eg, results from procedures performed during the previous study or as part of the subject’s 
routine care [if documentation is available] may be utilized for determining eligibility) 
Study visits consisting of clinical, laboratory, and disease assessments will be completed every 
28 days up to Cycle 22, then every 12 weeks. All study required laboratory assessments will be 
performed by a local laboratory and ECG assessments will be performed and interpreted by local 
departments. Following treatment, subjects will be followed for safety and disease status for a 
period of 30 days.
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  


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6.1.
Subject Enrollment and Treatment Assignment
A subject will be considered enrolled once enrolled in IXRS. It is the responsibility of the 
investigator to ensure that each subject is eligible for the study before enrollment. Details 
regarding treatment assignment and dosing are provided in Section 5.3.
6.2.
Description of Study Procedures 
During the treatment period, all visits may be performed within the specified window for that 
study visit (see Appendix 2).
6.2.1.
Written Informed Consent
All subjects must personally sign and date the institutional review board / independent ethics 
committee (IRB/IEC) approved informed consent form before any study procedures are 
performed (Section 9.1.3).
6.2.2.
Recording Medical History
Medical history from the previous study will not be reported in the electronic case report form 
(eCRF) for this study. Any ongoing AE from the previous study at the time of enrollment in this 
study will be considered medical history on this study and should be reported in the eCRFs and 
followed to resolution.
6.2.3.
Medication History
A current list of ongoing medications will be obtained prior to enrollment and recorded on the 
eCRF.
6.2.4.
Physical Examination
The Investigator or qualified designee will perform a physical examination at Screening and time 
points outlined in the Study Procedures Tables (Appendix 2). Screening and End of Treatment 
will be a complete physical examination. Beginning at Cycle 1 Day 1, a modified physical 
examination will be a performed to monitor for any changes (eg, lymph nodes, lung, cardiac, 
abdomen, skin, neurologic, and any systems, as clinically indicated). Abnormal findings prior to 
first dose of study treatment will be reported on the medical history page of the eCRF. Any 
changes from the prior to first dose of study treatment baseline physical examination which 
represent a clinically significant deterioration will be documented on the AE page of the eCRF.
Weight (without shoes) should be measured with each physical examination.
Height (without shoes) should be measured at Screening only.
6.2.5.
Vital Signs
Vital signs will include pulse, systolic and diastolic blood pressure, and body temperature. They 
should be collected per institutional guidelines.


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6.2.6.
Electrocardiogram
Twelve (12) lead ECGs will be obtained at the time points outlined in the Study Procedures 
Tables (Appendix 2). Subjects should be resting quietly for 5 minutes prior to ECG collection.
The Investigator or qualified designee will review all ECGs. The ECG tracings will be 
maintained in the source documentation of each subject and the appropriate data reported on the 
eCRF. 
6.2.7.
Laboratory Assessments
All samples collected in this study for laboratory assessments will be sent to local laboratories
with the exception of urine pregnancy test which may be completed at the site. Screening 
laboratory samples should be obtained within 30 days prior to the first dose of tirabrutinib taken 
on this study.
The local laboratory will be responsible for chemistry, CBC, coagulation, urinalysis, and serum 
pregnancy testing per Table 6-1. Any samples collected per the Schedule of Assessments 
(Appendix 2) may be analyzed for any tests necessary to ensure subject safety. The date and time 
of sample collection will be reported to the local laboratory.
Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology and Coagulation
Other Analytes
Albumin
Alkaline phosphatase
ALT
AST
Amylase
Bicarbonate
BUN
Calcium
Chloride
Creatininea
GGT
Glucose
LDH
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total protein
Uric acid
Color and appearance
Specific gravity
pH
Occult blood
Protein
Glucose
Bilirubin
Leukocyte esterase
Ketones
Nitrite
Urobilinogen
Microscopicc
Urine beta hCGb
Hematology
RBC
Hemoglobin
Hematocrit
Platelets
WBC
Differential
Neutrophils
Bands
Eosinophils
Basophils
Lymphocytes
Monocytes
% blasts
ANC
Coagulation
PT (INR)
PTT
Serum beta hCGb
Total IgA, IgG, IgM 
Immunoglobulin 
electrophoresis
ALT  alanine aminotransferase; AST  aspartate aminotransferase; BUN  blood urea nitrogen; 
GGT
gamma glutamyl transpeptidase; LDH  lactate dehydrogenase; PT  prothrombin time; 
PTT
partial thromboplastin time; RBC  red blood cell; WBC  white blood cell; hCG human chorionic gonadotropin
Note: Additional components, abnormal, and/or atypical cells will also be reported if present
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft Gault formula
b
If applicable, serum and urine pregnancy test should be obtained
c
Reflex testing based on other abnormalities


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6.2.8.
Pharmacokinetic Samples
Plasma samples for pharmacokinetics (PK) will be collected pre-dose (Cycles 2 and 3 only) and 
concentrations of tirabrutinib will be determined. Plasma concentrations of tirabrutinib
metabolites may be determined.
6.2.9.
Bone Marrow Examination
Bone marrow examination (core biopsy and/or aspirate as per local standard of care) will be 
performed for follow-up only (for both NHL and CLL subjects) if previously positive and/or to 
confirm CR, if physical examination and CT-scans demonstrate a CR.
6.2.10.
Treatment Response Assessment 
The determination of disease response and progression will be based on standardized criteria 
{Cheson 2007, Hallek 2008, Owen 2013}. During the course of the study, investigators will 
periodically assess the status of each subject’s disease. Treatment decisions by the investigator in 
this study will be based on these assessments. All relevant radiographic and clinical information 
required to make each tumor status assessment must be made available for source verification.
6.2.11.
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) performance status is an investigator 
assessment of the impact of the disease on the subject’s activities of daily living. ECOG will be 
scored using the scale index in Appendix 6.
6.2.12.
Tumor Imaging (CT)
CT with contrast or MRI (for subjects who cannot tolerate CT contrast) will be obtained to 
document disease, in accordance with the NHL and CLL response assessment guidelines 
{Cheson 1999, Hallek 2008}. If not performed in the previous 90 days prior to Cycle Day 1 on 
this study, imaging of the neck, chest, abdomen and pelvis by CT scan with contrast or MRI will 
be performed between C1D1 and C1D28, and at approximately week 12 and then every 
24 weeks. The timing of all scan should be regardless of cycle number or dose interruption.
Scans taken as part of procedures performed at a regular follow-up visit on subject’s previous 
tirabrutinib study may be used to fulfill the screening criteria up to 90 days prior to first dose of 
tirabrutinib. During the treatment, scans may be performed at time points other than specified, as 
clinically indicated to assess tumor progression. For subjects who stop study treatment in the 
absence of disease progression (eg, experienced unexpected toxicity), scans should continue to 
be collected approximately every 24 weeks until disease progression or initiation of systemic 
anti-tumor therapy other than the study treatment (whichever is earlier). Assessment of 
progression will be as determined by the investigator.


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As this is an extension protocol from ONOPOE00l [EudraCT Number: 2011-005033-39], the 
same imaging procedure and specifications ( eg, contrast agent, scaimer, slice thickness, etc.) 
used to define measurable target and non-target lesions from the time of initiation of treatment 
should be used throughout the study for each subject. 
CT scans may not be perfonned at sites or in countries where additional radiology approval is 
required, unless that approval is sought and granted. 
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Unscheduled visits 
Final 
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Unscheduled procedures, including, but not limited to, vital signs, 12-lead ECG, and CT or MRI, 
will be recorded on the applicable eCRFs. 
6.5. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perfonn the required study-related 
follow-up and procedures (see Section 3.5, Criteria for Discontinuation of Study Drug). If this is 
not possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study. 
6.6. 
End of Study 
End of study for a subject is defined as the date of the last study-related procedures or the date of 
death for an on-study subject or when a subject has reached the end of the study duration. 
See Section 9.3.4. 
Subjects will be contacted by phone 30 days ( ± 7 days) after the last dose of tirabrutinib to assess 
for AEs. For subjects who come off study for reasons other than disease progression, the site 
should also obtain infonn ation post-study anti-cancer therapies, surgeries, and date of definitive 
disease progression (if known). 
All treatment-emergent AEs and laboratory abnonnalities present at the end of study are to be 
followed until resolution or the event is detennined to be irreversible by the investigator. 
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6.7
Tirabrutinib Dose interruption and adjustment
The following are the guidelines for tirabrutinib dose interruption. 
Interruption of tirabrutinib administration of up to 28 days will be acceptable to allow for any 
reversal of toxicity. If the toxicity does not resolve to CTC Grade ≤ 2 or to baseline within 
2 weeks, tirabrutinib will be permanently discontinued. Additionally, tirabrutinib should be 
permanently discontinued if any Grade 4 study drug- related adverse event is observed. No dose 
reductions will be allowed.
If, in the opinion of the investigator, a subject who has been tolerating therapy well demonstrates 
a loss of clinical response, the dose of tirabrutinib may be increased to the MTD (600 mg for 
CLL and 480 mg for NHL). To be considered for a dose increase, the subject must not ever have
had a previous dose reduction of tirabrutinib due to a drug related adverse event or any Grade 3 
or higher drug related adverse event. It must be noted, that no data is available to inform whether 
a higher dose of tirabrutinib will overcome resistance to tirabrutinib and therefore an increased 
dose is allowed if thought to be in the best interest of the patient by the investigator, but not 
recommended.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an AE and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
first dose of study drug on the previous study, are considered medical history. If they 
occurred during the previous study, prior to the first dose of tirabrutinib on this study, but 
have not resolved, they are considered medical history on this study

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
Protocol-specific SAEs, in this study, is to be considered medically important and therefore 
“serious.” To maintain the integrity of the study, the following events that are assessed as 
unrelated to IMP will not be considered as SAEs:

Progression of malignancy being studied

Death due to malignancy being studied
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression and death 
should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.


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7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the IMP. For SAEs, an alternative 
causality must be provided (eg, pre-existing condition, underlying disease, intercurrent 
illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE Version 4.03. For each episode, the highest 
severity grade attained should be reported.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on eCRF: all SAEs and AEs related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead may 
request that certain AEs be followed beyond the protocol defined follow up period.


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All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the infonned consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Phannacovigilance and Epidemiology (PYE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures perfonned after infonned 
consent is signed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period. 
However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly docmnent 
and report the event to Gilead PYE. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event ( eSAE) Reporting Process 
• 
Site perso1mel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead PYE within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious AE reporting fonn and 
submit within 24 hours to: 
Gilead PVE 
Fax: 
E-mail: 
IPIPD 
IPIPD 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper fonn because the eCRF database has been locked, 
no further action is necessary. 
• 
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a docmnent to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
reports. 
• 
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn. 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the tirabrutinib IB. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to tirabrutinib interruption or discontinuation must be recorded as an AE, as 
well as an SAE, if applicable. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the CTCAE Version 4.03.
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
7.6.
Toxicity Management 
Dosing requirements for certain toxicities are specified in Section 5.3. The investigator may 
contact the medical monitor to review toxicities that are not directly discussed in the protocol. 
Laboratory abnormalities identified at Screening/Baseline and during study participation should 
be treated at the investigator’s discretion.


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7.6.1.
Warnings and Precautions
7.6.1.1.
Hemorrhage
Bleeding events have occurred in subjects with relapsed/refractory CLL and relapsed/refractory 
NHL who received tirabrutinib as monotherapy. These include minor hemorrhagic events such as 
contusion, hematoma, purpura, and petechiae, and major hemorrhagic events such as small 
intestinal hemorrhage and subdural hematoma. Subjects should be monitored for signs of 
bleeding and treated appropriately. Consider interrupting treatment with tirabrutinib for up to 
7 days prior to surgery or other interventions associated with a significant risk of bleeding and 
resuming treatment once hemostasis is achieved.
7.6.1.2.
Infections 
Infections, some with fatal outcome, have occurred in subjects with CLL and NHL who received 
tirabrutinib as monotherapy. Monitor subjects for fever and infections and treat appropriately.
7.6.1.3.
Hypersensitivity Reaction 
Hypersensitivity reactions (including an allergic reaction) have been observed in a small number 
of subjects who received tirabrutinib. If a subject experiences a hypersensitivity reaction, 
consider interruption or discontinuation of tirabrutinib.
7.6.1.4.
Embryo-Fetal Toxicity
Based on findings in animals, tirabrutinib may cause fetal harm when administered to a pregnant 
woman. Reproductive failure and embryo-fetal toxicity have been observed in rats and rabbits. In 
rabbits, post-implantation loss was observed at systemic exposures approximately 63 times 
greater than the expected exposure in rheumatoid arthritis (RA) subjects receiving 20 mg 
tirabrutinib once daily and approximately 4 times the mean exposure in CLL subjects receiving 
320 mg tirabrutinib once daily.
Women of childbearing potential should be advised of the risk of fetal harm during exposure to 
tirabrutinib. They should use highly effective contraception and have pregnancy testing during 
exposure to tirabrutinib. Women of childbearing potential should be advised to contact their 
physician immediately if they become pregnant or suspect they may be pregnant.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.


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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE.


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to or Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE.
Gilead PVE contact information is as follows: Fax number 
 or 
email
Refer to Appendix 8 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
PPD


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is to determine the long-term safety and tolerability of 
tirabrutinib in subjects who received tirabrutinib in the prior tirabrutinib study and whose disease 
had not progressed on the parent study.
The secondary objective of this study is to determine the long-term efficacy of tirabrutinib.
8.1.2.
Primary Endpoint
The primary endpoint is safety. Safety will be evaluated by the incidence and severity of AEs
and clinical laboratory abnormalities, as defined by Common Terminology Criteria for 
CTCAE v4.03.
8.1.3.
Secondary Endpoint
Secondary endpoints will include:

ORR: defined as the proportion of subjects who achieve PR or CR

DOR: defined as the interval from first documentation of CR or PR to the earlier of the 
first documentation of definitive disease progression as assessed by the investigator, or death 
from any cause

PFS: defined as the interval from date of the first dose of tirabrutinib on the parent study to 
the earlier of the first documentation of definitive disease progression as assessed by the 
investigator, or death from any cause

OS: defined as the interval from date of the first dose of tirabrutinib on the parent study until 
death from any cause.
8.2.
Analysis Sets
8.2.1.
Rollover Analysis Set
The Rollover Study Analysis Set consists of all subjects who are enrolled into this study. This 
analysis set will be used for the summary of subject characteristics, disposition, and study drug 
treatment administration.


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The Full Analysis Set consists of all subjects who are enrolled and treated in the parent study. 
This analysis set will be used for the smmnary of safety and efficacy endpoints. 
8.2.3. 
Pharmacokinetics Analysis Set 
The Phannacokinetic Analysis Set consists of all enrolled subjects who have at least 1 evaluable 
PK sample. 
-
8.3. 
Data Handling Conventions 
By-subject listings will be created for important variables from each eCRF module. Summary 
tables for continuous variables will contain the following statistics: N (nmnber in population), 
n (number with data), mean, standard deviation, 95% confidence intervals (Cls) on the mean, 
median, minimum, and maximum. Smmnary tables for categorical variables will include: N, n, 
percentage, and 95% Cls on the percentage. Unless otherwise indicated, 95% Cls for binary 
variables will be calculated using the binomial distribution ( exact method). Data will be 
described and summarized by phase and dose level, analysis set, and time point. As appropriate, 
changes from baseline to each subsequent time point will be described and summarized. 
Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, line plots) may be used when 
such methods are appropriate and infonnative. 
The baseline value used in each analysis will be the last (most recent) pre-treatment value on the 
parent study. Data from all sites will be pooled for all analyses. Analyses will be based upon the 
observed data unless methods for handling missing data are specified. If there is a significant 
degree of non-normality, analyses may be perfonned on log-transfonned data or nonparametric 
tests may be applied, as appropriate. 
8.4. 
Subject Disposition 
The nmnber and percentage of subjects who received study drug, completed each parent study, 
entered this study and discontinued from this study will be smmnarized. A smmnary of the 
reasons of the discontinuation from the study treatment will be provided separately for each 
study. 
8.5. 
Subject Characteristics 
Demographic and baseline measurements will be captured from parent study and smmnarized 
using standard descriptive methods. Demographic smmnaries will include sex, race/ethnicity, 
and age. Baseline data will include a smmnary of baseline ECOG perfonnance status and 
selected patient and disease characteristics. 
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8.6.
Efficacy Analysis
Subjects’ efficacy data will be integrated with the parent study. The efficacy analysis will be 
based on full analysis set defined based on the parent study. 
Tumor response will be based on investigator assessment. ORR will be estimated and its 
associated 95% confidence interval will be calculated using the exact method. Subjects who do 
not have sufficient baseline or on study tumor assessment to characterize response will be 
counted as non-responders.
DOR, PFS, and OS will be analyzed using Kaplan-Meier (KM) methods. The median will be 
provided along with the corresponding 95% CI. Additionally, the 25% and 75% percentiles for 
these endpoints will also be provided.
The data for DOR and PFS will be censored on the date of the last available disease assessment 
for subjects who are not known to have relapsed or died by the end of the study follow-up. The 
data for OS will be censored on the date of last known alive for subjects who are not known to 
have died by the end of the study follow-up.
8.7.
Safety Analysis
All safety data collected on or after the date tirabrutinib was first dispensed up to the date of 
last dose of tirabrutinib will be summarized by patient cohort and dose levels. 
8.7.1.
Extent of Exposure and Compliance
Descriptive information will be provided by phase and dose level regarding the number of doses 
of study treatment prescribed, the total number of doses taken, duration of treatment, and the 
number and timing of prescribed dose reductions and interruptions.
Tirabrutinib compliance will be described in terms of the proportion of study treatment actually 
taken based on returned pill count relative to the amount that was dispensed (taking into account 
physician-prescribed reductions and interruptions).
8.7.2.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs. 
A treatment-emergent AE is defined as an AE that occurs or worsens in the period from the 
first dose of study treatment in the parent study to 30 days after the last dose of study treatment
in the rollover study.
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA)
(http://www.meddramsso.com) with descriptions by System Organ Class (SOC), High-Level 
Group Term (HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term
(LLT). The severity of AEs will be graded by the investigator according to the CTCAE,
Version 4.03, whenever possible. If a CTCAE criterion does not exist for a specific type of AE, 
the grade corresponding to the appropriate adjective will be used by the investigator to describe 


