Conditions: Chronic Lymphocytic Leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine the preliminary efficacy of the combination of tirabrutinib (formerly GS-4059) and entospletinib with obinutuzumab in adults with relapsed or refractory chronic lymphocytic leukemia (CLL).

Detailed description:

Arms:
arm 1: Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks. arm 2: Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks + obinutuzumab 100 mg on Day 1, 900 mg on Day 1 or 2, and 1000 mg subsequently for up to 8 doses on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21.

Interventions: intervention 1: Tirabrutinib intervention 2: Entospletinib intervention 3: Obinutuzumab
Intervention descriptions: intervention 1: Administered orally once daily intervention 2: Administered orally once daily intervention 3: Administered intravenously

Protocol document:
SAP_002.pdf: 
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Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Title:
A Prospective, Open-Label, Multicenter, Phase 2 Trial to 
Evaluate the Safety and Efficacy of the Combination of 
Tirabrutinib (GS-4059) and Entospletinib with and without 
Obinutuzumab in Subjects with Chronic Lymphocytic 
Leukemia
Name of Test Drug:
Tirabrutinib (GS-4059)
Study Number:
GS-US-401-2076
Protocol Version (Date):
Amendment 4 (15 January 2019)
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 2.0
Analysis Plan Date:
13 January 2021
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(fJ GILEAU 


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................10
2.1.
Interim Analysis.....................................................................................................................................10
2.2.
Final Analysis ........................................................................................................................................10
2.3.
Follow-up Analysis ................................................................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................11
3.1.
Analysis Sets..........................................................................................................................................11
3.1.1.
All Enrolled Analysis Set.....................................................................................................11
3.1.2.
Full Analysis Set ..................................................................................................................11
3.1.3.
Safety Analysis Set...............................................................................................................11
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................12
3.2.
Subject Grouping ...................................................................................................................................12
3.3.
Strata and Covariates..............................................................................................................................12
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.................................................................................................................................13
3.7.
Data Handling Conventions and Transformations .................................................................................13
3.8.
Analysis Visit Windows.........................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Visit Windows.......................................................................................................14
3.8.2.1.
Analysis Visit Windows for Primary/Secondary Efficacy 
Endpoints........................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................15
4.
SUBJECT DISPOSITION ..................................................................................................................................16
4.1.
Subject Enrollment and Disposition.......................................................................................................16
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................17
4.2.1.
Duration of Exposure to Study Drug....................................................................................17
4.2.2.
Adherence to Study Drug.....................................................................................................17
4.3.
Protocol Deviations................................................................................................................................18
4.4.
Assessment of COVID-19 Impact..........................................................................................................19
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19....................................................19
4.4.2.
Protocol Deviations Due to COVID-19................................................................................19
4.4.3.
Missed and Virtual Visits Due to COVID-19 ......................................................................19
5.
BASELINE CHARACTERISTICS....................................................................................................................20
5.1.
Demographics ........................................................................................................................................20
5.2.
Other Baseline Characteristics ...............................................................................................................20


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5.3. 
Medical History ...................................................................................................................................... 20 
5.4. 
Prior Anti-cancer Therapy ...................................................................................................................... 21 
6. 
EFFICACY ANALYSES ................................................................................................................................... 22 
6.1. 
Primary Efficacy Endpoint.. ................................................................................................................... 22 
6.1.1. 
Definition of the Primary Efficacy Endpoint ....................................................................... 22 
6.1.2. 
Analysis ofthe Primary Efficacy Endpoint .......................................................................... 22 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 22 
6.2.1. 
Rates of CR/BM MRD- and CR/PB MRD- at Week 25 ...................................................... 23 
6.2.2. 
ORR at Week 25 .................................................................................................................. 23 
6.4. 
Change 
6.4.1. 
ORR ...................................................................................................................................... 27 
-
7. 
SAFETY ANALYSES ........................................................................................................................................ 29 
7.1. 
Adverse Events and Deaths .................................................................................................................... 29 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 29 
7.1.2. 
Adverse Event Severity ........................................................................................................ 29 
7 .1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 29 
7 .1.4. 
Serious Adverse Events ........................................................................................................ 29 
7 .1.5. 
Treatment-Emergent Adverse Events ................................................................................... 29 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 29 
7.1.5.2. 
Incomplete Dates ............................................................................................ 30 
7 .1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 30 
7 .1.6.1. 
Summaries of AE Incidence by Severity ........................................................ 30 
7.1.7. 
Adverse Events of Interest ................................................................................................... 32 
7 .2. 
Laboratory Evaluations .......................................................................................................................... 33 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 33 
7.2.2. 
Graded Laboratory Values ................................................................................................... 34 
7 .2.2.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 34 
7 .2.2.2. 
Summaries of Laboratory Abnormalities ........................................................ 34 
7.2.3. 
Liver-related Laboratory Evaluations ................................................................................... 34 
7.2.4. 
Shifts Relative to the Baseline Value ................................................................................... 35 
7.3. 
Body Weight and Yitai Signs ................................................................................................................. 35 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 35 
7.4.1. 
Prior Medications ................................................................................................................. 35 
7.4.2. 
Concomitant Medications ..................................................................................................... 36 
7.5. 
Electrocardiogram Results ..................................................................................................................... 36 
7 .5.1. 
Investigator Electrocardiogram Assessment ........................................................................ 36 
7.5.2. 
Corrected QT lntervals ......................................................................................................... 37 
7.5.3. 
PR and QRS lntervals ........................................................................................................... 37 
7 .6. 
Other Safety Measures ........................................................................................................................... 38 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 38 
8. 
PHARMACOKINETIC (PK) ANALYSES ........................................................................................................ 39 
8.1. 
PK Sample Collection ............................................................................................................................ 39 
8.2. 
PK Analyses ........................................................................................................................................... 39 
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9.
REFERENCES ...................................................................................................................................................40
10.
SOFTWARE.......................................................................................................................................................41
11.
SAP REVISION..................................................................................................................................................42
12.
APPENDICES ....................................................................................................................................................43
LIST OF TABLES
Table 1-1.
90% Confidence Intervals at Different CR Rates.....................................................................9


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BLQ
below the limit of quantitation
BM
bone marrow
BMI
body mass index
CCR
clinical complete response
CI
confidence interval
CLL
chronic lymphocytic leukemia
CPR
clinical partial response
CR
complete remission
CR/BM
MRD-
complete remission with bone marrow minimal residual disease negativity (<10-4 CLL cells
present)
CR/PB
MRD-
complete remission with peripheral minimal residual disease negativity (<10-4 CLL cells 
present)
CRi
complete remission with incomplete recovery of the bone marrow
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
ECG
electrocardiogram
EOT
End of Treatment
FAS
Full Analysis Set
HLT
high-level term
ID
identification
IWCLL
International Workshop on CLL
IWRS
Interactive Web Response System
LLT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NLP
Natural Language Processing
nPR
nodular partial response
ORR
overall response rate
PB
peripheral blood
PD
progressive disease
PP
per protocol
CCI
CCI
CCI
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PR
partial response
PR-L
partial response with lymphocytosis
PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAP
statistical analysis plan
SD
stable disease
SMQ
Standardized MedDRA Queries
StD
standard deviation
SI (units)
international system of units
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
VR
ventricular rate
WHO
World Health Organization
CCI
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Tirabrutinib (GS-4059) 
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Statistical Analysis Plan 
1. 
INTRODUCTION 
Version 2.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the synoptic clinical study 
report (CSR) for Study GS-US-401-2076. This SAP is based on the study protocol amendment4 
dated 15 January 2019 and the electronic case report fonn ( 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: 
• 
To detennine the preliminary efficacy of the combination of tirabrutinib and entospletinib 
with obinutuzumab in subjects with relapsed or refractory chronic lymphocytic leukemia 
(CLL) 
The secondary objective of this study is: 
• 
To evaluate the safety and tolerability of the combination of tirabrutinib and entospletinib 
with and without obinutuzumab 
I 
I 
1.2. 
Study Design 
This is a Phase 2, prospective, open-label, multicenter trial to evaluate the safety and efficacy of 
the combination of tirabrutinib and entospletinib with and without obinutuzumab in subjects with 
relapsed or refractory CLL. 
Eligible subjects will be randomized in a 1: 1 manner to one of the following two anns, stratified 
by the presence of 17p deletion/TP53 mutation ( del 17p/fP53mut) in CLL cells: 
• 
Ann A: tirabrutinib + entospletinib 
• 
Ann B: tirabrutinib + entospletinib + obinutuzumab 
With Amendment 3, randomization was discontinued. All subsequent subjects will be enrolled 
into Ann B. 
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Duration of Treatment:
Tirabrutinib 80 mg will be self-administered orally once daily and entospletinib 400 mg will be 
self-administered orally once daily. Dosing of both agents will begin on Week 1 Day 1 of the 
study and thereafter continue for up to 104 weeks in the absence of disease progression, 
unacceptable toxicity, or documentation of complete remission (CR) with bone marrow minimal 
residual disease (MRD) negativity (CR/BM MRD-). If CR/BM MRD- is documented on study, 
treatment will stop after the earlier of:
i)
an additional 3 months of therapy or 
ii) 104 weeks of total treatment.
Obinutuzumab will be administered as 8 intravenous infusions of 1000 mg each over 21 weeks. 
A test dose of 100 mg will be administered on Week 1 Day 1. If this dose is tolerated, the 
remainder of the full dose may be subsequently administered on Day 1. Alternatively, the 
remaining 900 mg will be administered on Day 2. Subsequent infusions will be administered on 
Week 2 Day 1, Week 3 Day 1, Week 5 Day 1 and then every 4 weeks through Week 21.
This study will continue to monitor subjects for up to 30 days post end of treatment, or up to 
Week 25 should a subject discontinue treatment prior to Week 25 for reasons other than disease 
progression.
Efficacy Assessment Schedule:
Tumor response assessment per modified International Workshop on CLL (IWCLL) 2008 
criteria will be performed at the Week 25 visit, with evaluation of areas affected by CLL during 
the screening evaluation. During the treatment phase, additional response assessment per IWCLL 
2008 criteria may be performed as clinically indicated. 
Clinical response based on physical exam, laboratory parameters and presence of B-symptoms 
will be performed every 4 weeks until Week 33 Day 1 (except for Week 25) and then every 
12 weeks starting Week 33 until Week 105 following the modified IWCLL 2008 criteria, with 
the exception of lymphadenopathy, hepatomegaly, splenomegaly, and bone marrow.
Bone marrow MRD will be assessed at Week 25. Additional bone marrow MRD may be 
assessed as clinically indicated. Peripheral blood MRD will be assessed on Day 1 of Weeks 1, 
13, 25, 33, 45, 105, and End of Treatment (EOT). EOT collection is not needed for subjects who 
complete the Week 105 visit.
The Schedule of Assessments is located in Appendix 1.


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1.3.
Sample Size and Power
The primary goal of this study is to evaluate the efficacy of the combination of tirabrutinib and 
entospletinib with obinutuzumab in relapsed and refractory CLL. The primary endpoint for this 
study is the rate of CR (including CR and CR with incomplete recovery of the bone marrow
(CRi)) at Week 25. The corresponding single-agent CR rate with BTK and SYK inhibitors in 
subjects with relapsed or refractory CLL is ≤5%. The 90% confidence interval (CI)
corresponding to different CR rates ranging from 20% to 60% for a sample size of 30 is provided 
in Table 1-1. With a sample size of 30, the lower bound of the 90% CI of an observed CR rate of 
20% or above will exclude 5%.
Table 1-1.
90% Confidence Intervals at Different CR Rates
Sample Size
CR Rate
90% Confidence Interval
using Clopper-Pearson Method
30
20%
(9.1%, 35.7%)
30
30%
(16.6%, 46.5%)
30
40%
(25.0%, 56.6%)
30
50%
(33.9%, 66.1%)
30
60%
(43.4%, 75.1%)
With Amendment 3, randomization was discontinued. All subsequent subjects will be enrolled to 
Arm B. A total of approximately 6 subjects in Arm A and 30 subjects in Arm B will be enrolled, 
thus the total sample size for the study will be approximately 36 subjects.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
No formal interim analysis is planned.
2.2.
Final Analysis
After all subjects have discontinued/completed 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 and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (StD) or standard error (SE), 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 
AEs, will be presented in chronological order within the subject. The treatment group to which 
subjects were randomized/initially assigned will be used in the listings. 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 eligible for inclusion will be 
summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
This study was initially designed as a randomized study. With Amendment 3, randomization was 
discontinued, and all subsequent subjects will be enrolled into Arm B. There is no intention to 
compare the treatments, so intent-to-treat Analysis Set will not be used; instead, All Enrolled 
Analysis Set defined in Section 3.1.1 and Full Analysis Set defined in Section 3.1.2 will be used.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized or enrolled subjects who received at least 
1 dose of any study drug with treatment group designated according to the planned treatment.
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.


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3.1.4. 
Pharmacokinetic Analysis Set 
Version 2.0 
The Phannacokinetic (PK) Analysis Set will include all randomized or enrolled subjects who 
took at least 1 dose of study drug and have at least 1 nomnissing postdose concentration value 
reported by the PK laboratory. This is the primary analysis set for all PK analyses. 
3.2. 
Subject Grouping 
For analyses based on FAS, subjects will be grouped according to the treatment they are assigned 
to at randomization or enrolhnent. For analyses based on the Safety Analysis Set, subjects will 
be grouped according to the actual treatment received. The actual treatment received will differ 
from the treatment assigned at randomization or enrollment only when their actual treatment 
differs from assigned treatment for the entire treatment duration. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via the interactive web response system 
(IWRS) in a 1: 1 ratio using a stratified randomization schedule. Stratification will be based on 
the presence of del 17p/TP53mut in CLL cells. If there are discrepancies in stratification factor 
values between the IWRS and the clinical database, the values recorded in the clinical database 
will be used for analyses. 
With Amendment 3, randomization was discontinued. All subsequent subjects were enrolled into 
Ann B. There is no intention to compare the treatments. No covariates will be included in 
efficacy analyses. 
3.4. 
Examination of Subject Subgroups 
Primary and secondary efficacy endpoints will be exa1nined in the subgroups based on 
randomization stratification factor either dell 7 or TP53mut versus neither del 17 nor 
TP53mut for each ann. 
3.5. 
Multiple Comparisons 
Not applicable. 
3.6. 
3.6.1. 
Missing Data and Outliers 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
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For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for CLL diagnosis is described in Section 5.3; for prior 
anti-cancer therapy in Section 5.4, for new anti-cancer therapy in Section 6.3.2, for death in 
Section 6.3.1, for AE onset in Section 7.1.5.2, and for prior and concomitant medications in 
Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed. In general, age collected at 
Day 1 (the first dosing date of study drug) (in years) will be used for analyses and presented 
in listings. If age at Day 1 is not available for a subject, then age derived based on date of 
birth and the Day 1 visit date will be used instead. If an enrolled subject was not dosed with 
any study drug, the randomization or enrollment date will be used instead of the Day 1 visit 
date. For screen failures, the date the first informed consent was signed will be used for the 
age derivation. Age required for longitudinal and temporal calculations and analyses 
(eg, estimates of creatinine clearance, age at date of AE) will be based on age derived from 
date of birth and the date of the measurement or event, unless otherwise specified.
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 to calculate 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 to 
calculate 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 to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate 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 to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).


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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.
Sparse PK concentration values that are 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 postdose time points for summary purposes. The following conventions will 
be used for the presentation of summary of PK concentrations: 

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 Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug 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
Therefore, study day 1 is the day of first dose of study drug administration.
3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. 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 dosing of study drug will be included in determining the 
maximum postbaseline toxicity grade.


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3.8.2.1.
Analysis Visit Windows for Primary/Secondary Efficacy Endpoints
The analysis windows for Week 25 response assessment and Week 25 MRD assessment are
defined as 24×7±28 days (inclusive) starting from first dose.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For baseline, the last nonmissing value on or prior to the 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.

For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data and the worse severity will be taken for categorical data, unless 
otherwise specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each investigator and 
overall. 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.
A listing of subjects with discrepancies in the value used for stratification assignment between 
the IWRS and the clinical database at the time of data finalization will be provided.
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects randomized or enrolled, the 
number of subjects who were randomized or enrolled but not dosed, and the number of subjects 
in each of the categories listed below by treatment group:

Safety Analysis Set

Tirabrutinib completion status
Completed study drug dosing as specified per protocol 
Discontinued study drug dosing with reasons

Entospletinib completion status
Completed study drug dosing as specified per protocol 
Discontinued study drug dosing with reasons

Obinutuzumab completion status
Completed study drug dosing as specified per protocol 
Discontinued study drug dosing with reasons

Study completion status
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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.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for study drug or study discontinuation

Reasons for screen failure (will be provided by screening ID number in ascending order)
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 to the study drug 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 using up to 1 decimal place (eg, 4.5 weeks). If the last study drug dosing date 
is missing, the latest date among the study drug end date, clinical visit date, laboratory sample 
collection date, and vital signs assessment date will be used.
The total duration of exposure to study drug will be summarized using descriptive statistics. For 
tirabrutinib and entospletinib, the number (ie, cumulative counts) and percentage of subjects 
exposed will be summarized by the following time periods: ≥1 day, ≥1 week, ≥2 weeks, 
≥3 weeks, ≥4 weeks, ≥6 weeks, ≥8 weeks, every 4 weeks starting from 8 weeks to 32 weeks, and 
then every 12 weeks starting from 32 weeks until 104 weeks (if appropriate). For obinutuzumab, 
the number of infusions will be summarized using descriptive statistics. Summaries will be 
provided by treatment group for the Safety Analysis Set.
The number and percentage of subjects who have dose reduction or interruptions, and the 
reasons, will be summarized by treatment.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The total amount of study drug administered (mg) will be summarized using descriptive 
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For tirabrutinib and entospletinib, the presumed total number of doses administered to a subject 
will be determined by the data collected on the drug accountability CRF using the following 
formula:
Total Amount of Study Drug Administered (mg) =
 No. of Doses Dispensed × strength − No. of Doses Returned × strength
The level of on-treatment adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug expected to be 
administered during a subject’s actual on-treatment period based on the study drug regimen.
Investigator-prescribed interruption, reductions and escalations as specified in the protocol will
be taken into account. If there are treatment periods that bottles are not returned or the return 
information is missing, these periods will be excluded from the on-treatment adherence 
calculation for both total amount of study drug administered and study drug expected to be 
administered. If subjects never returned any bottle, the adherence will be set as missing.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 75% and ≥ 75%) will be provided by treatment 
group for the Safety Analysis Set. 
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
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 treatment group 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 
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will be summarized by treatment group for the All Enrolled Analysis Set. A by-subject listing 
will be provided for those subjects with important protocol deviation.
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, 
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 2 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 3.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by treatment 
group and overall 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 
FAS.
A by-subject demographic listing, including the informed consent date, will be provided 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), Eastern Cooperative Oncology Group (ECOG) Performance Status, CIRS 
(Cumulative Illness Rating Scale), fluorescence in situ hybridization (FISH) results, TP53
mutation status, and IGHV mutation status. These baseline characteristics will be summarized by 
treatment group and overall 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 FAS. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history will be collected at screening for disease-specific and general conditions 
(ie, conditions not specific to the disease being studied). 
Disease-specific medical history will be summarized by treatment group and overall by the 
number and percentage of subjects with each prepopulated condition. The summary will be 
provided for FAS. Time since CLL diagnosis (years) will be calculated by (date of first dose of 
study drug date of CLL diagnosis) / 365.25. Time since CLL diagnosis will be summarized 
using summary statistics for a continuous variable. Disease stage at diagnosis and at screening
and cytogenetic risk group will be summarized using summary statistics for a categorical 
variable. No formal statistical testing is planned. A by-subject listing of disease-specific medical 
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In deriving the time since CLL diagnosis, all partial dates of diagnosis and last regimen will be 
identified, and the partial dates will be imputed as follows:

If day and month are missing but year is available, then the imputed day and month will be 
01 Jan.

If day is missing but the month and year are available, then the imputed day will be the 
first day of the month.

Partial date will not be imputed if the year is missing.
General medical history data will not be coded, but will be listed only. A by-subject listing of 
general medical history will be provided by subject ID number in ascending order.
5.4.
Prior Anti-cancer Therapy
Number of prior regimens, time since the completion of last regimen, and time since progression 
in the last regimen will be summarized by treatment group using descriptive statistics based on 
FAS. A partial completion date will be imputed using the algorithm defined in Section 5.3.
The regimens and prior therapies that the subjects received will be summarized. The last regimen 
subjects received prior to study entry and the best response and PD to the last regimen will be 
summarized.
Number of subjects who received prior radiation therapy and surgery will be listed.


