Clinical trial NCT01972529
Conditions: Thrombocytopenia Associated With Liver Disease
Keywords: Thrombocytopenia Chronic Liver Disease
Sponsor: Eisai Inc.
Start date: 2014-02-01; Completion date: 2017-02-27
Enrollment: 231 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study using avatrombopag to treat adults with thrombocytopenia associated with liver disease. The study will evaluate avatrombopag in the treatment of thrombocytopenia associated with liver disease prior to an elective procedure to reduce the need for platelet transfusions or any rescue procedure for bleeding due to procedural and post-procedural bleeding complications. Participants will be enrolled into 2 cohorts according to mean baseline platelet count and, within each baseline platelet count cohort will be further stratified by risk of bleeding associated with the elective procedure (low, moderate, or high) and hepatocellular carcinoma (HCC) status (Yes or No).

Detailed description:
This study will consist of 3 phases: Prerandomization, Randomization, and a Follow-up Phase. The Prerandomization Phase includes one Screening Visit that will take place from Day -14 through Day -1; the Randomization Phase includes the Baseline Period, Treatment Period, and Procedure Day Period (5 to 8 days after last dose of study drug \[Study Day 10 to 13\]). The Follow-up Phase comprises 2 visits: 7 days post Procedure Day and 30 days after receiving the last dose of study drug. Permitted procedures include: Paracentesis; Thoracentesis; Gastrointestinal endoscopy with or without plans for biopsy, colonoscopy, polypectomy, or variceal banding; Liver biopsy; Bronchoscopy with or without plans for biopsy; Ethanol ablation therapy or chemoembolization for HCC; Vascular catheterization (including right side procedures in participants with pulmonary hypertension); Transjugular intrahepatic portosystemic shunt; Dental procedures; Renal biopsy; Biliary interventions; Nephrostomy tube placement; Radiofrequency ablation; and Laparoscopic interventions.

Arms: arm 1: 60 mg avatrombopag (3 x 20 mg tablets) once daily on Days 1 through 5 arm 2: placebo (3 x 20 mg matching placebo tablets) once daily on Days 1 through 5 arm 3: 40 mg avatrombopag (2 x 20 mg tablets) once daily on Days 1 through 5 arm 4: placebo (2 x 20 mg matching placebo tablets) once daily on Days 1 through 5
Interventions: intervention 1: avatrombopag (lower baseline platelet count) intervention 2: placebo (lower baseline platelet count) intervention 3: avatrombopag (higher baseline platelet count) intervention 4: placebo (higher baseline platelet count)
Intervention descriptions: intervention 1: 60 mg avatrombopag (3 x 20 mg tablets) intervention 2: 60 mg placebo (3 x 20 mg matching placebo tablets) intervention 3: 40 mg avatrombopag (2 x 20 mg tablets) intervention 4: 40 mg placebo (2 x 20 mg matching placebo tablets)

Protocol documents:
Prot_000.pdf: 
Clinical Study Report 
E5501-G000-310 
 
16.1.1 
Protocol and Protocol Amendments 
The final study protocol is provided on the following pages. 
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Revisions to V6.0: 31 May 2016 (Amendment 03)
Date:  V7.0:  02 Dec 2016 (Amendment 04)
Change
Rationale
Affected Protocol Sections
Sample size reduced from 
approximately 300 subjects to 
approximately 200 subjects
After consultation with the FDA, it 
was decided that the current study 
has reached adequate enrollment 
to demonstrate the safety and 
benefit of avatrombopag in 
reducing the need for platelet 
transfusion in subjects with 
thrombocytopenia and liver 
disease undergoing an elective 
procedure.
Synopsis –

Number of Subjects

Sample Size 
Rationale
Section 9.3
Section 9.4.3
Section 9.7.2
The secondary endpoint, 
proportion of subjects with a 
World Health Organization
(WHO) bleeding score ≥2 
after randomization and up to 
7 days following an elective 
procedure, will be an 
exploratory endpoint
Given the rare occurrence of 
bleeding events (less than 
expected), this endpoint is better 
suited as an exploratory endpoint.
Synopsis –

Secondary 
Objectives

Exploratory 
Objectives

Secondary Endpoints

Exploratory 
Endpoints

Secondary Efficacy 
Variable Analyses

Exploratory Efficacy 
Variables
Section 8.2
Section 8.3
Section 9.7.1.1
Section 9.7.1.6
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Revisions to V5.0: 22 June 2015 (Amendment 02)
Date:  V6.0:  31 May 2016 (Amendment 03)
Change
Rationale
Affected Protocol Sections
Clarification to Inclusion 
Criteria #3:  replace the word 
"change" with the word 
"increase
Per FDA request
Synopsis –

Inclusion Criteria
Section 9.3.1
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REVISION HISTORY
Revisions to V4.0: 12 Nov 2013 (Amendment 01)
Date:  V5.0:  22 June 2015 (Amendment 02)
Change
Rationale
Affected Protocol Sections
Revised the risk of bleeding 
associated with procedures 
Additional procedures included in 
the source article (Malloy et al., 
2009) that originated the initial 
classification were added. 
Ongoing study observations, 
supported by key opinion leader 
(KOL) review and current 
literature review resulted in 
additional updates in the bleeding 
risk categories classification
Synopsis –
Study Design
Statistical Methods
Efficacy Analyses
Section 9.1.2.3
Table 1
Section 9.7.1.6
Clarification of Inclusion #3 
that subjects scheduled to 
undergo a permitted elective 
procedure who will require a 
platelet transfusion unless 
there is a clinically 
significant change to platelet 
count from baseline
Clarification 
Synopsis –

Inclusion Criteria
Section 9.3.1
Revised the exclusion around 
hemoglobin changing the 
upper limit from 16 to 17 g/dL 
and removed the white blood 
cell count and serum sodium 
levels exclusion criteria.  
Subjects who screen failed 
previously will be permitted 
to rescreen due to removal of 
this criteria.
Based upon feedback received 
from the KOL that these criteria 
are in contradiction with the 
requirement for platelet count 
<50 x 109/L (ie, subjects meeting 
such lab criteria would be 
relatively too healthy to present 
with such a low platelet count). 
Other existing criteria (eg, MELD 
score and BCLC) will ensure 
subjects are not too compromised.  
This also provides for a more 
diverse population by dropping 
these restrictions.
Synopsis –

Exclusion Criteria
Section 9.1.1.1
Section 9.3.2
Addition of eltrombopag and 
romiplostim as prohibited 
As eltrombopag and romiplostim
are used off-label for this 
indication, both approved 
Synopsis –
Prohibited Concomitant 
Therapy
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Revisions to V4.0: 12 Nov 2013 (Amendment 01)
Date:  V5.0:  22 June 2015 (Amendment 02)
Change
Rationale
Affected Protocol Sections
medication
thrombopoietin receptor agonists 
were added
Section 9.4.7.3
Added an evaluation for 
platelet aggregation to be 
measured at selected sites
Japan’s Pharmaceuticals and 
Medical Devices Agency (PMDA) 
requires exploratory assessment of 
platelet aggregation as part of the 
platelet function study.
Synopsis –
Safety Assessments
Section 9.5.1.5, 