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the maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the AE to the study treatment
will be categorized as related or unrelated.
Treatment-emergent AEs will be summarized by cohort. Summary tables will be presented to 
show the number of subjects reporting treatment-emergent AEs by severity grade and 
corresponding percentages. A subject who reports multiple treatment-emergent AEs within the 
same PT (or SOC) is counted only once for that PT (or SOC) using the worst severity grade. AE
descriptions will be presented in alphabetical order of System Organ Class, then by decreasing 
frequency in the “overall” column for a given Preferred Term. Separate listings and summaries 
will be prepared for the following types of treatment emergent AEs:

Study-drug-related AEs

AEs that are Grade ≥ 3 in severity

AEs leading to study treatment interruption and/or dose modification

AEs leading to study treatment discontinuation

SAEs
8.7.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data 
and will be reported using conventional units. The focus of laboratory data summarization will 
be on treatment-emergent laboratory abnormalities. A treatment emergent laboratory abnormality 
is defined as an abnormality that, compared to baseline, worsens by ≥1 grade in the period from 
the first dose of study treatment on the parent study to 30 days after the last dose of study 
treatment on the rollover study. If baseline data are missing, then any graded abnormality 
(ie, an abnormality that is Grade ≥in severity) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of study treatment or > 30 days after the 
last dose of study treatment will be included in data listings.
Hematological, serum biochemistry, and urine data will be programmatically graded according 
to CTCAE severity grade, when applicable. For parameters for which a CTCAE grade does not 
exist, reference ranges from the local laboratory will be used to determine programmatically if a 
laboratory parameter is below, within, or above the normal range for the subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized. 
Summary tables will be presented for each relevant assay to show the number of subjects by 
CTCAE severity grade with corresponding percentages. For parameters for which a CTCAE 
grade does not exist, the frequency of subjects with values below, within, and above the normal 
ranges will be summarized. Subjects will be characterized only once for a given assay, based on 
their worst severity grade observed during a period of interest (eg, during the study or from 
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Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to each visit. For parameters for which a CTCAE grade 
does not exist, shift tables will be presented showing change in results from baseline 
(nonnal, low and high [ or abnonnal] to each visit (nonnal, low and high [ or abnonnal]). Tables 
will be prepared to show frequencies adjusted for baseline values; for this frequency, subjects 
with the same or worse toxicity grade at baseline are not considered. 
8.8. 
Pharmacokinetic Analysis 
The concentration of tirabrutinib and, if applicable, metabolite(s) will be summarized by nominal 
sampling time using descriptive statistics. Population PK and exposure-response may be 
explored. 
8.10. 
Sample Size 
No fonnal hypothesis testing is plaimed for this study. The number of subjects enrolled will be 
detennined by the nmnber of subjects who completed a prior tirabrutinib study .. 
8.11. 
Data Monitoring Committee 
A Data Monitoring Co1mnittee will not be used in this study. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB or IEC-approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or 
local requirements. The consent form will inform subjects about genomic testing and sample 
retention, and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled


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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 


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the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (eg, data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:the results of the study 
in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, 
manuscript, or presentation form or the study has been completed at all study sites for at least 
2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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Asghar A, Naaz S, Agrawal D, Sharma PK. Morphometric Study of Spleen in North Indian 
Adult Population: CT Scan Image Based Study. Journal of Clinical and 
Diagnostic Research 2011;5 (5):974-77.
Bezerra AS, D'Ippolito G, Faintuch S, Szejnfeld J, Ahmed M. Determination of splenomegaly by 
CT: is there a place for a single measurement? AJR Am J Roentgenol 2005;184 
(5):1510-3.
Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus 
Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med 
2014.
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an 
international workshop to standardize response criteria for non-Hodgkin's 
lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999;17 
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Definitions of Response for Waldenstrom’s Macroglobulinemia
Appendix 4.
Modified International Workshop on Chronic Lymphocytic Lymphoma Leukemia 
(IWCLL) Criteria for Response Assessment
Appendix 5.
Follicular Lymphoma, Marginal Zone Lymphoma, and Small Lymphocytic 
Lymphoma Response Assessment
Appendix 6.
ECOG status
Appendix 7.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
An Open-label Study to Assess the Long-term Safety and Efficacy of Tirabrutinib 
(ONO/GS-4059) in Subjects with Relapsed/Refractory B-cell Malignancies 
GS-US-401-1787, Protocol Amendment 5, 29 October 2019 
This protocol has been approved by Gilead Scie ce,sJ ncJbe_folJo:wj niu;j1VJature_documents 
this a 
roval. 
Name (Printed) 
Author 
Date 
' 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 62 
29 October 2019 


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Appendix 2.
Study Procedures Table
Study Phase
Screening/
Enrollmenta
C1D1 a
(Baseline)
Day 1 of Each Cycle 
up to and including 
Cycle 22 (28 days)
Every 12 weeks 
starting with Cycle 
22 until EOT
60 Month Visit/
EOT/Early 
Withdrawal
30-Day Safety 
Follow-up Visit
Window (Days)
- 30
± 3
± 7
± 14
± 7
Informed Consent
X
General and Safety Assessments
Medication History
X
Physical Examinationb
X
X
X
X
X
Vital Signs
X
X
X
X
X
12-lead ECG
X
X
AE/Concomitant Medication
X
X
X
X
X
X
Disease Assessments
Response Assessment
X
X
X
X
X
ECOG
X
X
X
X
X
CT scan (neck, chest, 
abdomen, Pelvis) & Tumor 
Measurementsc
X
Xc
X
Bone Marrow Examinationd
X
Xd
X
Laboratory Assessments
Serum / Urine Pregnancy 
Teste
X
X
X
X
Chemistry
X
X
X
X
X
CBC and Differential
X
X
X
X
X
Coagulation
X
X


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Study Phase
Screening/
Enrollmenta
C1D1 a
(Baseline)
Day 1 of Each Cycle 
up to and including 
Cycle 22 (28 days)
Every 12 weeks 
starting with Cycle 
22 until EOT
60 Month Visit/
EOT/Early 
Withdrawal
30-Day Safety 
Follow-up Visit
Window (Days)
- 30
± 3
± 7
± 14
± 7
Total IgA, IgG, IgM 
Immunoglobulin 
electrophoresis
X
Xf
X
Urinalysis 
X
Xf
X
X
Sparse PKg
Xg
Investigational Product
Tirabrutinib Accountability 
and Dispensing 
Xh
X
X
X
Xi
a
Results from laboratory assessments and procedures performed up to 30 days prior may be utilized to determine eligibility and serve as study baseline
b
A complete physical examination will be performed at Screening and End of Treatment visit. Starting C1D1 a modified physical examination may be performed
c
For subjects who have not had tumor imaging in the 90 days prior to C1D1, a scan should be performed at baseline (between day 1 and day 28), at approximately 12 weeks
and then every 24 weeks (± 2 weeks). For subjects who have undergone tumor imaging within 90 days prior to C1D1, scan should be performed at approximately 12 weeks 
then every 24 weeks (± 2 weeks)
d
To confirm clinical response if physical exam and CT scan demonstrate possible CR
e
Pregnancy testing only in women per Appendix 8
f
Total IgA, IgG, IgM Immunoglobulin electrophoresis and Urinalysis every 3 cycles
g
PK samples collected pre dose on C2D1 and C3D1 only
h
Dispensing only
i
Accountability only
CCI


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Appendix 3.
Definitions of Response for Waldenstrom’s Macroglobulinemia

Complete response (CR): Absence of serum monoclonal IgM protein by immunofixation, 
Normal serum IgM level and complete resolution of extramedullary disease, i.e., 
lymphadenopathy and splenomegaly if present at baseline. Morphologically normal bone 
marrow aspirate and trephine biopsy.

Very good partial response: Monoclonal IgM protein is detectable. ≥ 90% reduction in serum 
IgM level from baseline. Complete resolution of extramedullary disease, i.e., 
lymphadenopathy and splenomegaly if present at baseline. No new signs or symptoms of 
active disease.

Partial response (PR): Monoclonal IgM protein is detectable. ≥ 50% but < 90% reduction in 
serum IgM level from baseline. Reduction of extramedullary disease, i.e., lymphadenopathy 
and splenomegaly if present at baseline. No new signs or symptoms of active disease.

Minor response: Monoclonal IgM protein is detectable. ≥ 25% but < 50% reduction in serum 
IgM level from baseline. No progression in extramedullary disease, i.e., 
lymphadenopathy/splenomegaly. No new signs or symptoms of active disease.

Stable disease: Monoclonal IgM protein is detectable. < 25% reduction and < 25% increase 
in serum IgM level from baseline. No new signs or symptoms of active disease.

Progressive disease: ≥ 25% increase in serum IgM level from lowest nadir 
(requires confirmation) and/or progression in clinical features attributable to the disease.


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Appendix 4.
Modified International Workshop on Chronic Lymphocytic 
Lymphoma Leukemia (IWCLL) Criteria for Response Assessment
The determination of CLL response and progression will be based on standardized International 
Workshop on CLL (IWCLL) Criteria {Hallek 2008}, as specifically modified for this study to 
reflect current recommendations which consider the mechanism of action of tirabrutinib, and 
similar drugs.
Note: As this is an extension protocol from ONO-POE001 (EudraCT Number: 
2011-005033-39), please monitor the same index and nodal index lesions that were 
previously identified at the initiation of treatment.
1.
Identification and Measurement of Tumor Lesions and Organomegaly
1.1
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the 
longest diameter (LD) × the longest perpendicular diameter (LPD) will be recorded (in cm) for 
each index lesion. The product of the perpendicular diameters (PPD) for each index lesion and 
the sum of greatest perpendicular diameters (SPD) for all index lesions will be calculated and 
recorded. The baseline SPD will be used as references by which objective tumor response will be 
characterized during treatment. The nadir LD of individual lesions and the nadir SPD will be 
used as references by which CLL progression will be characterized. All LD and LPD diameters 
will be reported in centimeters and all PPDs and SPDs will be reported in centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
Index lesions measuring > 1.5 cm in the LD and > 1.0 cm in the LPD, will be prioritized during 
baseline index lesion selection.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters > 0 cm and 
1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each 
diameter that meets these criteria and the resulting PPD will be used in SPD calculations. Based 
on this convention, a CR may be achieved even if an SPD value is > 0 cm2, (ie, if all lymph 
nodes measure < 1.0 cm2).


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A new node that measures > 1.5 cm in the LD and > 1.0 cm in the LPD will be considered 
progressive disease (PD).
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
1.2
Spleen and Liver
Both the spleen and liver will be should be assessed by CT/MRI scan at baseline and at the 
stipulated intervals during treatment. The baseline and nadir values for the longest vertical 
dimension (LVD) of each organ will be used as reference to further characterize the objective 
tumor response of the measurable dimensions of the CLL during treatment.
The spleen will be considered enlarged if it is > 12 cm in LVD {Asghar 2011, Bezerra 2005}, 
with the LVD being obtained by multiplying the number of sections on which the spleen is 
visualized by the thickness of the sections (eg, if the spleen is seen in 14 contiguous 
cross-sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm). 
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD. 
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to 12 cm in the LVD is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by 50% (minimum increase of 2 cm) from 
nadir is required for declaration of splenic progression. 
The liver will be considered enlarged if it is > 18 cm in LVD {Erturk 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or to 
18 cm in the LVD is required for declaration of a hepatomegaly response. Conversely, an 
increase in liver enlargement by 50% (minimum increase of 2 cm) from nadir is required for 
declaration of hepatic progression. .
1.3
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters < 1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, 
previously irradiated lesions, lesions with artifacts may be considered as non-index disease.


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The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as “present” or 
“absent”.
1.4
Definitions of Disease Response and Progression
Responses will be categorized by the Investigator as CR, PR, SD, or PD. In addition, a response 
category of non-evaluable (NE) is provided for situations in which there is inadequate 
information to otherwise categorize response status. A response category of ND is included for 
situations in which there is no evidence of tumor either at baseline or on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until PD/recurrence (taking as reference for PD the 
smallest measurements recorded since treatment started). Subjects with a best overall response of 
NE or ND will be included in the denominator in the analyses of disease response.
1.4.1. Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of < 4 x 109/L

Regression of all index lesions to normal size 1.5 cm in the LD 

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as < 30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular for 
age

Peripheral blood counts meeting all of the following criteria:
ANC > 1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)


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1.4.2. Partial Response
To satisfy criteria for a PR, all of the following criteria must be met: 

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; (2) Only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below: 
In a subject with baseline lymphocytosis (ALC 4 x 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to < 4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 1.2
In a subject with enlargement of the liver at baseline, a hepatomegaly response as defined 
in Section 1.2
A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC 1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin)
1.4.3. Stable Disease
To satisfy criteria for SD, the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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1.4.4. Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD: 

Evidence of any new disease:
A new node that measures > 1.5 cm in the LD and > 1.0 cm in the LPD 
New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL)

Evidence of worsening of index lesions, spleen or liver, or non-index disease: 
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass 
that now has an LD of > 1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression). 


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is < 100 x 109/L and there has been a decrease by > 50% from 
the highest on-study platelet count 
The current hemoglobin is < 110 g/L (11.0 g/dL) and there has been a decrease by 
> 20 g/L (2 g/dL) from the highest on-study hemoglobin 
1.4.5. Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
1.4.6. No Disease
Subjects have a status of ND if all of the following conditions occur: 

Index disease absent at both baseline and on-treatment. 

Non-index disease absent at both baseline and on-treatment.

Enlargement of the liver and spleen absent at both baseline and on-treatment

Abnormalities of peripheral blood counts (elevated ALC and abnormally low ANC, platelet 
count, and hemoglobin) and evidence of CLL in bone marrow (if available) absent at both 
baseline and on treatment
1.4.7. Lymphocytosis During Therapy

tirabrutinib, and other agents in class can mobilize CLL cells from tissues into the peripheral 
blood. This characteristic pharmacological action can be prominent early in therapy but can 
persist over time and should not be confused with disease progression in subjects who have 
persistent control of other CLL-related signs and symptoms.


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
In the absence of other objective evidence of disease progression, the occurrence of 
lymphocytosis will not preclude subjects from meeting the criteria for a PR if other criteria 
for PR are met and will not be considered evidence of CLL progression if occurring in 
isolation.

Subjects with lymphocytosis should be continued on tirabrutinib until the occurrence of 
definitive disease progression (ie, disease progression that is manifest by worsening 
CLL-related signs other than lymphocytosis alone), or the occurrence of another reason to 
discontinue study treatment as described in Section 3.5.
1.5
Definitive CLL Progression
Assessment of response and progression will be by the investigator. Subjects who progress will 
be discontinued from the study. 


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Appendix 5.
Follicular Lymphoma, Marginal Zone Lymphoma, and Small 
Lymphocytic Lymphoma Response Assessment
The determination of FL, MZL, and SLL response and progression will be based on standardized 
response criteria for malignant lymphoma {Cheson 2007}.
1.
Identification and Follow-up of Tumor Lesions and Organomegaly
Note: As this is an extension protocol from ONO-POE001 (EudraCT Number: 
2011-005033-39), please monitor the same index and nodal index lesions that were 
previously identified at the initiation of treatment.
1.1.
Index Lesions
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed extra-nodal 
masses) should be selected as index lesions that will be used to quantitate the status of the 
disease during study. Ideally, the index lesions should be located in disparate regions of the body 
and include mediastinal, abdominal, and retroperitoneal areas of disease whenever these sites are 
involved. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions LD × LPD will be recorded (in cm) for each index lesion. Using the 
LD and LPD, the product of the PPD for each index lesion will be calculated. The SPDs for all 
index lesions will be calculated and recorded. The baseline SPDs will be used as references by 
which objective tumor response will be characterized during treatment. The nadir LDs of 
individual lesions and the nadir SPDs will be used as references by which objective tumor 
progression will be characterized during study. All PPD and SPD measurements will be reported 
in centimeters squared.
1.2.
Nodal Index Lesions
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.0 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm. 
Abnormal, measurable nodal lesions will be subcategorized as either large or small. 

Large nodal lesions have an LD that is > 1.5 cm and an LPD that is 1.0 cm. 

Small nodal lesions have an LD that is > 1.0 cm and 1.5 cm and an LPD that is > 1.0 cm.
Index lesions measuring > 1.5 cm in the LD, regardless of the measurement of the LPD, will be 
prioritized during baseline index lesion selection.