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6.
EFFICACY ANALYSES
Efficacy analysis will be performed on FAS. The result summary will be provided by treatment 
group if not otherwise specified.
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint of this study is the rate of CR per modified IWCLL 2008 criteria
{Hallek 2008} at Week 25, which is defined as the proportion of subjects who achieved CR/CRi
at Week 25. Subjects who received anti-cancer therapy other than the study drug prior to 
achieving CR/CRi at Week 25, will be considered as nonresponders for CR/CRi and will be 
included in the denominator when calculating the CR rate at Week 25.
The analysis window of Week 25 response assessment is defined as 24×7±28 days (inclusive)
starting from first dose. If there are multiple assessments within the analysis window, records 
will be chosen based on rules specified in Section 3.8.3.
6.1.2.
Analysis of the Primary Efficacy Endpoint
The CR rate at Week 25 and the corresponding 2-sided 90% exact CIs based on Clopper-Pearson 
method will be presented.
6.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Rate of CR with MRD negativity (<10 4) in bone marrow (CR/BM MRD-) at Week 25, 
defined as the proportion of subjects who achieved CR/CRi and also achieved BM MRD 
negativity at Week 25

Rate of CR with MRD negativity (<10 4) in peripheral blood (CR/PB MRD-) at Week 25, 
defined as the proportion of subjects who achieved CR/CRi and also achieved PB MRD 
negativity at Week 25

Overall response rate (ORR) at week 25, defined as the proportion of subjects who achieved 
CR, CRi, partial response (PR), or PR with lymphocytosis at Week 25
The response assessment definition of each response category is based on Modified IWCLL 
2008 criteria and PR includes nodular partial response (nPR).
The MRD response is assessed with four-color-flow cytometry (FACS) and MRD negativity is 
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The analysis window of Week 25 response assessment is defined as 24x7±28 days(inclusive) 
starting from first dose. If there are multiple assessments within the analysis window, records 
will be chosen based on rules specified in Section 3.8.3. 
6.2.1. 
Rates of CR/BM MRD- and CR/PB MRD- at Week 25 
Subjects who received anti-cancer therapy other than the study drug prior to achieving CR with 
MRD negativity at Week 25 will be considered as nonresponders and will be included in the 
denominators of the response rates. 
The rates of CR/BM MRD- and CR/PB MRD- and the corresponding 2-sided 90% exact Cls 
based on Clopper-Pearson method will be presented. 
6.2.2. 
ORR at Week 25 
When calculating ORR at Week 25, subjects who received anti-cancer therapy other than the 
study drug prior to achieving responses at Week 25, will be considered as nonresponders and 
will be included in the denominator. 
ORR at Week 25 and the corresponding 2-sided 90% exact Cls based on Clopper-Pearson 
method will be presented. 
A by-subject listing of overall response based on modified IWCLL 2008 criteria will be 
provided. 
A by-subject listing of BM and PB MRD results will be provided. 
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As understanding of clinical response and response per modified IWCLL 2008 criteria beyond 
week 25 are desired, the following endpoints not defined by protocol will also be analyzed: 
• 
ORR, defined as the proportion of subjects achieving best overall response of CR, CRi, PR, 
or PR with lymphocytosis per Modified IWCLL 2008 criteria while on study 
• 
Time to clinical response, defined as the interval from first dose of study drug to the date of 
the first clinical response which includes clinical complete response (CCR) and clinical 
partial response (CPR) 
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Clinical response assessment is a qualitative treatment response assessment based on physical 
exam, laboratory parameters and presence of B-symptoms perfonned every 4 weeks until Week 
33 Day 1 and then at all scheduled visits thereafter following the modified IWCLL 2008 criteria, 
with the exception of lymphadenopathy, hepatomegaly, splenomegaly, and bone marrow. 
Clinical response categories are CCR, CPR, stable disease, and suspected progressive disease. 
The date of disease progression will be the time point at which progression is first identified by 
relevant radiographic imaging data or clinical data. 
6.4.1. 
ORR 
The analysis will be perfonned with data collected throughout the study. Subjects, who never 
achieved these responses or received anti-cancer therapy other than the study drug prior to 
achieving responses, will be considered as nonresponders and will be included in the 
denominator when calculating ORR. 
ORR and the corresponding 2-sided 90% exact Cls based on Clopper-Pearson method will be 
presented. A by-subject listing of overall response will be provided. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. 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. 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 CRF to the 
question of “Related to Study Treatment GS-4059”, “Related to Study Treatment Entospletinib”,
or “Related to Study Treatment Obinutuzumab”. 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 the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance 
and Epidemiology Department before data finalization.
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 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to discontinuation of study drug


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
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.
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.
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, HLT, PT, and treatment group. For the AE categories described below, 
summaries will be provided by SOC, PT, maximum severity, and treatment group:

TEAEs

TEAEs with Grade 3 or higher

TEAEs related to tirabrutinib

TEAEs related to entospletinib

TEAEs related to obinutuzumab


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
TEAEs related to tirabrutinib with Grade 3 or higher

TEAEs related to entospletinib with Grade 3 or higher

TEAEs related to obinutuzumab with Grade 3 or higher

TE SAEs

TE SAEs related to tirabrutinib

TE SAEs related to entospletinib

TE SAEs related to obinutuzumab

TEAEs leading to discontinuation of tirabrutinib

TEAEs leading to discontinuation of entospletinib

TEAEs leading to discontinuation of obinutuzumab

TEAEs leading to dose modification of tirabrutinib

TEAEs leading to dose modification of entospletinib

TEAEs leading to dose modification of obinutuzumab

TEAEs leading to temporary interruption of tirabrutinib

TEAEs leading to temporary interruption of entospletinib

TEAEs leading to temporary interruption of obinutuzumab

TEAEs leading to discontinuation of study

TEAEs leading to death (note that the severity will not be shown as all the TEAEs are 
Grade 5)
A brief, high-level summary of AEs described above will be provided by treatment group and by 
the number and percentage of subjects who experienced the above AEs. This summary table will 
also include TEAEs with Grade 3 or 4 and all deaths.
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, the most severe severity will be 
used for those AEs that occurred more than once in a given subject during the study.
In addition to the above summary tables, TEAEs, TEAEs of Grade 3 or higher, TE
treatment-related AEs, and TE SAEs will be summarized by PT only in descending order of total 
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In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs with Grade 3 or higher

All SAEs

All Deaths

AEs leading to death

AEs leading to discontinuation of study drug

AEs leading to discontinuation of study
7.1.6.1.1.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided by treatment group. 
The summary will include the following categories:

All deaths

Deaths within 30 days of the last dosing of study drug

Deaths beyond 30 days of the last dosing of study drug
The attribution of death will also be summarized.
7.1.7.
Adverse Events of Interest
The treatment-emergent AEs of interest (AEI) include:
AEI
Grouped Terms
Hemorrhage/Bleeding 
MST-CT Bleeding/Haemorrhage (Appendix 4)
Infections
SOC: Infections and infestations
Hypersensitivity
MST-CT Hypersensitivity (Appendix 5)
Cytopenia
MST: Anemia-related events, leukopenias, neutropenia, thrombocytopenias 
(Appendix 6)
Cardiac Arrhythmias
MST-CT Cardiac arrhythmia and bradycardia narrow (Appendix 7)
Diarrhoea
PT: Diarrhoea
Rash
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The following summaries will be provided for AEIs by SOC, PT, and maximum severity:
A) TEAE
B) TEAEs leading to dose modifications or temporary interruption of study drug
C) 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 data in Appendix 9 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. Hemolized test results will not be included in the analysis, 
but they will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and coagulation, separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on 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 will be provided by treatment group for each laboratory test specified in the 
study protocol as follows:

Baseline values 

Postbaseline maximum value

Postbaseline minimum value

Change and percentage change from baseline to postbaseline maximum value

Change and percentage change from baseline to postbaseline minimum value
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. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. 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 
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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 to assign 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.
7.2.2.2.
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 TE laboratory abnormalities

TE Grade 3 or 4 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.
A by-subject listing of treatment-emergent 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 and 
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


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
Total bilirubin: > 2 x ULN

Alkaline phosphatase (ALP) > 1.5 x ULN

AST or ALT > 3 x ULN and total bilirubin: (a) > 1.5 x ULN; (b) > 2 x ULN
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 up to 30 days after last dosing date. The percentage will be based on subjects 
with values available at both baseline and postbaseline.
7.3.
Body Weight and Vital Signs
Body weight and vital signs are collected at screening and may be collected at unscheduled 
visits. Thus, only a by-subject listing of vital signs will be provided by subject ID number and 
time visit in chronological order.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
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 


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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 medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken 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.
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. 
Summaries of investigator assessment of ECG readings and ECG data will be provided for the 
Safety Analysis Set. No formal statistical testing is planned.
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at worst outcome during study 
compared with baseline values will be presented by treatment group using the following 
categories: normal; abnormal, not clinically significant; abnormal, clinically significant; or 


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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 visit 
in chronological order.
7.5.2.
Corrected QT Intervals
The QT interval (measured in millisecond [msec]) is a measure of the time between the start of 
the Q wave and the end of the T wave in the heart’s electrical cycle. The QT interval represents 
electrical depolarization and repolarization of the ventricles. The QT interval is affected by heart 
rate, and a number of methods have been proposed to correct QT for heart rate. 
Corrected QT (QTc) intervals will be derived using Fridericia’s correction (QTcF) as follows:




√

where QT is measured in msec; RR
60/Heart Rate (beats per min [bpm]) and RR is 
measured in seconds
The maximum postdose QTcF interval values obtained during the study will be summarized 
within the following categories:

> 450 msec

> 480 msec

> 500 msec
The maximum postdose change in QTcF interval values obtained during the study will also be 
summarized within the following categories:

> 30 msec

> 60 msec
7.5.3.
PR and QRS Intervals
The PR interval (measured in msec) is a measure of the time between the start of the P wave 
(the onset of atrial depolarization) and the beginning of the QRS complex (the onset of 
ventricular depolarization). The QRS interval measures the duration of the QRS complex. The 
maximum ventricular rate (VR) and PR and QRS intervals observed during the study will be 
categorized. The number and percentage of subjects having values in the following ranges will 
be presented by treatment group:

VR > 100 bpm


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
PR interval > 200 msec

QRS interval > 110 msec
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 (PK) ANALYSES
8.1.
PK Sample Collection
A PK sample will be collected on Week 1 Day 1 at 2 (±1) hours (inclusive) post-dose of 
tirabrutinib and entospletinib. At the visits on Week 5, 13, and 21, a PK sample will be collected 
at pre-dose (within 2 hours prior to dosing) and 1 sample will be collected at 2 (±1) hours 
(inclusive) post-dose of tirabrutinib and entospletinib.
8.2.
PK Analyses
Individual subject concentration data for tirabrutinib and entospletinib will be listed and 
summarized using descriptive statistics by treatment. Summary statistics (n, mean, StD, 
coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for individual 
subject concentration data by time point by treatment. Moreover, the geometric mean and 95% 
CI of the natural log-transformed values will be presented.
Individual concentration data listings and summaries will include all subjects with concentration 
data. 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 for each analyte by treatment:

Individual subject concentration data and summary statistics
PK sampling details by subject, including procedures, differences in scheduled and actual draw 
times, and sample age will be provided in listings.


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9.
REFERENCES
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.


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


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
13 Jan 2021
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
13 Jan 2021
5.3
Revised the calculation of time 
since CLL diagnosis
To be consistent with the 
calculations of similar times


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12.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
COVID-19 SMQ with Broad Scope
Appendix 3.
Determining Missing and Virtual Visits Due to COVID-19
Appendix 4.
Bleeding/Haemorrhage Medical Search Term
Appendix 5.
Hypersensitivity Medical Search Term
Appendix 6.
Cytopenia Medical Search Term
Appendix 7.
Cardiac arrhythmia Medical Search Term
Appendix 8.
Rash Medical Search Term
Appendix 9.
List of Laboratory Tests for Safety Summary


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Appendix 1. 
Schedule of Assessments 
Screening 
24 Weeks 
Every 
12 weeks 
starting 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 33 
Day 
1 
2 
3 Day 
4 
5 
9 
13 
17 
21 Day 25 Day 
29Day 
until Week 
-28 
Day 1 
Day 1 
1 
Day JP Day 1 
Day 1 
Day 1 
Day 1 
1 
t• 
1 
105 
EOTq 
Visit Window (days) 
0 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±7 
±7 
±7 
±7 
Informed Consent 
X 
Medical and 
X 
Medication History" 
Physical Examinationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Yitai Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status I B-symptoms 
Binet/Rai Staging 
X 
G8 Geriatric Screening 
X 
X 
X 
X 
Toole 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events/ 
Concomitant 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
medications 
Tirabrutinib + 
entospletinib 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensinge 
Tirabrutinib + 
entospletinib 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Accountability 
Obinutuzumab 
X 
X 
X 
X 
X 
X 
X 
X 
Administrationf 
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Screening
24 Weeks
Week 
25 Day 
1s
Week 
29 Day 
1
Every 
12 weeks 
starting 
Week 33 
until Week 
105
EOTq
Day 
-28
Week 
1
Day 1
Week 
2
Day 1
Week 
3 Day 
1
Week 
4 
Day 1p
Week 
5
Day 1
Week 
9
Day 1
Week 
13 
Day 1
Week 
17 
Day 1
Week 
21 Day 
1
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/INR, 
aPTT)
X
X
Peripheral Blood 
MRDg
X
X
X
X
X
Urinalysis and Urine 
Chemistry
X
Pregnancy Testingh
X
X
X
X
X
X
X
X
X
X
X
Viral Serologiesi
X
PK samplingj
X
X
X
X
CLL phenotypingl
X
X
Radiographic Tumor 
evaluationm
X
X
Bone marrow 
evaluationn
X
X
Response Assessmento
X
X
X
X
X
X
X
X
X
a
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti cancer therapies, and any 
concurrent medical illnesses. History of smoking in the past 30 days and CIRS score should be determined at screening.
b
Screening and End of Treatment will be complete physical examinations. Beginning at Week 1 Day 1, a modified physical examination will be a performed to monitor for any 
changes (eg, lymph nodes, size of the liver and spleen, lung, cardiac, abdomen, skin, neurologic, and any system clinically indicated). Weight should be measured at each PE. 
Height should be measured at screening only.
c
The G8 screening questionnaire will be used for assessment of subjects aged > 70 years at Week 1 Day 1 and every 6 months until EOT.
CCI


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d 
Subjects should be resting quietly in supine position for 5 minutes prior to ECG collection. The Investigator or qualified designee will review all ECGs. 
e 
Study dmg is not dispensed at the Week 105 visit. 
Version 2 .0 
f 
Obinutuzumab: I 00 mg will be administered intravenously on Day I and 900 mg on either Day I or 2 (Week I); then I 000 mg on Day 8 (Week 2), Day 15 (Week 3), and on 
Weeks 5, 9, 13, 17 and 2 1 for a total of 8 doses of 1000 mg over 2 1 weeks. If the I 00 mg infusion on Day I is well tolerated, the remaining 900 mg (scheduled for Day 2) 
may be given on Day I. 
g 
Peripheral blood MRD will be assessed on Day I of Weeks I, 13, 25, 33, 45, I 05, and EOT. EOT collection is not needed for subjects who complete the Week I 05 visit. 
h 
Semm pregnancy test will be perfom1ed at screening for all women of childbearing potential. Urine pregnancy tests will be conducted prior to Week I Day I and then every 
4 weeks until the EOT visit. Pregnancy kits may be provided for home testing. The results must be confim1ed as negative prior to continued administration of study dmg. 
Hepatitis serology includes HBsAg, HBcAb, HCV Ab; patients with positive HBcAb and negative HBsAg should have HBV DNA PCR perfom1ed prior to treatment start to 
m le out occult infection, then monthly through 6 months and then at subsequent clinic visits for at least I year following the EOT visit. HIV testing and CMV IgG and IgM 
testing should be perfom1ed at screening. 
r 
A PK sample will be collected approximately 2 hours(± I hour) post dose on Week I, Day I. On Day I of Weeks 5, 13, and 2 1 a PK sample will be drawn at pre dose 
within 2 hours rior to AM dosing and at 2 hours ± I hour 
ost dose. 
CLL immunophenotyping, karyotyping and FISH, TP53 and IgHV mutation status, CD38 and ZAP70 expression will be evaluated from peripheral blood at screening. In the 
event of disease progression, only FISH and TP53 will be evaluated. 
m 
Tumor evaluation by CT scan (preferred) or MRI of neck, chest abdomen and pelvis will be perfom1ed at screening (unless scan was already completed up to 42 days prior to 
first dose). At the Week 25 visit, the same type of evaluation should be perfom1ed on those body regions which showed involvement by CLL at screening. An additional CT 
may be obtained on protocol per investigator discretion following evidence ofan improvement in clinical response if the response assessment at the Week 25 visit is less than 
a complete response or in the event of suspected disease progression. 
n 
A bone marrow evaluation is re.quired in the screening window for subjects without radiographic evidence of disease. Bone marrow aspirate and biopsy should be perfom1ed 
at Week 25 for subjects fulfilling clinical response criteria for complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi) per the modified 
IWCLL 2008 criteria. MRD should be assessed from bone marrow as irate at the reference laboratory in Kiel; the remainder of the aspirate sample should be sent for 
biobanking and 
. The analysis of the biopsy should be perfom1ed at the site's local laboratory. An 
additional bone marrow biopsy may be obtamed on protocol per mvesllgator discretion following evidence of an improvement in clinical response if the response assessment 
at the Week 25 visit is less than a complete response. 
o 
Qualitative treat111ent response assessment based on physical exam, laboratory parameters and presence of B symptoms should be perfom1ed every 4 weeks until Week 33 
Day I and then at all scheduled visits thereafter following the modified IWCLL 2008 criteria, with the exception of lymphadenopathy, hepatomegaly, splenomegaly, and bone 
marrow. Assessment of response per modified IWCLL 2008 criteria should also be recorded at the completion of 24 weeks on treat111ent and subsequent to any CT and/or 
bone marrow biopsy that is repeated while on study. 
p 
Following evaluation of the safety data for the first 6 subjects enrolled in each treat111ent ann, the Safety Review Team (SRT) will detem1ine if weekly clinical evaluation 
should continue for the duration of the study. 
q 
The EOT visit should be scheduled for approximately 30 days following discontinuation of all study treat111ent. For subjects that pem1anently discontinue all treat111ent prior to 
Week 25 Day I, the Week 25 Day I visit should also be perfom1ed and may satisfy the re.quirement for the EOT visit if falling into the +30 days ± 7 day window from all 
study dmg discontinuation. 
r 
Screening results should include creatinine clearance, and semm thymidine kinase, semm beta2 microglobulin and semm quantitative immunoglobulins. 
s 
The window for bone marrow assessments is 7 days or + 14 days as calculated from Week I Day I. 
CONFI DENT IAL 
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Appendix 2.
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 3.
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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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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Appendix 4.
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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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


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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


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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
Venous perforation
10075733
Ventricle rupture
10047279
Vertebral artery perforation
10075735
Vessel puncture site bruise
10063881
Vessel puncture site haematoma
10065902
MEDDRA Preferred Term 
PT Code
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


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Appendix 5.
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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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


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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


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CONFIDENTIAL
Page 62
13 January 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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CONFIDENTIAL
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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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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


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CONFIDENTIAL
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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


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Appendix 6.
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
Aplastic anaemia
10002967
Erythroblast count decreased
10058505
MEDDRA Preferred Term
PT Code
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
Bone marrow failure
10065553
Cytopenia
10066274
Febrile bone marrow aplasia
10053213
Full blood count decreased
10017413


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Version 2.0
CONFIDENTIAL
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MEDDRA Preferred Term
PT Code
Gelatinous transformation of the bone 
marrow
10078097
Pancytopenia
10033661
Panmyelopathy
10050026


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CONFIDENTIAL
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Appendix 7.
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 Preferred Term
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
Bundle branch block
10006578
Bundle branch block bilateral
10006579
Bundle branch block left
10006580
Bundle branch block right
10006582
MEDDRA Preferred Term
PT Code
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
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


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CONFIDENTIAL
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MEDDRA Preferred Term
PT Code
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
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
MEDDRA Preferred Term
PT Code
Wolff Parkinson White syndrome 
congenital
10049291
Bradycardia
10006093


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Appendix 8.
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 Preferred Term
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
Necrolytic migratory erythema
10060821
Neurodermatitis
10029263
MedDRA Preferred Term
PT Code
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
Seborrhoeic dermatitis
10039793
Skin disorder
10040831
Skin plaque
10067723
Skin reaction
10040914


Tirabrutinib (GS-4059)
GS-US-401-2076 
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 71
13 January 2021
MedDRA Preferred Term
PT Code
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)
GS-US-401-2076
Statistical Analysis Plan
Version 0.1
CONFIDENTIAL
Page 72
13 January 2021
Appendix 9.
List of Laboratory Tests for Safety Summary
Serum Chemistry
Hematology
Sodium
Potassium
Chloride
Glucose
Blood urea nitrogen or urea
Creatininea
ALT
AST
GGT
Cholesterol
Triglycerides
Uric Acid
Alkaline phosphatase
Total and direct bilirubin
Total protein
Albumin
Calcium
Magnesium
Phosphate
LDH
Amylase
Lipase
WBC
RBC
Hemoglobin
Hematocrit
Platelet Count
Neutrophils (ANC)
Lymphocytes
Monocytes
Basophils
Eosinophils
Coagulation
PT/INR
aPTT
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft Gault formula 
ALT  alanine aminotransferase; aPTT  activated partial thromboplastin time; AST  aspartate aminotransferase; BUN  blood 
urea nitrogen; GGT  gamma glutamyltransferase; INR  international normalized ratio; LDH
lactate dehydrogenase; PT  
prothrombin time; RBC  red blood cell; WBC  white blood cell


GS-US-401-2076 SAP V2.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
15-Jan-2021
22:52:21
Clinical Research eSigned 19-Jan-2021
18:42:16
PPD
PPD-

Prot_000.pdf: 
                   
CLINICAL STUDY PROTOCOL
Study Title:
A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate 
the Safety and Efficacy of the Combination of Tirabrutinib 
(GS-4059) and Entospletinib with and without Obinutuzumab in 
Subjects with Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
2016-002768-15
NCT02983617
Indication:
Chronic Lymphocytic Leukemia
Protocol ID:
GS-US-401-2076
GCLLSG Protocol ID:
CLLRUmbrella2
Gilead Clinical Program 
Manager:
Name:
Telephone:
+
Gilead Medical Monitor:
Name:
Telephone:
GCLLSG Global Principal 
Investigator:
Name:
Telephone:
+
GCLLSG Coordinating 
Physician:
Name:
 
Telephone:
+
Protocol Version/Date:
Original:
25 August 2016
Amendment 1: 
16 November 2016
Amendment 2:
02 February 2017
Amendment 3:     24 August 2017
Amendment 4:     15 January 2019
CONFIDENTIALITY STATEMENT
The information 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 information 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 
information to others without written authorization from Gilead Sciences, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
(r) GILEAiJ 
DEUTSCHE .. 
sruo1ENGRUPPE 


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 2
15 January 2019 
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.1.1.
Chronic Lymphocytic Leukemia..........................................................................................21
1.2.
Entospletinib ..........................................................................................................................................22
1.2.1.
General Information .............................................................................................................22
1.2.2.
Spleen Tyrosine Kinase in Hematologic Malignancies........................................................22
1.2.3.
Nonclinical Pharmacology and Toxicology of Entospletinib...............................................22
1.2.4.
Clinical Trials of Entospletinib ............................................................................................22
1.3.
Tirabrutinib ............................................................................................................................................23
1.3.1.
General Information .............................................................................................................23
1.3.2.
BTK in B-cell Malignancies.................................................................................................23
1.3.3.
Nonclinical Pharmacology and Toxicology of Tirabrutinib.................................................25
1.3.4.
Clinical Trials of Tirabrutinib ..............................................................................................25
1.4.
Obinutuzumab........................................................................................................................................27
1.5.
Rationale for This Study ........................................................................................................................28
1.5.1.
Rationale for Dose Selection................................................................................................28
1.6.
Risk/Benefit Assessment for the Study..................................................................................................30
1.7.
Compliance ............................................................................................................................................32
2.
OBJECTIVES.....................................................................................................................................................33
3.
STUDY DESIGN................................................................................................................................................34
3.1.
Study Design..........................................................................................................................................34
3.2.
Study Treatments ...................................................................................................................................34
3.3.
Duration of Treatment............................................................................................................................36
3.4.
Criteria for Discontinuation of Study Treatment....................................................................................37
3.5.
Duration of Study...................................................................................................................................37
3.6.
Criteria for Discontinuation from Study ................................................................................................37
3.7.
GCLLSG CLL Registry .........................................................................................................................38
3.8.
Post Study Care......................................................................................................................................38
4.
SUBJECT POPULATION..................................................................................................................................39
4.1.
Number of Subjects................................................................................................................................39
4.2.
Inclusion Criteria....................................................................................................................................39
4.3.
Exclusion Criteria...................................................................................................................................40
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................42
5.1.
Randomization .......................................................................................................................................42
5.2.
Description and Handling of Tirabrutinib, Entospletinib, and Obinutuzumab.......................................42
5.2.1.
Tirabrutinib ..........................................................................................................................42
5.2.2.
Entospletinib.........................................................................................................................43
5.2.3.
Obinutuzumab ......................................................................................................................44
5.3.
Dosage and Administration of Tirabrutinib, Entospletinib, and Obinutuzumab....................................45
5.3.1.
Tirabrutinib and Entospletinib..............................................................................................45
5.3.2.
Obinutuzumab ......................................................................................................................45
5.4.
Prior and Concomitant Medications.......................................................................................................48