Table 4, Table 5
Section 11.3
Updated study director and 
medical monitor information
Change in Eisai staffing
Protocol Signature Page
Clarified in the appendix the 
fasting glucose laboratory 
result should only be 
considered a 
treatment-emergent significant 
abnormality if the result is
within normal limits at baseline 
and has increased in severity to 
meet the sponsor’s grading 
criteria for laboratory values of 
Grade 3 or above when fasting.
Clarification
Appendix 2
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Revisions to previous V3.0, 29 Sep 2013
Date:  V4.0 (Amendment 01):  12 Nov 2013
Change
Rationale
Affected Protocol Sections
Addition of tranexanic acid as a 
rescue procedure when used 
specifically for bleeding
Changes were made upon 
regulatory agency request 
during a Voluntary 
Harmonisation Procedure 
submitted to the following 
EU Member States:  
Austria, Belgium, France, 
Germany, Hungary, Italy, 
Spain, and United 
Kingdom.
●Synopsis, Study Design
●Section 9.1.2.3
●Section 9.5.1.3

Inclusion of specific 
examples of genetic 
prothrombotic syndromes
(eg, Factor V Leiden; 
prothrombin G20210A; 
ATIII deficiency etc.)
For clarity
●Synopsis, Exclusion 
Criteria
●Section 9.3.2
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Revisions to previous Version 2.0,  24 Jul 2013
Date:  V3.0, 29 Sep 2013
Change
Rationale
Affected Protocol Sections
Removal of language indicating 
a training program will be 
implemented for the sonography 
operator
Administrative change –
incorrect language used to 
describe sonography 
operation
●Appendix 3
Medical monitor updated
Change in Eisai staffing
●Protocol Signature Page
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Revisions to previous Version 1.0, 21 Mar 2013
Date:  V2.0, 24 Jul 2013
Change
Rationale
Affected Protocol Sections
Sponsor information updated to 
title page
Japanese address required 
as 310 & 311 are global 
studies
●Title page
The higher baseline platelet 
count cohort was changed from 
40 to ≤50 × 109/L to 40 to 
<50 × 109/L which resulted in 
endpoints changing accordingly.
Required due to the 
inclusion criterion and 
baseline platelet count 
cohort change from 
≤50 × 109/L to <50
× 109/L.
●Synopsis – Objectives
●Synopsis – Study Design
●Synopsis – Exploratory 
Endpoints
●Section 7
●Section 8
●Section 9
Added exploratory objective
and endpoint to characterize 
platelet count changes from 
baseline, the extent of platelet 
transfusion use, and assess the 
severity of any bleeding events
Eisai agrees with CHMP 
that the BARC bleeding 
scale could be used in 
addition to the WHO 
bleeding score and 
therefore proposes it be 
included as an exploratory 
endpoint.
●Synopsis – Exploratory 
Objectives
●Synopsis – Exploratory 
Endpoints
●Section 8.3
Inclusion criteria age changed to 
include those subjects ≥18 years 
of age for both US and rest of 
world
Brings protocol into line 
with current pediatric
strategy
●Synopsis – Inclusion 
Criteria
●Section 9.3.1
Occurrence of bleeding as 
measured by World Health 
Organization (WHO) bleeding 
score and Bleeding Academic 
Research Consortium (BARC) 
bleeding scale
EMA requested that the 
BARC bleeding scale be 
used in addition to the
WHO bleeding score. 
EMA agreed to Eisai 
proposal for BARC scale
to be included as an 
exploratory endpoint.
●Synopsis – Efficacy 
Assessments
●Section 9.2
●Section 9.5
●Section 9.7.1
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Revisions to previous Version 1.0, 21 Mar 2013
Date:  V2.0, 24 Jul 2013
Change
Rationale
Affected Protocol Sections
The hypothesis testing for the 
combined group (regardless of 
baseline platelet count cohort) 
was removed from the primary 
efficacy analysis and the first 
2 secondary efficacy variable 
analyses. The primary efficacy 
variable analysis to clarify the 
null hypothesis will be tested 
separately within each baseline 
cohort. 
Agreed with both FDA 
and EMA
●Synopsis – Primary 
Efficacy Variable 
Analysis
●Section 9.7.1.6
This study will be considered as 
positive if statistical 
significance is achieved for the 
primary efficacy endpoint for 
both baseline platelet count 
cohorts.
Statistical analysis 
changes requested by the 
FDA 
●Synopsis – Primary 
Efficacy Variable 
Analysis
●Section 9.7.1.6
Clarification that the safety 
parameters the DSMB will 
review will include variables 
that are also being assessed in 
this study for efficacy 
Requested as clarification 
during PRC review 
●Synopsis, Interim 
Analysis
●Section 9.7.3
Sample size /power calculation 
was removed for the test on the  
combined group
Requested as clarification
by the FDA
●Synopsis, Sample Size 
Rationale
●Section 9.7.2
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E5501-G000-310
Study Protocol 
Title:
A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group 
Study to Evaluate the Efficacy and Safety of Once-daily Oral 
Avatrombopag for the Treatment of Adults with Thrombocytopenia 
Associated with Liver Disease Prior to an Elective Procedure
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake 
New Jersey 07677
US
Eisai Ltd.
European Knowledge 
Centre
Mosquito Way 
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd.
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E5501/avatrombopag maleate
Indication:
Treatment of Thrombocytopenia in Patients with Chronic Liver Disease 
Undergoing an Elective Procedure
Phase:
3
Approval Date:
V3.0
29 Sep 2013 (original protocol)
V4.0
12 Nov 2013 (Amendment 01)
V5.0
22 Jun 2015 (Amendment 02)
V6.0
31 May 2016 (Amendment 03)
V7.0
02 Dec 2016 (Amendment 04)
IND Number:
76,680
EudraCT Number:
2013-000965-34   
GCP Statement:
This study is to be performed in full compliance with International 
Conference 
on 
Harmonisation 
of 
Technical 
Requirements 
for 
Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
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Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.
E5501
Name of Active Ingredient
Avatrombopag maleate
Study Protocol Title
A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the 
Efficacy and Safety of Once-daily Oral Avatrombopag for the Treatment of Adults with 
Thrombocytopenia Associated with Liver Disease Prior to an Elective Procedure
Investigators
To be determined
Sites
Approximately 80 to 100 sites worldwide
Study Period and Phase of Development
Approximately 20 months
Phase 3
Objectives
Primary Objective
To confirm that avatrombopag (60 mg avatrombopag for subjects with platelet count 
<40 × 109/L and 40 mg avatrombopag for subjects with platelet count from 40 to <50 × 109/L) is 
superior to placebo in removing the need for platelet transfusions or any rescue procedure for 
bleeding after randomization and up to 7 days following an elective procedure in subjects with
chronic liver disease who have thrombocytopenia.
Secondary Objectives (revised per Amendment 04)

To confirm that avatrombopag is superior to placebo in achieving a platelet count of 
≥50 x 109/L on Procedure Day in the proposed target population

To confirm that avatrombopag is superior to placebo in elevating platelet counts from 
baseline on Procedure Day in the proposed target population

To evaluate the safety of avatrombopag in the proposed target population
Exploratory Objectives

To characterize the pharmacokinetics and the relationship between avatrombopag plasma 
concentrations and platelet count using the population approach