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At follow-up time points, the SPD of all nodal index lesions will be considered. Because nodal 
index lesions that have one or both diameters > 0 cm and 1.0 cm cannot be reliably measured, 
a default value of 1.0 cm will be assigned for each diameter that meets these criteria and the 
resulting PPD will be used in SPD calculations. Based on this convention, a CR may be achieved 
even if an SPD value is > 0 cm2 (ie, if all lymph nodes measure < 1.0 cm2).
New or enlarging nodal lesions that are still 1.0 cm by 1.0 cm will not be considered to 
represent recurrent disease or PD. A new node that measures > 1.5 cm in any diameter or a 
new node that measures > 1.0 cm to 1.5 cm in the LD and measures > 1.0 cm in the LPD will 
be considered PD.
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are > 1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Components that are ≤1.0 cm in the LD are assumed to be normal lymph 
node structures. PD will not be based on the growth of a lesion sub-component until it meets the 
criteria for abnormal. Lesion sub-components that are abnormal (> 1.0 cm in 1 diameter) will 
have the true PPDs calculated with the result used only for calculating an accurate nadir. Lesion 
sub-components that are normal (1.0 cm in the LD) will have the default PPD of 1.0 cm2
(1.0 cm x 1.0 cm) stored only for the purposes of calculating the nadir value. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
1.3.
Extra-Nodal Index Lesions 
An extra-nodal mass may be selected as an index lesion if it is both abnormal and measurable at 
baseline. An extra-nodal mass of any size is considered abnormal. It is considered measurable at 
baseline if it has 2 perpendicular diameters that can be accurately measured in cross section with 
the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the PPD of each single extra-nodal index lesion and the SPD of all 
extra-nodal index lesions will be considered. Because extra-nodal index lesions that have one or 
both diameters > 0 cm and < 1.0 cm cannot be reliably measured, a default value of 1.0 cm will 
be assigned for each diameter that meets these criteria and the resulting PPD will be used in 
SPD calculations. If an extra-nodal lesion is no longer clearly visible, it will be considered 
resolved and its PPD will be defined as 0 cm2. 
If an extra-nodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears 
unequivocally, the subject will be considered to have PD. A new unequivocal extra-nodal lesion 
of any size that appears at a site that was not previously involved with lymphoma and is 
discernible to the radiologist by CT scan will be considered PD.


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1.4.
Non-Index Lesions
Any other measurable and abnormal nodal or extra-nodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
iNHL such as abnormal, non-measurable nodal lesions, extra-nodal lesions with both diameters 
< 1.0 cm, bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis of the skin or lung, abdominal masses that are not confirmed and followed by 
imaging techniques, cystic lesions, previously irradiated lesions, or lesions with artifacts may be 
considered as non-index disease. 
If present at baseline, up to 6 non-index lesions should be recorded. Measurements are not 
required. 
Non-index disease will be used as a general reference to further characterize regression or 
progression of lymphoma during assessments of the objective tumor response during treatment. 
These lesions should be followed as “present” or “absent”.
1.5.
Definitions of Tumor Response and Progression
Responses will be categorized as CR, PR, SD, or PD. In addition, a response category of NE is 
provided for situations in which there is inadequate information to otherwise categorize response 
status. A response category of ND is included for situations in which there is no evidence of 
tumor both at baseline and on-treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of study drug until PD/recurrence (taking as reference for PD the 
smallest measurements recorded since study drug started). Subjects with a best overall response 
of NE or ND will be included in the denominators in calculations of tumor response rate.
1.5.1. Complete Response
To satisfy criteria for CR, all of the following criteria must be met:

No evidence of new disease

Regression of all index nodal lesions to normal size (≤1.5 cm in the LD for nodes that were 
considered large at baseline and < 1.0 cm in the LD and ≤1.0 cm in the LPD for nodes that 
were considered small at baseline) (see Section 1.2 for definitions of large and small nodes)

Regression to normal of all nodal non-index disease 

Disappearance of all detectable extra-nodal index and non-index disease


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
Normal spleen and liver size by imaging studies, no hepatic or splenic lymphoma nodules, 
and no new liver or spleen enlargement

Morphologically negative bone marrow based on an adequate unilateral core biopsy 
(> 20 mm unilateral core); if the sample is indeterminate by morphology, it should be 
negative by immunohistochemistry 

If PET performed (not required), no evidence of residual disease
1.5.2. Partial Response
To satisfy criteria for PR, all of the following criteria must be met except for subjects with WM 
as noted below:

No evidence of new disease

A 50% decrease from baseline in the SPD of the index lesions 

No increase in the size of non-index disease

No increase in the size of the liver or spleen and no new liver or spleen enlargement

Persistence of bone marrow involvement in a subject who meets other criteria for CR based 
on the disappearance of all nodal and extra-nodal masses

If PET performed (not required): 
Typically FDG-avid lymphoma: if no baseline PET scan or if the PET scan was positive 
before initiating study drug(s), the on-treatment PET is positive in 1 previously 
involved site. If baseline PET was performed and was negative, there is no new PET 
evidence of disease
Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan or if 
the pretreatment PET scan was negative for lymphoma, CT criteria should be used in 
assessing the tumor during study. If the PET scan was positive before initiating study 
drug(s), the on-treatment PET is positive in 1 previously involved site.
1.5.3. Stable Disease
To satisfy criteria for SD, all of the following criteria must be met:

No evidence of new disease

Neither sufficient tumor shrinkage from baseline to qualify for PR nor sufficient evidence of 
tumor growth to qualify for PD


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1.5.4. Progressive Disease
The occurrence of any of the following events indicates PD:

Evidence of any new disease that was not present at baseline:
A new node that measures > 1.5 cm in LD and > 1.0 cm in the LPD
A new node that measures > 1.0 cm to < 1.5 cm in the LD and > 1.0 cm in the LPD
Unequivocal reappearance of an extra-nodal lesion that had resolved (ie, had previously 
been assigned a PPD of 0 cm2)
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any size 
unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other 
non-radiologic confirmation to confirm disease attributable to lymphoma). 
New or recurrent bone marrow involvement with iNHL if the last prior bone marrow 
biopsy performed as part of the study (baseline or on-study) was negative for iNHL

Evidence of worsening of nodal or extra-nodal index lesions:
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass 
that now has an LD of > 1.5 cm and an LPD of > 1.0 cm 

Unequivocal increase in the size of non-index disease

Transformation to a more aggressive NHL histology as established by lymph node biopsy or 
cytology.

If PET performed (not required):The appearance of any new lesion compatible with 
lymphoma with confirmation by other radiographic or histological modalities
The reappearance of any activity in a pre-existent lesion that meets size criteria for a new 
lesion on CT
1.5.5. Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images.


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1.5.6. No Disease
In a subject who does not have evidence of PD, the occurrence of all of the following conditions 
indicates a response status of ND: 

Index disease absent at both baseline and on-study

Non-index disease absent at both baseline and on-study

Enlargement of the liver and spleen absent at both baseline and on-study


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Appendix 6.
ECOG status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg,, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
{Oken 1982}


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Appendix 7.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
CTCAE v4.03 can be accessed from the below link:
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf


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Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The risks of treatment with tirabrutinib during pregnancy have not been evaluated. There is no 
data available at this time to exclude the possibility that tirabrutinib has a drug-drug interaction 
(DDI) with hormones used for contraception. There is insufficient data to exclude the possibility 
of a clinically relevant interaction of tirabrutinib with hormonal contraception that results in 
reduced contraception efficacy. Therefore, contraceptive steroids are not recommended as a 
contraceptive method either solely or as a part of a contraceptive regimen. Please refer to the 
latest version of the tirabrutinib IB for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must also not rely on hormone-containing contraceptives as a form 
of birth control during the study. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. Pregnancy tests 
will be performed at each visit thereafter. Female subjects must agree to one of the following 
from Screening until 30 days following the end of relevant systemic exposure.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.


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Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
for countries where it’s available
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure. Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.7.2.1.


amd-5-prot-GS-US-401-1787
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
29-Oct-2019
17:05:18
Clinical Research eSigned
30-Oct-2019
21:51:39
PPD
PPD

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
An Open-label Study to Assess the Long-term Safety and 
Efficacy of Tirabrutinib in Subjects with Relapsed/Refractory 
B-cell Malignancies
Name of Test Drug:
Tirabrutinib (GS-4059)
Study Number:
GS-US-401-1787
Protocol Version (Date):
Amendment 5 (29 October 2019)
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 3.0
Analysis Plan Date:
10 February 2021
Analysis Plan Authors:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 2
10 February 2021
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................7
1.1.
Study Objectives........................................................................................................................................7
1.2.
Study Design .............................................................................................................................................7
1.2.1.
Study ONO-4059POE001 (Parent Study)...............................................................................7
1.2.2.
Study US-US-401-1787 (Rollover Study)...............................................................................8
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Interim Analyses........................................................................................................................................9
2.2.
Final Analysis............................................................................................................................................9
2.3.
Follow-Up Analysis...................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
All Enrolled Analysis Set ......................................................................................................10
3.1.2.
Full Analysis Set....................................................................................................................10
3.1.3.
Safety Analysis Set................................................................................................................10
3.1.4.
Pharmacokinetic Analysis Set ...............................................................................................10
3.2.
Subject Grouping.....................................................................................................................................11
3.3.
Strata and Covariates...............................................................................................................................11
3.4.
Examination of Subject Subgroups .........................................................................................................12
3.5.
Multiple Comparisons .............................................................................................................................12
3.6.
Missing Data and Outliers.......................................................................................................................12
3.6.1.
Missing Data..........................................................................................................................12
3.6.2.
Outliers ..................................................................................................................................12
3.7.
Data Handling Conventions and Transformations ..................................................................................12
3.8.
Analysis Visit ..........................................................................................................................................13
3.8.1.
Definition of Study Day ........................................................................................................13
3.8.2.
Analysis Visit Windows........................................................................................................13
3.8.3.
Selection of Data in the Event of Multiple Records at Baseline ...........................................14
3.9.
Changes From Protocol-Specified General Considerations....................................................................14
4.
SUBJECT DISPOSITION ...................................................................................................................................15
4.1.
Subject Enrollment and Disposition........................................................................................................15
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................15
4.2.1.
Duration of Exposure to Study Drug.....................................................................................15
4.2.2.
Adherence to Study Drug ......................................................................................................16
4.3.
Protocol Deviations .................................................................................................................................16
4.4.
Assessment of COVID-19 Impact...........................................................................................................16
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................17
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................17
4.4.3.
Missed and Virtual Visits Due to COVID-19 .......................................................................17
5.
BASELINE CHARACTERISTICS .....................................................................................................................18
5.1.
Demographics..........................................................................................................................................18
5.2.
Other Baseline Characteristics ................................................................................................................18
5.3.
Medical History.......................................................................................................................................18
5.4.
Disease History........................................................................................................................................18
5.5.
Prior Treatments ......................................................................................................................................19


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6.
EFFICACY ANALYSES.....................................................................................................................................20
6.1.
Definition of Efficacy Endpoint ..............................................................................................................20
6.2.
Analysis Methods for Efficacy Endpoints...............................................................................................20
6.2.1.
Overall Response Rate ..........................................................................................................20
6.2.2.
Progression-Free Survival .....................................................................................................21
6.2.3.
Duration of Response ............................................................................................................22
6.2.4.
Overall Survival.....................................................................................................................22
7.
SAFETY ANALYSES.........................................................................................................................................24
7.1.
Adverse Events and Deaths.....................................................................................................................24
7.1.1.
Adverse Event Dictionary .....................................................................................................24
7.1.2.
Adverse Event Severity .........................................................................................................24
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................24
7.1.4.
Serious Adverse Events.........................................................................................................24
7.1.5.
Treatment-Emergent Adverse Events....................................................................................25
7.1.5.1.
Definition of Treatment-Emergent Adverse Events........................................25
7.1.5.2.
Incomplete Dates .............................................................................................25
7.1.6.
Summaries of Adverse Events and Deaths............................................................................25
7.1.6.1.
Summaries of AE Incidence by Severity.........................................................25
7.1.7.
Treatment-Emergent Adverse Events of Interest ..................................................................27
7.2.
Laboratory Evaluations ...........................................................................................................................27
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................28
7.2.2.
Graded Laboratory Values ....................................................................................................28
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities .............................................28
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities................................29
7.2.2.3.
Summaries of Laboratory Abnormalities ........................................................29
7.2.3.
Liver-related Laboratory Evaluations....................................................................................29
7.2.4.
Shifts Relative to the Baseline Value ....................................................................................30
7.3.
Body Weight and Vital Signs..................................................................................................................30
7.4.
Prior and Concomitant Medications........................................................................................................30
7.4.1.
Prior Medications ..................................................................................................................30
7.4.2.
Concomitant Medications......................................................................................................31
7.5.
Electrocardiogram Results.......................................................................................................................32
7.6.
Other Safety Measures ............................................................................................................................32
7.7.
Changes From Protocol-Specified Safety Analyses................................................................................32
8.
PHARMACOKINETIC ANALYSES..................................................................................................................33
8.1.
Pharmacokinetics (PK) Sample Collection .............................................................................................33
8.2.
Statistical Analysis Methods ...................................................................................................................33
8.2.1.
Tirabrutinib Plasma Concentration........................................................................................33
8.3.
Changes From Protocol-Specified PK Analyses.....................................................................................33
9.
REFERENCES.....................................................................................................................................................34
10.
SOFTWARE.........................................................................................................................................................35
11.
SAP REVISION...................................................................................................................................................36
12.
APPENDICES......................................................................................................................................................37
Appendix 1.
COVID-19 SMQ with Broad Scope........................................................................................38
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19...................................................39
Appendix 3.
Bleeding/Haemorrhage Medical Search Term ........................................................................41
Appendix 4.
Hypersensitivity Medical Search Term ...................................................................................50
Appendix 5.
Cytopenia Medical Search Term .............................................................................................53


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Appendix 6.
Cardiac arrhythmia Medical Search Term...............................................................................55
Appendix 7.
Rash Medical Search Term......................................................................................................57
Appendix 8.
List of Laboratory Tests for Safety Summary.........................................................................59


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ALP
alkaline phosphatase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DMC
data monitoring committee
DOR
duration of response
ECG
Electrocardiogram
ECOG
Eastern Corporation Oncology Group
ET
early termination
FAS
Full Analysis Set
Gilead
Gilead Sciences
HLT
high-level term
LTT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NE
not evaluable
NHL
non-Hodgkin’s lymphoma
NLP
Natural Language Processing
ORR
overall response rate
OS
overall survival
PD
progressive disease
PK
pharmacokinetic
PR
partial response
PFS
progression-free survival
PT
preferred term
Q1, Q3
first quartile, third quartile
SAP
statistical analysis plan
SD
stable disease
SPD
sum of the products of the greatest perpendicular diameters 
StD
standard deviation


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SAE
serious adverse event(s)
SAP
statistical analysis plan
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for study GS-US-401-1787. This SAP is based on the study protocol amendment 5 dated 
29 October 2019 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To determine the long-term safety and tolerability of tirabrutinib in subjects in a prior 
tirabrutinib study ONO-4059POE001 (parent study) and whose disease had not progressed 
on the parent study. 
The secondary objective of this study is as follows:

To determine the long term efficacy of tirabrutinib
1.2.
Study Design
The analysis of this rollover study GS-US-401-1787 will integrate the data from the parent study. 
Thus, the study design of the parent study is also described in Section 1.2.1, followed by the 
rollover study design in Section 1.2.2.
1.2.1.
Study ONO-4059POE001 (Parent Study)
This is an open-label Phase 1 multi-center study with a non-randomized, adaptive dose-
escalating design, to investigate the safety and tolerability of tirabrutinib administered as 
monotherapy to subjects with relapsed/refractory NHL and CLL. Subjects with no therapy of 
higher priority available and for whom treatment with a BTK inhibitor is deemed appropriate 
will be eligible.
Tirabrutinib was administered orally at the assigned dose levels for up to 6 cycles of treatment. 
Each treatment cycle consists of 28 days of continuous dosing. Continuation of treatment beyond 
6 cycles is possible for subjects deriving clinical benefit from the treatment. Intra-patient dose 
escalation or dose de-escalation after completion of the initial 6 month treatment period is 
allowed to provide patients with an opportunity to maximize upon their already established 
clinical response. Patients may receive continuous treatment until disease progression as assessed 
by the investigator or until experiencing an intolerable AE leading to discontinuation of drug.