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Protocol GS-US-401-2076
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Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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5.4.1.
IVIg and G-CSF ...................................................................................................................49
5.4.2.
Prior and Concomitant Medications with Tirabrutinib.........................................................49
5.4.3.
Prior and Concomitant Medications with Entospletinib.......................................................49
5.4.4.
Prior and Concomitant Medications with Obinutuzumab ....................................................51
5.5.
Accountability for Tirabrutinib, Entospletinib, and Obinutuzumab.......................................................51
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................52
6.
STUDY PROCEDURES ....................................................................................................................................53
6.1.
Subject Enrollment, Randomization and Treatment Assignment...........................................................53
6.2.
Study Procedure Descriptions ................................................................................................................53
6.2.1.
Informed Consent.................................................................................................................53
6.2.2.
Medical and Medication History..........................................................................................53
6.2.3.
Physical Examination...........................................................................................................54
6.2.4.
Vital Signs............................................................................................................................54
6.2.5.
ECOG Performance Status/B-Symptoms.............................................................................54
6.2.6.
12-lead ECG.........................................................................................................................54
6.2.7.
Binet and Rai Staging...........................................................................................................54
6.2.8.
Geriatric assessment.............................................................................................................54
6.2.9.
Prior and Concomitant Medications.....................................................................................55
6.2.10.
Adverse Events.....................................................................................................................55
6.2.11.
Radiology Assessment .........................................................................................................55
6.2.12.
Blood and Urine Samples.....................................................................................................55
6.2.13.
Bone Marrow Assessment....................................................................................................56
6.2.14.
Laboratory Samples to Address the Study Objectives .........................................................56
6.2.15.
Samples for Optional Future Research.................................................................................57
6.2.16.
Pregnancy Test for Females of Childbearing Potential ........................................................57
6.2.17.
Pharmacokinetic Samples.....................................................................................................57
6.3.
Assessments for Premature Discontinuation from Study.......................................................................59
6.4.
Criteria for Discontinuation of Study Treatment....................................................................................59
6.5.
Dose Interruption and Reduction ...........................................................................................................59
6.6.
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions................................................................................................................64
6.6.1.
Hemorrhage..........................................................................................................................64
6.6.2.
Infectious Events..................................................................................................................64
6.6.3.
Dermatological and Hypersensitivity Events .......................................................................64
6.6.4.
Hepatic Events......................................................................................................................65
6.6.5.
Hematological Events...........................................................................................................65
6.6.6.
Progressive Multifocal Leukoencephalopathy (PML)..........................................................65
6.6.7.
Further Safety Information...................................................................................................65
6.7.
End of Treatment....................................................................................................................................66
6.8.
Unscheduled Procedures ........................................................................................................................66
6.9.
Post Study Care......................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69


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Gilead Sciences, Inc.
Amendment 4
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7.4.
Gilead Reporting Requirements.............................................................................................................71
7.5.
Toxicity Management ............................................................................................................................71
7.6.
Special Situations Reports......................................................................................................................72
7.6.1.
Definitions of Special Situations..........................................................................................72
7.6.2.
Instructions for Reporting Special Situations.......................................................................72
8.
STATISTICAL CONSIDERATIONS................................................................................................................74
8.1.
Analysis Objectives and Endpoints........................................................................................................74
8.1.1.
Analysis Objectives..............................................................................................................74
8.1.2.
Primary Endpoint .................................................................................................................74
8.1.3.
Secondary Endpoints............................................................................................................74
8.1.4.
Exploratory Endpoints..........................................................................................................74
8.2.
Analysis Conventions.............................................................................................................................75
8.2.1.
Analysis Sets ........................................................................................................................75
8.3.
Data Handling Conventions ...................................................................................................................76
8.4.
Demographic Data and Baseline Characteristics ...................................................................................76
8.5.
Efficacy Analysis ...................................................................................................................................77
8.5.1.
Primary Endpoint .................................................................................................................77
8.5.2.
Secondary Endpoints............................................................................................................77
8.6.
Safety Analysis.......................................................................................................................................77
8.6.1.
Extent of Exposure...............................................................................................................77
8.6.2.
Adverse Events.....................................................................................................................77
8.6.3.
Laboratory Evaluations ........................................................................................................78
8.7.
Pharmacokinetic Analysis......................................................................................................................79
8.8.
Biomarker Analysis................................................................................................................................79
8.9.
Sample Size............................................................................................................................................79
8.10.
External Data Monitoring Committee....................................................................................................79
8.11.
Endpoint Adjudication Committee.........................................................................................................80
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Independent Ethics Committee Review and Approval.........................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................86
9.3.4.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................91


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 5
15 January 2019 
Appendix 1.
       Investigator Signature Page.............................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................96
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................97
Appendix 5.
Eastern Cooperative Oncology Group (ECOG) Performance Status ...................................100
Appendix 6.
Modified IWCLL 2008 Response Criteria ...........................................................................101
Appendix 7.
Cumulative Illness Rating Scale (CIRS) ..............................................................................103
Appendix 8.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................104
Appendix 9.
Binet and Rai Staging Systems for the Classification of CLL..............................................105
Appendix 10.
The G8 Screening Questionnaire..........................................................................................106
LIST OF IN-TEXT TABLES
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study ...........................................50
Table 5-2.
Recommended dose limits for HMG-CoA reductase inhibitors.............................................50
Table 6-1.
Blood and Urine Samples Collected During the Course of the Study....................................58
Table 6-2.
Dose Adjustments, Withholding and Discontinuation Related to Entospletinib 
and/or Tirabrutinib..................................................................................................................60
Table 6-3.
Dose Adjustment Guidelines for Subjects Receiving Obinutuzumab ....................................62
Table 7-1.
Grading of Adverse Event Severity........................................................................................69
Table 8-1.
90% Confidence Intervals at Different CR Rates...................................................................79
LIST OF IN-TEXT FIGURES
Figure 1-1.
Inhibition of the BCR Pathway ..............................................................................................25


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 6
15 January 2019 
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate 
the Safety and Efficacy of the Combination of Tirabrutinib
(GS-4059) and Entospletinib with and without Obinutuzumab in 
Subjects with Chronic Lymphocytic Leukemia
IND Number:
EudraCT Number:
Clinical Trials.gov
Identifier:
This is a non-IND study
2016-002768-15
NCT02983617
Study Centers Planned:
Approximately 25 centers in Germany
Objectives:
Primary Objective:

To determine the preliminary efficacy of finite therapy with the 
combination of tirabrutinib, entospletinib with obinutuzumab in 
subjects with relapsed or refractory chronic lymphocytic 
leukemia (CLL)
Secondary Objective:

To evaluate the safety and tolerability of the combination of 
tirabrutinib and entospletinib with and without obinutuzumab
Exploratory Objectives:
 
Endpoints:
Primary Endpoint:
The primary endpoint is the rate of complete remission (CR) per 
modified International Workshop on CLL (IWCLL 2008) criteria
{Hallek 2008} at Week 25
Secondary Endpoints:

Rate of complete response (CR) with bone marrow minimal 
residual disease (MRD) negativity (CR/BM MRD-) at Week 25

Rate of CR with MRD negativity (<10-4) in peripheral blood 
(CR/PB MRD-) at Week 25
CCII 
I 


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 7
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
Overall response rate (ORR) at Week 25 including CR, CR with 
incomplete bone marrow recovery (CRi), partial remission 
(PR), and PR with lymphocytosis

Type, frequency, and severity of adverse events (AEs) and 
serious adverse events (SAEs)
Exploratory Endpoints:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCII 
I 
I 
I 
I 
I 
I 
I 
I 


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Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 8
15 January 2019 
Study Design:
This is a Phase 2, prospective, open-label, multicenter trial to 
evaluate the safety and efficacy of the combination of tirabrutinib 
(GS-4059) and entospletinib with and without obinutuzumab in 
subjects with relapsed or refractory CLL.
Eligible subjects will be treated with the combination of tirabrutinib
and entospletinib and stratified by the presence of 17p 
deletion/TP53 mutation (del17p/TP53mut) in CLL cells. Following 
stratification, subjects will be randomized 1:1 to treatment with the 
combination of tirabrutinib and entospletinib with or without 
obinutuzumab.

Arm A: tirabrutinib + entospletinib

Arm B: tirabrutinib + entospletinib + obinutuzumab


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 9
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Study Design Schema
With Amendment 3, randomization was discontinued. All 
subsequently enrolled subjects will enter Arm B (tirabrutinib + 
entospletinib + obinutuzumab).
With Amendment 4, the Post Treatment period will no longer be 
applicable.
Screening 
Arm A 
N =30 
/ 
ArmB 
N =30 
GS-4059 
Entospletinib 
1:1 Randomizat:ion 
GS-4059 
Entospletinib 
Obinutuzurnab 
Week 25 
~
-
........................................................ ......, 
Obinut uzumab: 21 weeks 
Gs.-4059 + Entosplet inib: Up to 104 weeks 
Total Duration: 5 years 
'Wttk:25 
. . 
----- ·~--------------
Tirt bn!tti'llb 
11:ntospletlnlb 
Ol)lnut11tumab 
oblnulllrurnab: 21 weelci 
Total 1Duradon: 5, yurs 
EOT 
EOT 
Post-Treatment 
On-Study 
Scheduled Assessments 
Polit-1r-Htm4t.llt 
On-Study_ 
EOS 
OS 


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 10
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Sueenllilg 
GS-4059 
Entos;p1etf n'lb 
1.1 R:andomlzatlo:n, 
GS-4059 
Entosple lnlb 
Oblnutuzumab 
O:b nlltuZiumab: 21 weeks 
w,eekzs 
GS-4059 + [ntosp' :ti'n b: Up to 104 w 
il!cs 
EOT 


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 11
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Enrollment will be paused following enrollment of the first 6 subjects
into Arm B, who will be observed for safety for 28 days following the 
first dose of study treatment including weekly evaluation through that 
period. Additional subjects may be enrolled into the safety cohort if any 
of the first 6 subjects in Arm B discontinue therapy during the initial 
28 days for reasons unrelated to toxicity. A Safety Review Team (SRT) 
will review 28-day safety data from the first 6 subjects in Arm B and 
determine whether enrollment may resume and if weekly clinical 
evaluation through the first 28 days should continue or may be reduced 
in frequency for the remainder of subjects enrolled in the study. The 
safety review will include assessment of the following:

Grade ≥ 4 hematological toxicities persisting for > 7 days

Grade ≥ 4 non-hematologic laboratory abnormalities except for 
asymptomatic AST/ALT elevation, LDH, or uric acid

Grade ≥ 3 non-hematological toxicities (except alopecia or the 
following that resolve within 72 hours with medical intervention: 
tumor lysis, nausea, vomiting, diarrhea, or constipation)

Grade ≥ 2 non-hematologic treatment-emergent adverse events 
(TEAE) that in the opinion of the investigator are of potential 
clinical significance such that further dosing would expose subjects 
to unacceptable risk
A decision to prematurely terminate the study will be made by the 
sponsor in consultation with the investigators in accordance with 
regulatory and ethical principles.
Criteria for termination of the study are:
1) An unacceptable safety profile or incidence of AEs or SAEs revealed 
in this or any other study in which the combination of agents is 
administered
2) Any other factor that in the view of the sponsor constitutes an 
adequate reason for terminating the study 
As agreed with the German Federal Institute for Drugs and Medical 
Devices Agency (BfArM), a safety report including the cumulative 
safety results and summary of the conclusion of the SRT following 
assessment of the safety cohort was submitted to BfArM shortly after 
the assessment.
The study steering committee, including representatives from the 
German CLL Study Group (GCLLSG) and Gilead, will review ongoing 
safety data at least quarterly throughout the treatment period and 
regularly for the complete duration of the study.


Tirabrutinib & Entospletinib
Protocol GS-US-401-2076
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Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 12
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Number of 
Subjects Planned:
Approximately 36 evaluable in total; 30 evaluable in Arm B and 
approximately 6 in Arm A
Target 
Population:
Adults with relapsed or refractory CLL
Duration of 
Treatment:
Obinutuzumab will be administered for up to 8 doses over 21 weeks to 
subjects randomized or enrolled to treatment with tirabrutinib + 
entospletinib + obinutuzumab (Arm B). Combination treatment with the 
oral agents will continue for all subjects for up to 104 weeks in the 
absence of disease progression, unacceptable toxicity or documentation 
of CR/BM MRD-. If CR/BM MRD- is documented on study, treatment 
will stop after the earlier of:
1) an additional 3 months of therapy or
2) 104 weeks of total treatment. 
Long-Term 
Follow-up After 
End of Study:
Consenting subjects for inclusion in the German CLL Study Group 
(GCLLSG) registry is requested at screening or as soon as possible 
thereafter.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all the following criteria to be eligible for 
participation in this study:
1) Documentation of relapsed or refractory CLL
2) Have an indication for treatment per modified IWCLL 2008 criteria; 
subjects without radiographically measureable disease (defined as ≥
1 lesion > 1.5cm in diameter as assessed by computer tomography 
(CT) or magnetic resonance imaging [MRI]) must have bone 
marrow evaluation at screening
3) Adequate hematologic function as indicated by a platelet count 
≥50 x 109/L, a neutrophil count ≥ 1 x 109/L and a hemoglobin 
≥8g/dL unless lower values are directly attributable to documented 
bone marrow burden of CLL
4) Adequate renal function as indicated by a CrCl ≥50 mL/min 
calculated by the modified Cockroft-Gault formula or from a 24h 
urine collection


Tirabrutinib & Entospletinib
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Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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5) Adequate liver function as indicated by total bilirubin 
≤1.5x institutional upper limit of normal (ULN) unless attributed to 
Gilbert’s syndrome and AST/ALT ≤ 2.5×ULN
6) Male or female ≥ 18 years of age
7) Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) ≤ 2
8) Absence of active HBV infection (serological testing within 6 weeks 
prior to randomization or enrollment with the following results: 
HBsAg negative AND anti-HBcAb negative, or if anti-HBcAb 
positive, HBV DNA PCR negative)
9) HCV Ab negative or if Ab positive, negative HCV RNA PCR within 
6 weeks prior to randomization or enrollment
10) Negative testing for HIV within 6 weeks prior to randomization or 
enrollment
11) Satisfies the following criteria:
a) For female subjects of childbearing potential, willingness to 
abstain from sexual intercourse or use a protocol-specified 
method of contraception as described in Appendix 4
b) Male subjects of reproductive potential who engage in sexual 
intercourse must agree to use protocol-specified method(s) of 
contraception as described in Appendix 4
12) Ability and willingness to provide written informed consent and 
adhere to protocol requirements including study visit schedule, drug 
administration plan, imaging studies, laboratory testing, other study 
procedures and restrictions
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible for participation in this study:
1) Known transformation of CLL (ie, Richter’s transformation, 
prolymphocytic leukemia)
2) Known CNS involvement
3) Progression on treatment with any inhibitor of BTK, SYK, PI3K, 
BCL-2, or obinutuzumab. The treatment and disease response 
history of subjects with prior treatment with agents in these classes 
should be reviewed by the sponsor or the GCLLSG study office
prior to enrollment to clarify sensitivity to these treatments.
4) Any treatment for CLL other than corticosteroids for symptomatic 
management within 28 days of the start of study treatment
5) Participation in a concurrent therapeutic clinical trial unless all 
treatment is complete with only ongoing surveillance


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6) Diagnosis of or concern for progressive multifocal 
leukoencephalopathy
7) History of myelodysplastic syndrome or another malignancy other 
than CLL, except for the following: any malignancy that has been in 
complete remission for 3 years, adequately treated local basal cell or 
squamous cell carcinoma of the skin, cervical carcinoma in situ, 
superficial bladder cancer, asymptomatic prostate cancer without 
known metastatic disease and with no requirement for therapy or 
requiring only hormonal therapy and with normal prostate-specific 
antigen for 1 year prior to start of study therapy.
8) Active infection requiring systemic therapy
9) Pregnant or nursing women (a negative pregnancy test is required 
for all women of childbearing potential within 7 days before start of 
treatment and monthly during therapy)
10) Active autoimmune disease including autoimmune hemolytic 
anemia or idiopathic thrombocytopenic purpura requiring a higher 
corticosteroid equivalent than prednisone 10 mg daily. Higher doses 
of corticosteroids prescribed for any indication must be stopped 
> 14 days prior to randomization or enrollment; exceptions may be 
made for corticosteroids prescribed specifically for management of 
CLL symptoms after discussion with the study medical monitor.
11) Diagnosis of inflammatory bowel disease or ongoing symptomatic 
pneumonitis
12) History of stroke or intracranial hemorrhage within 12 months of 
randomization or enrollment; subjects requiring therapeutic 
anticoagulation for any indication should be discussed with the 
GCLLSG coordinating physician and/or medical monitor prior to 
screening.
13) Legal incapacity, prisoners or subjects institutionalized by regulatory 
or court order, or any individual in dependence to study sponsor or 
any investigator
14) Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, 
moderate CYP2C9 inducers, or strong P-gp inducers while on study; 
use within 2 weeks of first dose of study treatment should be 
avoided.
15) Requirement for proton pump inhibitor (PPI) therapy
16) Demonstration of QTc interval >450 milliseconds or requirement for 
ongoing treatment with concomitant medications that prolong the 
QT interval
17) Known hypersensitivity to obinutuzumab, entospletinib, tirabrutinib,
or any of the excipients


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Test Product, Dose, 
and Mode of 
Administration:
Tirabrutinib and Entospletinib:
Tirabrutinib 80 mg will be self-administered orally once daily and 
entospletinib 400 mg will be self-administered orally once daily. Dosing 
of both agents will begin on Week 1 Day 1 of the study and thereafter 
continue at approximately the same time each day until the earlier of 
i) 3 months after documentation of CR/MRD- or ii) completion of 
104 weeks of treatment. Tirabrutinib is supplied as 20 mg (4 x 20 mg)
tablets, 40 mg (2 x 40 mg) tablets, or as 80 mg tablets. Entospletinib is 
supplied as 200 mg (2 x 200 mg) tablets.
Obinutuzumab:
Obinutuzumab will be administered as 8 intravenous infusions of 
1000 mg each over 21 weeks. A test dose of 100 mg will be 
administered on Week 1 Day 1. If this dose is tolerated, the remainder of 
the full dose may be subsequently administered on Day 1. Alternatively, 
the remaining 900 mg will be administered on Day 2.
Subsequent infusions will be administered on Week 2 Day 1, Week 3 
Day 1, Week 5 Day 1 and then every 4 weeks through Week 21.
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Safety:
Safety will be evaluated by the documentation of AEs and monitoring of 
clinical laboratory tests.
Efficacy:
Efficacy will be assessed per modified IWCLL 2008 criteria
{Hallek 2008}:

Lymph node, spleen and liver measurements by physical 
examination

Complete blood count

Lymph node, spleen and liver measurements by CT or MRI

Peripheral blood MRD assessment

Bone marrow assessment including standard histopathology and 
MRD assessment
Pharmacokinetics:
Plasma drug concentrations of tirabrutinib and entospletinib as assessed 
by validated bioanalytical methods


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Sample Size 
Determination
The primary goal of this study is to evaluate the efficacy of the 
combination of tirabrutinib and entospletinib with obinutuzumab in 
relapsed and refractory CLL. The primary endpoint for this study is the 
rate of CR at Week 25. The corresponding single-agent CR rate with 
BTK and SYK inhibitors in subjects with relapsed or refractory CLL is 
≤5%. The 90% CI corresponding to different CR rates ranging from 
20% to 60% for a sample size of 30 is provided in the table below. With 
a sample size of 30, the lower bound of the 90% CI of an observed CR 
rate of 20% or above will exclude 5%.
90% Confidence Intervals at Different CR Rates
Sample Size
Observed 
CR Rate
90% Confidence Interval
using Clopper-Pearson Method
30
20%
(9.1%, 35.7%)
30
30%
(16.6%, 46.5%)
30
40%
(25.0%, 56.6%)
30
50%
(33.9%, 66.1%)
30
60%
(43.4%, 75.1%)
With Amendment 3, randomization was discontinued. All subsequently 
enrolled subjects will enter Arm B. A total of approximately 6 subjects 
in Arm A and 30 subjects in Arm B will be enrolled, thus the total 
sample size for the study will be approximately 36 subjects.
Statistical Methods:
The Full Analysis Set (FAS) consists of all subjects randomized or 
enrolled to each study arm who received at least 1 dose of any study 
treatment. The per-protocol (PP) analysis set consists of all randomized
or enrolled subjects who received at least 1 dose of any study treatment 
and have a baseline disease assessment and at least 1 post-baseline 
response measurement. The safety analysis set consists of all 
randomized or enrolled subjects who received at least 1 dose of any 
study treatment.
All efficacy analyses will be based on the FAS and the analyses of 
response endpoints will be repeated using the PP analysis set.
Tumor response will be based on investigator’s assessment according to 
modified IWCLL 2008 criteria (see Appendix 6). CR rate, ORR, rate of 
CR/BM MRD-, and rate of CR/PB MRD- will be estimated for each arm 
and their associated 90% confidence intervals will be calculated using 
the Clopper-Pearson method.
Time-to-event endpoints (DOR, PFS, TTNT, and OS) will be analyzed 
using the Kaplan-Meier method. The median and quartiles and their 
associated 90% confidence intervals for these endpoints will be 
provided if estimable.


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Adverse events will be coded using the current version of MedDRA and 
graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) criteria and will be summarized 
by system organ class and preferred term and by severity and 
relationship to study treatment. Clinical laboratory tests and their 
changes from baseline will be summarized descriptively.
Subject enrollment and disposition will be summarized descriptively by 
treatment arms. Reasons for premature discontinuation from study 
treatment will be provided.
Subject demographics and baseline characteristics as well as baseline 
disease characteristics will be summarized descriptively by treatment 
arms using the FAS. Medical history and concomitant medication use 
will be summarized using the safety analysis set. In general, continuous 
variables will be summarized by sample size, mean, standard deviation, 
median, quartiles, minimum and maximum and categorical variables 
will be summarized by counts and percentages.
Treatment exposure and compliance will be summarized descriptively 
using treatment duration, number of doses, average dose, dose 
modifications, and treatment adherence rate based on the safety analysis 
set.
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
ADME
absorption, distribution, metabolism, and excretion 
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
aPTT
activated partial thromboplastin time
ANC
absolute neutrophil count
AST
aspartate transaminase 
AUC0-24h
mean exposure
BCL-2
B-cell lymphoma 2
BCR
B-cell receptor
BHCG
Beta-human chorionic gonadotropin
BID
twice daily
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CIRS
cumulative illness rating scale
CI
confidence interval
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma/serum concentration of drug
CMV
Cytomegalovirus
CNS
central nervous system
CR
complete response/complete remission
CR/BM MRD-
complete response with bone marrow minimal residual disease negativity (<10-4 CLL cells 
present)
CR/PB MRD-
complete response with peripheral minimal residual disease negativity (<10-4 CLL cells present)
CrCl
creatinine clearance
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
Ctau
observed drug concentration at the end of the dosing interval
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450 enzyme
DDI
drug-drug interaction
del17p
deletion of short arm of chromosome 17
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response


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ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end of treatment
EU
European Union
eSAE 
electronic serious adverse event
FAS
full analysis set
FDA
Food and Drug Administration
FL
follicular lymphoma
FSH 
follicle stimulating hormone
GCB 
germinal center B-cell lymphoma
GCLLSG
German CLL Study Group
GCP
good clinical practice
GGT
gamma-glutamyltransferase
HBcAb
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDPE
high density polyethylene 
HIV
human immunodeficiency virus
HNSTD
highest toxic dose
IB
Investigator’s Brochure
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IMP
investigational medicinal product
iNHL
indolent non-Hodgkin lymphoma
INR 
international normalized ratio
IP
investigational product
IRC
independent review committee
IWCLL
International Workshop on CLL
LDH
lactate dehydrogenase
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
MRD
minimal residual disease, with positivity defined as >1/104 CLL cells present in a sample
MRI
magnetic resonance imaging
MTD
maximum tolerated dose


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MZL
marginal zone lymphoma
NA
not applicable
NCI
National Cancer Institute
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PK
Pharmacokinetics
PP
per protocol
PPI
proton pump inhibitor
PS
performance status
PR
partial response/partial remission
PT
prothrombin time
PVE
(Gilead) Pharmacovigilance and Epidemiology
QT 
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to occur
QTc
corrected QT
RBC
red blood cell
SADR
serious adverse drug reaction
SAE
serious adverse event
SD
stable disease
SLL
small lymphocytic lymphoma 
SOP
standard operating procedure
SPD
sum of the products of greatest perpendicular diameters
SRT
safety review team
StD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
TLR
Toll-like receptor
TP53mut
mutation within TP53 genomic locus
TTNT
time to next therapy
ULN
upper limit of normal
US
United States
WBC
white blood cell
WM
Waldenstrom's macroglobulinemia


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most commonly occurring leukemia in Europe and 
the United States (US) with an estimated lifetime risk of 1:167 in the US (NIH SEER database)
{Sant 2010, Surveillance Epidemiology and End Results (SEER) Program 2011}. CLL is 
marked by the progressive accumulation of functionally impaired monoclonal B lymphocytes in 
blood, bone marrow, lymph nodes, spleen, and liver {Dighiero 2008}. Symptoms include fever, 
night sweats, and weight loss, and disease progression is often accompanied by 
lymphadenopathy, splenomegaly, or hepatomegaly. The course of CLL is highly variable, with a 
median survival of more than 10 years in low-risk patients compared with 2 years in high-risk 
subjects. CLL is largely a disease of the elderly; at diagnosis, 70% of subjects are ≥65 years of 
age and the median age is 71 years {National Cancer Institute (NIH) 2016}. Subjects with CLL 
harboring a deletion of the short arm of chromosome 17 (del17p) or an inactivating mutation in
the TP53 gene (TP53mut) are a particularly high risk CLL population and have shorter intervals 
prior to disease progression and shorter overall survival (OS) {Stephens 2015}.
For the majority of patients, chemoimmunotherapy remains the current standard of care for 
initial treatment {Gribben 2011}. The CLL8 study of the German CLL Study Group (GCLLSG)
comparing FC (fludarabine and cyclophosphamide) vs FCR (FC and CD20) {Hallek 2010}
established the benefit of addition of an anti-CD20 monoclonal antibody to a combination of a 
purine analog and alkylating agent in achieving a durable remission and prolonging survival
{Byrd 2005, Catovsky 2007, Hallek 2010, Robak 2010}. The subsequent CLL-10 study of FCR 
vs. BR (bendamustine and CD20) {Eichhorst 2016} clarified the role of both regimens in the 
initial treatment of CLL. However, for the overwhelming majority of subjects, these treatments 
are not curative; the disease will usually relapse and further intervention is required to obtain and 
maintain tumor control. While repeat treatment with chemoimmunotherapy can be pursued at the 
time of disease relapse, it has toxicity, including myelosuppression and fatigue. These toxicities
limit the suitability of FCR and BR in subjects with significant comorbidities or limited 
functional status. Similarly, subjects with a limited response to initial therapy (refractory) and 
those who have recurrent disease within 3 years are poorly served by repeated treatment with 
chemoimmunotherapy.
The approval and ongoing development of new, effective, oral small molecule targeted agents 
for the treatment of relapsed and refractory CLL has changed the treatment landscape. For 
subjects with del17p or TP53mut who respond poorly to chemoimmunotherapy in the frontline 
setting, these agents have yielded meaningful improvements in response rate and duration of 
response.
How best to combine targeted agents remains an area of interest due to the potential to achieve 
deeper and more durable responses in the treatment of CLL.