To characterize platelet count changes from baseline, the extent of platelet transfusion 
use, evaluate the incidence of bleeding events, and assess the severity of any bleeding 
events (revised per Amendment 04)
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
To assess the health economic impact associated with minimizing the need for platelet 
transfusions and any rescue procedure for bleeding associated with an elective procedure
Study Design
This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study 
using avatrombopag to treat adults with thrombocytopenia associated with liver disease.  
Subjects will be enrolled into 2 cohorts according to mean baseline platelet count and, within 
each baseline platelet count cohort will be further stratified by risk of bleeding associated with 
the elective procedure (low, moderate, or high) and hepatocellular carcinoma (HCC) status (Yes 
or No). Neither baseline platelet count cohort will comprise greater than 55% of the total 
number of subjects enrolled into the study.
Within the lower baseline platelet count cohort (<40 × 109/L) and each stratum, subjects will be 
randomized in a 2:1 ratio to receive avatrombopag or placebo as follows: 

60 mg avatrombopag on Days 1 to 5 (Group A: avatrombopag, lower baseline platelet 
count)

Matching placebo on Days 1 to 5 (Group B: placebo, lower baseline platelet count)
Within the higher baseline platelet count cohort (from 40 to <50 × 109/L) and each stratum, 
subjects will be randomized in a 2:1 ratio to receive avatrombopag or placebo as follows: 

40 mg avatrombopag on Days 1 to 5 (Group C: avatrombopag, higher baseline platelet 
count)

Matching placebo on Days 1 to 5 (Group D: placebo, higher baseline platelet count)
Platelet counts must be measured on 2 separate occasions, during the Screening Period and at 
Baseline, and must be performed at least 1 day apart with neither platelet count >60 × 109/L.  
The mean of these 2 platelet counts (mean baseline platelet count <50 × 109/L) will be used for 
entry criteria.  
This study will consist of 3 phases: Prerandomization, Randomization, and a Follow-up Phase.  
The Prerandomization Phase includes 1 Screening Visit that will take place from Day -14 
through Day -1; the Randomization Phase includes the Baseline Period, Treatment Period, and 
Procedure Day Period (5 to 8 days after last dose of study drug [Study Day 10 to 13]).  The 
Follow-up Phase comprises 2 visits: 7 days post Procedure Day and 30 days after receiving the 
last dose of study drug.
The elective procedure for those subjects whose preprocedural platelet count is >200 × 109/L on 
Visit 4 (Procedure Day) may be delayed at the discretion of the investigator until platelet counts 
are below 200 × 109/L.  All subjects whose platelet count exceeds 200 × 109/L will be required to 
have a Doppler assessment at Visit 5.  For any subjects where the presence of a portal vein 
thrombosis (PVT) is suspected, confirmation of diagnosis via computerized tomography (CT) 
scan or magnetic resonance imaging (MRI) should be performed and treatment for PVT initiated 
per local guidelines.
Permitted procedures and the risk of bleeding associated with each procedure are listed in the 
following table. It is planned that no fewer than 10% of subjects will be enrolled into the high 
risk group and no more than 60% of subjects in the low risk group.  
(table revised per Amendment 02)
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Risk of Bleeding 
Associated 
with 
Procedure
Procedure
Low risk 
Paracentesis
Thoracentesis
Gastrointestinal endoscopy with or without plans for biopsy, 
colonoscopy, polypectomy, or variceal banding 
Moderate risk 
Liver biopsy
Bronchoscopy with or without plans for biopsy
Ethanol ablation therapy or chemoembolization for HCC
High risk 
Vascular catheterization (including right side procedures in subjects 
with pulmonary hypertension)
Transjugular intrahepatic portosystemic shunt
Dental procedures
Renal biopsy
Biliary interventions
Nephrostomy tube placement
Radiofrequency ablation
Laparoscopic interventions
Level of risk based on key opinion leader (KOL) input and Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis 
RB, et al. for the Standards of Practice Committee with Cardiovascular and Interventional Radiological Society of Europe 
(CIRSE) Endorsement. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in 
percutaneous image-guided interventions. J Vasc Interv Radiol 2009; 20:S240–9.
Subjects who have an International Normalization Ratio (INR) >1.6 should be treated with fresh 
frozen plasma (FFP) or other appropriate therapies, where indicated, as per local guidelines and 
practices. 
The following are considered as rescue procedures when used specifically for bleeding:

Platelet transfusion

FFP

Cryoprecipitate

Vitamin K (phytonadione)

Desmopressin

Recombinant activated factor VII

Aminocaproic acid

Tranexanic acid (added per Amendment 01)

Whole blood transfusion

Packed red cell transfusion

Surgical intervention or interventional radiology 
The end of the study will be the date of the clinical database lock (ie, when all study data are 
collected and data validation is complete).
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Number of Subjects
Approximately 200 subjects (revised per Amendment 04)
Inclusion Criteria
1. Subjects ≥18 years of age at Screening with chronic liver disease
2. Subjects who have a mean baseline platelet count of <50 × 109/L. Platelet counts must be 
measured on 2 separate occasions, during the Screening Period and at Baseline, and must 
be performed at least 1 day apart with neither platelet count >60 × 109/L.  The mean of 
these 2 platelet counts (mean baseline platelet count) will be used for entry criteria and 
for assignment to the low or high baseline platelet count cohort.
3. Subjects scheduled to undergo a permitted elective procedure who, in the opinion of the 
investigator, will require a platelet transfusion to address a risk of bleeding associated 
with the procedure unless there is a clinically significant increase in platelet count from 
baseline (revised per Amendments 02 and 03)
4. Model For End-stage Liver Disease (MELD) score ≤24 at Screening
5. If taking inhibitors of P glycoprotein (P-gp), except for verapamil, dose must be stable for 
7 days prior to Screening  
6. Provide written informed consent
7. Willing and able to comply with all aspects of the protocol
Exclusion Criteria (revised per Amendment 02)
1. Any history of arterial or venous thrombosis, including partial or complete thrombosis
2. Evidence of thrombosis (partial or complete) in the main portal vein, portal vein 
branches, or any part of the splenic mesenteric system at Screening
3. Portal vein blood flow velocity rate <10 cm/second at Screening
4. Hepatic encephalopathy that cannot be effectively treated
5. Subjects with HCC with Barcelona Clinic Liver Cancer (BCLC) staging classification C 
or D
6. Platelet transfusion or receipt of blood products containing platelets within 7 days of 
Screening. However packed red blood cells are permitted.
7. Heparin, warfarin, nonsteroidal anti-inflammatory drugs (NSAID), aspirin, verapamil, 
and antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists 
(eg, tirofiban) within 7 days of Screening
8. Use of erythropoietin stimulating agents within 7 days of Screening
9. Interferon (IFN) use within 14 days of Screening
10. Estrogen-containing hormonal contraceptive or hormone replacement therapy use within 
30 days of Screening 
11. Active infection requiring systemic antibiotic therapy within 7 days of Screening.  
However, prophylactic use of antibiotics is permitted.
12. Alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence within 
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6 months of the study start (unless participating in a controlled rehabilitation program) or 
acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the 
study start
13. Elective procedure performed prior to Visit 4 (Procedure Day)
14. Known to be human immunodeficiency virus positive
15. Any clinically significant acute or active bleeding (eg, gastrointestinal, central nervous 
system)
16. Known history of any primary hematologic disorder (eg, immune thrombocytopenic 
purpura, myelodysplastic syndrome)
17. Known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden; 
prothrombin  G20210A; ATIII deficiency etc.) (revised per Amendment 01)
18. Subjects with a history of significant cardiovascular disease (eg, congestive heart failure 
New York Heart Association Grade III/IV, arrhythmia known to increase the risk of 
thromboembolic events [eg, atrial fibrillation], coronary artery stent placement, 
angioplasty, and coronary artery bypass grafting)
19. Females of childbearing potential who have had unprotected sexual intercourse within 
30 days before study entry and who do not agree to use a highly effective method of 
contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such 
as condom plus diaphragm with spermicide], a progesterone-only contraceptive 
implant/injection, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study period and for 30 days after study drug discontinuation.  If 
currently abstinent, the subject must agree to use a double-barrier method as described 
above if she becomes sexually active during the study period or for 30 days after study 
drug discontinuation. All females will be considered to be of childbearing potential 
unless they are postmenopausal (at least 12 months consecutive amenorrhea in the 
appropriate age group and without other known or suspected cause) or have been 
sterilized surgically (ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) 
at least 1 month before dosing. 
20. Females who are lactating or pregnant at Screening or Baseline (as documented by a 
positive serum beta-human chorionic gonadotropin [β-hCG] test with a minimum 
sensitivity 25 IU/L or equivalent units of β-hCG).  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before 
the first dose of study drug.
21. Post liver transplant subjects
22. Any subject who has previously received avatrombopag
23. Hypersensitivity to avatrombopag maleate or any of its excipients
24. Hemoglobin levels ≤8.0 or ≥18.0 g/dL for men and >15 for women at Screening, with 
hematocrit  ≥54% for men and ≥45% for women
25. Current malignancy including solid tumors and hematologic malignancies (except HCC)
26. Any history of concomitant medical condition that, in the opinion of the investigator(s), 
would compromise the subject’s ability to safely complete the study
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27. Currently enrolled in another clinical trial with any investigational drug or device within 
30 days of Screening
Study Treatments
Test drug 
Subjects will be instructed to take avatrombopag 20-mg tablets or matching placebo orally, once 
daily, with a meal, as follows:

Group A (avatrombopag, lower baseline platelet count):  60 mg avatrombopag
(3 × 20-mg tablets) once daily on Days 1 through 5 

Group B (placebo, lower baseline platelet count):  placebo (3 × 20-mg matching placebo 
tablets) once daily on Days 1 through 5

Group C (avatrombopag, higher baseline platelet count):  40 mg avatrombopag 
(2 × 20-mg tablets) once daily on Days 1 through 5 

Group D (placebo, higher baseline platelet count):  placebo (2 × 20-mg matching placebo 
tablets) once daily on Days 1 through 5
Duration of Treatment
Each subject will receive study drug for 5 days
Concomitant Drugs/Therapy
Permitted Concomitant Therapy
Subjects should be instructed to contact site personnel before starting any new medications or 
treatments.  Medications or treatments not specified as prohibited (see below) are permitted 
during the study.  Medications used by the subject during the month before Visit 1 (Screening) 
will be recorded in the subject’s case report form.  
All prescription drugs, herbal products, nutritional supplements (including vitamins), and 
over-the-counter medications are to be recorded, as well as any changes in concomitant 
medications, including dose, after Visit 1 and while the subject is in the study. Stable doses of 
inhibitors of P-gp (excluding verapamil) are permitted during the study.
The dose of these 
medications should remain unchanged until the first postprocedure visit (Visit 5). 
Subjects may receive therapy if clinically indicated as rescue therapy for bleeding.  
Prohibited Concomitant Therapy
Erythropoietin stimulating agents are prohibited throughout the study. 
Interferon use is 
prohibited during the study; however, at the investigator’s discretion, subjects may restart IFN 
therapy if clinically indicated during the Follow-up Phase.
Eltrombopag, romiplostim, heparin, warfarin, NSAIDs, aspirin, verapamil, estrogen, and 
antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) are 
prohibited. (revised per Amendment 02) Aspirin, for antiplatelet therapy, can be prescribed at 
the discretion of the investigator in subjects in which the platelet count rises and who are 
believed to have an increased risk of thrombosis.  In subjects where use of aspirin is 
contraindicated, an alternate antiplatelet therapy such as a platelet adenosine diphosphate 
receptor inhibitor (eg, clopidogrel) can be prescribed.  It should be noted that clopidogrel should 
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be used with due consideration in subjects with liver disease.  Lack of activation due to liver 
disease could lead to a reduction in activation of the prodrug.  In addition, as clopidogrel is 
activated by the cytochrome P450 (CYP) system, care is required when administering 
clopidogrel to liver patients and co-administering clopidogrel with agents that are substrates or 
inhibitors of CYP.
Assessments
Efficacy Assessments

The number of transfusions administered and units given per transfusion 

Any rescue procedure for bleeding

Platelet counts as measured by local laboratory will be measured at Screening (Days -14 
to -1) and at Baseline (Day 1), then on the Procedure Day (Day 10), 7 days postprocedure 
and Day 35

Occurrence of bleeding as measured by World Health Organization (WHO) bleeding 
score and Bleeding Academic Research Consortium (BARC) bleeding scale
Pharmacokinetic Assessments
The pharmacokinetics of avatrombopag and effects of covariates will be assessed using 
population modeling.  A total of 3 blood samples for pharmacokinetic (PK) analysis will be 
collected. One sample will be collected on Day 1 between 2 to 6 hours postdose. Two samples 
will be collected on Day 4 (±1 day):  a predose sample within 2 hours prior to dosing and a 
second sample between 2 to 6 hours postdose.
Pharmacodynamic Assessments  
Platelet count will be measured by local laboratory in all subjects at least 1 day apart at 
Screening (Days -14 to -1) and Baseline (Day 1), then on the Procedure Day (Day 10), 7 days 
postprocedure, and Day 35.
Pharmacokinetic/Pharmacodynamic Assessments  
The relationship between avatrombopag plasma concentrations and platelet count will be 
evaluated using population PK/pharmacodynamic (PD) modeling. Effects of covariates on the
PD parameters will be evaluated.
Pharmacogenomic/Pharmacogenetic Assessments  
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording of all adverse events (AEs) and 
serious adverse events (SAEs), including platelet transfusion-related complications; routine 
laboratory evaluation for hematology, serum chemistry, and urine values; periodic measurement 
of vital signs and electrocardiograms (ECGs); the performance of physical examinations; and 
Doppler sonography.  An independent Data Safety Monitoring Board (DSMB) will be 
established in order to ensure the safety of the subjects.
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At selected sites, platelet function will also be measured using specified flow cytometric markers
or platelet aggregometry.  (revised per Amendment 02)
Health Economic Assessments
The health economic assessment consists of translating the primary efficacy variable, reduced 
need or reduction in the proportion of platelet transfusions in the avatrombopag study arm 
compared to the placebo arm. Specifically, the following health care resource utilization is 
assessed: (including any rescue treatment, procedure, and laboratory test for bleeding including 
the number of transfused platelet units, the supply from which the transfused platelet units were 
procured including whole blood platelets from a random donor pool (if known) with or without 
leukocyte depletion, as an apheresis product (as platelets alone) from a single donor and/or 
autologous blood donation, number of hospital days, number of intensive care bed-days, number 
of outpatient visits to the hospital’s outpatient department, the clinic, the physician’s office, 
home health care or other place of service, and health care resource utilization related to other 
transfusion-related complications during all scheduled and unscheduled visits will be collected
during all scheduled and unscheduled visits.
Bioanalytical Methods
Plasma samples will be assayed for avatrombopag concentrations using a validated liquid 
chromatography-tandem mass spectrometry method.  Lower limit of quantification is 
1.00 ng/mL.
Statistical Methods
Study Endpoints
Primary Endpoint
Proportion of subjects who do not require a platelet transfusion or any rescue procedure for 
bleeding after randomization and up to 7 days following an elective procedure
Secondary Endpoints