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CT with contrast or MRI assessment at screening served as the baseline of efficacy evaluation. 
The response was assessed every 3 months during the first year of treatment and then every 
6 months thereafter using the appropriate response criteria for CLL and NHL.
Study ONO-4059POE001 has completed and all subjects are now off study or have rolled over 
to study GS-US-401-1787. The full CSR of study ONO-4059POE001 has been completed. 
Adverse events and laboratory abnormalities were graded using the Common Terminology for 
Adverse Events (CTCAE), Version 4.0, adverse events preferred terms were coded using 
MedDRA 18.1, and concomitant medications were coded using WHODRUG Q2-2015.
1.2.2.
Study US-US-401-1787 (Rollover Study)
This study is an open-label rollover study for subjects who have tolerated and achieved stable 
disease or responded to tirabrutinib treatment while enrolled in the parent study 
ONO-4059POE001. 
Subjects who meet eligibility criteria will continue to receive tirabrutinib. Each cycle will consist 
of 28 days of therapy. If there is no evidence of disease progression by clinical assessment or by 
CT (or MRI), a subject may continue receiving tirabrutinib until disease progression (clinical or 
radiographic) for a maximum duration of 5 years from the start of this rollover study 
GS-US-401-1787. After discontinuation of treatment, subjects will be followed for safety for 
30 days.
CT with contrast or MRI will be obtained to document disease, in accordance with the NHL and 
CLL response assessment guidelines. If not performed in the previous 90 days prior to Cycle 1 
Day 1 on study GS-US-401-1787, CT scan with contrast or MRI will be performed between 
C1D1 and C1D28, and at approximately week 12 and then every 24 weeks. Bone marrow 
examination (core biopsy and/or aspirate as per local standard of care) will be performed for 
follow-up only (for both NHL and CLL subjects) if previously positive and/or to confirm CR, 
if physical examination and CT-scans demonstrate a CR. 
1.3.
Sample Size and Power
The number of subjects enrolled will be determined by the number of subjects who complete a 
prior tirabrutinib study who are still alive without disease progression, wish to continue therapy 
with tirabrutinib, and meet the study entry criteria.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
No formal interim analysis is planned.
This study does not have a data monitoring committee (DMC). Therefore, no analyses will be 
conducted for the DMC.
2.2.
Final Analysis
After all subjects have completed/discontinued the study, outstanding data queries have been 
resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the final 
analysis of the data will be performed.
2.3.
Follow-Up Analysis
No follow-up analysis is planned.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number, percentage, and 95% confidence intervals (CIs) on the percentage of subjects in each 
category will be presented; for continuous variables, the number of subjects (n), mean, standard 
deviation (StD), 95% CIs on the mean, median, first quartile (Q1), third quartile (Q3), minimum, 
and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted 
by subject ID number, visit date, and time (if applicable). Data collected on log forms, such as 
adverse events (AEs), will be presented in chronological order within subject. Age, sex at birth, 
race, and ethnicity for each subject will be presented in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects will be summarized.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set consists of all subjects who were enrolled in the GS-US-401-1787 
study. This analysis set will be used for the listings.
3.1.2.
Full Analysis Set
The Full Analysis Set consists of all enrolled subjects who took at least 1 dose of study drug in 
the GS-US-401-1787 study. This analysis set will be used for the efficacy endpoints.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug in the 
GS-US-401-1787 study. This is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set consists of all subjects who enrolled in the GS-US-401-1787 
study and have at least 1 evaluable PK sample. 


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3.2.
Subject Grouping
For analyses based on the All Enrolled Analysis Set and Full Analysis Set, subjects will be 
grouped according to the treatment to which they were initially assigned at the entry of 
GS-US-401-1787. For analyses based on the Safety Analysis Set, subjects will be grouped 
according to the actual treatment with the longest exposure duration in parent and rollover study. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they received 
prior to the PK sampling time.
All analyses will be performed for CLL and NHL subjects separately, unless otherwise specified. 
The applicable dose levels of tirabrutinib are:
Dose Levels for CLL
Dose Levels for NHL
20mg QD
20mg QD
40mg QD
40mg QD
80mg QD
80mg QD
160mg QD
160mg QD
320 mg QD
320 mg QD
400 mg QD
400 mg QD
500 mg QD
480 mg QD
600 mg QD
600 mg QD
300mg BID 
240mg BID
Summary of efficacy will be presented by integrating the parent study data and rollover study 
data, using only subjects who rolled over to GS-US-401-1787.
Summary of safety will be presented using only subjects who rolled over to GS-US-401-1787:

All safety summaries will be provided combining data from both parent study 
(ONO-4059POE001) and rollover study (GS-US-401-1787).

Selected safety summaries will also be provided only using data from rollover study 
GS-US-401-1787.
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule in enrolling subjects. No covariates 
will be included in efficacy and safety analyses.


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3.4.
Examination of Subject Subgroups
Due to the limited sample size at each dose level, no subgroup analysis will be performed.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2, for 
death in Section 6.2.4, for new anticancer therapy in Section 6.2.2, for AE onset is described in 
Section 7.1.5.2.
3.6.2.
Outliers
Unless otherwise specified, outliers will not be excluded from the analysis in general.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug in the parent study will be 
used for analyses and presentation in listings. If only birth year is collected on the CRF, 
“01 July” will be used for the unknown birth day and month for the purpose of age calculation. If 
only birth year and month are collected, “01” will be used for the unknown birth day.
Non-PK Data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics 
if the datum is reported in the form of “ x” (where x is considered the LOQ). For example, 
if the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used 
for calculation of summary statistics. An exception to this rule is any value reported as < 1 or 
<0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used 
for calculation of summary statistics.

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the datum is reported in the 
form of “≤ x” or “≥ x” (where x is considered the LOQ).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.


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Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 
at predose time points, and one-half the value of the LOQ at postbaseline time points, where 
LOQ is corrected for the dilution factor (ie, reported LOQ/dilution factor) for determination of 
summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.8.
Analysis Visit
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug in parent study 
ONO-4059POE001 and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study day 1 is the day of first dose of study drug administration in the parent study.
3.8.2.
Analysis Visit Windows
Baseline is defined as the last nonmissing value on or prior to first dosing date of study drug, 
unless specified differently.
For postbaseline, nominal visit as recorded on the CRF will be used when data are summarized 
by visit, if any. Any data relating to unscheduled visits will not be assigned to a particular visit or 
time point. However, the following exceptions will be made:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dose of study drug will be included in order to determine the 
maximum post-baseline toxicity grade. 


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3.8.3.
Selection of Data in the Event of Multiple Records at Baseline
For baseline, the last nonmissing value on or prior to first dosing date of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no time 
recorded on the same day, the baseline value will be the average of the measurements for 
continuous data, or the measurement with the lowest severity (eg, normal will be selected over 
abnormal for safety electrocardiogram [ECG] findings) for categorical data.
3.9.
Changes From Protocol-Specified General Considerations
In protocol, the Full Analysis Set is defined as all subjects who enrolled and treated in the parent 
study, and will be used for the safety and efficacy endpoints analysis. Given the study objective 
is to determine the long-term safety and efficacy in subjects who were in the parent study and 
whose disease had not progressed on the parent study (a.k.a. the rollover patient), analysis only 
include these rollover patient is better aligned with the study objective. Thus, in this SAP, the 
efficacy and safety analysis will only include subjects who enrolled in the GS-US-401-1787 
study as specified in Section 3.1 and Section 3.2.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by disease type (CLL, NHL) and dose level 
for each country, investigator, and overall as specified in Section 3.2 using All Enrolled Analysis 
Set. The summary will present the number and percentage of subjects enrolled. For each column, 
the denominator for the percentage calculation will be the total number of subjects analyzed for 
that column.
This summary will present the number of subjects screened, the number of subjects who met all 
eligibility criteria but were not enrolled with reasons subjects not enrolled, the number of 
subjects enrolled, and the number of subjects in each of the categories listed below:

Enrolled in Study GS-US-401-1787

Treated in Study GS-US-401-1787

Completed study drug per protocol specified duration

Discontinued study drug in GS-US-401-1787 with reason

Discontinued Study GS-US-401-1787 with reasons
For the status of study drug and study completion and reasons for discontinuation, the number 
and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the All Enrolled Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
A by-subject listing will be provided by subject identification (ID) number in ascending order to 
support the above summary table.
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence relative to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks and cycles using up to 1 decimal place (eg, 4.5 weeks). If the last study drug 
dosing date is missing, the following imputation rule will be applied: 

If the study drug is permanently withdrawn, the latest date among the study drug end date, 
clinical visit date, laboratory sample collection date, and vital signs assessment date will be 
used.


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The total duration of exposure to study drug and the total number of cycles a subject was 
exposed to study drug, and number and percentage of subjects who have dose reduction or 
interruptions will be summarized using descriptive statistics. The number (ie, cumulative counts) 
and percentage of subjects exposed to study drug will be summarized by cycle, where each cycle 
consists of 28 days of therapy. Summaries will be provided by dose level for the Safety Analysis 
Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
ONO-4059POE001 collected number of doses dispensed but didn’t collect dose strength of the 
drug kit. GS-US-401-1787 collected number of tablets/capsules dispensed but subjects may 
receive different strength of tablets/capsules throughout the study. Due to the inconsistent way of 
drug dispensation data collection in the two studies, it’s not feasible to track total number of 
doses or total amount drug administered. Thus, drug adherence analysis will not be performed. 
A by-subject listing of study drug administration and drug accountability will be provided by 
subject ID number (in ascending order), and visit (in chronological order). 
A by-subject listing of study drug administration for subjects with dose modifications at any time 
will also be provided. 
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number of subjects who did not meet specific criteria by disease and dose level based on the 
All Enrolled Analysis Set. A by-subject listing will be provided for those subjects who did not 
meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the eligibility 
criterion (or criteria if more than 1 deviation) that subjects did not meet and related comments, 
if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by disease type and dose level for the All Enrolled Analysis Set. A 
by-subject listing will be provided for those subjects with important protocol deviation and will 
be sorted by subject ID number (in ascending order), and visit (in chronological order).
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (2019 nCOV [COVID-19]) pandemic, and 
the COVID-19 pandemic has caused a disruption in the regular visit schedules for this study. 
Some subjects were unable to attend onsite visits due to shelter in place guidelines, site closures, 


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or other reasons. This section provides how to handle special situations due to COVID-19 in the 
analysis.
Adverse events (AEs) due to COVID-19 will be included in AE analyses if applicable. A by-
subject listing of Adverse Events due to COVID-19 may be provided. The COVID-19 
Standardized MedDRA Queries (SMQ) with Broad Scope in Appendix 1 will be implemented.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-subject listing of reasons for premature study drug or study discontinuation due to COVID-
19 will be created.
4.4.2.
Protocol Deviations Due to COVID-19
A by-subject listing will be provided for subjects with important protocol deviation related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviation related to COVID-19.
4.4.3.
Missed and Virtual Visits Due to COVID-19
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
by subject ID number in ascending order .
Information regarding virtual or missed visits due to COVID-19 was collected as free text in the 
CRF comment fields. The determination of missing or virtual visits due to COVID-19 was done 
using Natural Language Processing (NLP) to search the CRF comment fields.  A detailed 
explanation of the algorithm is given in Appendix 2.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) were collected in the parent 
study, and will be summarized by disease type and dose level using descriptive statistics for age, 
and using number and percentage of subjects for sex, race, and ethnicity. The summary of 
demographic data will be provided for the FAS.
A by-subject demographic listing, including the informed consent date, will be provided and 
sorted by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include body weight (in kg), height (in cm), body mass index 
(BMI; in kg/m2), and ECOG Performance Status. These baseline characteristics were collected in 
the parent study, and will be summarized by disease type and dose level using descriptive 
statistics for continuous variables and using number and percentage of subjects for categorical 
variables. The summary of baseline characteristics will be provided for the FAS. No formal 
statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided and sorted by subject ID 
number in ascending order.
5.3.
Medical History
Medical history will be based on data collected in the parent study, and ongoing AE from the 
parent study collected as general medical history in the rollover study. 
Medical history data in the rollover study will not be coded. All medical history data including 
parent and rollover study will be listed only.
5.4.
Disease History
The disease history was collected in the parent study. A summary of disease-specific medical 
history will be provided for the Full Analysis Set.
Time since initial diagnosis (years) will be calculated as (first dosing date of study drug – date of 
initial diagnosis + 1) / 365.25. Time since initial diagnosis will be summarized using descriptive 
statistics for a continuous variable. 
Disease stage at screening will be summarized using number and percentage of subjects. History 
of the disease staging or prognostic characterization including FLIPI (follicular lymphoma 
international prognostic index), IPI (international prognostic index), or MIPI (Mantle cell 
lymphoma International prognostic index) for NHL subjects and Binet/Rai staging for CLL 
subjects, will be summarized.


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NHL disease subtypes (Diffuse Large B Cell Lymphoma [DLBCL], Mantle Cell Lymphoma 
[MCL], Follicular Lymphoma [FL], Small Lymphocytic Lymphoma [SLL], Waldenstrom’s 
macroglobulinemia [WM], and Other) as well as DLBCL subtypes will be summarized.
The DLBCL category may be further broken down to

DLBCL (ABC)

DLBCL (GCB)

DLBCL (other non-specified)
For CLL subjects, disease will be classified according to results for CLL prognostic markers as:

11q deletion (yes/no)

17p deletion (yes/no)

TP53 mutation (yes/no)

IgVh mutation (yes/no)
For both NHL and CLL, disease will also be classified based on response to last treatment as:

Refractory

Relapsed
A listing of disease-specific history will be provided.
5.5.
Prior Treatments
Prior treatments including prior systemic therapy, radio therapies, transplants and surgeries are 
collected in the parent study. The number of prior treatments a subject used in each of these 
categories will be summarized by disease type and dose level using the FAS. 
A listing will be provided for each category of the prior treatments.


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6.
EFFICACY ANALYSES
6.1.
Definition of Efficacy Endpoint
Subjects’ efficacy data will be integrated with the parent study as specified in Section 3.2. The 
efficacy analysis will be based on FAS defined in Section 3.1.2. 
The efficacy endpoints are: 

Overall response rate (ORR): defined as the proportion of subjects who achieve partial 
response (PR) or complete response (CR) in either the parent or roll-over study 

Progression free survival (PFS): defined as the interval from date of the first dose of 
tirabrutinib on the parent study to the earlier of the first documentation of definitive disease 
progression as assessed by the investigator, or death from any cause

Duration of response (DOR): defined as the interval from first documentation of CR or PR to 
the earlier of the first documentation of definitive disease progression as assessed by the 
investigator, or death from any cause in subjects who achieve a response.

Overall Survival (OS): defined as the interval from date of the first dose of tirabrutinib on the 
parent study until death from any cause
The response or definitive disease progression for ORR, PFS, and DOR are based on the 
Modified IWCLL Criteria {Hallek 2008} for CLL subjects and standardized response criteria for 
malignant lymphoma for NHL subjects {Cheson 2007, Owen 2013}.
6.2.
Analysis Methods for Efficacy Endpoints
6.2.1.
Overall Response Rate
Best overall response (BOR) is defined as the best response recorded after first dose and prior to 
the time of initiation of anti-cancer therapy other than the study treatment. BOR could be 
assessed as CR, PR, Stable Disease (SD), or Progressive Disease (PD). In addition, a response 
category of Not Evaluable (NE) is provided for situation in which there is inadequate 
information to otherwise categorize response status. 
Based on the investigator assessments, the following will be performed for the FAS by disease 
type and dose level: 

BOR will be summarized using the number and the percentage of subjects in each category.

ORR will be presented with corresponding 2-sided 95% exact confidence intervals (CIs) 
based on Clopper-Pearson method. Subjects who do not have sufficient baseline or on-study 
tumor assessments to characterize response will be counted as non-responders and included 
in the denominator in calculate of response rates.


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A by-subject listing of response will be provided by subject ID and by visit in ascending order. A 
by-subject listing of bone marrow results for those with CR will be provided by subject ID and 
by visit in ascending order.
6.2.2.
Progression-Free Survival
The date of definitive progression will be the time point at which progression is first identified 
by relevant radiographic, imaging, or clinical data. Subjects without progression or death will be 
censored at the last adequate post-baseline tumor assessment time. If subjects received the anti-
cancer therapy or have ≥ 2 consecutive missing post-baseline tumor assessments immediately 
before documented progression or death, they will be censored at the last adequate post-baseline 
tumor assessment time before starting anti-cancer therapy or before ≥ 2 consecutive missing 
assessments, whichever is earlier. If subjects don’t have an adequate baseline tumor assessment 
or any adequate post-baseline tumor assessments, they will be censored on the date of Study Day 
1 unless they died before or on the 2nd scheduled post-baseline tumor assessment without 
receiving anti-cancer therapy.
PFS in months = (date of event/censoring – date of first dose + 1) / 30.4375.
When imaging examinations for one visit are conducted on various dates, the following rules 
apply for the calculation of the assessment date:

The response date will be the last date associated with that particular imaging time point.

The progression date will be the first date associated with that particular imaging time point.
When the date of initiation of anticancer therapy other than the study treatment is incomplete or 
missing, the following algorithm will be followed:

If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month.

If day and month are missing but year is available, then the imputed day and month will be 
01Jan or the last day of the month for the last adequate disease assessment if they have the 
same year, whichever is later.
In case that PFS event is a death with incomplete date, the imputation algorithm is as specified in 
section 6.2.4.
The analysis of PFS will be performed using the Kaplan-Meier method for FAS. Medians, Q1, 
Q3, the proportion of subjects who are progression-free at 6, 12, 18, 24, 30, 36, 42, 48, and 
60 months from Study Day 1 will be provided along with corresponding 95% CIs. Kaplan-Meier 
curves will be provided. 
The follow-up time for PFS, defined as the interval from the first dosing date of study drug to the 
loss to PFS follow-up, will be summarized by treatment groups using statistics such as median, 


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Q1, Q3 with corresponding 95% CIs estimated with the reverse K-M method. The reverse K-M 
model switches the event/censoring indicators of subjects in the original PFS analysis with 
Kaplan-Meier method. It considers subjects lost to PFS follow-up as achieving the full 
follow-up, and the full follow-up time of those subjects who had disease progression or died 
could not be observed as it is “censored” by the event.
A listing will be provided for the information of subject PFS, date of progression or censor, and 
reason.
A listing will be provided for the information of post-treatment anticancer therapy.
6.2.3.
Duration of Response
DOR will be evaluated using investigator assessments based on subset of FAS subjects who 
achieve a CR or PR and maintain the response. DOR will be summarized using Kaplan-Meier 
methods (median, Q1, Q3, and corresponding 95% CI). The same censoring rules as for PFS will 
be applied to DOR.
DOR in months = (date of event/censoring – date of first response [CR or PR] + 1) / 30.4375.
A by-subject listing of DOR will be provided by subject ID number in ascending order.
6.2.4.
Overall Survival
Subjects who are lost to follow-up or survived until the end of study will be censored at the last 
date that they were known to be alive.
Every attempt will be made to ensure that complete death dates are recorded. In those rare 
instances where complete death dates are not recorded, the following algorithm will be used:

If day is missing but the month and year are available, then the imputed date will be the 
1st day of the month or the last known alive date + 1, whichever is later.