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1.2.
Entospletinib
1.2.1.
General Information
Entospletinib is a potent and highly selective inhibitor of spleen tyrosine kinase (SYK) that is 
being developed by Gilead for oral administration in the treatment of hematologic malignancies 
and chronic graft versus host disease.
1.2.2.
Spleen Tyrosine Kinase in Hematologic Malignancies
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily 
expressed in cells of hematopoietic lineage. It is an important mediator of immunoreceptor 
signaling in macrophages, neutrophils, mast cells, and B cells. SYK contains 2 adjacent SH2 
domains that bind to immunoreceptor tyrosine-based activation motifs (ITAMs) to 
autophosphorylate and activate the enzyme. This allows SYK to phosphorylate its specific 
substrates including other enzymes and adaptor proteins, orchestrating a complex series of 
cellular responses such as cell proliferation, differentiation, survival, and phagocytosis.
Recent studies have suggested a role for the dysregulation of the tyrosine kinase SYK in B-cell 
malignancies. SYK is expressed in B cells and is essentially involved in multiple signal 
transduction pathways downstream of the B-cell receptor (BCR). In this process, SYK 
trans-autophosphorylates, and activates effector molecules such as PLC, PI3K, and 
mitogen-activated protein kinase (MAPK) and their associated signaling pathways, to induce a 
variety of responses including: proliferation, survival, differentiation, anergy, and apoptosis 
(Figure 1-1). In B cells, entospletinib effectively blocks BCR-mediated activation and 
proliferation (data on file). Additionally, the BCR can deliver antigen-independent signals that 
have also been postulated to require SYK activity. Both antigen-dependent and independent 
signals have been implicated in the pathogenesis of several common B-cell malignancies, 
including CLL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell 
lymphoma (MCL), marginal zone lymphoma (MZL), and B-lineage acute lymphoblastic 
leukemia (B-ALL) {Efremov 2011}. As a result, inhibitors of SYK activity are an attractive 
therapeutic option for hematopoietic B-cell lymphomas and other NHL varieties where SYK 
inhibition would prevent B-cell receptor-mediated signaling and therefore the uncontrolled 
growth of lymphoma cells.
1.2.3.
Nonclinical Pharmacology and Toxicology of Entospletinib
Please refer to the entospletinib IB for information regarding the nonclinical pharmacology, 
absorption, distribution, metabolism, and elimination (ADME) and nonclinical toxicity of 
entospletinib.
1.2.4.
Clinical Trials of Entospletinib
To date, 16 clinical studies have been initiated with entospletinib including treatment of over 
300 healthy subjects, 75 subjects with CLL and 150 with NHL. For complete details on the 
completed and ongoing studies with entospletinib, please refer to the entospletinib IB.


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The spray-dried dispersion formulation of the entospletinib tablet will be used in the current 
study and its superiority to prior tablet formulations in bioavailability and drug-drug interactions 
was established by Study GS-US-339-0111: A Phase 1 Open-Label, Adaptive Study of Novel 
Entospletinib Tablets Formulations to Evaluate the Effect of Acid Reducing Agents and Food on 
Entospletinib PK and Relative Bioavailability of the Novel Entospletinib Tablet Formulations.
The PK and PD of this formulation were further evaluated in healthy volunteers in Study 
GS-US-245-1222. A less-than-proportional increase in exposure was seen with repeated dosing 
of 400 mg entospletinib in comparison with 200 mg entospletinib. While there was no clinically 
meaningful effect of coadministration of a PPI (omeprazole) on entospletinib PK with 
entospletinib 200 mg once daily, entospletinib exposure (AUCtau) was significantly reduced
(59%) at a dose of entospletinib 400 mg twice daily.
The single agent entospletinib treatment experience in the ongoing Phase 2 GS-US-339-0102 
study showed a benefit in relapsed and refractory CLL. The primary efficacy endpoint for a CLL 
specific cohort with 41 subjects was PFS rate at 24 weeks and was assessed by the independent 
review committee (IRC) to be 69% (95% CI: 51.3, 82.7). With a median exposure of 36 weeks 
(range of 1 to 131 weeks), the safety data for the 41 subjects in the CLL cohort showed 
entospletinib treatment to be generally well tolerated. Treatment emergent AEs with an incidence 
over 15% in the study overall were as follows: fatigue, nausea, diarrhea, decreased appetite, 
constipation, cough, headache, dizziness, pyrexia, anemia, vomiting, dyspnea, and insomnia. The 
most frequently reported SAEs included dyspnea (4%), pneumonia (4%), febrile neutropenia 
(3%), dehydration (3%), and pyrexia (2%).
The ongoing Phase 1b GS-US-401-1757 study is evaluating the safety and tolerability of the 
combination of entospletinib with tirabrutinib and provides the primary supportive data for this 
Phase 2 study. The preliminary safety results from this study are summarized in the dose 
rationale Section 1.5.1.
1.3.
Tirabrutinib
1.3.1.
General Information
Tirabrutinib (also known as 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.
1.3.2.
BTK in 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 


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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 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, diffuse large B-cell lymphoma [DLBCL], mantle cell 
lymphoma [MCL], and lymphocytic lymphoma/Waldenstrom’s macroglobulinemia [WM]). A 
first-in-class BTK inhibitor, ibrutinib (Imbruvica®), has demonstrated clinical benefit to subjects
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}.


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Figure 1-1.
Inhibition of the BCR Pathway
Adapted from {Herrera 2014}
1.3.3.
Nonclinical Pharmacology and Toxicology of Tirabrutinib
Please refer to the tirabrutinib IB for information regarding the nonclinical pharmacology, 
absorption, distribution, metabolism, and elimination (ADME) and nonclinical toxicity of 
tirabrutinib.
1.3.4.
Clinical Trials of Tirabrutinib
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 {Walter 2015}. This study 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 
GS-40$9 
,entosphttinib 
act~ loo 


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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. For CLL patients, the most common AEs were contusion, neutropenia, anemia, and 
nasopharyngitis and the most frequent AEs attributed to tirabrutinib were hematoma, macule, dry 
skin, neutropenia, pruritus, diarrhea and contusion. The most frequent ≥ Grade 3 AEs were 
neutropenia, anemia, thrombocytopenia, and lower respiratory tract infection.
All subjects continuing on tirabrutinib treatment have been transitioned to the GS-US-401-1787 
continuation study; as of 01 June 2016, 27 subjects (18 with CLL) are continuing on treatment 
with tirabrutinib doses ranging from 80 to 600 mg once daily.
Study ONO-4059-01 is an ongoing open-label, multi-center, non-randomized Phase 1 
dose-escalation study of tirabrutinib monotherapy in Japanese subjects with relapsed/refractory 
B-NHL and CLL. This study utilizes a 3+3 design with dose levels ranging from 160 to 600 mg
daily. As of 05 May 2016, 17 subjects had enrolled. The only AEs attributable to study drug 
were Mallory-Weiss syndrome (1), HBV reactivation (1), and pneumonitis (1; subject had 
pre-existing organizing pneumonia). All subjects resumed treatment with lower doses of study 
drug. Rash, anemia, lymphopenia, hypophosphatemia, hypokalemia and emesis were the only 
AEs reported in more than 1 subject (n=2 for all except n=5 for rash).
Study GS-US-401-1767 is a Phase 1, partially-blinded, single-dose, crossover, multiple-cohort 
study of capsule and tablet formulations of tirabrutinib to evaluate the relative bioavailability 
(rBA), food effect, and interaction with a PPI, omeprazole, in healthy subjects. PK data from this 
study show no difference in plasma exposure (Cmax and AUC) of tirabrutinib between the capsule 
formulation and the low and high drug load (10% and 33% w/w, respectively) formulation 
tablets when administered as a single 100-mg dose in the fasted state. This data supports 
switching from capsules to tablets without adjusting dosage. There was no clinically relevant 
effect of food (high-fat meal) on the PK of a single 100-mg dose of tirabrutinib administered as 
the low and high drug load formulation tablets; as such, tirabrutinib tablets may be administered 
without regard to food. There was no clinically relevant effect of multiple doses of omeprazole 
on the PK of a single 100-mg dose of tirabrutinib administered as the low drug load formulation 
tablet and tirabrutinib tablets may be co-administered with PPIs such as omeprazole.
Study GS-US-401-1765 is an open-label, crossover, Phase 1 study to evaluate the effects of an 
OATP1B1/1B3 inhibitor, single dose rifampin, and a strong CYP3A4/p-gp inducer, multiple 
doses of rifampin, on the PK of tirabrutinib in healthy subjects. The slight increase in tirabrutinib
exposure observed in combination with single dose rifampin is not considered clinically relevant 
and does not preclude coadministration of OATP1B1/1B3 inhibitors. The half-life of tirabrutinib
was unchanged and the exposure (Cmax and AUC) of tirabrutinib was significantly decreased 
(~70%) following multiple doses of the inducer rifampin. Strong CYP3A4/P-gp inducers such as
rifampin have the potential to decrease efficacy by reducing exposure.


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Study GS-US-401-1768 is a single-center, open-label, Phase 1, mass-balance study of 
tirabrutinib administered as a single, oral dose of radiolabeled 14C-tirabrutinib in healthy subjects
with preliminary results showing extensive metabolism after oral administration by oxidation, 
reduction, hydrolysis, N-acetylation, sulfation, glutathione conjugation and glucuronidation.
Study GS-US-401-1757, an ongoing Phase 1b dose-escalation study of tirabrutinib in 
combination with other anti-cancer therapy, provides the primary supportive data for this Phase 2 
trial. This study used a 3+3 dose-escalation and dose-expansion design to establish a safe and 
well-tolerated dose of tirabrutinib in combination with entospletinib. Tirabrutinib administered at 
doses up to 160 mg once daily combined with entospletinib administered at doses up to 400 mg 
once daily has been well tolerated with no DLTs. Further safety results are discussed in the dose 
rationale Section 1.5.1.
For additional information, refer to the tirabrutinib IB.
1.4.
Obinutuzumab
Obinutuzumab (GA-101) is a humanized and glycoengineered monoclonal antibody (mAb),
derived by humanization of the parental B-Ly1 mouse antibody and subsequent
glycol-engineering leading to the following characteristics {Mössner 2014}:

High affinity binding to CD20 type II epitope.

Increased antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP)
{Herter 2014} related to an improved binding of the antibody to the different allotypes of 
FcγRIIIa expressed by natural killer (NK) cells and monocytes.

Low complement-dependent cytotoxicity (CDC) activity related to the recognition of the
CD20 type II epitope and the lack of CD20 localization into lipid rafts after binding of mAb 
to CD20.

Increased direct cell death induction related to an elbow hinge amino exchange of the
Fragment antigen-binding (Fab) region and the recognition of CD20 type II epitope.
The CLL11 study, led by Roche and the GCLLSG, compared the safety and efficacy of 
3 regimens: Chlorambucil vs. Rituximab + Chlorambucil (R/Chl) vs. Obinutuzumab (GA-101) + 
Chlorambucil (G/Chl) in previously untreated patients with CLL with either cumulative illness 
rating scale (CIRS) score >6 or CrCl <70 mL/min {Goede 2014}. The median age of subjects 
was 73 years. The results show superiority of G/Chl, with median PFS of 11, 16, and 27 months 
in Chl, R/Chl and G/Chl respectively. There was a statistically significant improvement in OS 
with G/Chl vs. Chl (hazard ratio for death of 0.41; 95% CI, 0.23 to 0.74; P = 0.002). The CR rate 
was 21% with G/Chl vs. 7% with R/Chl. MRD negativity in the marrow was achieved in 19.5% 
of G/Chl subjects vs. only 2.6% of those receiving R/Chl. Infusion-related reactions and 
neutropenia were more common with G/Chl than with R/Chl, but the risk of infection was not 
increased. Most infusion-related reactions occurred with the first infusion of both CD20 
antibodies, with overall frequency of 65% with obinutuzumab (20% Gr 3/4) and 27% with 


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rituximab (3% Gr 3/4). Due to the high frequency of Day 1 infusion-related reactions, the study 
was amended to split the first dose of 1000 mg over 2 days (100 mg on Day 1 and 900 mg on 
Day 2), this leading to partial amelioration of the reactions.
Obinutuzumab (Gazyva®/Gazyvaro®) is approved in the US and EU for use in combination with 
chlorambucil for the treatment of patients with previously untreated CLL.
For further information on obinutuzumab, refer to the local prescribing information (PI).
1.5.
Rationale for This Study
Despite an increase in therapeutic options for CLL, few subjects are cured with current therapy. 
Small molecule targeted therapy for CLL avoids many of the toxicities of chemoimmunotherapy 
but requires chronic administration due to generally low CR rates. Novel regimens combining 
targeted therapy have the potential to improve CR rates, PFS and OS while limiting toxicity.
Tirabrutinib and entospletinib each show significant single-agent clinical activity in CLL. The 
addition of an anti-CD20 antibody to CLL therapy has an established benefit {Hallek 2010} with 
the potential superiority of obinutuzumab in comparison with rituximab {Goede 2014}.
Preliminary in vitro data from primary CLL samples have shown additive or synergistic growth 
inhibition when combining tirabrutinib and entospletinib, suggesting the possibility of improved 
depth of response with combination treatment. While single mutations in drug targets have been 
shown to be sufficient for resistance to single-agent therapy, combination therapy has the 
potential to improve duration of response by creating a higher threshold for the emergence of 
drug-resistant malignant clones. Even with doses reduced from those used as single-agents, 
combining tirabrutinib and entospletinib in vitro had striking efficacy, supporting the possibility 
of improving efficacy with low toxicity.
As of June 7, 2017 10 subjects with CLL have been treated on Phase 1b Study GS-US-401-1757 
with the combination of tirabrutinib and entospletinib with a median exposure of 43 weeks 
(range: 18-55). All 10 subjects continue on study and treatment at this time; however no CLL 
subjects have achieved a CR. Given the lack of CRs in the ongoing treatment experience with the 
combination of tirabrutinib and entospletinib, enrollment into the doublet combination of 
tirabrutinib and entospletinib was discontinued with Amendment 3. Arm B continued enrollment 
as the safety and preliminary efficacy of the combination with the addition of obinutuzumab 
retains the potential to be safe and achieve a high rate of deep response.
1.5.1.
Rationale for Dose Selection
This Phase 2 study will evaluate the efficacy and safety of the combination of tirabrutinib and 
entospletinib with and without obinutuzumab in subjects with relapsed or refractory CLL.
In the combination proposed for this study, the doses of both tirabrutinib and entospletinib have 
been reduced from the maximal safe doses previously used as single agent therapy. Prior 
single-agent dose-ranging with tirabrutinib in the ONO-4059POE001/GS-US-401-1787 study


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did not identify a MTD in subjects with CLL at doses up to tirabrutinib 600 mg daily. Similarly, 
there was no MTD identified for entospletinib as monotherapy in subjects with CLL at doses up 
to 400 mg twice daily. The tirabrutinib dose of 80 mg once daily used in this study is 
approximately 13% of highest safe single-agent dose in ONO-4059POE001; the entospletinib 
dose of 400 mg once daily represents a 50% reduction from that used in Phase 2 monotherapy 
treatment for CLL in the GS-US-339-0102 study. The combination of tirabrutinib 80 mg once 
daily and entospletinib 400 mg once daily was shown to be safe and tolerable in the Phase 1b 
GS-US-401-1757 study.
Based on data as of 22 July 2016, the median time on treatment with tirabrutinib and 
entospletinib in the GS-US-401-1757 study was 114 days (range: 29-239) in 17 subjects with 
lymphoid malignancies, of whom 3 had CLL. Two subjects reported a Grade 3 or 4 AE that was 
attributed by the investigator to be related to treatment. One subject with DLBCL at the 
tirabrutinib 150 mg/entospletinib 200 mg dose level experienced Grade 4 hyperglycemia; the 
subject remained on therapy throughout with standard-of-care management. One subject with 
WM at the tirabrutinib 40 mg/entospletinib 400 mg dose level developed Grade 3 neutropenia 
that resolved with conservative management within 2 weeks while remaining on treatment.
Three subjects reported an SAE on study. One subject with WM at the tirabrutinib
40 mg/entospletinib 200 mg dose level reported an SAE of pneumonia that did not necessitate
interruption of treatment. One subject with FL at the tirabrutinib 80 mg/entospletinib 200 mg 
dose level had pyrexia and atrial fibrillation in the context of a pneumonia requiring 
hospitalization for management. One subject with DLBCL at the tirabrutinib 80 mg/entospletinib 
400 mg dose level reported hematemesis in the 30-day window following treatment 
discontinuation due to progressive disease.
Data from both the single-agent treatment experience and the combination Phase 1b 
GS-US-401-1757 study support the potential efficacy of the combination of tirabrutinib 80 mg
once daily and entospletinib 400 mg once daily.
Preliminary BTK occupancy data in peripheral blood mononuclear cells demonstrates no 
detectable free BTK at tirabrutinib doses of 40 mg once daily and higher. At doses of tirabrutinib
≥80 mg daily in the ONO-4059POE001 single-agent dose escalation study with tirabrutinib, 20 
of 21 evaluable subjects with CLL had at least a PR; at a tirabrutinib dose of 20 mg or 40 mg, 2/3 
subjects at each dose level had a PR or better. Entospletinib demonstrates 40% inhibition of 
B-cell receptor pathway activation with a dose of 400 mg daily. In the combination Phase 1b 
GS-US-401-1757 study, 8 subjects treated with tirabrutinib and entospletinib are evaluable for 
response across dose levels, of whom, 4 have had a best response of a PR.
Obinutuzumab will be used at the approved 1000 mg dose and schedule. The safety of the 
addition of obinutuzumab to the combination of tirabrutinib 80 mg daily and entospletinib 
400 mg once daily will be initially evaluated in the safety run-in before additional subjects are 
enrolled.


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1.6.
Risk/Benefit Assessment for the Study
Tirabrutinib
In the completed single-agent Phase 1 study ONO-4059POE001, 28 subjects with 
relapsed/refractory CLL were treated with tirabrutinib at doses ranging from 20 to 600 mg per 
day for up to 3 years. Observed AEs were mainly Grades 1 and 2 in severity, and were most 
commonly infections, hematological abnormalities, skin disorders, gastrointestinal disorders, and 
general disorders. The majority of AEs were assessed by the investigator as not related to 
tirabrutinib. Hematological disorders and infections have been observed: irrespective of severity, 
the majority of these events did not preclude ongoing treatment. Grade 1 and 2 diarrhea, 
respectively, was observed in 20% and 4% of study participants. No Grade 3 or higher diarrhea 
attributed to tirabrutinib by the investigator has been reported as of October 2015. Bruising was 
observed frequently; however, clinically-significant bleeding events (such as those requiring 
transfusions) were unusual and hemorrhage did not limit the ability to continue on therapy for 
the majority of subjects.
In ongoing Study GS-US-401-1787 (rollover from Study ONO-4059POE001), AEs ≥ Grade 3 
assessed cumulatively from the beginning of Study ONO-4059POE001 (N = 90) were reported 
for 61 subjects (67.8%), most frequently neutropenia and thrombocytopenia (each 16 subjects, 
17.8%) followed by anemia (10 subjects, 11.1%) and lower respiratory tract infection (8 
subjects, 8.9%). Overall, SAEs were reported for 44 subjects (48.9%).
Entospletinib
Entospletinib has been well tolerated across the 16 clinical studies in which it has been
evaluated. Treatment-emergent AEs commonly reported across the studies involving healthy 
volunteer subjects include headache, somnolence, and GI symptoms (nausea and abdominal 
pain), all of which were mild and reversible. Increased transaminases were noted in some 
subjects and were reversible. The safety profile for subjects with CLL treated with entospletinib 
is described in Section 1.2.4.
Entospletinib is an inhibitor of UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at 
the expected clinical concentrations. Administration of drugs such as entospletinib that inhibit 
UGT1A1 are expected to increase total bilirubin due to decreased conjugation rather than liver 
dysfunction. The elevations in indirect bilirubin observed in clinical trials with entospletinib 
were generally self-limited and did not result in discontinuation of entospletinib.
Obinutuzumab
Obinutuzumab (Gazyva®/Gazyvaro®) is an anti-CD20 mAb which is approved in the US and EU 
for use in combination with chlorambucil for the treatment of patients with previously untreated 
CLL. The safety reference documents for obinutuzumab will be the Summary of Product 
Characteristics (SmPC). Please refer to the SmPC for further information.