Proportion of subjects who achieve platelet counts of ≥50 × 109/L on Procedure Day 
(ie, prior to receiving a platelet transfusion or undergoing the elective procedure)

Change from baseline in platelet count on Procedure Day (ie, prior to receiving a platelet 
transfusion or undergoing the elective procedure)
(revised per Amendment 04)
Exploratory Endpoints

Platelet count and change from baseline in platelet count at each visit 

Proportion of subjects who achieve platelet count of ≥50 × 109/L, ≥75 × 109/L, or 
≥200 × 109/L at each visit

Number of platelet units used per platelet transfusion episode

Severity of bleeding events assessed by WHO bleeding score and BARC bleeding scale

Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 
7 days following an elective procedure (revised per Amendment 04)
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
Health economics assessed by resource use
Analysis Sets
Full Analysis Set (FAS):  The FAS is the group of randomized subjects. The FAS will be 
analyzed “as randomized”. 
Per Protocol Set (PP):  The PP Set is the group of all randomized subjects who receive 
protocol-assigned study drug and do not meet any of the following criteria:

Subjects who have any major protocol violations (major inclusion/exclusion violations or 
other major protocol violations that impact the evaluation of efficacy)

Subjects who use a prohibited concomitant medication that affects the assessment of 
study endpoints

Subjects who are noncompliant in terms of study medication
A comprehensive list of subjects to be excluded from the PP will be agreed upon by the study 
team prior to database lock.
Safety Analysis Set:  The Safety Analysis Set is the group of subjects who receive at least 1 dose 
of study drug and have at least 1 postdose safety assessment.  This set will be analyzed “as 
treated.”
PK Analysis Set:  The PK Analysis Set is the group of randomized subjects who receive at least 
1 dose of avatrombopag and have at least 1 quantifiable avatrombopag concentration with a 
documented dosing history.
PK/PD Analysis Set:  The PK/PD Analysis Set is the group of randomized subjects who receive 
at least 1 dose of avatrombopag, have at least 1 quantifiable avatrombopag concentration, and at 
least 1 platelet count, with a documented dosing history.
Efficacy Analyses
The FAS will be used as the primary population for all efficacy analyses, while the PP will be 
used as the supportive population.  All analyses of platelet counts will be based on local 
laboratory results.
Primary Efficacy Variable Analysis
The null hypothesis is that the proportion of subjects not requiring a platelet transfusion or any 
rescue procedure for bleeding after randomization and up to 7 days following an elective 
procedure is the same between the avatrombopag and placebo treatment groups.  The 
corresponding alternative hypothesis is that the proportion of subjects not requiring a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure is not the same between avatrombopag and placebo. This hypothesis will 
be tested separately within each baseline platelet cohort.
The proportion of subjects not requiring a platelet transfusion or any rescue procedure for 
bleeding will be tested between the individual avatrombopag treatment group (40 or 60 mg) and 
matching placebo within each baseline platelet count cohort (<40 × 109/L or from 40 to 
<50 × 109/L), each at a significance level of α=0.05, using the generalized Cochran Mantel 
Haenszel (CMH) test adjusting for risk of bleeding associated with the elective procedure (low, 
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moderate, or high based on Amendment 02 categorization).  

For subjects with platelet count <40 x 109/L at baseline, the treatment comparison will be 
carried out between the 60 mg avatrombopag treatment group versus matching placebo.

For subjects with platelet count from 40 to <50 × 109/L at baseline, the treatment 
comparison will be carried out between the 40 mg avatrombopag treatment group versus 
matching placebo.
This study will be considered as positive if statistical significance is achieved for the primary 
efficacy endpoint for both baseline platelet count cohorts.
The 95% confidence interval (CI) for the proportion of subjects not requiring a platelet 
transfusion or any rescue procedure for bleeding will be calculated for each treatment group 
within each baseline platelet count cohort.  In addition, the 95% CI for the difference between 
avatrombopag and matching placebo will be provided within each baseline platelet count cohort.
Since the HCC status is included in the randomization stratification for safety purposes only, not 
for efficacy consideration, HCC will not be included in the CMH model for the primary efficacy 
analysis.
Subjects with missing information about the primary efficacy outcome due to early withdrawal 
or other reasons will be considered as having received a transfusion for the primary analysis.
Subgroup analyses and additional sensitivity analyses will be performed, as appropriate.  
Secondary Efficacy Variable Analyses
The analysis of the secondary efficacy variables as defined above will proceed following a 
sequential gatekeeping testing procedure with the multiplicity adjustment to  control the Type I 
error rate at significance level α=0.05.  
The proportion of subjects who achieve platelet counts of ≥50 × 109/L on the Procedure Day will 
be analyzed first.  The proportion of subjects with platelet counts of ≥50 × 109/L on the 
Procedure Day will be tested between the individual avatrombopag treatment group (40 or 
60 mg) and matching placebo separately within each baseline platelet count cohort (<40 × 109/L 
or from 40 to <50 × 109/L), each at a significance level of α=0.05, using the generalized CMH 
test adjusting for risk of bleeding associated with the elective procedure (low, moderate, or high
based on Amendment 02 categorization).  
The second secondary efficacy variable, change from baseline in platelet count on the Procedure 
Day, will be analyzed only if the test for the first secondary efficacy variable is statistically 
significant for both baseline platelet count cohorts.  The change from baseline in platelet count 
will be analyzed using the Wilcoxon rank sum test separately within each baseline platelet count 
cohort (<40 × 109/L or from 40 to <50 × 109/L), each at a significance level of α=0.05.  (revised 
per Amendment 04)
Exploratory Efficacy Variables

Platelet count and change from baseline in platelet count at each visit 

Proportion of subjects who achieve platelet count of ≥50 × 109/L, ≥75 × 109/L, or 
≥200 × 109/L at each visit
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
Number of platelet units used per platelet transfusion episode

Severity of bleeding events assessed by WHO bleeding score and BARC bleeding scale

Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 
7 days following an elective procedure (revised per Amendment 04)
Additional analyses may be performed as needed.
Further details of the proposed statistical 
analyses will be included in the Statistical Analysis Plan.
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic Analyses
Pharmacokinetic Analyses
Plasma concentration versus time data will be listed. 
The data will be analyzed using a 
population PK approach to estimate population PK parameters and the effect of covariates on the 
PK parameters will be evaluated. 
Pharmacokinetic/Pharmacodynamic Analyses
The data will be analyzed using a population PK/PD approach to estimate population PD 
parameters.
The population PK and PK/PD analyses will be detailed in a separate analysis plan.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluation of safety will be performed on the Safety Analysis Set.  Safety assessments will be 
summarized for overall and within each baseline platelet count cohort as appropriate.
Safety 
assessments including AEs, laboratory tests, vital signs, ECG, and Doppler sonography will be 
summarized by treatment groups using descriptive statistics (mean, standard deviation, median 
and range) or frequency count as appropriate.  No hypothesis testing will be performed for safety 
assessment.
All AEs will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities.  The incidence of AEs, SAEs, AEs leading to discontinuation of study 
drug, and AEs of special interest will be summarized by treatment group, as well as by severity 
and by relationship to study drug.  Mean and mean change from baseline of laboratory tests, vital 
signs, and ECG parameters will also be summarized by treatment group.  
Other Analyses
Details of the health economic analyses will be provided in a separate analysis plan.
Interim Analyses
An independent DSMB will be established to monitor the ongoing safety data.  Some of the 
safety parameters that DSMB will review will include variables that are also being assessed in 
this study for efficacy (eg, platelet count to ensure there are not too many subjects with a platelet 
count that exceeds 200 × 109/L and bleeding).  No interim efficacy analysis is planned, and 
therefore no adjustment of the P-value for the final efficacy analysis is needed.  
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Sample Size Rationale
The proposed sample size is based on comparisons of the primary efficacy variable, with the 
response rate defined as the proportion of subjects who do not require a platelet transfusion or 
any rescue procedure for bleeding after randomization and up to 7 days following an elective 
procedure.  Based on clinical opinion and the published results of a similar compound in adults 
with thrombocytopenia associated with liver disease (ELtrombopag EValuated for its Ability to 
overcome Thrombocytopenia and Enable procedures [ELEVATE] study), the response rate in 
the placebo group is assumed to be 18%.  With each baseline platelet count cohort, a sample size 
of 100 randomized subjects, 67 subjects for avatrombopag and 33 subjects for placebo, will have 
greater than 90% power to detect an absolute difference of 35% between the avatrombopag 
response rate and the placebo response rate assuming 18% response rate for placebo using 
Fisher’s Exact tests with a 2-sided α=0.05.  (revised per Amendment 04)  The hypothesized 
treatment group difference is based on platelet count changes found in the Phase 2 study (E5501-
G000-202) and dose-response modeling using data from that study and others in the project 
development. Based on the baseline data in the Phase 2 study and assuming these are projected
to be similar for this study, it is anticipated that this study will enroll roughly half of the total 
number of subjects in each of the 2 baseline platelet count cohorts to make the total sample size 
of 200 randomized subjects, 133 subjects for avatrombopag and 67 subjects for placebo.  
(revised per Amendment 04)
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3
TABLE OF CONTENTS
1
TITLE PAGE
1
2
CLINICAL PROTOCOL SYNOPSIS
3
3
TABLE OF CONTENTS
15
LIST OF IN-TEXT TABLES
18
LIST OF IN-TEXT FIGURES
18
LIST OF APPENDICES
18
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
19
5
ETHICS
21
5.1
Institutional Review Boards/Independent Ethics Committees
21
5.2
Ethical Conduct of the Study
22
5.3
Subject Information and Informed Consent
22
6
INVESTIGATORS AND STUDY PERSONNEL
24
7
INTRODUCTION
25
7.1
Indication
25
7.1.1
Current Therapeutic Options
26
7.1.2
Avatrombopag
26
7.1.2.1
Mechanism of Action
26
7.1.2.2
Nonclinical Pharmacology
26
7.1.2.3
Effects in Humans
27
7.1.2.4
Common Serious Adverse Events Expected to Occur in 
the Study Population Even in the Absence of Study 
Drug Exposure
28
7.2
Study Rationale
28
7.2.1
Risk Mitigation
29
8
STUDY OBJECTIVES
31
8.1
Primary Objective
31
8.2
Secondary Objectives
31
8.3
Exploratory Objectives
31
9
INVESTIGATIONAL PLAN
32
9.1
Overall Study Design and Plan
32
9.1.1
Prerandomization Phase
35
9.1.1.1
Screening Period (Visit 1)
35
9.1.2
Randomization Phase
36
9.1.2.1
Baseline Period (Visit 2)
36
9.1.2.2
Treatment Period (Visit 3)
37
9.1.2.3
Procedure Day (Visit 4)
37
9.1.3
Follow-up Phase (Visits 5 and 6)
39
9.2
Discussion of Study Design, Including Choice of Control Groups
39
9.3
Selection of Study Population
40
9.3.1
Inclusion Criteria
40
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9.3.2
Exclusion Criteria (revised per Amendment 02)
41
9.3.3
Removal of Subjects From Therapy or Assessment
43
9.4
Treatments
43
9.4.1
Treatments Administered
43
9.4.2
Identity of Investigational Products
44
9.4.2.1
Generic and Chemical Name
44
9.4.2.2
Comparator Drug
44
9.4.2.3
Labeling for Study Drugs
44
9.4.2.4
Storage Conditions
44
9.4.3
Method of Assigning Subjects to Treatment Groups
44
9.4.4
Selection of Doses in the Study
45
9.4.5
Selection and Timing of Dose for Each Subject
45
9.4.6
Blinding
45
9.4.7
Prior and Concomitant Therapy
46
9.4.7.1
Permitted Prior Therapy
46
9.4.7.2
Permitted Concomitant Therapy
46
9.4.7.3
Prohibited Concomitant Therapy
46
9.4.8
Treatment Compliance
47
9.4.9
Drug Supplies and Accountability
47
9.5
Study Assessments
48
9.5.1
Assessments
48
9.5.1.1
Demography
48
9.5.1.2
Baseline Assessments
48
9.5.1.3
Efficacy Assessments
49
9.5.1.4
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Assessments
51
9.5.1.5
Safety Assessments
52
9.5.1.6
Other Assessments
59
9.5.2
Schedule of Procedures/Assessments
59
9.5.2.1
Schedule of Procedures/Assessments
59
9.5.3
Appropriateness of Measurements
64
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Other 
Events of Interest
64
9.5.4.1
Reporting of Serious Adverse Events
64
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug 
Through Breastfeeding
65
9.5.4.3
Reporting of Other Events of Interest
65
9.5.4.4
Expedited Reporting
66
9.5.4.5
Breaking the Blind
67
9.5.4.6
Regulatory Reporting of Adverse Events
67
9.5.5
Completion/Discontinuation of Subjects
67
9.5.6
Abuse or Diversion of Study Drug
68
9.5.7
Confirmation of Medical Care by Another Physician
68
9.6
Data Quality Assurance
68
9.6.1
Data Collection
68
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9.6.2
Clinical Data Management
68
9.7
Statistical Methods
68
9.7.1
Statistical and Analytical Plans
69
9.7.1.1
Study Endpoints
69
9.7.1.2
Definitions of Analysis Sets
70
9.7.1.3
Subject Disposition
70
9.7.1.4
Demographic and Other Baseline Characteristics
70
9.7.1.5
Prior and Concomitant Therapy
71
9.7.1.6
Efficacy Analyses
71
9.7.1.7
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses
74
9.7.1.8
Safety Analyses
74
9.7.1.9
Other Analyses
77
9.7.2
Determination of Sample Size
77
9.7.3
Interim Analysis
77
9.7.4
Other Statistical/Analytical Issues
78
9.7.5
Procedure for Revising the Statistical Analysis Plan
78
10
REFERENCE LIST
79
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES)
81
11.1
Changes to the Protocol
81
11.2
Adherence to the Protocol
81
11.3
Monitoring Procedures
81
11.4
Recording of Data
82
11.5
Identification of Source Data
82
11.6
Retention of Records
82
11.7
Auditing Procedures and Inspection
83
11.8
Handling of Study Drug
83
11.9
Publication of Results
83
11.10 Disclosure and Confidentiality
84
11.11 Discontinuation of Study
84
11.12 Subject Insurance and Indemnity
84
12
APPENDICES
85
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LIST OF IN-TEXT TABLES
Table 1
Permitted Procedures and the Risk of Bleeding Associated with Each 
Procedure (revised per Amendment 02)
38
Table 2
WHO Bleeding Score Categories
51
Table 3
BARC Bleeding Scale Categories
51
Table 4
Clinical Laboratory Tests
57
Table 5
Schedule of Procedures/Assessments in Study E5501-G000-310
60
LIST OF IN-TEXT FIGURES
Figure 1
Study Design
34