If day and month are missing but year is available, then the imputed date and month will be 
01Jan or the last known alive date + 1, whichever is later.


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If the last known alive date is not complete, the following algorithm will be used:

If day is missing but the month and year are available, then the imputed date will be the 
1st day of the month. 

If day and month are missing but year is available, then the imputed date and month will be 
01Jan
The analysis of OS will be performed using the Kaplan-Meier method for FAS. Medians, Q1, 
Q3, the proportion of subjects who are alive at 6, 12, 18, 24, 30, 36, 42, 48, and 60 months from 
Study Day 1 will be provided along with corresponding 95% CIs. Kaplan-Meier curves will be 
provided. A listing will be provided for the information of subject OS, date of death or censor, 
and reason.
The follow-up time for OS, defined as the interval from the first dosing date of study drug to the 
loss to follow-up, will be summarized by treatment groups using statistics such as median, Q1, 
Q3 with corresponding 95% CIs estimated with the reverse Kaplan-Meier (K-M) method. The 
reverse K-M model switches the event/censoring indicators of subjects in the original OS 
analysis with Kaplan-Meier method. It considers subjects lost to follow-up as achieving the full 
follow-up, and the full follow-up time of those subjects who died could not be observed as it is 
“censored” by death.


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7.
SAFETY ANALYSES
As specified in Section 3.2, subjects’ safety data of GS-US-401-1787 will be integrated with the 
parent study for all safety analysis. Some selected safety summaries will also be provided only 
using data from rollover study GS-US-401-1787.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) for the rollover study GS-US-401-1787 will be 
coded using the current version of MedDRA. The coding of clinical and laboratory adverse 
events for the completed parent study ONO-4059POE001 will be upversioned to the current 
version of MedDRA, and integrated with GS-US-401-1787 for analysis. System organ class 
(SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), and 
lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to CTCAE 
Version 4.03 in 401-1787, and CTCAE Version 4.0 in ONO-4059POE001. The severity grade of 
events for which the investigator did not record severity will be categorized as “missing” for 
tabular summaries and data listings. The missing category will be listed last in summary 
presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE case report form 
(CRF) to the question of “Related to Study Treatment.” Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE that were specified in the study protocol. Serious adverse events captured and stored in 
the clinical database will be reconciled with the SAE database from the Gilead 
Pharmacovigilance and Epidemiology Department before data finalization.


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7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date of parent study and no later 
than 30 days after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.
7.1.5.2.
Incomplete Dates
In case when the AE onset date is incomplete and needs to be imputed, the following algorithm 
will be followed:

If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the first dosing date if they have the same month and year, 
whichever is later.

If the day and month are missing but year is available, then the imputed day and month will 
be 01Jan or the first dosing date if they have the same year, whichever is later.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE Incidence by Severity 
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, and dose level. For other AEs described below, summaries will be 
provided by SOC, PT, maximum severity and dose level:

TEAEs

TEAEs of Grade 3 or higher

TE Treatment-related TEAEs

TE Treatment-related TEAEs of Grade 3 or higher


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
TE SAEs

TE treatment-related SAEs

TEAEs leading to dose modification of study drug

TEAEs leading to temporary interruption of study drug

TEAEs leading to discontinuation of study drug

TEAEs leading to discontinuation of study

TEAEs leading to death
A brief, high-level summary of AEs described above will be provided by dose level and by the 
number and percentage of subjects who experienced the above AEs. In addition, all death will 
also be included in this high-level summary. 
In addition, TEAE by PT only will also be summarized. 
In addition to the above summary tables, the following AE tables will also be provided using 
different grouping rule or data scope:
Data Scope
Grouping Rule
AE Summaries
Integrate data from both 
ONO-4059POE001 and GS-US-401-
1787

Combine all subjects 
regardless of disease type or 
dose level
Brief high-level summary of AE
TEAE, TEAEs of Grade 3 or higher, SAE, 
TEAE leading to death by SOC, PT, and 
Severity
Only data from GS-US-401-1787

Separate table by NHL and 
CLL

Combine all subjects 
regardless of disease type or 
dose level
Brief high-level summary of AE
TEAE, TEAEs of Grade 3 or higher, SAE, 
TEAE leading to death by SOC, PT, and 
Severity
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual subject during the study. 
In addition, data listings will be provided for the following:

All AEs

All AEs of Grade 3 or higher

SAEs


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
AEs leading to death

Deaths

AEs leading to discontinuation of study drug

AEs leading to dose modifications or temporary interruption of study drug

AEs leading to discontinuation of study
7.1.7.
Treatment-Emergent Adverse Events of Interest
The treatment-emergent AEs of interest (AEI) include:
AEI
Grouped Terms
Hemorrhage/Bleeding 
MST-CT Bleeding/Haemorrhage (Appendix 3)
Infections
SOC: Infections and infestations
Hypersensitivity
MST-CT Hypersensitivity (Appendix 4)
Cytopenia
MST: Anemia-related events, leukopenias, neutropenia, thrombocytopenias (Appendix 5)
Cardiac Arrhythmias
MST-CT Cardiac arrhythmia and bradycardia_narrow (Appendix 6)
Diarrhoea
PT: Diarrhoea
Rash
MST-CT Rash - specific to ONC (Appendix 7)
The following summaries will be provided for AEIs by SOC, PT, and maximum severity:

TEAE

TEAEs leading to dose modifications or temporary interruption of study drug

TEAEs leading to discontinuation of study drug
A data listing of AEIs will be provided by alphabetic ascending order of AEI name, then by 
subject ID.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory parameters listed in Appendix 8 
will be provided for the Safety Analysis Set and will include data collected up to the last dose of 
study drug plus 30 days for subjects who have permanently discontinued study drug. The 
analysis will be based on values reported in conventional units. When values are below the LOQ, 
they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. 


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A by-subject listing for laboratory test results will be provided by subject ID number and time 
point in chronological order for hematology, serum chemistry, and urinalysis separately. Values 
falling outside of the relevant reference range and/or having a severity grade of 1 or higher on 
the CTCAE severity grade will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics of selected laboratory results will be provided by treatment group as 
follows:

Baseline values 

Postbaseline maximum

Postbaseline minimum 

Change from baseline to postbaseline maximum

Change from baseline to postbaseline minimun
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug in parent study. Change from baseline to a postbaseline visit 
will be defined as the visit value minus the baseline value. Laboratory test results collected at 
unscheduled visits will be included for the baseline and postbaseline maximum and minimum 
value selection. The mean, median, Q1, Q3, minimum, and maximum values will be displayed to 
the reported number of digits; StD values will be displayed to the reported number of digits 
plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
7.2.2.
Graded Laboratory Values
CTCAE Version 4.03 will be used for assigning toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If the 
relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent. Local labs will be 
graded based on the central lab normal ranges with in-house macro. In the event that both central 
and local lab results are collected in the clinical database, the worst toxicity grade will be used 
for the summary of lab toxicities. All central and local laboratory values will be listed.


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7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from 
baseline by at least 3 toxicity grades at any postbaseline time point, up to and including the date 
of the last dose of study drug plus 30. If the relevant baseline laboratory value is missing, any 
Grade 3 or 4 values observed within the timeframe specified above will be considered 
treatment-emergent marked abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dosing date.
In addition to the summary above, the Graded laboratory abnormalities and Grade 3 or 4 
laboratory abnormalities will also be summarized using only the data from GS-US-401-1787.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities and marked 
laboratory abnormalities will be provided by subject ID number and visit in chronological order. 
This listing will include all test results that were collected throughout the study for the lab test of 
interest, with all applicable severity grades or abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements:

Aspartate aminotransferase (AST): (a) > 3 times of the upper limit of reference range (ULN); 
(b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Alanine aminotransferase (ALT): (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; 
(d) > 20 x ULN

AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Total bilirubin: > 2 x ULN

Alkaline phosphatase (ALP) > 1.5 x ULN

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The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, 
subjects will be counted once when the criteria are met at the same postbaseline visit date. The 
denominator is the number of subjects in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. A listing of subjects 
who met at least 1 of the above criteria will be provided.
7.2.4.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing change in severity grade from baseline to the worst 
postbaseline grade.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight, BMI, and vital signs 
as follows:

Baseline value

Postbaseline maximum

Postbaseline minimum

Change and percent change from baseline to postbaseline maximum

Change and percent change from baseline to postbaseline minimum
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug in the parent study. Change from baseline to a postbaseline visit will 
be defined as the postbaseline value minus the baseline value. Body weight and vital signs 
measured at unscheduled visits will be included for the baseline value selection, and postbaseline 
maximum and minimum value selection. 
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. Body weight and BMI will be included in the vital signs listing, if space 
permits. If not, they will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected in the GS-US-401-1787 study will be coded using the current version of 
the World Health Organization (WHO) Drug dictionary. The coding of Medications collected in 
the parent study ONO-4059POE001 will be upversioned to the current version of WHODrug, 
and integrated with GS-US-401-1787 for analysis.
7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study drug 
of parent study.


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Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class 
Level 2 and preferred name using the number and percentage of subjects for each treatment 
group and overall. A subject reporting the same medication more than once will be counted only 
once when calculating the number and percentage of subjects who received that medication. The 
summary will be ordered alphabetically by ATC medical class and then by preferred term in 
order of descending overall frequency within each ATC medical class. For drugs with the same 
frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the 
first dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
drug class Level 2 and preferred name using the number and percentage of subjects for each 
treatment group. A subject reporting the same medication more than once will be counted only 
once when calculating the number and percentage of subjects who received that medication. The 
summary will be ordered alphabetically by ATC medical class and then by preferred term in 
descending overall frequency within each ATC medical class. For drugs with the same 
frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to or on the first dosing date 
of study drug and continued to take after the first dosing date, or started after the first dosing date 
but prior to or on the last dosing date of study drug will be considered concomitant medications. 
Medications started and stopped on the same day as the first dosing date or the last dosing date of 
study drug will also be considered concomitant. Medications with a stop date prior to the date of 
first dosing date of study drug or a start date after the last dosing date of study drug will be 
excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Summaries will be based on the Safety Analysis Set. No formal statistical testing is 
planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.


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7.5.
Electrocardiogram Results
Electrocardiogram (ECG) analysis results are intended to identify meaningful changes in the QT 
interval. If potential abnormalities of interest are identified, further analyses may be conducted. 
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by treatment group using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline or postbaseline will not be included in the denominator 
for percentage calculation. No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and time 
point in chronological order.
7.6.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
Pharmacokinetics (PK) Sample Collection
Plasma samples for PK will be collected to measure concentrations of tirabrutinib at pre-dose of 
GS-US-401-1787 Cycles 2 and 3 only.
8.2.
Statistical Analysis Methods
8.2.1.
Tirabrutinib Plasma Concentration
PK concentration data from GS-US-401-1787 will be summarized. PK analysis set will be 
grouped as specified in Section 3.2.
Tirabrutinib plasma concentration data will be summarized using descriptive statistics for 
subjects in the PK Analysis Set by time point and visit. Subjects in different dose levels will be 
presented separately. The sample size for each time point will be based on the number of 
subjects with nonmissing concentration data at that time point. The number of subjects with 
concentration BLQ will be presented for each time point. For summary statistics, BLQ values 
will be treated as 0 at predose and one-half of the lower limit of quantitation (LLOQ) for 
postdose time points.
The following table will be provided by disease type and dose level:

Individual subject concentration data and summary statistics
Tirabrutinib plasma concentration data and PK sampling details will be listed for all subjects in 
the PK Analysis Set.
8.3.
Changes From Protocol-Specified PK Analyses
There are no deviations from the protocol-specified pharmacokinetic analyses.


Tirabrutinib (GS-4059)
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Statistical Analysis Plan – Final Analysis
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9.
REFERENCES
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25 (5):579-86.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines 
for the diagnosis and treatment of chronic lymphocytic leukemia: a report from 
the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56.
Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response assessment 
in Waldenstrom macroglobulinaemia: update from the VIth International 
Workshop. Br J Haematol 2013;160 (2):171-6.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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Statistical Analysis Plan – Final Analysis
Version 3.0
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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
10 Apr 2020, version 2.0
1.2.2
Update the 401-1787 study design to 
maximum duration of 5 years 
treatment, per the protocol 
amendment 5 dated 29 October 2019
Align with protocol amendment 
5 dated 29 October 2019
10 Apr 2020, version 2.0
2.1, 
3.1.2, 
6
Administrative changes 
Language clarification
10 Apr 2020, version 2.0
6.2.2
Added PFS follow-up time analysis
To add additional analysis per 
new Gilead oncology standard
10 Apr 2020, version 2.0
6.2.2
Revised the data imputation rule for 
incomplete date of anti-cancer 
therapy
Update per Gilead oncology 
standard
10 Apr 2020, version 2.0
6.2.4
Added OS follow-up time analysis
To add additional analysis per 
new Gilead oncology standard
10 February 2021, version 
3.0
4.4
Added the section to provide how to 
handle special situations due to 
COVID-19 in the analysis
To assess the COVID-19 
impact


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Statistical Analysis Plan – Final Analysis
Version 3.0
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12.
APPENDICES
Appendix 1.
COVID-19 SMQ with Broad Scope
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19
Appendix 3.
Bleeding/Haemorrhage Medical Search Term
Appendix 4.
Hypersensitivity Medical Search Term
Appendix 5.
Cytopenia Medical Search Term
Appendix 6.
Cardiac arrhythmia Medical Search Term
Appendix 7.
Rash Medical Search Term
Appendix 8.
List of Laboratory Tests for Safety Summary


Tirabrutinib (GS-4059)
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Statistical Analysis Plan – Final Analysis
Version 3.0
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Appendix 1.
COVID-19 SMQ with Broad Scope
Note: The list presented below is based on MedDRA Version 23.1. The actual list will be 
up-versioned to the MedDRA version used at the time of database finalization.
MedDRA Preferred Term
PT Code
Asymptomatic COVID-19
10084459
Coronavirus infection
10051905
Coronavirus test positive
10070255
COVID-19
10084268
COVID-19 immunisation
10084457
COVID-19 pneumonia
10084380
COVID-19 prophylaxis
10084458
COVID-19 treatment
10084460
Exposure to SARS-CoV-2
10084456
Multisystem inflammatory syndrome in children
10084767
Occupational exposure to SARS-CoV-2
10084394
SARS-CoV-2 antibody test positive
10084491
SARS-CoV-2 carrier
10084461
SARS-CoV-2 sepsis
10084639
SARS-CoV-2 test false negative
10084480
SARS-CoV-2 test positive
10084271
SARS-CoV-2 viraemia
10084640
Suspected COVID-19
10084451
Antiviral prophylaxis
10049087
Antiviral treatment
10068724
Coronavirus test
10084353
Coronavirus test negative
10084269
Exposure to communicable disease
10049711
Pneumonia viral
10035737
SARS-CoV-2 antibody test
10084501
SARS-CoV-2 antibody test negative
10084509
SARS-CoV-2 test
10084354
SARS-CoV-2 test false positive
10084602
SARS-CoV-2 test negative
10084273


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Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm used to determine which visits were 
missing and which visits were virtual.
Data collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by data 
management to instruct clinical trial sites with respect to data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic.  If a visit was missed, sites should enter “Visit 
missed due to COVID-19.”  If an in-person visit was conducted virtually, sites should enter 
“Virtual visit due to COVID-19.”  
Determination of Missed and Virtual visits
NLP was used to search the CRF comment fields to identify instances of “COVID-19” (or 
synonyms, see the table below) and “Virtual” (or synonyms, see the table below).  The search 
terms are maintained in a global lookup table and can be modified to tune the NLP model.  For 
any comments with COVID-19 search terms, assign “Missed visit” or “Virtual visit as follows:
i.
If COVID-19 terms are identified through NLP and the visit date is missing, then 
result is “Missed Visit”
ii.
If COVID-19 and Virtual terms are identified through NLP for a visit, then result 
is “Virtual Visit”. When there are multiple records for the same subject and the 
same visit, NLP will be based on multiple records to ensure 1 unique category per 
subject per visit
iii.
Otherwise result is missing
 


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Statistical Analysis Plan – Final Analysis
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Examples of Search Terms for “COVID-19” and “Virtual” Used to Identify Missed and 
Virtual Visits
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE 
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