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In a Phase 3 trial, patients were treated with chlorambucil alone, GAZYVARO in combination 
with chlorambucil, or rituximab product in combination with chlorambucil. The Stage 1 analysis 
compared GAZYVARO in combination with chlorambucil vs. chlorambucil alone, and Stage 2 
compared GAZYVARO in combination with chlorambucil vs. rituximab product in combination 
with chlorambucil.
The most common Grade 3 to 4 adverse reactions (incidence ≥10%) observed in patients with 
CLL in the GAZYVARO containing arm of clinical trials were neutropenia, infusion reactions, 
and thrombocytopenia.
The most common adverse reactions (incidence ≥10%) observed in patients with CLL in the 
GAZYVARO containing arm were infusion reactions, neutropenia, thrombocytopenia, anemia, 
pyrexia, cough, nausea, and diarrhea.
The most common adverse reactions (incidence ≥10%) observed in patients with CLL in the 
GAZYVARO containing arm were infusion related reactions, neutropenia, thrombocytopenia, 
anemia, pyrexia, cough, nausea, and diarrhea.
The most common obinutuzumab-related events are infusion-related reactions and tumor lysis 
syndrome, most commonly during the initial administration, hypersensitivity (immediate or 
delayed onset), and worsening of pre-existing cardiac conditions. Some patients receiving 
obinutuzumab have experienced cytopenias or infections. Obinutuzumab use has been associated 
with hepatitis B virus (HBV) reactivation and very rare cases of progressive multifocal 
leukoencephalopathy. Mitigation strategies are defined in this protocol. To reduce the incidence 
and severity of obinutuzumab-related infusion reactions, established premedication regimens and 
infusion modification algorithms have been included (Section 5.3.2). To mitigate the risk of 
Pneumocystis jirovecii pneumonia, antibiotic prophylaxis is mandated unless medically 
contraindicated.
To mitigate the risk of HBV reactivation in subjects treated with an anti-CD20 antibody, 
hepatitis B virus screening will be performed. Subjects who are hepatitis B core antibody 
positive at screening may be enrolled only if the plasma DNA PCR test is negative, and will be 
monitored for potential HBV reactivation (manifested as detectable HBV DNA by quantitative 
PCR). Subjects will be tested monthly for the duration of CD20 therapy and every 3 months 
thereafter for 1 year from the last dose of CD20 during study participation. Specific instructions 
for supportive care in response to myelosuppression are described. Investigators are instructed to 
institute prophylaxis and monitoring for tumor lysis syndrome for subjects with a high tumor 
burden, high circulating lymphocyte count (>25x109/L) or renal impairment (CrCl <70mL/min).
Combination therapy
Although new toxicities due to the combination of agents remains a possibility, the safety and 
tolerability of tirabrutinib combined with entospletinib has been previously evaluated in Study
GS-US-401-1757. Entospletinib 400 mg once daily does not increase the exposure of tirabrutinib
significantly based on preliminary PK data from this study.


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The safety of the combination of tirabrutinib 80 mg once daily and entospletinib 400 mg once
daily will be further evaluated in this Phase 2 study through a review of the safety data for the 
initial 6 subjects treated with the combination through 28 days of therapy prior to the enrollment 
of additional subjects. Similarly, the safety of the addition of obinutuzumab to the combination 
of tirabrutinib and entospletinib will be evaluated through a review of the safety data for the 
initial 6 subjects treated through 28 days of therapy prior to the enrollment of additional subjects 
on this treatment arm. Study visits including laboratory monitoring will occur weekly for the first 
28 days of treatment for close monitoring. Following evaluation of the safety data for the first 
6 subjects in each treatment arm, the SRT will determine if weekly visits for the first 28 days 
should continue or may be reduced in frequency for the remainder of subjects enrolled in the 
study.
Benefits from combination therapy include the potential to achieve higher rates of response and 
improve DOR and the potential for reduced toxicity with increased efficacy by the use of lower 
individual study drug doses in combination.
1.7.
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 preliminary efficacy of the combination of tirabrutinib and entospletinib
with obinutuzumab in subjects with relapsed or refractory CLL
The secondary objective of this study is:

To evaluate the safety and tolerability of the combination of tirabrutinib and entospletinib
with and without obinutuzumab
The exploratory objectives of this study are:
 
 
CCII 
I 


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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 2, prospective, open-label, multicenter trial to evaluate the safety and efficacy of 
the combination of tirabrutinib (GS-4059) and entospletinib with and without obinutuzumab in 
subjects with relapsed or refractory CLL.
3.2.
Study Treatments
Combination therapy of tirabrutinib (BTK inhibitor) 80 mg once daily and entospletinib 
(SYK inhibitor) 400 mg once daily with and without obinutuzumab will be evaluated for 
efficacy, safety, and tolerability.
Eligible subjects will be treated with the combination of tirabrutinib and entospletinib and
stratified by the presence of del17p/TP53mut in CLL cells. Following stratification, subjects will 
be randomized 1:1 to treatment with the combination of tirabrutinib and entospletinib with or 
without obinutuzumab.
Study Design Schema
Screening 
ArmA 
N = 30 
Arm8 
N =30 
<»-4059 
Ent ospletrnib 
1:1 Randomization 
<»-4059 
Entospletinib 
Obinutuzurnab 
Obinut uzumab: 21 w eeks 
Week25 
G.s--4059 + Ent osplet inib: Up t o 104 w eeks 
Total Du rat ion: 5 years 
EOT 
Post-Treatment 
On-Study 
Scheduled Assessments 
EOS 


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With Amendment 3, randomization was discontinued. All subsequently enrolled subjects entered 
Arm B (tirabrutinib + entospletinib + obinutuzumab).
With Amendment 4, the Post Treatment period will no longer be applicable.
Enrollment will be temporarily paused following enrollment of the first 6 subjects into Arm B, 
who will be observed for safety for 28 days following the first dose of study treatment including 
weekly evaluation through that period. Additional subjects may be enrolled into the safety cohort 
if any of the first 6 subjects in Arm B discontinue therapy during the initial 28 days for reasons 
unrelated to toxicity. A Safety Review Team (SRT) will review 28-day safety data from the first 
6 subjects in Arm B and determine whether enrollment may resume and if weekly clinical 
evaluation through the first 28 days should continue or may be reduced in frequency for the 
remainder of subjects enrolled in the study.
Oblnucuzumab 
oblrwbii11mab: ;n w• 
GS-4059 
Entospletlnlb 
Gs-4059 
IEnto1pletlnlb, 
Oblnutuzumab 
WHU'S 
Oblnutuwm 'b: 21 weaks 
Weakl:5 
GS ,059 + Ent05pletlrr1lb/ lcil 'lallsib: Up t,o 104 weeks 
EOT 
Post-Trotme11t 
0 ~ 
E-0S, 
SCMdultdAs-
EOT 


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The SRT will consist of at least one investigator from the GCLLSG and Gilead Sciences, Inc. 
(Gilead) study team members including but not limited to: the medical monitor, representatives 
from Pharmacovigilance and Epidemiology (PVE), and Biostatistics.
The safety review will include the assessment of the following:

Grade ≥ 4 hematological toxicities persisting for > 7 days

Grade ≥ 4 non-hematologic laboratory abnormalities except for asymptomatic AST/ALT 
elevation, LDH, or uric acid

Grade ≥ 3 non-hematological toxicities (except for alopecia or the following that resolve 
within 72 hours with medical intervention: tumor lysis, nausea, vomiting, diarrhea, or 
constipation)

Grade ≥ 2 non-hematologic treatment-emergent adverse events (TEAE) that in the opinion of 
the investigator are of potential clinical significance such that further dosing would expose 
subjects to unacceptable risk
Criteria for termination of the study are:
1) An unacceptable safety profile or incidence of AEs or SAEs revealed in this or any other 
study in which the combination of agents is administered
2) Any other factor that in the view of the sponsor constitutes an adequate reason for 
terminating the study 
As agreed with the German Federal Institute for Drugs and Medical Devices Agency (BfArM), a
safety report including the cumulative safety results and summary of the conclusion of the SRT 
following assessment of the safety cohort was submitted to BfArM shortly after the assessment.
The study steering committee, including representatives from the GCLLSG and Gilead, will 
review ongoing safety data at least quarterly throughout the treatment period and regularly for 
the complete duration of the study.
3.3.
Duration of Treatment
Obinutuzumab will be administered for up to 8 doses over 21 weeks to subjects randomized or 
enrolled to Arm B (tirabrutinib + entospletinib + obinutuzumab). Combination treatment with the 
oral agents (tirabrutinib and entospletinib) will continue for all subjects for up to 104 weeks in 
the absence of disease progression, unacceptable toxicity, or documentation of CR/BM MRD-. If 
CR/BM MRD- is documented on study, treatment will stop after the earlier of:
1) an additional 3 months of therapy or
2) 104 weeks of total treatment


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3.4.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Documented progression of CLL

Non-study treatment for CLL

Development of malignant disease requiring systemic therapy

Pregnancy

Investigator discretion

Non-compliance with study treatment

Severe protocol violation

Subject request to discontinue for any reason

Lost to follow-up

Death

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 6.5), 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
3.5.
Duration of Study
This study will continue to monitor subjects for up to 30 days post end of treatment, or up to 
Week 25 should a subject discontinue treatment prior to Week 25 for reasons other than disease 
progression.
3.6.
Criteria for Discontinuation from Study
Subjects may be removed from the study for the following reasons:

Death

Investigator discretion


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
Withdrawal of consent

Study termination by the sponsor
3.7.
GCLLSG CLL Registry
Consenting subjects for inclusion in the GCLLSG registry is requested at screening or as close 
thereafter as possible.
3.8.
Post Study Care
At this time, there is no plan to provide post-study care to subjects who have participated in this 
study.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The study will enroll approximately 36 subjects in total; 30 subjects in Arm B and approximately 
6 subjects in Arm A.
4.2.
Inclusion Criteria
Subjects must meet all the following criteria to be eligible for participation in this study:
1) Documentation of relapsed or refractory CLL
2) Have an indication for treatment per modified IWCLL 2008 criteria; subjects without
radiographically measureable disease (defined as ≥ 1 lesion > 1.5cm in diameter as assessed 
by CT or MRI) must have bone marrow evaluation at screening
3) Adequate hematologic function as indicated by a platelet count ≥50 x 109/L, a neutrophil 
count ≥ 1 x 109/L and a hemoglobin ≥8g/dL unless lower values are directly attributable to 
documented bone marrow burden of CLL
4) Adequate renal function as indicated by a CrCL ≥50 mL/min calculated by the modified 
Cockroft-Gault formula or from a 24h urine collection
5) Adequate liver function as indicated by total bilirubin ≤1.5x institutional upper limit of 
normal (ULN) unless attributed to Gilbert’s syndrome and AST/ALT ≤ 2.5xULN
6) Male or female ≥ 18 years of age
7) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
8) Absence of active HBV infection (serological testing within 6 weeks prior to randomization 
or enrollment with the following results: HBsAg negative AND anti-HBcAb negative, or if 
anti-HBcAb positive, HBV DNA PCR negative)
9) HCV Ab negative or if Ab positive, negative HCV RNA PCR within 6 weeks prior to 
randomization or enrollment
10) Negative testing for HIV within 6 weeks prior to randomization or enrollment
11) Satisfies the following criteria:
a) For female subjects of childbearing potential, willingness to abstain from sexual 
intercourse or use a protocol-specified method of contraception as described in 
Appendix 4
b) Male subjects of reproductive potential who engage in sexual intercourse must agree to 
use protocol-specified method(s) of contraception as described in Appendix 4


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12) Ability and willingness to provide written informed consent and adhere to protocol
requirements including study visit schedule, drug administration plan, imaging studies, 
laboratory testing, other study procedures and restrictions
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible for participation in this 
study:
1) Known transformation of CLL (ie, Richter’s transformation, prolymphocytic leukemia)
2) Known CNS involvement
3) Progression on treatment with any inhibitor of BTK, SYK, PI3K, BCL-2, or obinutuzumab.
The treatment and disease response history of subjects with prior treatment with agents in 
these classes should be reviewed by the sponsor or the GCLLSG study office prior to 
enrollment to clarify sensitivity to these treatments.
4) Any treatment for CLL other than corticosteroids for symptomatic management within 
28 days of the start of study treatment
5) Participation in a concurrent therapeutic clinical trial unless all treatment is complete with 
only ongoing surveillance
6) Diagnosis of or concern for progressive multifocal leukoencephalopathy
7) History of myelodysplastic syndrome or another malignancy other than CLL, except for the 
following: any malignancy that has been in complete remission for 3 years, adequately 
treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, 
superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease 
and with no requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for 1 year prior to start of study therapy.
8) Active infection requiring systemic therapy
9) Pregnant or nursing women (a negative pregnancy test is required for all women of 
childbearing potential within 7 days before start of treatment and monthly during therapy)
10) Active autoimmune disease including autoimmune hemolytic anemia or idiopathic 
thrombocytopenic purpura requiring a higher corticosteroid equivalent than prednisone 
10 mg daily. Higher doses of corticosteroids prescribed for any indication must be stopped 
> 14 days prior to randomization or enrollment; exceptions may be made for corticosteroids 
prescribed specifically for management of CLL symptoms after discussion with the study 
medical monitor.
11) Diagnosis of inflammatory bowel disease or ongoing symptomatic pneumonitis


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12) History of stroke or intracranial hemorrhage within 12 months of randomization or 
enrollment; subjects requiring therapeutic anticoagulation for any indication should be 
discussed with the GCLLSG coordinating physician and/or medical monitor prior to
screening
13) Legal incapacity, prisoners or subjects institutionalized by regulatory or court order, or any 
individual in dependence to study sponsor or any investigator
14) Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, moderate CYP2C9 inducers,
or a strong P-gp inducers while on study; use within 2 weeks of first dose of study treatment
should be avoided.
15) Requirement for PPI therapy
16) Demonstration of QTc interval > 450 milliseconds or requirement for ongoing treatment with 
concomitant medications that prolong the QT interval
17) Known hypersensitivity to obinutuzumab, entospletinib, tirabrutinib, or any of the excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
It is the responsibility of the Investigator to ensure that subjects are eligible for the study prior to 
randomization or enrollment. Subjects will be assigned a unique screening number at the time of 
consent. A medical review of selected screening data will be performed by members of the 
GCLLSG to confirm eligibility and must be completed prior to randomization or enrollment.
Once eligibility is confirmed, subjects will be assigned a unique subject number from the 
interactive web response system (IWRS), randomized in a 1:1 ratio to treatment with the 
combination of tirabrutinib and entospletinib with and without obinutuzumab. The 
randomization will be stratified by the presence of del17p/TP53mut in CLL cells. Once a subject 
number is assigned to a subject, it will not be reassigned to another subject. This is an open-label 
study.
With Amendment 3, randomization of subjects will no longer be performed as only Arm B of the 
study will continue to enroll.
All Day 1 tests and procedures must be completed prior to the dispensation and administration of 
the first dose of study treatment on Week 1 Day 1.
5.2.
Description and Handling of Tirabrutinib, Entospletinib, and Obinutuzumab
5.2.1.
Tirabrutinib
5.2.1.1.
Formulation
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, 40 mg, contain the equivalent of 40 mg tirabrutinib as the 
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is an orange, plain-
faced, round, film-coated tablet. The tirabrutinib film-coated tablets, 40 mg, contain the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, FD&C yellow #6/sunset yellow FCF aluminium lake, and iron oxide yellow.


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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.
5.2.1.2.
Packaging and Labeling
Tirabrutinib tablets, 20 mg, 40 mg, and 80 mg, are 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. Tirabrutinib shall be labeled to 
meet applicable requirements of the EU Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products) and/or other local regulations.
5.2.1.3.
Storage and Handling
Tirabrutinib should be stored at controlled room temperature of 25°C (77°F); excursions are 
permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are specified on the label. 
Until dispensed to the subjects, all bottles of study drugs should be stored in a securely locked 
area, accessible only to authorized site personnel. To ensure the stability and proper 
identification, study drug(s) should not be stored in a container other than the container in which 
they were supplied. Keep the bottle tightly closed to protect from moisture.
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 when handling.
5.2.2.
Entospletinib
5.2.2.1.
Formulation
Entospletinib tablets, 200 mg strength, are available as blue, capsule-shaped film-coated tablets 
that are plain-faced. In addition to the active ingredient, entospletinib tablets contain the 
following inactive ingredients: methanesulfonic acid, hydroxypropyl methylcellulose 
(hypromellose), mannitol, microcrystalline cellulose, crospovidone, poloxamer 188, silicon 
dioxide, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
FD&C blue #2 aluminum lake.
Entospletinib tablets, 200 mg strength, are also available as beige, capsule-shaped film-coated 
tablets debossed with “GSI” on one side and “9973” on the other side. In addition to the active 
ingredient, entospletinib tablets contain the following inactive ingredients: methanesulfonic acid, 
hydroxypropyl methylcellulose (hypromellose), mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, ferrosoferric oxide/black iron oxide, iron oxide red, and 
iron oxide yellow.


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5.2.2.2.
Packaging and Labeling
Entospletinib tablets are packaged in white, high-density polyethylene bottles with silica gel 
desiccant, and polyester packing material in each bottle. Each bottle contains 60 tablets and is 
capped with a child-resistant polypropylene screw cap fitted with an induction-sealed, 
aluminum-faced liner.
Entospletinib to be distributed to centers in the EU shall be labeled to meet applicable 
requirements of the EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational 
Medicinal Products), and/or other local regulations.
5.2.2.3.
Storage and Handling
Entospletinib tablets should be stored at a controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, study drug(s) should not be stored in a container other than the container in 
which they were supplied. Keep the bottle tightly closed to protect from moisture.
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 when handling.
5.2.3.
Obinutuzumab
5.2.3.1.
Formulation
Please refer to the Gazyvaro (obinutuzumab) SmPC.
5.2.3.2.
Packaging and Labeling
Commercially available product of obinutuzumab will be used for this study.
Obinutuzumab to be distributed to centers in the EU shall be labeled to meet applicable 
requirements of the EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational 
Medicinal Products), and/or other local regulations.
5.2.3.3.
Storage and Handling
Commercially available obinutuzumab will be used for this study. Further information regarding 
storage and handling are available in the Gazyvaro (obinutuzumab) SmPC.


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5.3.
Dosage and Administration of Tirabrutinib, Entospletinib, and 
Obinutuzumab
5.3.1.
Tirabrutinib and Entospletinib
Tirabrutinib and entospletinib will be provided by Gilead Sciences, Inc. Tirabrutinib tablets 
(4 x 20 mg, 2 x 40 mg, or 1 x 80 mg) and entospletinib tablets (2 x 200 mg) will be self-
administered orally once daily. Dosing with both agents will begin on Week 1 Day 1 of the study 
and thereafter at approximately the same time each day until end of treatment. Study drugs 
should be swallowed whole with water. Tirabrutinib may be administered without regard to food.
Subjects will be instructed to take entospletinib at least 1 hour before and at least 2 hours after a 
meal.
For patients assigned to the 20 mg tirabrutinib dose, 40 mg tirabrutinib tablets may be exchanged 
for 20 mg tirabrutinib tablets leading to an increase in total daily dose from 20 mg to 40 mg. 
Based on the range of exposures of tirabrutinib observed in subjects with B-cell malignancies,
the slight increase in daily dose is not considered clinically relevant.
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 12 hours has elapsed since the scheduled time of the missed dose
for study drugs administered once daily. In this case, the subject should be instructed to wait and 
take the next dose at the regularly scheduled time.
5.3.2.
Obinutuzumab
Liquid concentrate of obinutuzumab intended for IV infusion is prepared by diluting the drug
product to the final concentration into an infusion bag containing 0.9 % Sodium Chloride (NaCl).
All patients should receive premedication before administration of obinutuzumab as 
follows:
First infusion of obinutuzumab
The following premedication should be administered (unless contraindicated) prior to the start of 
the first dosage of obinutuzumab (Days 1 [and 2 in case of dose splitting]) to avoid infusion
related reactions (IRRs):

Prednisolone or prednisone 100 mg IV ≥ 1 hrs before starting the obinutuzumab infusion 
(an equivalent dose of dexamethasone [20 mg] or methylprednisolone [80 mg] is permitted, 
but hydrocortisone should not be used)

Acetaminophen/paracetamol 1000 mg p.o. ≥ 30 min before starting the obinutuzumab 
infusion

Antihistamines including a H1-antagonist (eg, dimentindene 4 mg IV) and a H2-antagonist
(eg, ranitidine 50 mg IV) ≥ 30 min before starting the obinutuzumab infusion


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Please note that withholding of antihypertensive treatments should be considered for 12 hours 
prior to, throughout, and for the first hour after each obinutuzumab infusion as hypotension may 
occur as a result of an IRR. Antihypertensive treatment can still be used to treat IRR triggered 
hypertension, if required.
Subsequent infusions of obinutuzumab
All patients should receive oral acetaminophen/paracetamol (1000 mg) p.o. ≥ 30 min ahead of 
every obinutuzumab infusion (unless contraindicated). The antihistamine premedication may be 
omitted at the investigator’s discretion for the following obinutuzumab infusions if the 
previously administered obinutuzumab infusion did not result in an IRR CTCAE Grade > 1 
(ie, no medication was required to treat the IRR and there was no interruption of the infusion). A 
corticosteroid should be administered for premedication if the patient experienced a Grade 3 IRR 
during the previous infusion, the patient´s lymphocyte count is > 25,000/μl and at the
investigator‘s discretion. As during the first cycle, the investigator should consider withholding 
antihypertensive medication 12 hours prior and until 1 hour after the obinutuzumab infusion.
Patients with a history of cardiac disease should be monitored closely. In addition these patients
should be hydrated with caution in order to prevent a potential fluid overload.
Patients with a high tumor burden (leukocyte counts ≥ 25 x 109/L and/ or bulky 
lymphadenopathy) and/or renal impairment (CrCl <70 mL/min) are at risk for developing a 
tumor-lysis syndrome (TLS). These patients with a high tumor burden and also all other patients 
considered at risk for TLS by the investigator must receive prophylaxis for TLS prior to the 
initiation of treatment with obinutuzumab and ahead of all subsequent administrations of 
obinutuzumab until the tumor burden is reduced and risk for development of a TLS is 
minimized. Possible preventive measures include:

adequate hydration (eg, intravenous administration of 1000 – 4000 mL NaCl 0.9 % starting
12 – 24 hours before treatment),

prophylactic administration of an uric acid reducer (eg, allopurinol 300 mg once daily
starting 12 – 24 hours prior to initiation of treatment) and/or

rasburicase (Fasturtec®).
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium and uric 
acid levels must be performed. Patients with TLS should be treated per institutional practice 
(including correction of electrolyte abnormalities, monitoring of renal function and fluid balance, 
administration of supportive care, including dialysis as indicated).
Infusion Rates
First infusion: All subjects will receive an infusion of the fixed dose of 100 mg obinutuzumab 
administered at a fixed rate of 25 mg/hr over 4 hours. If the first 100 mg obinutuzumab is 
tolerated well and completed without interruptions or adjustments of infusion rate and it is 


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possible from an organizational and medical point of view (enough time, medical supervision 
available throughout the infusion), patients are allowed to continue with the remaining 900 mg
infusion on the same day. Otherwise this infusion should be started the next day. The infusion 
with 900 mg obinutuzumab should be started at a rate of 50 mg/hr in all patients and the infusion 
rate may be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 
400 mg/hr.
Subsequent infusions: If the first infusion of obinutuzumab was well tolerated (defined by an 
absence of IRRs during a final infusion rate of ≥100 mg/hr), subsequent infusions will be 
administered at an initial rate of 100 mg/hr. The infusion rate may be increased by 100 mg/hr
increments at 30-minute intervals, as tolerated, to a maximum rate of 400 mg/hr. Alternatively, if 
an IRR was present during the first infusion, the administration may be per the guidance from the 
first infusion with a maximum rate that which has been previously tolerated by the subject. At 
the investigator’s discretion, obinutuzumab infusions may be split and administered over 2 days.
Dose of Obinutuzumab
Rate of Infusion (in the absence of infusion 
reactions/hypersensitivity during previous infusions)
Day 1
100 mg
Administer at 25 mg/hr over 4 hours.
Do not increase the infusion rate.
Day 1 or 2
900 mg
Administer at 50 mg/hr. The rate of the infusion can be escalated in 
increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
Subsequent
1000 mg
Infusions can be started at a rate of 100 mg/hr and increased by 
100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
Management of infusion-related reactions (IRRs)
In case of IRR, the following measures should be considered depending on the severity of the 
IRR:

Acetaminophen/paracetamol 1000 mg if not administered during the last 4 hrs

Antihistamines including a H1- (eg, dimetindene 4 mg IV) and a H2-antagonist (eg. rantidine 
50 mg IV) if not administered during the last 4 hours

Prednisolone or prednisone 100 mg IV in case of urticarial, bronchospasm and dyspnea

Intravenous fluids

Bronchodilators and oxygen in case of bronchospasm and dyspnea

Vasopressors in case of hypotension


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Once symptoms have resolved completely, obinutuzumab may be resumed at 50% of the
infusion-rate used prior to the interruption. If no infusion related symptoms occur, the rate of the
infusion may be escalated stepwise with 50 mg/hr every 30 minutes to a maximum rate of 
400 mg/hr, except for the first administration of obinutuzumab. The first obinutuzumab 
administration (100 mg) may be re-started at half initial rate (12.5 mg/hr) upon complete 
resolution of symptoms; if this is tolerated well for an hour, the rate may be increased to a 
maximum of 25 mg/hr.
It needs to be stressed that in the event of a life-threatening (which may include pulmonary or 
cardiac events), prolonged or recurrent IRR, obinutuzumab should be discontinued immediately 
and no further obinutuzumab should be administered.
Patients experiencing Grade 3 or 4 IRRs twice should receive aggressive symptomatic treatment 
and will be discontinued from further study treatment with obinutuzumab. Treatment with oral 
agents should be continued with the subject remaining on study.
For guidance on the management of infusion-related reactions (IRRs) see the following table:
IRR Severity (NCI CTCAE v4.0)
Recommendation
Grade 1-2
Reduce the infusion rate or hold infusion
Administer supportive treatment
Upon symptom resolution, restart infusion at no more than half the 
previous rate (the rate being used at the time that the IRR occurred) and, if 
patient does not experience any IRR symptoms, infusion rate escalation 
may resume at the increments and intervals as appropriate for the 
treatment dose
Grade 3
Discontinue infusion immediately
Administer supportive treatment (as described in Section 8.5.1)
Upon symptom resolution, may resume infusion rate escalation, at the 
investigator’s discretion
Treatment must be permanently discontinued, if same adverse event recurs 
with same severity.
Grade 4
Discontinue infusion immediately
Treat symptoms aggressively
Do not restart obinutuzumab
Reductions in obinutuzumab dosing are not planned. Repeat obinutuzumab administrations may 
be delayed to allow subjects to recover from obinutuzumab-related AEs or intercurrent illness.
5.4.
Prior and Concomitant Medications
Subjects must not have previously progressed on treatment with inhibitors of BTK, SYK, PI3K, 
BCL-2 or obinutuzumab.