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
86
Appendix 2
List of P-glycoprotein Inhibitors
88
Appendix 3
Guidelines for Doppler Sonography Measurements
89
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
β-hCG
beta-human chorionic gonadotropin
AE
adverse event
BARC
Bleeding Academic Research Consortium
BCLC
Barcelona Clinic Liver Cancer
CA
Competent Authority
CABG
coronary artery bypass graft
CI
confidence interval
CMH
Cochran Mantel Haenszel
CPK
creatinine phosphokinase
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Child-Turcotte-Pugh
CYP
cytochrome P450
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
ELEVATE
ELtrombopag 
EValuated 
for 
its 
Ability 
to 
overcome 
Thrombocytopenia and Enable procedures
EU
European Union
FAS
Full Analysis Set
FFP
fresh frozen plasma
GCP
Good Clinical Practice
HCC
hepatocellular carcinoma
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
INR
International Normalized Ratio
IRB
Institutional Review Board
ITP
Immune Thrombocytopenic Purpura
IxRS
interactive voice and web response system
KOL
key opinion leader
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model For End-stage Liver Disease
MRI
magnetic resonance imaging
NOAEL
no-observed-adverse-effect-level
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Abbreviation
Term
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamic
P-gp
P-glycoprotein
PK
pharmacokinetic
POC
proof of concept
PP
Per Protocol Set
PT
preferred term
PVT
portal vein thrombosis
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory value
TPO
thrombopoietin
US
United States
WBC
white blood cell
WHO
World Health Organization
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5
ETHICS
5.1
INSTITUTIONAL REVIEW BOARDS/INDEPENDENT ETHICS COMMITTEES
The protocol, informed consent form (ICF), and appropriate related documents must be reviewed 
and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
constituted and functioning in accordance with International Conference on Harmonisation 
(ICH) E6 (Good Clinical Practice [GCP]), Section 3, and any local regulations.  Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, change in 
clinical research associate[s] [CRA], change of telephone number[s]).  Documentation of 
IRB/IEC compliance with the ICH E6 and any local regulations regarding constitution and 
review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to the 
site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or 
terminate the study, the investigator will immediately send the notice of study suspension or 
termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to the 
IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide the 
IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority (CA) 
within 90 days.  The end of the study will be the date of the clinical database lock (ie, when all 
study data are collected and data validation is complete).  The sponsor should also provide the 
IRB/IEC with a summary of the study’s outcome (within a year of the end of the study for the 
European Union [EU]).  
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons for 
the termination/halt should be given.
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5.2
ETHICAL CONDUCT OF THE STUDY
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required by 
the following:
●
Principles of the World Medical Association Declaration of Helsinki (2008)
●
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
●
Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312
●
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions will be reported, as required, to the CAs of all involved EU 
member states.
●
Other applicable regulatory authorities’ requirements or directives
5.3
SUBJECT INFORMATION AND INFORMED CONSENT
As part of administering the informed consent document, the investigator must explain to each 
subject (or guardian/legally authorized representative) the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to the 
subject, and the extent of maintaining confidentiality of the subject’s records.  Each subject must 
be informed that participation in the study is voluntary, that he/she may withdraw from the study 
at any time, and that withdrawal of consent will not affect his/her subsequent medical treatment 
or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and dating it 
and will be given a copy of the signed document.  If a subject is unable to read or if a legally 
acceptable representative is unable to read, an impartial witness should be present during the 
entire informed consent discussion.  After the ICF and any other written information to be 
provided to subjects is read and explained to the subject or the subject’s legally acceptable 
representative, and after the subject or the subject’s legally acceptable representative has orally 
consented to the subject’s participation in the study and, if capable of doing so, has signed and 
personally dated the ICF, the witness should sign and personally date the consent form.  The 
subject will be asked to sign an ICF at the Screening Visit before any study-specific procedures 
are performed.  No subject can enter the study before his/her informed consent has been 
obtained.
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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations.  Each subject must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The original, 
signed ICF for each subject will be verified by the sponsor and kept on file according to local 
procedures at the site.  
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study.  The communication of this information should be 
documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 80 to 100 investigational sites worldwide.
The names and telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and the designated contract research organization (CRO) are listed in the Regulatory 
Binder provided to each site.
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7
INTRODUCTION
7.1
INDICATION 
Thrombocytopenia is the occurrence of low platelets in the blood and, in severe cases, can be 
associated with significant morbidity and mortality.
Patients with chronic liver disease can 
develop thrombocytopenia from decreased production of thrombopoietin (TPO), as well as from 
increased destruction of platelets from auto-antibodies or platelet sequestration with 
splenomegaly. In addition, depending upon the etiology of the liver disease, additional factors 
can 
contribute 
to 
thrombocytopenia, 
such 
as 
viral-induced 
myeloid 
suppression.  
Thrombocytopenia is a common problem in patients with liver disease, with the extent of 
thrombocytopenia often worsening with the degree of cirrhosis.
Patient treatment decisions are guided by platelet count measurements, as well as by clinical 
judgment on the risk of bleeding.  Patients with moderate to severe thrombocytopenia (<50 x 
109/L) associated with liver disease are commonly administered platelet transfusions 
immediately prior to elective diagnostic or therapeutic procedures in order to mitigate the risk of 
bleeding. The extent of the bleeding risk relates to the degree of thrombocytopenia, the extent of 
other coexisting coagulopathy(ies), and the type of elective procedure.  While temporarily 
effective, platelet transfusion therapy can have significant health and economic consequences, 
including the development of refractoriness to subsequent platelet transfusions, potential 
transmission of infectious agents, transfusion reactions, and, in rare cases, fatality.  
Unfortunately, in patients requiring repeated platelet transfusions, both the magnitude of the 
platelet increase and the duration of that increase declines with increasing numbers of 
transfusions.1
This refractoriness to treatment can pose a major challenge for patients 
undergoing procedures in preparation for liver transplant or other procedures pertinent to their 
care. 
For patients who have acquired refractoriness to platelet transfusion, an unintended 
consequence is often the need to delay or even cancel important procedures.  Additionally, like 
all blood products, platelets are a precious commodity with a limited shelf life. Approximately 
9 million units of platelets are transfused each year in the US;2 40% in surgical settings.3 Liver 
disease patients are believed to represent a significant proportion of the patient population 
regularly receiving platelet transfusions.4 A recent assessment at the University of Colorado 
Denver Medical School revealed that up to 20% of all platelet transfusions were given to liver 
disease patients.
E5501/avatrombopag (formerly known as AKR-501 monomaleate and YM477) is an orally 
administered, small molecule c-Mpl receptor agonist that mimics the biological effects of TPO in 