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Version 3.0
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Appendix 3.
Bleeding/Haemorrhage Medical Search Term
Note: The list presented below is based on MedDRA Version 22.0. The actual list will be 
up-versioned to the MedDRA version used at the time of database finalization.
MedDRA Preferred Term 
PT Code
Abdominal wall haematoma
10067383
Haemorrhagic adrenal infarction
10079902
Eye haematoma
10079891
Spontaneous hyphaema
10080110
Anal fissure haemorrhage
10079765
Paranasal sinus haemorrhage
10080108
Peripheral artery aneurysm rupture
10079908
Aortic annulus rupture
10079586
Peripheral artery haematoma
10081077
Subgaleal haemorrhage
10080900
Von Willebrand's factor antibody
10080829
Nephritis haemorrhagic
10029132
Renal cyst haemorrhage
10059846
Renal haematoma
10038459
Renal haemorrhage
10038460
Ureteric haemorrhage
10065743
Extraischaemic cerebral haematoma
10080347
Gastrointestinal vascular malformation 
haemorrhagic
10080561
Abdominal wall haemorrhage
10067788
Abnormal clotting factor
10049862
Abnormal withdrawal bleeding
10069195
Acquired dysfibrinogenaemia
10051122
Acquired haemophilia
10053745
Acquired haemophilia with anti FVIII, XI, 
or XIII
10056496
Acquired protein S deficiency
10068370
Acquired Von Willebrand's disease
10069495
Activated partial thromboplastin time 
abnormal
10000631
Activated partial thromboplastin time 
prolonged
10000636
MedDRA Preferred Term 
PT Code
Activated partial thromboplastin time ratio 
abnormal
10075284
Activated partial thromboplastin time ratio 
fluctuation
10075286
Activated partial thromboplastin time ratio 
increased
10075287
Acute haemorrhagic leukoencephalitis
10058994
Acute haemorrhagic ulcerative colitis
10075634
Administration site bruise
10075094
Administration site haematoma
10075100
Administration site haemorrhage
10075101
Adrenal haematoma
10059194
Adrenal haemorrhage
10001361
Anal haemorrhage
10049555
Anal ulcer haemorrhage
10063896
Anastomotic haemorrhage
10056346
Anastomotic ulcer haemorrhage
10002244
Aneurysm ruptured
10048380
Angina bullosa haemorrhagica
10064223
Anorectal varices haemorrhage
10068925
Anti factor IX antibody positive
10058748
Anti factor V antibody positive
10058745
Anti factor VII antibody positive
10058746
Anti factor VIII antibody positive
10049013
Anti factor X activity abnormal
10077670
Anti factor X activity increased
10077671
Anti factor X antibody positive
10058747
Anti factor XI antibody positive
10058749
Anti factor XII antibody positive
10058750
Antithrombin III increased
10051115
Aortic aneurysm rupture
10002886
Aortic dissection rupture
10068119
Aortic intramural haematoma
10067975


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MedDRA Preferred Term 
PT Code
Aortic perforation
10075729
Aortic rupture
10060874
Aponeurosis contusion
10075330
Application site bruise
10050114
Application site haematoma
10068317
Application site haemorrhage
10072694
Application site purpura
10050182
Arterial haemorrhage
10060964
Arterial intramural haematoma
10074971
Arterial ligation
10003165
Arterial perforation
10075732
Arterial rupture
10003173
Arteriovenous fistula site haematoma
10055150
Arteriovenous fistula site haemorrhage
10055123
Arteriovenous graft site haematoma
10055152
Arteriovenous graft site haemorrhage
10055126
Atrial rupture
10048761
Auricular haematoma
10003797
Basal ganglia haematoma
10077031
Basal ganglia haemorrhage
10067057
Basilar artery perforation
10075736
Benign familial haematuria
10060876
Bladder tamponade
10062656
Bleeding time abnormal
10049227
Bleeding time prolonged
10005140
Bleeding varicose vein
10005144
Blood blister
10005372
Blood fibrinogen abnormal
10005518
Blood fibrinogen decreased
10005520
Blood thrombin abnormal
10005818
Blood thrombin decreased
10005820
Blood thromboplastin abnormal
10005824
Blood thromboplastin decreased
10005826
Blood urine
10005863
Blood urine present
10018870
MedDRA Preferred Term 
PT Code
Bloody discharge
10057687
Bloody peritoneal effluent
10067442
Bone contusion
10066251
Bone marrow haemorrhage
10073581
Brain contusion
10052346
Brain stem haematoma
10073230
Brain stem haemorrhage
10006145
Brain stem microhaemorrhage
10071205
Breast haematoma
10064753
Breast haemorrhage
10006254
Broad ligament haematoma
10006375
Bronchial haemorrhage
10065739
Bronchial varices haemorrhage
10079163
Bursal haematoma
10077818
Capillary fragility abnormal
10007192
Capillary fragility increased
10007194
Capillary permeability increased
10007200
Cardiac contusion
10073356
Carotid aneurysm rupture
10051328
Carotid artery perforation
10075728
Catheter site bruise
10063587
Catheter site haematoma
10055662
Catheter site haemorrhage
10051099
Central nervous system haemorrhage
10072043
Cephalhaematoma
10008014
Cerebellar haematoma
10061038
Cerebellar haemorrhage
10008030
Cerebellar microhaemorrhage
10071206
Cerebral aneurysm perforation
10075394
Cerebral aneurysm ruptured syphilitic
10008076
Cerebral arteriovenous malformation 
haemorrhagic
10008086
Cerebral artery perforation
10075734
Cerebral haematoma
10053942
Cerebral haemorrhage
10008111


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MedDRA Preferred Term 
PT Code
Cerebral haemorrhage foetal
10050157
Cerebral haemorrhage neonatal
10008112
Cerebral microhaemorrhage
10067277
Cervix haematoma uterine
10050020
Cervix haemorrhage uterine
10050022
Chest wall haematoma
10076597
Choroidal haematoma
10068642
Choroidal haemorrhage
10008786
Chronic gastrointestinal bleeding
10050399
Chronic pigmented purpura
10072726
Ciliary body haemorrhage
10057417
Circulating anticoagulant
10053627
Clot retraction abnormal
10009669
Clot retraction time prolonged
10009675
Coagulation disorder neonatal
10009732
Coagulation factor decreased
10009736
Coagulation factor deficiency
10067787
Coagulation factor IX level abnormal
10061770
Coagulation factor IX level decreased
10009746
Coagulation factor mutation
10065442
Coagulation factor V level abnormal
10061771
Coagulation factor V level decreased
10009754
Coagulation factor VII level abnormal
10061772
Coagulation factor VII level decreased
10009761
Coagulation factor VIII level abnormal
10061773
Coagulation factor VIII level decreased
10009768
Coagulation factor X level abnormal
10061774
Coagulation factor X level decreased
10009775
Coagulation factor XI level abnormal
10061775
Coagulation factor XI level decreased
10009779
Coagulation factor XII level abnormal
10061776
Coagulation factor XII level decreased
10009783
Coagulation factor XIII level abnormal
10061777
Coagulation factor XIII level decreased
10009787
Coagulation time abnormal
10009791
MedDRA Preferred Term 
PT Code
Coagulation time prolonged
10009799
Coagulopathy
10009802
Coital bleeding
10065019
Colonic haematoma
10009996
Congenital coagulopathy
10063563
Congenital dysfibrinogenaemia
10051123
Conjunctival haemorrhage
10010719
Contusion
10050584
Corneal bleeding
10051558
Cullen's sign
10059029
Cystitis haemorrhagic
10011793
Deep dissecting haematoma
10074718
Diarrhoea haemorrhagic
10012741
Dilutional coagulopathy
10060906
Disseminated intravascular coagulation
10013442
Diverticulitis intestinal haemorrhagic
10013541
Diverticulum intestinal haemorrhagic
10013560
Duodenal ulcer haemorrhage
10013839
Duodenitis haemorrhagic
10013865
Dysfunctional uterine bleeding
10013908
Ear haemorrhage
10014009
Ecchymosis
10014080
Encephalitis haemorrhagic
10014589
Endometriosis
10014778
Enterocolitis haemorrhagic
10014896
Epidural haemorrhage
10073681
Epistaxis
10015090
Ethanol gelation test positive
10062650
Exsanguination
10015719
Extra-axial haemorrhage
10078254
Extradural haematoma
10015769
Extravasation blood
10015867
Eye contusion
10073354
Eye haemorrhage
10015926
Eyelid bleeding
10053196


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MedDRA Preferred Term 
PT Code
Eyelid contusion
10075018
Eyelid haematoma
10064976
Factor I deficiency
10016075
Factor II deficiency
10016076
Factor III deficiency
10052473
Factor IX deficiency
10016077
Factor V deficiency
10048930
Factor VII deficiency
10016079
Factor VIII deficiency
10016080
Factor X deficiency
10052474
Factor Xa activity abnormal
10078667
Factor Xa activity decreased
10078676
Factor XI deficiency
10016082
Factor XII deficiency
10051806
Factor XIII deficiency
10016083
Femoral artery perforation
10075739
Femoral vein perforation
10075745
Fibrin abnormal
10016575
Fibrin D dimer decreased
10016579
Fibrin D dimer increased
10016581
Fibrin decreased
10016584
Fibrin degradation products
10016585
Fibrin degradation products increased
10016588
Fibrinolysis abnormal
10016604
Fibrinolysis increased
10016607
Foetal-maternal haemorrhage
10016871
Fothergill sign positive
10081749
Gardner-Diamond syndrome
10078888
Gastric haemorrhage
10017788
Gastric occult blood positive
10067855
Gastric ulcer haemorrhage
10017826
Gastric ulcer haemorrhage, obstructive
10017829
Gastric varices haemorrhage
10057572
Gastritis alcoholic haemorrhagic
10017857
Gastritis haemorrhagic
10017866
MedDRA Preferred Term 
PT Code
Gastroduodenal haemorrhage
10053768
Gastrointestinal angiectasia
10078142
Gastrointestinal haemorrhage
10017955
Gastrointestinal organ contusion
10078655
Gastrointestinal polyp haemorrhage
10074437
Gastrointestinal ulcer haemorrhage
10056743
Genital contusion
10073355
Genital haemorrhage
10061178
Gingival bleeding
10018276
Graft haemorrhage
10063577
Grey Turner's sign
10075426
Haemarthrosis
10018829
Haematemesis
10018830
Haematochezia
10018836
Haematocoele
10018833
Haematoma
10018852
Haematoma evacuation
10060733
Haematoma infection
10051564
Haematosalpinx
10050468
Haematospermia
10018866
Haematotympanum
10063013
Haematuria
10018867
Haematuria traumatic
10018871
Haemobilia
10058947
Haemophilia
10061992
Haemophilia A with anti factor VIII
10056492
Haemophilia A without inhibitors
10056493
Haemophilia B with anti factor IX
10056494
Haemophilia B without inhibitors
10056495
Haemophilic arthropathy
10065057
Haemophilic pseudotumour
10073770
Haemoptysis
10018964
Haemorrhage
10055798
Haemorrhage coronary artery
10055803
Haemorrhage foetal
10061191


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MedDRA Preferred Term 
PT Code
Haemorrhage in pregnancy
10018981
Haemorrhage intracranial
10018985
Haemorrhage neonatal
10061993
Haemorrhage subcutaneous
10018999
Haemorrhage subepidermal
10019001
Haemorrhage urinary tract
10055847
Blood loss anaemia
10082297
Haemorrhagic arteriovenous malformation
10064595
Haemorrhagic ascites
10059766
Haemorrhagic breast cyst
10077443
Haemorrhagic cerebral infarction
10019005
Haemorrhagic cyst
10059189
Haemorrhagic diathesis
10062713
Haemorrhagic disease of newborn
10019008
Haemorrhagic disorder
10019009
Haemorrhagic erosive gastritis
10067786
Haemorrhagic hepatic cyst
10067796
Haemorrhagic infarction
10019013
Haemorrhagic necrotic pancreatitis
10076058
Haemorrhagic ovarian cyst
10060781
Haemorrhagic pneumonia
10077933
Haemorrhagic stroke
10019016
Haemorrhagic thyroid cyst
10072256
Haemorrhagic transformation stroke
10055677
Haemorrhagic tumour necrosis
10054096
Haemorrhagic urticaria
10059499
Haemorrhagic varicella syndrome
10078873
Haemorrhagic vasculitis
10071252
Haemorrhoidal haemorrhage
10054787
Haemostasis
10067439
Haemothorax
10019027
Henoch-Schonlein purpura
10019617
Hepatic haemangioma rupture
10054885
Hepatic haematoma
10019676
Hepatic haemorrhage
10019677
MedDRA Preferred Term 
PT Code
Hereditary haemorrhagic telangiectasia
10019883
Hermansky-Pudlak syndrome
10071775
Hyperfibrinolysis
10074737
Hyphaema
10020923
Hypocoagulable state
10020973
Hypofibrinogenaemia
10051125
Hypoprothrombinaemia
10021085
Hypothrombinaemia
10058517
Hypothromboplastinaemia
10058518
Iliac artery perforation
10075731
Iliac artery rupture
10072789
Iliac vein perforation
10075744
Immune thrombocytopenic purpura
10074667
Implant site bruising
10063850
Implant site haematoma
10063780
Implant site haemorrhage
10053995
Incision site haematoma
10059241
Incision site haemorrhage
10051100
Increased tendency to bruise
10021688
Induced abortion haemorrhage
10052844
Inferior vena cava perforation
10075742
Infusion site bruising
10059203
Infusion site haematoma
10065463
Infusion site haemorrhage
10065464
Injection site bruising
10022052
Injection site haematoma
10022066
Injection site haemorrhage
10022067
Instillation site bruise
10073630
Instillation site haematoma
10073609
Instillation site haemorrhage
10073610
Internal haemorrhage
10075192
International normalised ratio abnormal
10022592
International normalised ratio increased
10022595
Intestinal haematoma
10069829
Intestinal haemorrhage
10059175


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MedDRA Preferred Term 
PT Code
Intestinal varices haemorrhage
10078058
Intra-abdominal haematoma
10056457
Intra-abdominal haemorrhage
10061249
Intracerebral haematoma evacuation
10062025
Intracranial haematoma
10059491
Intracranial tumour haemorrhage
10022775
Intraocular haematoma
10071934
Intrapartum haemorrhage
10067703
Intraventricular haemorrhage
10022840
Intraventricular haemorrhage neonatal
10022841
Iris haemorrhage
10057418
Joint microhaemorrhage
10077666
Kidney contusion
10023413
Lacrimal haemorrhage
10069930
Large intestinal haemorrhage
10052534
Large intestinal ulcer haemorrhage
10061262
Laryngeal haematoma
10070885
Laryngeal haemorrhage
10065740
Lip haematoma
10066304
Lip haemorrhage
10049297
Liver contusion
10067266
Lower gastrointestinal haemorrhage
10050953
Lower limb artery perforation
10075730
Lymph node haemorrhage
10074270
Mallory-Weiss syndrome
10026712
Mediastinal haematoma
10049941
Mediastinal haemorrhage
10056343
Medical device site bruise
10075570
Medical device site haematoma
10075577
Medical device site haemorrhage
10075578
Melaena
10027141
Melaena neonatal
10049777
Meningorrhagia
10052593
Menometrorrhagia
10027295
Menorrhagia
10027313
MedDRA Preferred Term 
PT Code
Mesenteric haematoma
10071557
Mesenteric haemorrhage
10060717
Metrorrhagia
10027514
Mouth haemorrhage
10028024
Mucocutaneous haemorrhage
10076048
Mucosal haemorrhage
10061298
Muscle contusion
10070757
Muscle haemorrhage
10028309
Myocardial haemorrhage
10048849
Myocardial rupture
10028604
Naevus haemorrhage
10062955
Nail bed bleeding
10048891
Nasal septum haematoma
10075027
Neonatal gastrointestinal haemorrhage
10074159
Nipple exudate bloody
10029418
Occult blood positive
10061880
Ocular retrobulbar haemorrhage
10057571
Oesophageal haemorrhage
10030172
Oesophageal intramural haematoma
10077486
Oesophageal ulcer haemorrhage
10030202
Oesophageal varices haemorrhage
10030210
Oesophagitis haemorrhagic
10030219
Optic disc haemorrhage
10030919
Optic nerve sheath haemorrhage
10030941
Oral contusion
10078170
Oral mucosa haematoma
10074779
Osteorrhagia
10051937
Ovarian haematoma
10033263
Ovarian haemorrhage
10065741
Palpable purpura
10056872
Pancreatic contusion
10078654
Pancreatic haemorrhage
10033625
Pancreatitis haemorrhagic
10033650
Papillary muscle haemorrhage
10059164
Paranasal sinus haematoma
10069702