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Pneumocystis jirovecii pneumonia (PJP) prophylaxis is mandated unless medically 
contraindicated throughout the course of active treatment.
Strong CYP3A4/CYP2C9/P-gp inducers or moderate CYP2C9 inducers should be avoided 
within 2 weeks of study treatment initiation; if administration of such an agent is medically
needed after study initiation, this situation should be immediately discussed with the study 
medical monitor.
Subjects should not receive PPI therapy within 2 weeks of study treatment initiation; if 
administration of such an agent is required after study initiation, this situation should be 
immediately discussed with the study medical monitor.
Immunization with live or attenuated viral vaccines is not recommended while on treatment 
during this study.
5.4.1.
IVIg and G-CSF
Administration of IVIg or G-CSF is permitted per institutional standard of care.
5.4.2.
Prior and Concomitant Medications with Tirabrutinib
In vitro data indicate tirabrutinib is a substrate of CYP3A4 and P-gp. Co-administration of 
CYP3A4 inhibitors may increase tirabrutinib exposure. Preliminary PK data from study 
GS-US-401-1757 indicates tirabrutinib is not a sensitive CYP3A4 substrate. As such, 
co-administration of strong CYP3A4 inhibitors with study drug is allowed in this study, but 
caution should be exercised. Co-administration of the strong CYP3A4/P-gp inducer, rifampin, 
resulted in a significant decrease in tirabrutinib exposure (~70%). As such, potent CYP3A4/P-gp
inducers are prohibited while subjects are on study drug and should be avoided within 2 weeks 
prior to study drug administration. Examples of strong CYP3A4/P-gp inducers are provided in 
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.
5.4.3.
Prior and Concomitant Medications with Entospletinib
In vitro and in vivo data indicates that entospletinib is a substrate of CYP2C9 and CYP3A. In a 
study in healthy subjects, co-administration of the strong CYP3A4 / CYP2C9 inducer rifampin 
resulted in a significant decrease in entospletinib exposure (~70%). As such, co-administration of 
strong CYP3A and CYP2C9 inducers, and moderate CYP2C9 inducers are prohibited in this 
study. In addition, administration of strong CYP3A and CYP2C9 inducers and moderate 
CYP2C9 inducers should be avoided for 2 weeks prior to study drug administration. Caution 
should be exercised when co-administering drugs that are moderate/strong inhibitors of CYP2C9 
(eg. fluconazole, voriconazole or amiodarone) as they may increase entospletinib exposure.


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Studies in healthy volunteers have demonstrated a significant reduction in entospletinib exposure 
when proton pump inhibitors are co-administered. Therefore, proton pump inhibitors are 
prohibited in combination with entospletinib. Use of a proton pump inhibitor should be avoided 
for 1 week prior to study drug administration. H2 blockers and antacids will be allowed for use 
during the protocol.
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study
Strong
Moderate
CYP3A/P-gp Inducer
carbamazepine, phenytoin, rifampin, St. 
John’s Wort, enzalutamide, rifabutin, 
phenobarbital, mitotane, avasimibe
Not prohibited
CYP2C9 Inducer
carbamazepine, rifampin, ritonavir, 
enzalutamide
Proton Pump Inhibitors
omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole
In vitro data indicates that entospletinib has the potential to inhibit several drug transporters and 
the metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when co-administering 
medications that are transported by OATP1B1, OATP1B3, MATE1, P-gp and BCRP or 
metabolized by UGT1A1; dose adjustment or switching to an alternative medication may be 
necessary if clinically indicated.
In a study in healthy subjects, entospletinib 400 mg twice daily increased rosuvastatin exposure 
by approximately 3.8-fold. In reviewing the safety of subjects whom have received a statin with 
entospletinib there have been no reports of rhabdomyolysis or a different adverse event profile, 
but in the interest of caution, restrictions apply to the use of HMG-CoA reductase inhibitors with 
entospletinib in this study (Table 5-2).
Table 5-2.
Recommended dose limits for HMG-CoA reductase inhibitors
Concomitant Medication
Restriction
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 40 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg BID or 40 mg QD
Pitavastatin
Maximum dose 1 mg QD


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5.4.4.
Prior and Concomitant Medications with Obinutuzumab
In accordance with current obinutuzumab prescribing information, subjects should be 
premedicated with an antipyretic and an antihistamine to reduce the incidence and severity of 
infusion reactions. A recommended regimen is diphenhydramine, 25 to 50 mg orally, and 
acetaminophen (paracetamol) 650 to 1000 mg orally, both given approximately 30 minutes prior 
to each obinutuzumab administration. In addition, an intravenous corticosteroid should also be 
administered as a premedication on Days 1, 2, 8, and 15 for all subjects, completed at least 
1 hour prior to administration of obinutuzumab, and then only as indicated per the prescribing 
information. Local practices and guidelines may be followed.
5.4.4.1.
Tumor Lysis Syndrome
Subjects with a high tumor burden (WBC ≥ 25 x 109/L or bulky lymphadenopathy) must receive 
prophylaxis for tumor lysis syndrome (TLS) prior to the initiation of treatment. Prophylaxis for 
subjects with renal impairment (CrCl < 70mL/min) should also be considered. Subjects must be 
well hydrated. It is desirable to maintain a fluid intake of approximately 3 liters per day, 1-2 days 
before the first dose of obinutuzumab. All subjects with high tumor burden must be treated with 
allopurinol (≥300 mg p.o./day) or a suitable alternative treatment (eg, rasburicase) starting 
12-24 hours prior to the first infusion. Subjects should continue to receive repeated prophylaxis 
with allopurinol and adequate hydration prior to each subsequent infusion, if deemed appropriate 
by the investigator. Older and frail subjects will need special individualized care in fluid 
management, as 3 liters per day may not be tolerated. Rasburicase may be particularly indicated 
in such subjects. For all subjects, electrolytes should be monitored and corrected, fluid balance 
and renal function should be monitored, and supportive care should be administered, including 
dialysis as indicated. Hospitalization, particularly for older and frail subjects, should be 
considered.
5.4.4.2.
Antihypertensive Medication
As infusion related reactions may include hypotension, the investigator should consider 
withholding antihypertensive treatments for 12 hours prior to and throughout each obinutuzumab 
infusion and for the first hour after completion of the infusion.
5.5.
Accountability for Tirabrutinib, Entospletinib, and Obinutuzumab
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug bottles and vials. This includes acknowledgement of receipt of each shipment of IMP 
(quantity and condition). All used and unused IMP bottles dispensed to subjects must be returned 
to the site.
Tirabrutinib, entospletinib, and obinutuzumab accountability records will be provided to each 
study site to:

Record the date received and quantity of IMP bottles and vials


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
Record the date, subject number, subject initials, and the quantity of IMP bottles and vials
dispensed

Record the date, quantity of used and unused IMP bottles returned, along with the initials of 
the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. All study drug returned by the subject should be retained for review by 
the study site monitor prior to destruction.
Please see Section 9.1.7 for more information.


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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.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
The study steering committee, including representatives from the GCLLSG and Gilead, will 
meet at least monthly throughout the treatment period and regularly for the complete duration of 
the study to review ongoing safety data.
6.1.
Subject Enrollment, Randomization and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before randomization or enrollment. Please refer to Section 5.1 for details about randomization
and treatment assignment. With Amendment 3, all subsequent subjects will be enrolled in Arm 
B.
6.2.
Study Procedure Descriptions
During the treatment period, all visits may be performed within the specified window for that 
study visit (see Appendix 2).
6.2.1.
Informed Consent
All subjects must sign and date the most recent IEC approved informed consent form before any 
study procedures are performed. Optional procedures may require separate subject consent, 
either within the main informed consent form or on a separate informed consent form, per IEC 
requirements.
Subjects who screen fail must re-sign the informed consent, if any screening procedures will be 
performed outside of the 28-day screening window from the time of the first informed consent.
6.2.2.
Medical and Medication History
A complete medical history will be obtained by the Investigator or designee. Medical history will 
include information on the subject’s significant past medical events (eg, prior hospitalizations or 
surgeries), a review of the disease under study, prior anti-cancer therapies, and any concurrent 
illnesses. History of smoking in the past 30 days and CIRS score should be determined at 
screening.


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6.2.3.
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 
(EOT) will be a complete physical examination. Beginning at Week 1 Day 1, a modified 
physical examination will be performed to monitor for any changes (lymph nodes, size of liver 
and spleen, lung, cardiac, abdomen, skin, neurologic, and any other systems, as clinically 
indicated). Physical examination findings will either be reported as medical history or AEs based 
on the requirements in Section 7.
Weight should be measured with each physical examination.
Height will be measured at Screening only.
6.2.4.
Vital Signs
Vital signs, including blood pressure, respiratory rate, pulse, and temperature will be measured at 
the time points listed in the Study Procedures Tables in Appendix 2. Only the screening 
measurements will be recorded on the appropriate eCRF page with appropriate source 
documentation. Any abnormal measurements may be repeated and reported as AEs if 
appropriate. All measures of blood pressure will be performed using standard 
sphygmomanometry. Measurements of blood pressure should be taken per institutional 
guidelines.
6.2.5.
ECOG Performance Status/B-Symptoms
ECOG PS and B-Symptoms will be performed at the time points listed in the Study Procedures 
Tables (Appendix 2). ECOG will be scored using the scale index in Appendix 5.
6.2.6.
12-lead ECG
A 12-lead ECG will be obtained at the time points listed in the Study Procedures Table 
(Appendix 2).
6.2.7.
Binet and Rai Staging
Binet and Rai staging will be assessed at the time points listed in the Study Procedures Table 
(Appendix 2). CLL staging will be evaluated using the table in Appendix 9.
6.2.8.
Geriatric assessment
The G8 geriatric screening tool (Appendix 10) will be used for assessment for subjects aged 
> 70 years as outlined in the Study Procedures Table (Appendix 2).


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6.2.9.
Prior and Concomitant Medications
At Screening, all medication taken up to 30 days prior to the screening visit will be recorded on 
the eCRF. At each study visit, the site will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription and non-prescription medications, pre-infusion medications (eg, anti-emetics), and 
vitamins and minerals.
In addition, supportive therapies given during the course of the study (eg, blood transfusion, 
growth factor) should be collected and recorded on the eCRF.
6.2.10.
Adverse Events
Subjects will be assessed for AEs per guidelines in the National Cancer Institute (NCI) CTCAE 
(version 4.03) at the time points outlined in the Study Procedures Tables (Appendix 2). After 
informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the electronic case report form eCRF: AEs related to protocol-mandated 
procedures, and all SAEs.
Any AEs reported after informed consent is obtained and throughout the study will be recorded 
on the eCRF with appropriate source documentation. Please refer to Appendix 3 for CTCAE 
grading criteria.
Please refer to Section 7 for additional information on AE reporting.
6.2.11.
Radiology Assessment
The radiology assessment in this study is consistent with the European Society for Medical 
Oncology (ESMO) clinical practice guidelines for CLL {Eichhorst 2015}. Imaging of the neck, 
chest, abdomen and pelvis by CT scan (preferred) or MRI will be performed at screening. Scans
already completed up to 42 days prior to the first dose of treatment may be used for the screening 
assessment. One additional radiologic evaluation is specified per protocol, at the Week 25 visit, 
with evaluation of areas affected by CLL during the screening evaluation. During the treatment 
phase, if an improvement in clinical response is noted following the Week 25 assessment or if 
disease progression is suspected, additional scans may be performed as clinically indicated. 
Scans should continue to be performed at Week 25 for subjects who stop study treatment but did 
not have disease progression (e.g. experienced unexpected toxicity) unless radiographic 
progression is previously documented or unless the subject starts on subsequent therapy for CLL.
6.2.12.
Blood and Urine Samples
Blood and urine for laboratory safety tests will be collected according to the Study Procedures 
Tables (Appendix 2). The date and time of blood and urine collection will be recorded in the 
subject’s source documentation. The volume of blood phlebotomized will be roughly 100 mL at 
Screening and subsequently is not to exceed 200 mL every 3 months. The date and time of 
previous tirabrutinib and entospletinib administration, and whether the dose was taken with or 


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without food, will be recorded in the subject’s source documentation on days when blood for PK 
analysis is collected. The tests will be analyzed using standard procedures. All laboratory tests 
must be reviewed for clinical significance by the Investigator or qualified designee.
The analytes listed in Table 6-1 will be tested.
6.2.13.
Bone Marrow Assessment
For subjects without radiographic evidence of disease at screening, a bone marrow biopsy 
including aspirate is required within the screening window.
A bone marrow biopsy including aspirate is required at Week 25 for subjects who otherwise 
would meet criteria for a CR or complete remission with incomplete bone marrow recovery 
(CRi).
An additional bone marrow biopsy, including aspirate, may be obtained on protocol per 
investigator discretion following evidence of an improvement in clinical response.
Any bone marrow aspirate obtained should be sent for central MRD assessment, 
immunophenotyping, bio-banking, and follow-up research.
6.2.14.
Laboratory Samples to Address the Study Objectives
The biological specimens described herein will be collected in this study and will be used to 
evaluate the association of systemic and/or tissue specific biomarkers with study drug response 
including efficacy and/or AEs, as well as to increase knowledge and understanding of the 
biology of these and related diseases and possible companion diagnostics development. Because 
biomarker science is a rapidly evolving area of investigation, it is not possible to specify 
prospectively all tests that will be done on the specimens provided. The testing outlined below is 
based upon the current state of scientific knowledge. It may be modified during or after the end
of the study to remove tests no longer indicated and/or to add new tests based upon the growing 
state of the art knowledge. Biomarker samples may also be used for potential assay development 
of companion diagnostics.
Specimens will be collected from all subjects. These samples will be destroyed and tested no 
later than the end of study, unless a subject consents to the optional future storage samples.
Biomarker testing will include but not limited to the following:
6.2.14.1.
Laboratory Samples

Assessment by fluorescence in situ hybridization (FISH) and mutation analysis of TP53 and 
IGHV will be performed from peripheral blood at Screening at the GCLLSG molecular 
cytogenetics reference laboratory in Ulm.


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
Immunophenotyping for confirmation of diagnosis as well as assessment of CD38 and 
ZAP70 and karyotyping will be performed from peripheral blood at Screening at the 
GCLLSG reference laboratory in Cologne.

MRD assessments of peripheral blood and bone marrow are to be performed at Week 1 
Day 1 and at intervals specified in Study Procedures Table (Appendix 2) on samples sent to 
the Durchflußzytometrisches Labor at the Hämatologielabor Kiel.

Pharmacodynamic activity of tirabrutinib and entospletinib may be assessed through 
proteomic analysis and rare cell analysis may be performed to detect resistant CLL clones.
 
 
 

Immune cell phenotyping may be performed to monitor changes in immune cell subsets over 
time.
6.2.15.
Samples for Optional Future Research
 
 
 
 
6.2.16.
Pregnancy Test for Females of Childbearing Potential
All female subjects of childbearing potential (as defined in Appendix 4) will have a serum 
pregnancy test at Screening and a urine pregnancy test prior to Week 1 Day 1 dosing and 
throughout the study as indicated in the Study Procedures Table (Appendix 2). The results must 
be confirmed as negative prior to continued administration of study drug.
6.2.17.
Pharmacokinetic Samples
A PK sample will be collected on Week 1 Day 1 at 2 (1) hours (inclusive) post-dose of
tirabrutinib and entospletinib. At the visits on Week 5, 13, and 21, a PK sample will be collected 
at pre-dose (within 2 hours prior to dosing) and 1 sample will be collected at 2 (1) hours 
(inclusive) post-dose of tirabrutinib and entospletinib. Subjects should be instructed to hold their 
dose of tirabrutinib and entospletinib on the morning of the visit at Weeks 5, 13, and 21 until 
after collection of the pre-dose PK sample.
CCI
CCI
I 


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Plasma concentrations of tirabrutinib and entospletinib will be determined. Plasma 
concentrations of metabolites may be determined. Plasma protein binding of each analyte may be 
evaluated.
Table 6-1.
Blood and Urine Samples Collected During the Course of the Study
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Glucose
Blood urea nitrogen or urea
Creatininea
ALT
AST
GGT
Cholesterol
Triglycerides
Uric Acid
Alkaline phosphatase
Total and direct bilirubin
Total protein
Albumin
Calcium
Magnesium
Phosphate
LDH
Amylase
Lipase
WBC
RBC
Hemoglobin
Hematocrit
Platelet Count
Neutrophils (ANC)
Lymphocytes
Monocytes
Basophils
Eosinophils
Reticulocytes
Tirabrutinib, entospletinib, plasma 
concentrations
Other metabolites of tirabrutinib and 
entospletinib may be measured
FISH/Karyotyping
TP53 Status
IGHV status
MRD
Immunophenotyping
Serum Beta2- Microglobulin
Serum Thymidine kinase
Blood Pharmacodynamic Biomarkers
CLL mutational and phenotypic 
analysis HBsAG
Hepatitis B core antibody
HBV DNA if HBVcAb+
Hepatitis C antibody
HCV PCR if HCVAb+
CMV IgG, IgM
HIV serology
Serum quantitative immunoglobulins
Coagulation
PT/INR
aPTT
Pregnancy Testing
Urinalysisb
Serum Qualitative -HCG (females)
Urine Pregnancy (females)
pH
Occult blood
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
Microscopicb
WBC/High Power Field
RBC/High Power Field
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft-Gault formula
(see Appendix 8 for formula)
b
Dipstick will be used for Screening urinalysis: Microscopic evaluation to be performed only if the dipstick results are 
abnormal Note: Additional components, abnormal, and/or atypical cells should also be reported if present
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; CMV = cytomegalovirus; GGT = gamma-glutamyltransferase; INR = international normalized ratio; 
LDH = lactate dehydrogenase; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell


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6.3.
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 perform the required study-related 
follow-up and procedures (see Section 6.4 Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study. Long-term follow-up within the GCLLSG registry is recommended.
6.4.
Criteria for Discontinuation of Study Treatment
See Sections 3.4 and 3.6 for discontinuation criteria.
6.5.
Dose Interruption and Reduction
The following are the guidelines for dose interruption and/or reduction. If an AE is attributed to 
study drug, the investigator’s discretion will be used to determine if the drug not attributed to the 
AE will be withheld based on the investigator’s assessment of risk-benefit of withholding the 
study drug.
An interruption of tirabrutinib and/or entospletinib administration will be acceptable to allow for 
any reversal of toxicity of tirabrutinib and/or entospletinib. Unless the toxicity is deemed related 
to the subject’s underlying disease in the opinion of the investigator, subsequent treatment with 
the suspected offending agent should only be undertaken after reevaluation of the potential risk. 
If the toxicity is deemed to be related to one agent, resuming single-agent therapy with the other 
drug should be considered.
A subject who discontinues obinutuzumab for any reason other than progression should remain 
on study and may continue receiving the combination of tirabrutinib and entospletinib in 
accordance with the guidelines in Table 6-2 and Table 6-3.
Subjects experiencing a related or non-related AE at any point during the study that takes longer 
than 2 weeks to resolve will be reviewed on a case-by-case basis by the investigator and the
sponsor. Upon resolution of the AE, or in the opinion of the Investigator if the AE is considered 
to be well controlled and if the subject is deemed to be gaining clinical benefit from treatment 
with tirabrutinib and/or entospletinib, a subject may continue to receive tirabrutinib and/or 
entospletinib at their assigned dose or at a lower dose (consistent with Table 6-2). The dose may 
subsequently be increased back to the original dose level if considered safe to do so by the 
treating investigator and upon approval by the sponsor.
The dose modification instructions focus on the types of events most commonly attributed to 
each of the study agents. The recommendations provided in Table 6-2, and Table 6-3 comprise
only guidelines; variations from these recommendations may be warranted based on an 
investigator’s individual judgment in considering potential risks, benefits, and therapeutic 
alternatives available to each subject.