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Version 3.0
CONFIDENTIAL
Page 47
10 February 2021
MedDRA Preferred Term 
PT Code
Parathyroid haemorrhage
10059051
Parotid gland haemorrhage
10051166
Pelvic haematoma
10054974
Pelvic haematoma obstetric
10034248
Pelvic haemorrhage
10063678
Penile contusion
10073352
Penile haematoma
10070656
Penile haemorrhage
10034305
Peptic ulcer haemorrhage
10034344
Pericardial haemorrhage
10034476
Perineal haematoma
10034520
Periorbital haematoma
10034544
Periorbital haemorrhage
10071697
Periosteal haematoma
10077341
Peripartum haemorrhage
10072693
Perirenal haematoma
10049450
Peritoneal haematoma
10058095
Peritoneal haemorrhage
10034666
Periventricular haemorrhage neonatal
10076706
Petechiae
10034754
Pharyngeal haematoma
10068121
Pharyngeal haemorrhage
10034827
Pituitary haemorrhage
10049760
Placenta praevia haemorrhage
10035121
Plasminogen activator inhibitor
10059620
Plasminogen activator inhibitor decreased
10059619
Plasminogen decreased
10035493
Plasminogen increased
10035495
Platelet factor 4 decreased
10060220
Polymenorrhagia
10064050
Post abortion haemorrhage
10036246
Post procedural contusion
10073353
Post procedural haematoma
10063188
Post procedural haematuria
10066225
Post procedural haemorrhage
10051077
MedDRA Preferred Term 
PT Code
Post transfusion purpura
10072265
Postmenopausal haemorrhage
10055870
Postpartum haemorrhage
10036417
Post-traumatic punctate intraepidermal 
haemorrhage
10071639
Procedural haemorrhage
10071229
Proctitis haemorrhagic
10036778
Prostatic haemorrhage
10036960
Protein C increased
10060230
Protein S abnormal
10051736
Protein S increased
10051735
Prothrombin level abnormal
10037048
Prothrombin level decreased
10037050
Prothrombin time abnormal
10037057
Prothrombin time prolonged
10037063
Prothrombin time ratio abnormal
10061918
Prothrombin time ratio increased
10037068
Pulmonary alveolar haemorrhage
10037313
Pulmonary contusion
10037370
Pulmonary haematoma
10054991
Pulmonary haemorrhage
10037394
Puncture site haemorrhage
10051101
Purpura
10037549
Purpura fulminans
10037556
Purpura neonatal
10037557
Purpura non-thrombocytopenic
10057739
Purpura senile
10037560
Putamen haemorrhage
10058940
Radiation associated haemorrhage
10072281
Rectal haemorrhage
10038063
Rectal ulcer haemorrhage
10038081
Renal artery perforation
10075737
Respiratory tract haemorrhage
10038727
Respiratory tract haemorrhage neonatal
10038728
Retinal aneurysm rupture
10079121


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 48
10 February 2021
MedDRA Preferred Term 
PT Code
Retinal haemorrhage
10038867
Retinopathy haemorrhagic
10051447
Retroperitoneal haematoma
10058360
Retroperitoneal haemorrhage
10038980
Retroplacental haematoma
10054798
Ruptured cerebral aneurysm
10039330
Russell's viper venom time abnormal
10059759
Scleral haemorrhage
10050508
Scrotal haematocoele
10061517
Scrotal haematoma
10039749
Shock haemorrhagic
10049771
Skin haemorrhage
10064265
Skin neoplasm bleeding
10060712
Skin ulcer haemorrhage
10050377
Small intestinal haemorrhage
10052535
Small intestinal ulcer haemorrhage
10061550
Soft tissue haemorrhage
10051297
Spermatic cord haemorrhage
10065742
Spinal cord haematoma
10076051
Spinal cord haemorrhage
10048992
Spinal epidural haematoma
10050162
Spinal epidural haemorrhage
10049236
Spinal subarachnoid haemorrhage
10073564
Spinal subdural haematoma
10050164
Spinal subdural haemorrhage
10073563
Spleen contusion
10073533
Splenic artery perforation
10075738
Splenic haematoma
10041646
Splenic haemorrhage
10041647
Splenic varices haemorrhage
10068662
Splinter haemorrhages
10041663
Spontaneous haematoma
10065304
Spontaneous haemorrhage
10074557
Stoma site haemorrhage
10074508
Stomatitis haemorrhagic
10042132
MedDRA Preferred Term 
PT Code
Subarachnoid haematoma
10076701
Subarachnoid haemorrhage
10042316
Subarachnoid haemorrhage neonatal
10042317
Subchorionic haematoma
10072596
Subchorionic haemorrhage
10071010
Subclavian artery perforation
10075740
Subclavian vein perforation
10075743
Subcutaneous haematoma
10042345
Subdural haematoma
10042361
Subdural haematoma evacuation
10042363
Subdural haemorrhage
10042364
Subdural haemorrhage neonatal
10042365
Subgaleal haematoma
10069510
Subretinal haematoma
10071935
Superior vena cava perforation
10075741
Testicular haemorrhage
10051877
Thalamus haemorrhage
10058939
Third stage postpartum haemorrhage
10043449
Thoracic haemorrhage
10062744
Thrombin time abnormal
10051319
Thrombin time prolonged
10051390
Thrombin-antithrombin III complex 
abnormal
10053972
Thrombin-antithrombin III complex 
increased
10053968
Thrombocytopenic purpura
10043561
Thrombotic thrombocytopenic purpura
10043648
Thyroid haemorrhage
10064224
Tongue haematoma
10043959
Tongue haemorrhage
10049870
Tonsillar haemorrhage
10057450
Tooth pulp haemorrhage
10072228
Tooth socket haemorrhage
10064946
Tracheal haemorrhage
10062543
Traumatic haematoma
10044522
Traumatic haemorrhage
10053476


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 49
10 February 2021
MedDRA Preferred Term 
PT Code
Traumatic haemothorax
10074487
Traumatic intracranial haematoma
10079013
Traumatic intracranial haemorrhage
10061387
Tumour haemorrhage
10049750
Ulcer haemorrhage
10061577
Umbilical cord haemorrhage
10064534
Umbilical haematoma
10068712
Umbilical haemorrhage
10045455
Upper gastrointestinal haemorrhage
10046274
Urethral haemorrhage
10049710
Urinary bladder haemorrhage
10046528
Urogenital haemorrhage
10050058
Uterine haematoma
10063875
Uterine haemorrhage
10046788
Vaccination site bruising
10069484
Vaccination site haematoma
10069472
Vaccination site haemorrhage
10069475
Vaginal haematoma
10046909
Vaginal haemorrhage
10046910
Varicose vein ruptured
10046999
Vascular access site bruising
10077767
Vascular access site haematoma
10077647
Vascular access site haemorrhage
10077643
Vascular access site rupture
10077652
Vascular graft haemorrhage
10077721
Vascular pseudoaneurysm ruptured
10053949
Vascular purpura
10047097
Vascular rupture
10053649
Vein rupture
10077110
Venous haemorrhage
10065441
MedDRA Preferred Term 
PT Code
Venous perforation
10075733
Ventricle rupture
10047279
Vertebral artery perforation
10075735
Vessel puncture site bruise
10063881
Vessel puncture site haematoma
10065902
Vessel puncture site haemorrhage
10054092
Vitreous haematoma
10071936
Vitreous haemorrhage
10047655
Von Willebrand's disease
10047715
Von Willebrand's factor antibody positive
10066358
Von Willebrand's factor multimers 
abnormal
10055165
Vulval haematoma
10047756
Vulval haematoma evacuation
10047757
Vulval haemorrhage
10063816
White nipple sign
10078438
Withdrawal bleed
10047998
Wound haematoma
10071504
Cerebral cyst haemorrhage
10082099
Pituitary apoplexy
10056447
Haematoma muscle
10055890
Battle's sign
10082307
Puncture site bruise
10082035
Haemorrhagic cholecystitis
10082088
Puncture site haematoma
10081957
Subendocardial haemorrhage
10082459
Acute haemorrhagic oedema of infancy
10070599
Wound haemorrhage
10051373


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 50
10 February 2021
Appendix 4.
Hypersensitivity Medical Search Term
Note: The list presented below is based on a SMQ in MedDRA Version 22.0. The actual list will 
be up-versioned to the MedDRA version used at the time of database finalization. 
MedDRA Preferred Term
PT Code
Acute respiratory failure
10001053
Alveolitis
10001889
Anaphylactic reaction
10002198
Anaphylactic shock
10002199
Anaphylactoid reaction
10002216
Anaphylaxis treatment
10002222
Angioedema
10002424
Application site dermatitis
10003036
Application site rash
10003054
Asthma
10003553
Asthma late onset
10003559
Atopy
10003645
Auricular swelling
10003800
Blepharitis allergic
10005149
Blister
10005191
Blood immunoglobulin A abnormal
10005584
Blood immunoglobulin A increased
10005586
Blood immunoglobulin E abnormal
10005589
Blood immunoglobulin E increased
10005591
Blood immunoglobulin G abnormal
10005594
Blood immunoglobulin G increased
10005596
Blood immunoglobulin M abnormal
10005599
Blood immunoglobulin M increased
10005601
Bromoderma
10006404
Bronchospasm
10006482
Bullous impetigo
10006563
Charcot-Leyden crystals
10008413
Cheilitis
10008417
Choking
10008589
Choking sensation
10008590
Circulatory collapse
10009192
Conjunctival oedema
10010726
MedDRA Preferred Term
PT Code
Conjunctivitis
10010741
Conjunctivitis allergic
10010744
Contrast media reaction
10010836
Corneal oedema
10011033
Cutaneous vasculitis
10011686
Dermatitis
10012431
Dermatitis acneiform
10012432
Dermatitis allergic
10012434
Dermatitis atopic
10012438
Dermatitis bullous
10012441
Dermatitis contact
10012442
Dermatitis exfoliative
10012455
Dermatitis exfoliative generalised
10012456
Dermatitis herpetiformis
10012468
Dermatitis infected
10012470
Drug eruption
10013687
Drug hypersensitivity
10013700
Ear swelling
10014025
Eczema
10014184
Eczema infantile
10014198
Eczema nummular
10014201
Encephalopathy allergic
10014627
Eosinophil count increased
10014945
Eosinophilia
10014950
Eosinophilia myalgia syndrome
10014952
Eosinophilic pneumonia
10014962
Epidermolysis bullosa
10014989
Epiglottic oedema
10015029
Erythema
10015150
Erythema multiforme
10015218
Erythema nodosum
10015226
Eye allergy
10015907


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Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 51
10 February 2021
MedDRA Preferred Term
PT Code
Eye swelling
10015967
Eyelid oedema
10015993
Face oedema
10016029
Fixed eruption
10016741
Flushing
10016825
Generalised oedema
10018092
Genital rash
10018175
Giant papillary conjunctivitis
10018258
Gingival swelling
10018291
Henoch-Schonlein purpura
10019617
Hereditary angioedema
10019860
Hypersensitivity
10020751
Hypersensitivity vasculitis
10020764
Idiopathic urticaria
10021247
Immunoglobulins abnormal
10021497
Immunoglobulins increased
10021500
Injection site dermatitis
10022056
Injection site hypersensitivity
10022071
Injection site rash
10022094
Injection site urticaria
10022107
Interstitial lung disease
10022611
Laryngeal oedema
10023845
Laryngospasm
10023891
Laryngotracheal oedema
10023893
Lip oedema
10024558
Lip swelling
10024570
Mouth ulceration
10028034
Mucocutaneous ulceration
10028084
Mucosa vesicle
10028103
Mucosal ulceration
10028124
Multiple allergies
10028164
Nephritis allergic
10029120
Neurodermatitis
10029263
Nikolsky's sign
10029415
Occupational dermatitis
10030012
MedDRA Preferred Term
PT Code
Oculomucocutaneous syndrome
10030081
Oedema mouth
10030110
Oedema mucosal
10030111
Orbital oedema
10031051
Oropharyngeal spasm
10031111
Oropharyngeal swelling
10031118
Panniculitis
10033675
Penile swelling
10034319
Perioral dermatitis
10034541
Periorbital oedema
10034545
Pharyngeal oedema
10034829
Photosensitivity reaction
10034972
Pneumonitis
10035742
Prurigo
10037083
Pruritus
10037087
Pulmonary eosinophilia
10037382
Radioallergosorbent test positive
10037789
Rash
10037844
Rash erythematous
10037855
Rash follicular
10037857
Rash generalised
10037858
Rash macular
10037867
Rash maculo-papular
10037868
Rash morbilliform
10037870
Rash neonatal
10037871
Rash papulosquamous
10037879
Rash pruritic
10037884
Rash pustular
10037888
Rash scarlatiniform
10037890
Rash vesicular
10037898
Reaction to azo-dyes
10037973
Reaction to colouring
10037974
Reaction to food additive
10037977
Red man syndrome
10038192
Respiratory arrest
10038669


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 52
10 February 2021
MedDRA Preferred Term
PT Code
Respiratory distress
10038687
Respiratory failure
10038695
Rhinitis allergic
10039085
Rhinitis perennial
10039094
Scrotal oedema
10039755
Scrotal swelling
10039759
Serum sickness
10040400
Serum sickness-like reaction
10040402
Shock
10040560
Shock symptom
10040581
Skin erosion
10040840
Skin exfoliation
10040844
Skin necrosis
10040893
Skin reaction
10040914
Skin test positive
10040934
Sneezing
10041232
Solar urticaria
10041307
Solvent sensitivity
10041316
Status asthmaticus
10041961
Stevens-Johnson syndrome
10042033
Stomatitis
10042128
Stridor
10042241
Suffocation feeling
10042444
Swelling face
10042682
Swelling of eyelid
10042690
Swollen tongue
10042727
Throat tightness
10043528
Tongue oedema
10043967
Toxic epidermal necrolysis
10044223
Tracheal obstruction
10044291
Tracheal oedema
10044296
Tracheostomy
10044320
Type I hypersensitivity
10045240
Urticaria
10046735
Urticaria cholinergic
10046740
MedDRA Preferred Term
PT Code
Urticaria contact
10046742
Urticaria papular
10046750
Urticaria physical
10046751
Urticaria pigmentosa
10046752
Urticaria vesiculosa
10046755
Vaginal ulceration
10046943
Vasculitic rash
10047111
Vulval oedema
10047763
Vulval ulceration
10047768
Wheezing
10047924
Acute generalised exanthematous 
pustulosis
10048799
Urticarial vasculitis
10048820
Seasonal allergy
10048908
Localised oedema
10048961
Allergic sinusitis
10049153
Gingival oedema
10049305
Rash maculovesicular
10050004
Application site eczema
10050099
Application site urticaria
10050104
Vulvovaginal ulceration
10050181
Allergic pharyngitis
10050639
Cytokine storm
10050685
Anti-neutrophil cytoplasmic antibody 
positive vasculitis
10050894
Complement factor C3 decreased
10050981
Complement factor C4 decreased
10050983
Scleritis allergic
10051126
Allergic cystitis
10051394
Complement factor C1 decreased
10051552
Complement factor C2 decreased
10051555
Generalised erythema
10051576
Infusion related reaction
10051792
Kaposi's varicelliform eruption
10051891
Cytokine release syndrome
10052015
Iodine allergy
10052098


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 53
10 February 2021
MedDRA Preferred Term
PT Code
Eye oedema
10052139
Eosinophil percentage increased
10052222
Circumoral oedema
10052250
Catheter site rash
10052271
Catheter site urticaria
10052272
Laryngeal dyspnoea
10052390
Urticaria chronic
10052568
Pruritus generalised
10052576
Allergic bronchitis
10052613
Eosinophilic pneumonia acute
10052832
Eosinophilic pneumonia chronic
10052833
Epidermolysis
10053177
Skin swelling
10053262
Injection site photosensitivity reaction
10053396
Type IV hypersensitivity reaction
10053613
Type III immune complex mediated 
reaction
10053614
Allergic cough
10053779
Streptokinase antibody increased
10053797
Anti-insulin antibody positive
10053814
Anti-insulin antibody increased
10053815
Type II hypersensitivity
10054000
Allergy to fermented products
10054929
Allergy to vaccine
10055048
Eczema weeping
10055182
Allergy test positive
10056352
Encephalitis allergic
10056387
Periorbital swelling
10056647
Mucocutaneous rash
10056671
Bronchial oedema
10056695
Palpable purpura
10056872
Septal panniculitis
10056876
Palatal oedema
10056998
Allergic keratitis
10057380
Scleral oedema
10057431
MedDRA Preferred Term
PT Code
Toxic skin eruption
10057970
Rash rubelliform
10057984
Gastrointestinal oedema
10058061
Eosinophil percentage abnormal
10058133
Dermatitis psoriasiform
10058675
Skin oedema
10058679
Eczema vesicular
10058681
Application site photosensitivity reaction
10058730
Hand dermatitis
10058898
Stoma site rash
10059071
Epidermal necrosis
10059284
Allergic colitis
10059447
Haemorrhagic urticaria
10059499
Laryngeal obstruction
10059639
Infusion site rash
10059830
Alpha tumour necrosis factor increased
10059982
Allergic oedema
10060934
Complement factor decreased
10061048
Eosinophil count abnormal
10061125
Immunology test abnormal
10061214
Mucosal erosion
10061297
Antibody test abnormal
10061425
Antibody test positive
10061427
Arthritis allergic
10061430
Allergic otitis media
10061557
Allergy to chemicals
10061626
Reversible airways obstruction
10062109
Heparin-induced thrombocytopenia
10062506
Necrotising panniculitis
10062579
Dennie-Morgan fold
10062918
Mesenteric panniculitis
10063031
Anaphylactoid shock
10063119
Blood immunoglobulin D increased
10063244
Pruritus allergic
10063438
Allergic respiratory symptom
10063527


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Version 3.0
CONFIDENTIAL
Page 54
10 February 2021
MedDRA Preferred Term
PT Code
Allergic respiratory disease
10063532
Application site hypersensitivity
10063683
Implant site rash
10063786
Implant site urticaria
10063787
Vaginal oedema
10063818
Implant site dermatitis
10063855
Implant site hypersensitivity
10063858
Antiallergic therapy
10064059
Eosinophilic oesophagitis
10064212
Lip exfoliation
10064482
Vaginal exfoliation
10064483
Penile exfoliation
10064485
Mucosal exfoliation
10064486
Oral mucosal exfoliation
10064487
Tongue exfoliation
10064488
Corneal exfoliation
10064489
Exfoliative rash
10064579
Immune complex level increased
10064650
Leukotriene increased
10064663
Reaction to preservatives
10064788
Asthmatic crisis
10064823
Laryngitis allergic
10064866
Neutralising antibodies positive
10064980
Non-neutralising antibodies positive
10064982
Perivascular dermatitis
10064986
Infusion site dermatitis
10065458
Infusion site hypersensitivity
10065471
Infusion site photosensitivity reaction
10065486
Infusion site urticaria
10065490
Antiendomysial antibody positive
10065514
Eosinophilic bronchitis
10065563
Visceral oedema
10065768
Eczema vaccinatum
10066042
Bronchial hyperreactivity
10066091
Allergic transfusion reaction
10066173
MedDRA Preferred Term
PT Code
Injection site eczema
10066221
Penile oedema
10066774
Injection site recall reaction
10066797
Gleich's syndrome
10066837
Contrast media allergy
10066973
Anaphylactic transfusion reaction
10067113
Haemolytic transfusion reaction
10067122
Immediate post-injection reaction
10067142
Oculorespiratory syndrome
10067317
Contact stomatitis
10067510
Genital swelling
10067639
Upper airway obstruction
10067775
HLA marker study positive
10067937
Oropharyngeal blistering
10067950
Interstitial granulomatous dermatitis
10067972
Mucosal necrosis
10067993
Injection site vasculitis
10067995
Anti-insulin receptor antibody positive
10068225
Anti-insulin receptor antibody increased
10068226
Oral allergy syndrome
10068355
Capillaritis
10068406
Mechanical urticaria
10068773
Palisaded neutrophilic granulomatous 
dermatitis
10068809
Vaccination site hypersensitivity
10068880
Kounis syndrome
10069167
Henoch-Schonlein purpura nephritis
10069440
Vaccination site dermatitis
10069477
Vaccination site rash
10069482
Vaccination site exfoliation
10069489
Vaccination site urticaria
10069622
Vaccination site vesicles
10069623
Administration related reaction
10069773
Limbal swelling
10070492
Distributive shock
10070559


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Version 3.0
CONFIDENTIAL
Page 55
10 February 2021
MedDRA Preferred Term
PT Code
Immune tolerance induction
10070581
Respiratory tract oedema
10070774
Reactive airways dysfunction syndrome
10070832
Occupational asthma
10070836
Injection related reaction
10071152
Administration site rash
10071156
Allergic hepatitis
10071198
Vulvovaginal swelling
10071211
Chronic hyperplastic eosinophilic sinusitis
10071380
Chronic eosinophilic rhinosinusitis
10071399
Vulvovaginal rash
10071588
Device allergy
10072867
Incision site dermatitis
10073168
Blister rupture
10073385
Incision site rash
10073411
Implant site photosensitivity
10073415
Drug reaction with eosinophilia and 
systemic symptoms
10073508
Instillation site hypersensitivity
10073612
Instillation site rash
10073622
Instillation site urticaria
10073627
Catheter site dermatitis
10073992
Catheter site eczema
10073995
Catheter site hypersensitivity
10073998
Catheter site vasculitis
10074014
Allergy to immunoglobulin therapy
10074079
Pathergy reaction
10074332
Drug provocation test
10074350
Palatal swelling
10074403
Stoma site hypersensitivity
10074509
Immune thrombocytopenic purpura
10074667
Noninfective conjunctivitis
10074701
Infusion site eczema
10074850
Infusion site vasculitis
10074851
Caffeine allergy
10074895
MedDRA Preferred Term
PT Code
Transplantation associated food allergy
10075008
Allergic otitis externa
10075072
Aspirin-exacerbated respiratory disease
10075084
Administration site dermatitis
10075096
Administration site eczema
10075099
Administration site hypersensitivity
10075102
Administration site urticaria
10075109
Allergic eosinophilia
10075185
Mouth swelling
10075203
Airway remodelling
10075289
Allergic gastroenteritis
10075308
Perineal rash
10075364
Allergy alert test positive
10075479
Medical device site dermatitis
10075572
Medical device site eczema
10075575
Medical device site hypersensitivity
10075579
Medical device site rash
10075585
Medical device site urticaria
10075588
Nodular rash
10075807
Administration site photosensitivity 
reaction
10075961
Administration site recall reaction
10075964
Administration site vasculitis
10075969
Application site recall reaction
10076024
Application site vasculitis
10076027
Infusion site recall reaction
10076085
Medical device site photosensitivity 
reaction
10076137
Medical device site recall reaction
10076140
Vaccination site eczema
10076161
Vaccination site photosensitivity reaction
10076186
Vaccination site recall reaction
10076188
Vaccination site vasculitis
10076191
Intestinal angioedema
10076229
Documented hypersensitivity to 
administered product
10076470


Tirabrutinib (GS-4059)
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Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
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10 February 2021
MedDRA Preferred Term
PT Code
Mast cell degranulation present
10076606
Dialysis membrane reaction
10076665
Asthma-chronic obstructive pulmonary 
disease overlap syndrome
10077005
Vessel puncture site rash
10077117
Allergy to surgical sutures
10077279
Immune-mediated adverse reaction
10077665
Vessel puncture site vesicles
10077813
Eosinophilic granulomatosis with 
polyangiitis
10078117
Symmetrical drug-related intertriginous 
and flexural exanthema
10078325
Nasal crease
10078581
Oropharyngeal oedema
10078783
Allergic reaction to excipient
10078853
Allergic stomatitis
10079554
Therapeutic product cross-reactivity
10079645
Reaction to excipient
10079925
Vulvovaginitis allergic
10080783
Procedural shock
10080894
Hereditary angioedema with C1 esterase 
inhibitor deficiency
10080955
Vernal keratoconjunctivitis
10081000
Hypersensitivity myocarditis
10081004
Acquired C1 inhibitor deficiency
10081035
Scrotal exfoliation
10081178
Childhood asthma
10081274
Atopic cough
10081492
Circumoral swelling
10081703
Hypersensitivity pneumonitis
10081988
Human anti-hamster antibody increased
10082107
Human anti-hamster antibody positive
10082109
Pharyngeal swelling
10082270
Urticarial dermatitis
10082290
Immune-mediated pneumonitis
10082452


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 53
10 February 2021
Appendix 5.
Cytopenia Medical Search Term
Note: The list presented below is based on MedDRA Version 22.0. The actual list will be 
up-versioned to the MedDRA version used at the time of database finalization. 
MedDRA Preferred Term
PT Code
Acquired amegakaryocytic 
thrombocytopenia
10076747
Megakaryocytes decreased
10027119
Mononuclear cell count decreased
10082036
Platelet count decreased
10035528
Platelet maturation arrest
10035537
Platelet production decreased
10035540
Platelet toxicity
10059440
Thrombocytopenia
10043554
Febrile neutropenia
10016288
Neutropenia
10029354
Neutrophil count decreased
10029366
Agranulocytosis
10001507
Autoimmune neutropenia
10055128
Transfusion-related alloimmune 
neutropenia
10081503
Granulocytopenia
10018687
Idiopathic neutropenia
10051645
Neutropenic colitis
10062959
Neutropenic infection
10059482
Neutropenic sepsis
10049151
Neutrophil count abnormal
10061313
Band neutrophil count decreased
10057950
Band neutrophil percentage decreased
10059130
Neutrophil percentage abnormal
10058134
Neutrophil percentage decreased
10052223
Granulocyte count decreased
10018681
Granulocytes abnormal
10018685
Anaemia macrocytic
10002064
Aplasia pure red cell
10002965
MedDRA Preferred Term
PT Code
Aplastic anaemia
10002967
Erythroblast count decreased
10058505
Erythroid maturation arrest
10015279
Erythropenia
10015287
Hypoplastic anaemia
10021074
Microcytic anaemia
10027538
Proerythroblast count decreased
10060229
Red blood cell count decreased
10038153
Reticulocyte count decreased
10038790
Reticulocytopenia
10038795
Anaemia
10002034
Anaemia neonatal
10002068
Erythroblast count abnormal
10058508
Erythropoiesis abnormal
10049467
Foetal anaemia
10077577
Haematocrit abnormal
10049221
Haematocrit decreased
10018838
Haemoglobin abnormal
10018879
Haemoglobin decreased
10018884
Leukoerythroblastic anaemia
10053199
Normochromic anaemia
10029782
Normochromic normocytic anaemia
10029783
Normocytic anaemia
10029784
Proerythroblast count abnormal
10060227
Red blood cell count abnormal
10038151
Reticulocyte count abnormal
10038788
Reticulocyte percentage decreased
10059921
Autoimmune aplastic anaemia
10071576
Bicytopenia
10058956


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 54
10 February 2021
MedDRA Preferred Term
PT Code
Bone marrow failure
10065553
Cytopenia
10066274
Febrile bone marrow aplasia
10053213
Full blood count decreased
10017413
Gelatinous transformation of the bone 
marrow
10078097
Pancytopenia
10033661
Panmyelopathy
10050026


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 55
10 February 2021
Appendix 6.
Cardiac arrhythmia Medical Search Term
Note: The list presented below is based on MedDRA Version 22.0. The actual list will be 
up-versioned to the MedDRA version used at the time of database finalization. 
MedDRA PreferredTerm
PT Code
Accelerated idioventricular rhythm
10049003
Neonatal bradyarrhythmia
10082054
Neonatal tachyarrhythmia
10082055
Congenital supraventricular 
tachycardia
10082343
Frederick's syndrome
10082089
Accessory cardiac pathway
10067618
Adams-Stokes syndrome
10001115
Agonal rhythm
10054015
Anomalous atrioventricular excitation
10002611
Arrhythmia
10003119
Arrhythmia neonatal
10003124
Arrhythmia supraventricular
10003130
Arrhythmogenic right ventricular 
dysplasia
10058093
Atrial conduction time prolongation
10064191
Atrial fibrillation
10003658
Atrial flutter
10003662
Atrial parasystole
10071666
Atrial tachycardia
10003668
Atrioventricular block
10003671
Atrioventricular block complete
10003673
Atrioventricular block first degree
10003674
Atrioventricular block second degree
10003677
Atrioventricular conduction time 
shortened
10068180
Atrioventricular dissociation
10069571
Atrioventricular node dispersion
10077893
Bifascicular block
10057393
Bradyarrhythmia
10049765
Brugada syndrome
10059027
MedDRA PreferredTerm
PT Code
Bundle branch block
10006578
Bundle branch block bilateral
10006579
Bundle branch block left
10006580
Bundle branch block right
10006582
Cardiac fibrillation
10061592
Cardiac flutter
10052840
Chronotropic incompetence
10068627
Conduction disorder
10010276
Defect conduction intraventricular
10012118
Electrocardiogram delta waves 
abnormal
10014372
Electrocardiogram PQ interval 
prolonged
10053656
Electrocardiogram PQ interval 
shortened
10075328
Electrocardiogram PR prolongation
10053657
Electrocardiogram PR shortened
10014374
Electrocardiogram QRS complex 
prolonged
10014380
Electrocardiogram QT prolonged
10014387
Electrocardiogram repolarisation 
abnormality
10052464
Electrocardiogram U wave present
10057913
Electrocardiogram U wave inversion
10062314
Electrocardiogram RR interval 
prolonged
10067652
Electrocardiogram U-wave 
abnormality
10055032
Extrasystoles
10015856
Foetal arrhythmia
10016847
Foetal heart rate disorder
10061158
Foetal tachyarrhythmia
10077575


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 56
10 February 2021
MedDRA PreferredTerm
PT Code
Heart alternation
10058155
Heart block congenital
10019263
Heart rate irregular
10019304
Junctional ectopic tachycardia
10074640
Lenegre's disease
10071710
Long QT syndrome
10024803
Long QT syndrome congenital
10057926
Lown-Ganong-Levine syndrome
10024984
Nodal arrhythmia
10029458
Nodal rhythm
10029470
Pacemaker generated arrhythmia
10053486
Pacemaker syndrome
10051994
Parasystole
10033929
Paroxysmal arrhythmia
10050106
Paroxysmal atrioventricular block
10077503
Pulseless electrical activity
10058151
Reperfusion arrhythmia
10058156
Rhythm idioventricular
10039111
Sinoatrial block
10040736
Sinus arrest
10040738
Sinus arrhythmia
10040739
Sinus bradycardia
10040741
Sinus node dysfunction
10075889
Sinus tachycardia
10040752
Sudden cardiac death
10049418
Supraventricular extrasystoles
10042602
Supraventricular tachyarrhythmia
10065342
Supraventricular tachycardia
10042604
Tachyarrhythmia
10049447
Torsade de pointes
10044066
Trifascicular block
10044644
Ventricular arrhythmia
10047281
Ventricular asystole
10047284
MedDRA PreferredTerm
PT Code
Ventricular dyssynchrony
10071186
Ventricular extrasystoles
10047289
Ventricular fibrillation
10047290
Ventricular flutter
10047294
Ventricular parasystole
10058184
Ventricular pre-excitation
10049761
Ventricular tachyarrhythmia
10065341
Ventricular tachycardia
10047302
Wandering pacemaker
10047818
Withdrawal arrhythmia
10047997
Wolff-Parkinson-White syndrome
10048015
Wolff-Parkinson-White syndrome 
congenital
10049291
Bradycardia
10006093


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 57
10 Februray 2021
Appendix 7.
Rash Medical Search Term
Note: The list presented below is based on MedDRA Version 22.0. The actual list will be 
up-versioned to the MedDRA version used at the time of database finalization. 
MedDRA Term Name
PT Code
Acute generalised exanthematous 
pustulosis
10048799
Angina bullosa haemorrhagica
10064223
Autoimmune dermatitis
10075689
Blister
10005191
Blister rupture
10073385
Butterfly rash
10067982
Cervical bulla
10050019
Dermatitis exfoliative
10012455
Dermatitis exfoliative generalised
10012456
Dermatosis
10048768
Drug eruption
10013687
Drug reaction with eosinophilia and 
systemic symptoms
10073508
Eosinophilic pustular folliculitis
10052834
Epidermolysis
10053177
Epidermolysis bullosa
10014989
Eruptive pseudoangiomatosis
10068095
Erythema multiforme
10015218
Erythema nodosum
10015226
Erythrosis
10056474
Exfoliative rash
10064579
Fixed eruption
10016741
Flagellate dermatitis
10075467
Interstitial granulomatous dermatitis
10067972
Lichenoid keratosis
10064000
Macule
10025421
Mucocutaneous rash
10056671
Mucocutaneous ulceration
10028084
Mucosa vesicle
10028103
MedDRA Term Name
PT Code
Necrolytic migratory erythema
10060821
Neurodermatitis
10029263
Oculomucocutaneous syndrome
10030081
Oral mucosal blistering
10030995
Oropharyngeal blistering
10067950
Palmar-plantar erythrodysaesthesia 
syndrome
10033553
Palmoplantar pustulosis
10050185
Palpable purpura
10056872
Papule
10033733
Paraneoplastic rash
10074687
Pemphigoid
10034277
Pemphigus
10034280
Penile blister
10052898
Prurigo
10037083
Rash
10037844
Rash erythematous
10037855
Rash follicular
10037857
Rash generalised
10037858
Rash macular
10037867
Rash maculo-papular
10037868
Rash maculovesicular
10050004
Rash morbilliform
10037870
Rash papular
10037876
Rash papulosquamous
10037879
Rash pruritic
10037884
Rash pustular
10037888
Rash rubelliform
10057984
Rash scarlatiniform
10037890
Rash vesicular
10037898


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 58
10 Februray 2021
MedDRA Term Name
PT Code
Seborrhoeic dermatitis
10039793
Skin disorder
10040831
Skin plaque
10067723
Skin reaction
10040914
Skin toxicity
10059516
Stevens-Johnson syndrome
10042033
Symmetrical drug-related 
intertriginous and flexural exanthema
10078325
Toxic epidermal necrolysis
10044223
Toxic erythema of chemotherapy
10074982
Toxic skin eruption
10057970
Umbilical erythema
10055029
Urticarial vasculitis
10048820
Vaginal exfoliation
10064483
Vasculitic rash
10047111
Viral rash
10047476
Skin lesion inflammation
10081154
Target skin lesion
10081998
Plethoric face
10081808
Vulvovaginal rash
10071588


Tirabrutinib (GS-4059)
Study GS-US-401-1787
Statistical Analysis Plan – Final Analysis
Version 3.0
CONFIDENTIAL
Page 59
10 Februray 2021
Appendix 8.
List of Laboratory Tests for Safety Summary
Serum Chemistry
Hematology
Albumin
Alkaline phosphatase
ALT
Amylase
AST
Bicarbonate
BUN
Calcium
Chloride
Creatininea
GGT
Glucoseb
LDH
Lipase
Potassium
Sodium
Total bilirubin
Total Protein
Uric Acid
WBC
Hemoglobin
Hematocrit
Platelet Count
Basophils
Monocytes
Eosinophils
Neutrophils
Lymphocytes
Red Blood Cells
a
Both creatinine and creatinine clearance rate will be included in the safety summary. Estimated creatinine clearance rate will 
be calculated based on the Cockcroft-Gault formula
b
If fasting status is not unknown, non-fasting criteria will be applied for toxicity grading.


SAP GS-US-401-1787 v3.0
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Biostatistics eSigned
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