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Table 6-2.
Dose Adjustments, Withholding and Discontinuation Related to 
Entospletinib and/or Tirabrutinib
Entospletinib
Tirabrutinib
Starting dose
400 mg
80 mg
Dose level -1
200 mg
40 mg
NCI CTCAE Grade
Recommendation
Entospletinib
Tirabrutinib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade ≤ 3 Neutropenia
Maintain current dose level and 
schedule.
Maintain current dose level and schedule.
Grade 4 neutropenia (or 
occurrence of neutropenic 
fever or infection
Withhold tirabrutinib and entospletinib until resolved to Grade ≤ 3 or baseline; 
consider G-CSF. Tirabrutinib and entospletinib may be reinitiated at the previous 
dose. If the toxicity recurs, decrease tirabrutinib or entospletinib by one dose level. If 
toxicity recurs and persists following a dose reduction in both tirabrutinib and 
entospletinib, discontinue tirabrutinib and/or entospletinib.
Thrombocytopenia
Grade 3 Thrombocytopenia
In the absence of symptomatic 
bleeding, maintain current dose level
and schedule. With bleeding, withhold 
entospletinib until Grade ≤ 2.
In the absence of symptomatic bleeding,
maintain current dose level and schedule.
With bleeding, withhold tirabrutinib until 
Grade ≤ 2.
Grade 4 Thrombocytopenia
Withhold tirabrutinib and entospletinib until resolved to Grade ≤ 2 or baseline. 
Tirabrutinib and entospletinib may be reinitiated at the previous dose. If the toxicity 
recurs, decrease tirabrutinib or entospletinib by one dose level. If toxicity persists or 
recurs following a dose reduction in both tirabrutinib and entospletinib, discontinue 
tirabrutinib and/or entospletinib.
NON-HEMATOLOGICAL ADVERSE EVENTS
Dermatological
Grade ≤ 2
Maintain current dose level and 
schedule.
Maintain current dose level and schedule.
Grade 3 or 4
Withhold study treatment until resolved to Grade 1 or baseline. Tirabrutinib and 
entospletinib may be reinitiated at the previous dose. If the toxicity recurs, decrease 
tirabrutinib or entospletinib by one dose level. If toxicity persists or recurs following 
a dose reduction in both tirabrutinib and entospletinib, discontinue tirabrutinib
and/or entospletinib.
Diarrhea
Grade ≤ 1
Provide anti-diarrheal (eg, loperamide) and maintain current tirabrutinib and 
entospletinib dose level and schedule
Grade 2
Withhold tirabrutinib and entospletinib until resolved to Grade 1 or baseline. 
Tirabrutinib and entospletinib may be reinitiated at the previous dose. If the toxicity 
recurs, decrease tirabrutinib or entospletinib by one dose level. If toxicity persists or 
recurs following a dose reduction in both tirabrutinib and entospletinib, discontinue 
tirabrutinib and/or entospletinib.


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NCI CTCAE Grade
Recommendation
Entospletinib
Tirabrutinib
Grade 3 or 4
Withhold all study treatment until Grade ≤1. Consider anti-diarrheal (eg, 
loperamide) and/or anti-inflammatory (eg budesonide). Consider resuming with 
lower dose level of both tirabrutinib and/or entospletinib. If toxicity persists or 
recurs following dose reduction of both tirabrutinib and entospletinib, discontinue 
tirabrutinib and/or entospletinib.
Hepatic Adverse Events (elevations in ALT, AST or bilirubin)
Grade 1
(ALT/AST ≤3xULN)
(Bilirubin ≤1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST > 3-5xULN)
(Bilirubin>1.5 -≤3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at
least 1x per week.
Grade 3
(ALT/AST > 5-20xULN)
(Bilirubin > 3-10xULN)
Withhold all study treatment. Monitor ALT, AST, ALP, and bilirubin at least 1x per
week until all abnormalities are Grade ≤ 1 or baseline. If bilirubin abnormality was 
Grade < 3, resume tirabrutinib and entospletinib at previous dose level or at lower 
dose level per investigator discretion. If bilirubin abnormality was Grade ≥ 3, discuss 
with medical monitor prior to resuming tirabrutinib or entospletinib.
Grade 4
(ALT/AST > 20xULN)
(Bilirubin > 10xULN)
Withhold all study treatment. Monitor ALT, AST, ALP, and bilirubin at least 1x per
week until all abnormalities are Grade ≤ 1 or baseline. If bilirubin abnormality was 
Grade ≤ 3, resume tirabrutinib at previous or lower dose level and entospletinib at 
lower dose level. If bilirubin was Grade 4, discontinue tirabrutinib and entospletinib.
Pneumonitis 
Grade 1
Maintain current dose level and schedule. Consider Pneumocystis treatment.
Grade 2
Withhold all study treatment until Grade ≤ 1, consider systemic corticosteroids and
Pneumocystis treatment. Upon resolution discuss with medical monitor prior to 
study drug reinitiation.
Grade 3 or 4
Discontinue all study treatment, consider systemic corticosteroids. 
Progressive Multifocal Leukoencephalopathy (PML)
Any Grade
Discontinue all study treatment; refer subject to a neurologist for further evaluation 
(see Section 6.6.6).
Hypersensitivity
Any Grade
Consider interrupting or discontinuing tirabrutinib treatment (see Section 6.6.3).
OTHER NON-HEMATOLOGICAL ADVERSE EVENTS
Grade 1
Maintain current dose level and schedule
Grade 2
Withhold tirabrutinib and entospletinib until Grade ≤1 or baseline. May resume
tirabrutinib and/or entospletinib at initial or lower dose level or discontinue
tirabrutinib and/or entospletinib at investigator discretion.
Grade 3
Withhold tirabrutinib and entospletinib until Grade ≤1 or baseline. May resume
tirabrutinib and/or entospletinib at lower dose level or discontinue tirabrutinib and/or 
entospletinib at investigator discretion.
Grade 4
Discontinue all study treatment. Discuss with medical monitor prior to reinitiation of 
any treatment.
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Table 6-3.
Dose Adjustment Guidelines for Subjects Receiving Obinutuzumab
NCI CTCAE Grade
Recommendation
Toxicity attributable to obinutuzumab
HEMATOLOGICAL ADVERSE EVENTS*
Neutropeniaa
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
Maintain current dose level and schedule. Consider G-CSF support.
Grade 4 neutropenia 
(or occurrence of 
neutropenic fever or 
infection)
Delay all study treatment until Grade 2 (ANC ≥1 × 109/L) and/or neutropenic fever 
or infection is resolved; thereafter, resume at full dose. Consider G-CSF support to 
avoid delays. If delay is > 4 weeks, discontinue obinutuzumab.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
Delay all study treatment until Grade 2 or baseline; thereafter, resume at full dose. If 
delay is > 4 weeks, discontinue obinutuzumab, unless the Grade 4 thrombocytopenia 
occurred after the first 3 weekly doses.
Hemorrhage
N/A
Hold obinutuzumab in case of platelets < 20,000/µL. If Day 8 is delayed then skip 
Day 8 and administer Day 15 as previously scheduled (if symptomatic bleeding has
resolved). If Day 15 is delayed then skip Day 15 dosing and administer Day 29 of 
obinutuzumab as scheduled.
At the discretion of the study investigator, for subjects who are on low molecular 
weight heparin (LMWH), when thrombocytopenia with platelets <20,000/µL develops, 
reduce the dose of LMWH or new oral anticoagulants (NOAC) used.
Hold all study medication for clinically significant bleeding (irrespective of platelet 
count) until it resolves.
NON-HEMATOLOGICAL ADVERSE EVENTS
Cutaneous
Grade 2
Maintain current dose level and schedule.
Grade 3 or 4
Delay all study treatment until Grade 1; thereafter, may resume at full dose or 
discontinue obinutuzumab at investigator discretion.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Maintain current dose level and schedule.
Grade 2
Maintain current dose level and schedule.
Grade 3
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule.
Grade 4
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule or discontinue at investigator discretion.
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3×ULN)
(Bilirubin1.5×ULN)
Maintain current dose level and schedule.


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NCI CTCAE Grade
Recommendation
Toxicity attributable to obinutuzumab
Grade 2
(ALT/AST>3-5×ULN)
(Bilirubin>1.5-3×ULN)
Maintain current dose level and schedule.
Grade 3
(ALT/AST>5-20×ULN)
(Bilirubin>3-10×ULN)
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule.
Grade 4
(ALT/AST>20×ULN)
(Bilirubin>10×ULN)
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule or discontinue at investigator discretion.
Pneumonitis
Grade 1
Maintain current dose level and schedule.
Grade 2
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to receive 
further treatment; thereafter maintain full dose and schedule.
Grade 3
Discontinue all study treatment, consider systemic corticosteroids.
Progressive Multifocal Leukoencephalopathy (PML)
Any Grade
Discontinue all study treatment; refer subject to a neurologist for further evaluation (see 
Section 6.6.6).
Hypersensitivity
Any Grade
Stop the infusion and discontinue obinutuzumab treatment (see section 6.6.3)
Other Non-hematological Adverse Events
Grade 2
Maintain current dose level and schedule.
Grade 3
If felt to be related to obinutuzumab, delay obinutuzumab as necessary to ensure subject 
is sufficiently stable to receive further treatment; thereafter maintain full dose and 
schedule or discontinue obinutuzumab at investigator discretion.
Grade 4
Delay all study treatment until subject is sufficiently stable to receive further treatment. 
Discuss with medical monitor prior to reinitiation of treatment or discontinue treatment 
at investigator discretion.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
ANC=absolute neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte
colony-stimulating factor, NCI=National Cancer Institute, ULN=upper limit of normal
a
Neutropenia and thrombocytopenia should not necessarily lead to delay in dosing of study treatment if it is believed that the 
cytopenia is due to CLL, and not to the treatment(s).


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6.6.
Recommendations for Evaluation, Intervention, and Drug Discontinuation 
for Specific Adverse Events or Conditions
6.6.1.
Hemorrhage
Bleeding events have occurred in subjects with relapsed/refractory chronic lymphocytic 
leukemia (CLL) and relapsed/refractory non-Hodgkin’s lymphoma (NHL) who received 
tirabrutinib as monotherapy. These include minor hemorrhagic events such as contusion, 
hematoma, and petechiae, and major hemorrhagic events such as small intestinal hemorrhage and 
subdural hematoma.
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.
Subjects should be monitored for signs of bleeding and treated appropriately.
6.6.2.
Infectious Events
Subjects with lymphoid cancers receiving tirabrutinib or obinutuzumab have developed serious 
and fatal infections during therapy. Monitor subjects for fever and infections and treat 
appropriately. Therapy should not be initiated in the context of an active infection.
6.6.3.
Dermatological and Hypersensitivity Events
Subjects receiving entospletinib or tirabrutinib with ≥Grade 3 rash have generally presented 
with a maculopapular rash on the trunk and extremities that is occasionally associated with fever 
and/or pruritus and responded to treatment with diphenhydramine and/or topical or oral 
corticosteroids.
For subjects who develop a severe rash for which an underlying etiology cannot be identified 
(e.g., infection, co-suspect drug), study treatment should be interrupted. Resumption of study 
treatment should be considered once rash resolves.
Hypersensitivity symptoms can occur after previous exposure and very rarely with the first 
infusion of obinutuzumab. If a hypersensitivity reaction is suspected during or after an infusion, 
the infusion must be stopped and treatment permanently discontinued. Patients with known 
hypersensitivity to obinutuzumab must not be treated. Subjects receiving obinutuzumab may also 
experience hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. 
serum sickness); these may be difficult to distinguish from infusion related reactions. 
If a hypersensitivity reaction is suspected during or after an obinutuzumab infusion, the infusion 
must be stopped and treatment permanently discontinued. If patients experience a 
hypersensitivity reaction whilst on tirabrutinib, consideration should be given to interruption or 
discontinuation.


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6.6.4.
Hepatic Events
Transaminase Elevations: Reversible asymptomatic ALT/AST increases have been observed 
with entospletinib in subjects with hematologic malignancies. Successful rechallenge after 
resolution at either the same or lower dose level of entospletinib has been achieved in the 
majority of subjects. Close monitoring of hepatic laboratory tests during therapy is important to 
allow for appropriate treatment interruption and reinstitution.
HBV Reactivation: HBV reactivation can occur with treatment, most commonly in patients 
treated with obinutuzumab. The risk is very low among patients with negative anti-HBc serology
and/or undetectable HBV DNA as assessed by quantitative PCR. Although some subjects who 
are HBc antibody positive with negative PCR may have had passive transfer of antibody from 
intravenous IgG, it cannot be known for certain that any such subject did not have natural HBV 
infection. Therefore, all subjects who are HBc antibody positive at screening will be monitored 
for potential HBV reactivation (manifest as detectable HBV DNA by quantitative PCR).
Surveillance of subjects who test positive for HBc antibody for HBV reaction will be performed 
according to the Study Procedures Table (Appendix 2). If there is evidence of HBV reactivation 
immediately stop study treatment and start appropriate treatment for HBV. In the event of HBV 
reactivation, please contact the Medical Monitor prior to re-initiation of study treatment.
6.6.5.
Hematological Events
Treatment-emergent Grade 3 or 4 neutropenia events including those accompanied by fever or 
infection have occurred in subjects treated with entospletinib.Neutropenia and anemia have also 
occurred in subjects treated with tirabrutinib. The anemia in subjects treated with tirabrutinib has 
generally been self-limiting, without the requirement for intervention and with improvement on 
continued therapy.
Management of neutropenia, including administration of G-CSF should be per established 
clinical guidelines and institutional standard of care.
6.6.6.
Progressive Multifocal Leukoencephalopathy (PML)
PML has been reported in patients treated with obinutuzumab and should be considered in any 
patient presenting with new-onset or changes to pre-existing neurologic manifestations. Therapy 
with all medications should be withheld during investigation of potential PML and permanently 
discontinued in case of confirmed PML. The subject should be referred to a neurologist for the 
evaluation and treatment of PML with evaluation including, but not limited to, brain MRI and 
lumbar puncture with cerebrospinal fluid testing (include testing for John Cunningham viral 
DNA).
6.6.7.
Further Safety Information
Further safety information regarding the study drug may be found in the Investigator’s Brochures
for entospletinib and tirabrutinib and the current product labeling for obinutuzumab.


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6.7.
End of Treatment
The EOT visit should be scheduled for 30 days following discontinuation of all study treatment 
to satisfy the requirement for a 30-day post-treatment safety assessment. Please consider 
enrollment of subjects at EOT in the non-interventional GCLLSG CLL registry for subjects that 
did not enroll at screening.
For subjects that permanently discontinue all study treatments prior to the Week 25 visit without 
experiencing disease progression, the Week 25 Day 1 visit should be performed on schedule per 
the Study Procedures Table (Appendix 2).
6.8.
Unscheduled Procedures
Unscheduled procedures will be recorded on the applicable eCRFs.
6.9.
Post Study Care
At this time there is no plan to provide post-study care to subjects who have participated on this 
study.


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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, 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 adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae

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 
eCRF.
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.
7.1.3.
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 (e.g., 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 (e.g., 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).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., 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 adverse event reporting.


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The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g.., venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be recorded and graded according to the NCI CTCAE, Version 4.03, 
published 14 June 2010.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the intensity of the AE. For purposes of consistency with the CTCAE, 
these intensity grades are defined in Table 7-1.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a clinically 
significant effect on the subject’s overall health and well-being, does not interfere with 
the subject’s usual function, and is not likely to require medical attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-
threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met 1 of the 
criteria for serious events listed in Section 7.1.2.
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 the eCRF: adverse events related to protocol-mandated procedures, and all 
SAEs.


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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 adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 30 day post treatment follow-up period, which concludes 
at the EOT visit, must be reported to the eCRF database and Gilead Pharmacovigilance and 
Epidemiology (PVE) as instructed. This also includes any SAEs resulting from protocol-
associated procedures performed after informed consent is signed.
Investigators are not obligated to actively seek beyond the end of study; 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 document and report the event to 
Gilead PVE.
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 personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE 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 information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead PVE:
Fax:
Email: 

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 form because the eCRF database has been locked, no 
further action is necessary.
PPD
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
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 document to the subject identifiers.

Additional information 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 form.
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 investigator’s brochure or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the 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.
Toxicity Management
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. Whether or not considered treatment-related, 
all subjects experiencing AEs must be monitored periodically until symptoms subside, any 
abnormal laboratory values have resolved or returned to baseline levels or they are considered 
irreversible, or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
as soon as practical to do so, and preferably within 3 calendar days after receipt of the original 
test results. Any questions regarding toxicity management should be directed to the 
Gilead Sciences Medical Monitor or designee.
Please refer to the current tirabrutinib or entospletinib IB and local obinutuzumab prescribing
information for information related to toxicity management. See Section 6.6 for more
information related to recommended dose modifications associated with toxicities.


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7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events 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.
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.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
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 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.


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A spontaneous abortion is always considered to be an SAE and will be reported as such.
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.
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:
Fax:
Email: 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
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 do 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 preliminary efficacy of the combination of tirabrutinib and entospletinib
with obinutuzumab in subjects with relapsed or refractory CLL
The secondary objective of this study is:

To evaluate the safety and tolerability of the combination of tirabrutinib and entospletinib
with and without obinutuzumab
The exploratory objectives of this study are:
 
 
8.1.2.
Primary Endpoint
The primary endpoint is the rate of CR per modified IWCLL 2008 {Hallek 2008} criteria at 
Week 25
8.1.3.
Secondary Endpoints
The secondary endpoints of this study are:

Rate of CR/BM MRD- at Week 25

Rate of CR/PB MRD- at Week 25

ORR at Week 25 including CR, CRi, PR, and PR with lymphocytosis

Type, frequency, and severity of AEs and SAEs
8.1.4.
Exploratory Endpoints
CCI
CCI
I 
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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is the Full Analysis Set (FAS), which is defined as 
all subjects randomized or enrolled into each study arm who received at least 1 dose of any study 
treatment. Following the ITT principle, subjects are analyzed according to the study treatment 
they are assigned to at randomization or enrollment.
The PP analysis set is defined as all randomized or enrolled subjects who received at least 1 dose 
of any study treatment and had disease assessment at baseline and at least 1 evaluable response 
assessment post baseline. This analysis set will be used in the supplementary analysis of 
response endpoints.
8.2.1.2.
Safety
The primary analysis set for safety analyses is the safety analysis set, which is defined as all 
randomized or enrolled subjects who received at least 1 dose of any study treatment, with study 
treatment assignment designated according to the actual treatment received.
CCII 
I 
I 
I 
I 
I 
I 
I 
I 


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8.2.1.3.
Pharmacokinetics
The pharmacokinetic (PK) analysis set includes all subjects who received at least 1 dose of study 
treatment and had at least 1 non-missing post-dose concentration value for the corresponding 
analyte in plasma.
8.2.1.4.
Biomarkers
The biomarker analysis set consists of randomized or enrolled subjects who have at least 
1 evaluable biomarker sample in this study.
8.3.
Data Handling Conventions
By-subject listings will be presented for all randomized or enrolled subjects in the FAS and 
sorted by subject ID number, visit date, and time if applicable. Data collected on log forms, such 
as AEs, will be presented in chronological order within subject. Summary tables for continuous 
variables will contain the following statistics: N (number in population), n (number with data), 
mean, standard deviation, median, minimum, and maximum. Summary tables for categorical 
variables will include: N, n, and percentage.
The baseline value is generally defined as the last (most recent) pre-treatment value in safety 
analyses and the last (most recent) pre-randomization value for efficacy analyses. Data from all 
sites will be pooled for all analyses. If there is a significant degree of non-normality, analyses 
may be performed on log-transformed data, as appropriate.
In general, missing data will not be imputed. For response endpoints, if a subject is missing 
baseline or post baseline assessments, the subject will be treated as non-responders. For duration 
of response, PFS, OS and TTNT, if the outcome event is not observed, the data will be 
right-censored at the date of last adequate assessment. Methods for imputing partially missing 
dates and laboratory results beyond limit of quantification will be provided in the SAP.
8.4.
Demographic Data and Baseline Characteristics
Subject demographic variables (age, sex, race and ethnicity), baseline characteristics (including 
body weight, height, body mass index, and ECOG Performance Status) as well as baseline 
disease characteristics (including time since initial diagnosis, disease staging at study entry, 
cytogenetic risk group, refractory and relapse status) will be summarized descriptively by 
treatment arms and overall based on the FAS. Medical history and concomitant medication use 
will be summarized using safety analysis set.
In general, continuous variables will be summarized by sample size, mean, standard deviation, 
median, quartiles, minimum and maximum and categorical variables will be summarized by 
counts and percentages.


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8.5.
Efficacy Analysis
8.5.1.
Primary Endpoint
Tumor response will be based on investigator’s assessment according to the modified IWCLL 
2008 criteria (see Appendix 6).
Rate of CR will be calculated by treatment arms using the FAS. The 2-sided 90% exact 
confidence interval (CI) of CR will be estimated using the Clopper-Pearson method.
No inferential test will be performed. The goal of this analysis is to obtain preliminary estimates
of the CR rate.
In addition, the analysis of the primary endpoint will be performed using the PP analysis set.
8.5.2.
Secondary Endpoints
ORR and rate of CR/MRD- will be estimated for each arm and their associated 90% confidence 
intervals will be calculated using the exact method.
 
 
For subjects who have not experienced disease progression or death, their data for DOR and PFS 
will be censored on the date of the last available valid disease assessment. Detailed censoring 
rules will be described in the SAP.
8.6.
Safety Analysis
8.6.1.
Extent of Exposure
Treatment exposure and compliance will be summarized descriptively by treatment group based 
on safety analysis set. Summaries will include treatment duration, number of doses, average 
dose, dose modifications, and treatment adherence rate.
8.6.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the current version of Medical 
Dictionary for Regulatory Activities (MedDRA). The severity of AEs will be graded according 
to the NCI-CTCAE, Version 4.03. The relationship of the AE to the study treatment will be 
assessed by the investigator as related or unrelated.
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs 
(TEAEs). A TEAE is defined as an AE that occurs or worsens in severity on or after the date of 
the first dose of study treatment but no later than 30 days after the last dose of study treatment.
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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC
and PT) will be provided by treatment group:

All TEAEs

TEAEs of Grade 3 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

All treatment-emergent SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of study drug

All AEs leading to dose modification or temporary interruption of study drug

All SAEs leading to death (ie, outcome of death)
8.6.3.
Laboratory Evaluations
Safety laboratory results will be graded according to NCI-CTCAE Version 4.03. Summaries of 
laboratory data will be provided for the safety analysis set and will include data collected up to 
the last dose of study drug plus 30 days. The analysis will be based on values reported in 
conventional units.
Descriptive statistics will be provided by treatment groups for each safety laboratory test as 
follows:

Baseline values (defined as the last measurement obtained on or prior to the date/time of 
first dose of study drug)

Post baseline maximum value

Change from baseline to post baseline maximum value

Post baseline minimum value

Change from baseline to post baseline minimum value
In addition, treatment-emergent laboratory abnormalities will be summarized descriptively using 
number and percentages of subjects by treatment group for the following:

Grade 3 or 4 laboratory abnormalities


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
Shift from baseline in laboratory toxicity grade
Subjects will be categorized according to the most severe post baseline abnormality grade for a 
given lab test.
8.7.
Pharmacokinetic Analysis
Plasma concentrations will be listed and summarized using descriptive statistics (eg, sample size, 
arithmetic mean, geometric mean, % coefficient of variation, standard deviation, median, 
minimum, and maximum).
8.8.
Biomarker Analysis
Changes from baseline in biomarkers will be summarized descriptively. Data explorations may 
be performed to evaluate potential associations between biomarkers and subject characteristics or 
outcome measures.
8.9.
Sample Size
The primary goal of this study is to evaluate the efficacy of the combination of tirabrutinib and 
entospletinib with obinutuzumab in relapsed and refractory CLL. The primary endpoint for this 
study is the rate of CR at Week 25. The corresponding single-agent CR rate with BTK and SYK 
inhibitors in subjects with relapsed or refractory CLL is ≤5%. The 90% CI corresponding to 
different CR rates ranging from 20% to 60% for a sample size of 30 is provided in the table 
below. With a sample size of 30, the lower bound of the 90% CI of an observed CR rate of 20% 
or above will exclude 5%.
Table 8-1.
90% Confidence Intervals at Different CR Rates
Sample Size
CR Rate
90% Confidence Interval
using Clopper-Pearson Method
30
20%
(9.1%, 35.7%)
30
30%
(16.6%, 46.5%)
30
40%
(25.0%, 56.6%)
30
50%
(33.9%, 66.1%)
30
60%
(43.4%, 75.1%)
With Amendment 3, randomization was discontinued. All subsequently enrolled subjects will 
enter Arm B. A total of approximately 6 subjects in Arm A and 30 subjects in Arm B will be 
enrolled, thus the total sample size for the study will be approximately 36 subjects.
8.10.
External Data Monitoring Committee
No external independent Data Monitoring Committee is used in this study.


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8.11.
Endpoint Adjudication Committee
No independent endpoint adjudication committee is 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 EU 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 sub-investigators 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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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.
Independent Ethics Committee 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 IEC. The investigator will not begin any study subject activities until 
approval from the IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial 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 IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 


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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 IEC local 
requirements. The consent form will inform subjects about pharmacogenomic testing and sample 
retention, and their right to receive clinically relevant pharmacogenomic 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, 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, eCRF and query forms, IEC
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 adverse events 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. eCRFs should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. 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 


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described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that 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 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 IEC in 
accordance with local requirements and receive documented 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) 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
Aoki Y, Isselbacher KJ, Pillai S. Bruton tyrosine kinase is tyrosine phosphorylated and activated 
in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci U S A 
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Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, et al. Addition of 
rituximab to fludarabine may prolong progression-free survival and overall 
survival in patients with previously untreated chronic lymphocytic leukemia: an 
updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. 
Blood 2005;105 (1):49-53.
Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, et al. Assessment of 
fludarabine plus cyclophosphamide for patients with chronic lymphocytic 
leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370 
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Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel targeted agents and 
the need to refine clinical end points in chronic lymphocytic leukemia. J Clin 
Oncol 2012;30 (23):2820-2.
de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active 
BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled 
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de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ, et 
al. The Bruton's tyrosine kinase gene is expressed throughout B cell 
differentiation, from early precursor B cell stages preceding immunoglobulin gene 
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1993;23 (12):3109-14.
Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet 2008;371 (9617):1017-29.
Efremov DG, Laurenti L. The Syk kinase as a therapeutic target in leukemia and lymphoma. 
Expert opinion on investigational drugs 2011;20 (5):623-36.
Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line 
chemoimmunotherapy with bendamustine and rituximab versus fludarabine, 
cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic 
leukaemia (CLL10): an international, open-label, randomised, phase 3, non-
inferiority trial. Lancet Oncol 2016;17 (7):928-42.


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Eichhorst B, Robak T, Montserrat E, Ghia P, Hillmen P, Hallek M, et al. Chronic lymphocytic 
leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol 2015;26 Suppl 5:v78-84.
Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, et al. Expression of 
Bruton's tyrosine kinase protein within the B cell lineage. European journal of 
immunology 1994;24 (12):3100-5.
Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus 
chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 
2014;370 (12):1101-10.
Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 
2011;29 (5):544-50.
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.
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of 
rituximab to fludarabine and cyclophosphamide in patients with chronic 
lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376 
(9747):1164-74.
Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton's tyrosine kinase in B cell malignancies. 
Nature reviews. Cancer 2014;14 (4):219-32.
Herrera AF, Jacobsen ED. Ibrutinib for the treatment of mantle cell lymphoma. Clin Cancer Res 
2014;20 (21):5365-71.
Herter S, Birk MC, Klein C, Gerdes C, Umana P, Bacac M. Glycoengineering of therapeutic 
antibodies enhances monocyte/macrophage-mediated phagocytosis and 
cytotoxicity. J Immunol 2014;192 (5):2252-60.
Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton 
tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in 
models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A 
2010;107 (29):13075-80.
Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, et al. Bruton's tyrosine kinase is 
a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear 
factor kappaB activation by Toll-like receptor 4. J Biol Chem 2003;278 
(28):26258-64.


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Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, et al. Increasing the efficacy 
of CD20 antibody therapy through the engineering of a new type II anti-CD20 
antibody with enhanced direct- and immune effector cell-mediated B-cell 
cytotoxicity. Blood 2014:1-26.
National Cancer Institute (NIH). SEER*Stat Databases: November 2015 Submission.  Available 
at: http://seer.cancer.gov/data/seerstat/nov2015/. Accessed on 23 August.  2016:
Pharmacyclics Inc., Janssen Biotech Inc. IMBRUVICA® (ibrutinib) capsules, for oral use. US 
Prescribing Information. Revised January 2015:
Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell 
malignancies. Nature reviews 2013;13 (8):578-91.
Robak T, Dmoszynska A, Solal-Celigny P, Warzocha K, Loscertales J, Catalano J, et al. 
Rituximab plus fludarabine and cyclophosphamide prolongs progression-free 
survival compared with fludarabine and cyclophosphamide alone in previously 
treated chronic lymphocytic leukemia. J Clin Oncol 2010;28 (10):1756-65.
Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of 
hematologic malignancies in Europe by morphologic subtype: results of the 
HAEMACARE project. Blood 2010;116 (19):3724-34.
Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of 
Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-
regulated in T lymphocytes and plasma cells. J Immunol 1994;152 (2):557-65.
Stephens DM, Ruppert AS, Weirda WG, Jones JA, Woyach JA, Maddocks K, et al. Externally 
validated predictive clinical model for untreated del(17p13.1) chronic 
lymphocytic leukemia patients [Accepted Article]. Am J Hematol 2015.
Surveillance Epidemiology and End Results (SEER) Program. SEER Stat Fact Sheets: Chronic 
Lymphocytic Leukemia. Available at: 
http://seer.cancer.gov/statfacts/html/clyl.html. Accessed 12 May 2011.
Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression 
of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. 
Cell 1993;72 (2):279-90.
Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in 
X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine 
kinases. Nature 1993;361 (6409):226-33.
Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, et al. A phase 1 clinical trial of the 
selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell 
malignancies. Blood 2015.


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Wilson WH, Gerecitano JF, Goy A, de Vos S, Kenkre VP, Barr PM, et al. The Bruton's Tyrosine 
Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), Has Preferential Activity in the 
ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma 
(DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study [Abstract 
686]. American Society of Hematology (ASH) Annual Meeting; 2012 December 
08-11; Atlanta, GA. 


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11.
APPENDICES
Appendix 1.
       Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
Eastern Cooperative Oncology Group (ECOG) Performance Status
Appendix 6.
Modified IWCLL 2008 Response Criteria
Appendix 7.
Cumulative Illness Rating Scale (CIRS)
Appendix 8.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 9.
Binet and Rai Staging Systems for the Classification of CLL
Appendix 10.
The G8 Screening Questionnaire


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Appendix 2.
Study Procedures Table
Screening
24 Weeks
Week 
25 Day 
119
Week 
29 Day 
1
Every 
12 weeks 
starting 
Week 33 
until Week 
105
EOT17
Day 
-28
Week 
1
Day 1
Week 
2
Day 1
Week 
3 Day 
1
Week 
4 
Day 
116
Week 
5
Day 1
Week 
9
Day 1
Week 
13 Day 
1
Week 
17 Day 
1
Week 
21 Day 
1
Visit Window (days)
0
2
2
2
2
2
2
2
2
7
7
7
7
Informed Consent
X
Medical and Medication 
History1
X
Physical Examination2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status / B-symptoms
X
X
X
X
X
X
X
X
X
X
X
Binet/Rai Staging
X
G8 Geriatric Screening 
Tool3
X
X
X
X
12-lead ECG4
X
X
X
X
X
X
X
X
X
Adverse events/ 
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tirabrutinib + 
entospletinib 
Dispensing5
X
X
X
X
X
X
X
X
X
Tirabrutinib + 
entospletinib 
Accountability
X
X
X
X
X
X
X
X
X
Obinutuzumab 
Administration6
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening
24 Weeks
Week 
25 Day 
119
Week 
29 Day 
1
Every 
12 weeks 
starting 
Week 33 
until Week 
105
EOT17
Day 
-28
Week 
1
Day 1
Week 
2
Day 1
Week 
3 Day 
1
Week 
4 
Day 
116
Week 
5
Day 1
Week 
9
Day 1
Week 
13 Day 
1
Week 
17 Day 
1
Week 
21 Day 
1
Chemistry18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/INR, 
aPTT)
X
X
Peripheral Blood MRD7
X
X
X
X
X
Urinalysis and Urine 
Chemistry
X
Pregnancy Testing8
X
X
X
X
X
X
X
X
X
X
X
Viral Serologies9
X
PK sampling10
X
X
X
X
CLL phenotyping12
X
X
Radiographic Tumor 
evaluation13
X
X
Bone marrow 
evaluation14
X
X
Response Assessment15
X
X
X
X
X
X
X
X
X
1
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti-cancer therapies, and any 
concurrent medical illnesses. History of smoking in the past 30 days and CIRS score should be determined at screening.
2
Screening and End of Treatment will be complete physical examinations. Beginning at Week 1 Day 1, a modified physical examination will be a performed to monitor for any 
changes (eg, lymph nodes, size of the liver and spleen, lung, cardiac, abdomen, skin, neurologic, and any system clinically indicated). Weight should be measured at each PE. 
Height should be measured at screening only.
3
The G8 screening questionnaire will be used for assessment of subjects aged > 70 years at Week 1 Day 1 and every 6 months until EOT.
4
Subjects should be resting quietly in supine position for 5 minutes prior to ECG collection. The Investigator or qualified designee will review all ECGs.
5
Study drug is not dispensed at the Week 105 visit.
CCI


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6
Obinutuzumab: 100 mg will be administered intravenously on Day 1 and 900 mg on either Day 1 or 2 (Week 1); then 1000 mg on Day 8 (Week 2), Day 15 (Week 3), and on 
Weeks 5, 9, 13, 17 and 21 for a total of 8 doses of 1000 mg over 21 weeks. If the 100 mg infusion on Day 1 is well tolerated, the remaining 900 mg (scheduled for Day 2) 
may be given on Day 1.
7
Peripheral blood MRD will be assessed on Day 1 of Weeks 1, 13, 25, 33, 45, 105, and EOT. EOT collection is not needed for subjects who complete the Week 105 visit.
8
Serum pregnancy test will be performed at screening for all women of childbearing potential (defined in Appendix 4). Urine pregnancy tests will be conducted prior to 
Week 1 Day 1 and then every 4 weeks until the EOT visit. Pregnancy kits may be provided for home testing. The results must be confirmed as negative prior to continued 
administration of study drug.
9
Hepatitis serology includes HBsAg, HBcAb, HCV Ab; patients with positive HBcAb and negative HBsAg should have HBV DNA PCR performed prior to treatment start to 
rule out occult infection, then monthly through 6 months and then at subsequent clinic visits for at least 1 year following the EOT visit. HIV testing and CMV IgG and IgM 
testing should be performed at screening.
10
A PK sample will be collected approximately 2 hours (± 1 hour) post-dose on Week 1, Day 1. On Day 1 of Weeks 5, 13, and 21 a PK sample will be drawn at pre-dose 
(within 2 hours prior to AM dosing) and at 2 hours (± 1 hour) post-dose.
 
12
CLL immunophenotyping, karyotyping and FISH, TP53 and IgHV mutation status, CD38 and ZAP70 expression will be evaluated from peripheral blood at screening. In the 
event of disease progression, only FISH and TP53 will be evaluated.
13
Tumor evaluation by CT scan (preferred) or MRI of neck, chest abdomen and pelvis will be performed at screening (unless scan was already completed up to 42 days prior to 
first dose). At the Week 25 visit, the same type of evaluation should be performed on those body regions which showed involvement by CLL at screening. An additional CT 
may be obtained on protocol per investigator discretion following evidence of an improvement in clinical response if the response assessment at the Week 25 visit is less than 
a complete response or in the event of suspected disease progression.
14
A bone marrow evaluation is required in the screening window for subjects without radiographic evidence of disease. Bone marrow aspirate and biopsy should be performed 
at Week 25 for subjects fulfilling clinical response criteria for complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi) per the modified 
IWCLL 2008 criteria. MRD should be assessed from bone marrow aspirate at the reference laboratory in Kiel; 
 
 The analysis of the biopsy should be performed at the site´s local laboratory. An 
additional bone marrow biopsy may be obtained on protocol per investigator discretion following evidence of an improvement in clinical response if the response assessment 
at the Week 25 visit is less than a complete response.
15
Qualitative treatment response assessment based on physical exam, laboratory parameters and presence of B-symptoms should be performed every 4 weeks until Week 33 
Day 1 and then at all scheduled visits thereafter following the modified IWCLL 2008 criteria, with the exception of lymphadenopathy, hepatomegaly, splenomegaly, and bone 
marrow. Assessment of response per modified IWCLL 2008 criteria should also be recorded at the completion of 24 weeks on treatment and subsequent to any CT and/or 
bone marrow biopsy that is repeated while on study.
16
Following evaluation of the safety data for the first 6 subjects enrolled in each treatment arm, the Safety Review Team (SRT) will determine if weekly clinical evaluation 
should continue for the duration of the study.
17
The EOT visit should be scheduled for approximately 30 days following discontinuation of all study treatment. For subjects that permanently discontinue all treatment prior to
Week 25 Day 1, the Week 25 Day 1 visit should also be performed and may satisfy the requirement for the EOT visit if falling into the +30 days ± 7 day window from all 
study drug discontinuation.
18
Screening results should include creatinine clearance, and serum thymidine kinase, serum beta2-microglobulin and serum quantitative immunoglobulins.
19
The window for bone marrow assessments is -7 days or +14 days as calculated from Week 1 Day 1.
CCI
CCI


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Protocol GS-US-401-2076
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Amendment 4
CONFIDENTIAL
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Appendix 3.
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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Amendment 4
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Appendix 4.
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 to be 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
Tirabrutinib is contraindicated in pregnancy as the risks of treatment during pregnancy have not 
been evaluated. Entospletinib is contraindicated in pregnancy due to a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical studies in rats and rabbits 
that have demonstrated teratogenic effects.
Currently, insufficient data exists for any of the study investigational products to exclude the 
possibility of a clinically relevant interaction 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 in this study. There are no data with 
obinutuzumab use in pregnant women to inform a drug-associated risk. For further information 
on obinutuzumab, refer to the SmPC.
For additional information on any of these study investigational products, please refer to the 
latest version of the relevant IB or label in the applicable country.


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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. Also, subjects must 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 urine pregnancy test on the Week 1, Day 1 visit prior to dosing. 
Pregnancy tests will be performed at the timepoints specified in the Study Procedures Table 
(Appendix 2). Female subjects of childbearing potential must agree to one of the following from 
Screening until 30 days following the final dose of either tirabrutinib or entospletinib or 
18 months from the last dose of obinutuzumab (whichever is later).

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.
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
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 following the final dose of either tirabrutinib or entospletinib or 
18 months from the last dose of obinutuzumab (whichever is later).
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 
following the final dose of either tirabrutinib or entospletinib or 18 months from the last dose of 
obinutuzumab (whichever is later). 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 
following the final dose of either tirabrutinib or entospletinib or 18 months from the last dose of 
obinutuzumab (whichever is later).


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Amendment 4
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4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, 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
Female 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 the final dose of either tirabrutinib
or entospletinib or 18 months from the last dose of obinutuzumab (whichever is later). 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. Male subjects whose 
female 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 7.6.2.1.


Tirabrutinib & Entospletinib
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Gilead Sciences, Inc.
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Appendix 5.
Eastern Cooperative Oncology Group (ECOG) Performance 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 self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead


Tirabrutinib & Entospletinib
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Gilead Sciences, Inc.
Amendment 4
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Appendix 6.
Modified IWCLL 2008 Response Criteria
The determination of CLL response and progression will be based on standardized International 
Workshop on CLL (IWCLL) 2008 criteria {Hallek 2008}, as specifically modified for this study 
to reflect current recommendations which consider the mechanism of action of small molecule 
targeted therapy {Cheson 2012}.
Complete remission (CR):
All below listed criteria must be fulfilled and no disease related symptoms should be present.
Complete remission with incomplete recovery of the bone marrow (CRi):
All below listed criteria must be fulfilled, except for an incomplete recovery of the bone marrow 
with persisting anemia, thrombocytopenia and/or neutropenia (related to toxicity of treatment 
and not due to CLL) and no disease related symptoms should be present.
Partial response (PR):
Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled.
Partial response with lymphocytosis (PR-L):
Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled, 
however, a lymphocytosis related to treatment may be present.
Nodular partial response (nPR):
All criteria for a CR/CRi are fulfilled, but the bone marrow shows lymphoid nodules. As in a lot 
of cases these nodules are related to bone marrow proliferation during recovery, efforts should be 
made to prove that these lymphocytes are no CLL cells by 4-colour-flow cytometry to be able to 
define these patients as CR/CRi. If this cannot be proved by either FACS or MRD from the bone 
marrow patients will be considered PR and therefore this category will not appear on the eCRF.
Stable disease (SD):
Failure to achieve a PR and absence of PD.
Progressive disease (PD):
Presence of at least 1 of the below enlisted criteria or appearance of new lymph nodes > 1.5 cm,
hepato- or splenomegaly or organ infiltration by CLL.


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Response criteria
Parameter
CR
CRi
PR
PR-L
PD
Group A (indicating tumor load)
Lymphadenopathy1
none > 1.5 cm
decrease ≥50 %
increase by ≥50 %
or new lymph nodes
≥1.5 cm
Hepatomegaly
none
decrease ≥50 %
Increase by ≥50 %
Splenomegaly
none
decrease ≥50 %
Increase by ≥50 %
Blood lymphocytes
< 4000/µL
decrease of
≥50 % from
baseline
increase
Increase by ≥50% 
over baseline2 to 
≥5000/µL
Bone marrow
Normocellular
hypocellular
50% reduction in BM 
infiltrates3
irrelevant
30 % lymphocytes, no 
B-lymphoid nodules
Group B (indicating function of the hematopoietic system)
Platelet count
≥100000/µL
Irrelevant
≥100000/µL or increase by
≥50 % from baseline
Decrease by ≥50 %
due to CLL
Hemoglobin
> 11 g/dL
irrelevant
> 11 g/dL or increase by
≥50 % from baseline
Decrease by 
> 2 g/dL
Neutrophil count
> 1500/µL
Irrelevant
> 1500/µL or increase by
≥50% from baseline
irrelevant
1
Assessed as sum of the products of multiple lymph nodes, if available an indicator lymph node (the largest palpable) from
every region should be compared in every staging.
2
Patients with treatment-related lymphocytosis should not be rated PD and remain on study treatment if other criteria for
progressive disease are absent.
3
In case of B-lymphoid nodules a 4-colour-flow cytometry is recommended to clarify if this is related to CLL, if FACS is 
negative these patients can be rated as CR/CRi, if all other criteria are fulfilled.
MRD response rate
The MRD response is assessed with four-color-flow cytometry (FACS) and MRD negativity is
defined as one CLL cell per 10,000 leukocytes [0.01 %], ie, <10-4 and patients are defined as 
MRD negative if their disease burden is below this threshold MRD in the bone marrow will be 
assessed after the completion of 24 weeks of treatment and MRD in the peripheral blood will be 
assessed in the schedule outlined in Appendix 2 in the event that peripheral blood ALC<4K/µL.
I 


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Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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Appendix 7.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions. For each condition selected from the CIRS List of Comorbid 
Conditions, please rate the severity of that condition. For the severity rating, please use the 
scoring guidelines shown in the table below, considering the magnitude of symptoms, how 
manageable the condition is, and the extent of intervention required.
Please take into account that CLL induced illness or organ damage are not included in this rating 
scale. The goal of this rating scale is to assess comorbidity other than CLL in the patient. If there 
are two or more illnesses/impairments of one organ system, the illness/impairment with the 
highest severity should be evaluated.
CIRS Rating Strategy of Comorbidity
Score
Severity
Findings
0
No problem
Organ system not compromised
1
Mild
Illness/impairment with/without requirement of therapy, excellent prognosis, 
patient with normal activity
2
Moderate
Illness/impairment requiring therapy, good prognosis, compromised activity of 
patient
3
Severe
Illness/impairment with urgent requirement of therapy, prognosis unclear, marked 
restriction in activity
4
Extremely severe
Life threatening illness/impairment, emergency case of therapy, adverse prognosis
CIRS List of Comorbid Conditions
Organ System
If illness/impairment present, please specify
Score
Heart
Blood Pressure
Vascular
Respiratory
Eye/ear/nose/throat/larynx
Upper gastrointestinal
Lower gastrointestinal
Liver
Renal
Genitourinary
Musculoskeletal
Endocrine/metabolic
Neurological
Psychiatric
Total Score


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Appendix 8.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dL]
Females eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dL]
mol/L
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mol /L]
Females eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mol /L]
Abbreviation: eCcr=estimated creatinine clearance


Tirabrutinib & Entospletinib
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Appendix 9.
Binet and Rai Staging Systems for the Classification of CLL
Binet
Stage
Lymph Node Areas
Hemoglobin
< 10 g/dL
Platelet
< 100 x 109/L
A
< 3
No
No
B
≥3
No
No
C

Either present
Rai
Stage
Lymphocytosis
Lymph Node 
Enlargement
Spleen/Liver 
Enlargement
Hemoglobin 
< 11 g/dL
Platelet
< 100 x 109/L
0
Yes
No
No
No
No
I
Yes
Yes
No
No
No
II
Yes

Yes
No
No
III
Yes


Yes
No
IV
Yes



Yes


Tirabrutinib & Entospletinib 
Protocol GS-US-401-2076 
Gilead Sciences, Inc. 
Appendix 10. 
The GS Screening Questionnaire 
• 8 questions 
• Nurse administered 
• Takes 5-10 minutes to 
perform 
-
Appetite, weight loss, 
BMI 
-
Mobility 
-Mood and cognition 
-
Nwnberof 
medications 
-
Patient-related health 
-
Age categories 
• Abnormal if score:::; 14 
-
Preliminary analysis 
-
Sensitivity: 89.6% 
-
Specificity: 60.4% 
CONFIDENTIAL 
A 
B 
C 
E 
F 
-
H 
p 
,-
II 
Items 
II 
Has food intake declined over the 
past 3 months due to loss of 
appetite, digestive problems, or 
chewing 01· swallowing difficulties? 
Weight loss during the last 
3 months 
II 
Mobility 
II 
Neuropsychological problems 
II 
Body mass index 
(BMI weight in kg) / (height in m)2 
Takes more than 3 prescription 
dmgs per day 
In comparison with other people 
of the same age how do they 
consider their health status? 
Age 
Total Score 
Page 106 
Final 
Amendment4 
Possible answers (score) 
O: severe decrease in food intake 
1: moderate decrease in food intake 
2: no decrease in food intake 
0: weight loss > 3 kg 
1: does not know 
2: weight loss between 1 and 3 kg 
3: no weight loss 
0: bed or chair bound 
1: able to get out of bed/chair but does not go out 
2: goes out 
O: severe dementia or depression 
1: mild dementia or depression 
2: no psychological problems 
0: BMI < 18.5 
1: BMl = 18.5 to BMI < 21 
2: BMI= 21 toBM1 < 23 
3: BMI = 23 and > 23 
0: yes 
1: no 
0: not as good 
0.5: does not know 
1: as good 
2: better 
0: > 85 yr 
1: 80-85 yr 
2: <80yr 
0-17 
15 Januruy 2019