vitro and in vivo. Thrombopoietin, the principal physiologic regulator of platelet production, 
exerts its effect on megakaryocytopoiesis and thrombocytopoiesis via binding and activation of 
the c-Mpl receptor, which is expressed on hematopoietic stem cells, on cells of the 
megakaryocytic lineage, and on platelets. Like TPO, avatrombopag also binds to the human 
c-Mpl receptor and affects signal transduction through the induction of downstream signaling, 
thereby enhancing human megakaryocytic proliferation and differentiation. 
A proof of concept (POC) study (E5501-G000-202) has demonstrated the efficacy, safety, and 
tolerability of avatrombopag in elevating platelet counts in this group of patients with 
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thrombocytopenia associated with liver disease prior to elective procedures.  Modeling and 
simulation based on a final pharmacokinetic (PK)/pharmacodynamic (PD) model, of the POC 
study data, allowed an optimal dosing regimen for Phase 3 to be identified. These simulations 
showed that the achievement of the appropriate platelet count and a high response rate is affected 
by baseline platelet count and that dosing avatrombopag is best stratified by baseline platelet 
count.  The simulations also demonstrated that there is no advantage in having a loading dose as 
was used in the POC study. Theses simulations have been important because in the POC study 
the primary endpoint only related to elevation in platelet count, whereas in Phase 3 the primary 
endpoint will link to the clinical endpoint of platelet transfusion.
The current study will evaluate avatrombopag in the treatment of thrombocytopenia associated 
with liver disease prior to an elective procedure to reduce the need for platelet transfusions due to 
procedural and postprocedural bleeding complications.   
7.1.1
Current Therapeutic Options 
Currently, platelet transfusion is the standard of care for patients with thrombocytopenia who 
must undergo an invasive procedure.  While 2 TPO-receptor agonists (romiplostim [Amgen] and 
eltrombopag [GlaxoSmithKline]) are approved for use in adults with chronic immune 
(idiopathic) thrombocytopenic purpura (ITP), and eltrombopag is approved in the US for the 
treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and 
maintenance of interferon-based therapy, neither product is approved for the treatment of 
thrombocytopenia associated with liver disease in patients undergoing an elective procedure.  
Avatrombopag is being developed to provide an alternative to the standard of care (platelet 
transfusion) by providing a 5-day course of once daily therapy and eliminating the need for 
platelet transfusions and the potential associated side effects.
7.1.2
Avatrombopag 
7.1.2.1
Mechanism of Action
Avatrombopag is an orally administered, small molecule c-Mpl agonist that mimics the 
biological effects of TPO in vitro and in vivo.  Avatrombopag activates human c-Mpl through a 
mechanism that is different from endogenous TPO binding, but is still capable of stimulating 
signal transduction and mimicking the biological effects of TPO. 
7.1.2.2
Nonclinical Pharmacology
Nonclinical pharmacology studies show that avatrombopag stimulates proliferation of cultured 
human c-Mpl–Ba/F3 cells and promotes differentiation of human cord blood CD34+ cells to 
human megakaryocytes in a concentration-dependent manner with a maximum effect similar to 
that of recombinant human TPO.  In vitro, avatrombopag has been shown to stimulate human 
megakaryocyte proliferation and differentiation without affecting platelet function, either 
activation or aggregation.  The pharmacologic effect of avatrombopag is highly species-specific, 
with signaling occurring only in chimpanzees and humans but not in any other species tested.  
Avatrombopag was stable in mouse, dog, or human liver microsomal enzyme incubations in 
vitro, indicating slow metabolism. 
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In addition, avatrombopag (up to 10 μmol/L) did not inhibit the major human liver cytochrome 
P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6,
and CYP3A4).  
Avatrombopag (0.1 to 5 μmol/L) did not induce CYP1A, CYP2B6, CYP2C19, or CYP3A.  
However, it weakly induced CYP2C8 and CYP2C9.  Therefore, the potential for drug-drug 
interactions is low.
Absolute bioavailability was evaluated in the mouse, rat, dog, and monkey.  Overall, 
avatrombopag was well absorbed, but highly variable, and the fraction absorbed ranged from 
approximately 50% to 90%.
Nonclinical toxicology studies have indicated that avatrombopag was well tolerated.  The 
primary toxicity of avatrombopag was identified as dose-related changes in the stomachs of rats, 
mice, and monkeys, with an elevation of serum gastrin levels in repeated-dose studies.  The 
gastric changes showed a clear trend towards recovery after a recovery period.  Exposures (area 
under the concentration-time curve and maximum plasma concentration) at the no-observed-
adverse-effect-levels in animals, in pivotal studies, are sufficiently above the clinical exposures 
at the current maximum therapeutic dose.  Avatrombopag was negative in the standard battery of 
genotoxicity tests.  Avatrombopag has no effect on reproductive toxicity, except for the higher 
sensitivity to toxicity in neonates/juvenile rats in the pre-and postnatal development study.  In the 
2-year carcinogenicity studies, neuroendocrine cell (enterochromaffin-like [ECL] cell) 
hyperplasia (rats only), and ECL cell tumors (carcinoids, both mice and rats) occurred in the 
stomach.  The mechanism of action for gastric changes by avatrombopag was confirmed to be 
compatible with a gastrin hypothesis, similar to the cases of antisecretory agents such as proton 
pump inhibitors and H2 blockers based on mechanistic studies, leading to the conclusion that the 
results are not relevant to humans.  Avatrombopag had no ocular or dermal irritation, no dermal 
sensitization, and no phototoxicity potential in nonclinical studies.
Overall, nonclinical data suggest that avatrombopag is a promising candidate for use in the 
treatment of thrombocytopenia of diverse etiologies, including thrombocytopenia associated with 
liver disease.
7.1.2.3
Effects in Humans
Avatrombopag has been studied in humans in single- and multiple-dose Phase 1, dose-rising 
safety and tolerability studies.  In healthy human subjects, single and multiple doses of 
avatrombopag oral suspension showed a dose-dependent increase in peripheral platelets and no
safety issues were reported.  A comparative bioavailability study of avatrombopag suspension 
and tablets showed that avatrombopag tablets produced significantly lower exposure 
(approximately 67%) than the oral suspension.  A food-effect arm demonstrated a high-fat meal 
mildly increased avatrombopag exposure. 
A total of 12 Phase 1 clinical pharmacology studies have been completed to date.  Based on 
Phase 1 study results, avatrombopag was generally well tolerated and no major safety issues 
were identified during treatment.  The subject population in the clinical pharmacology studies 
included 390 healthy volunteers, age 18 to 64, of which two-thirds were men (men: 263/390, 
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67.4%; women: 127/390, 32.6%).  A total of 350 of the 390 subjects received at least 1 dose of 
avatrombopag.
Three Phase 2 efficacy and safety studies have been completed to date (Study 501-CL-003 and 
the rollover Study 501-CL-004, and Study E5501-G000-202).  
Study E5501-G000-202 evaluated the efficacy, safety, and population PK of once-daily oral 
avatrombopag dosing, in subjects with chronic liver diseases and thrombocytopenia prior to 
elective surgical or diagnostic procedures.  The primary efficacy endpoint was the proportion of 
responders with platelet count increases from baseline of ≥20 × 109/L and a platelet count 
of ≥50 × 109/L once from Day 4 through Day 8.  The proportion of responders for all 
avatrombopag-treated subjects was 48.4% compared with 8.1% in the combined placebo group 
(P<0.0001).  All doses of avatrombopag achieved a significantly higher proportion of responders 
compared with their respective cohort placebo arms and the highest platelet count responses 
were observed between Days 10 to 14 after first dose.  In addition, avatrombopag appeared well 
tolerated in this patient population.  There was no clear trend regarding the incidences of AEs
between placebo and avatrombopag treatment groups, and the commonly reported 
treatment-emergent adverse events (TEAEs) and serious TEAEs were consistent with the disease 
state of the patient population.  The findings from Study E5501-G000-202 suggest that 
avatrombopag would be an effective therapy for the treatment of thrombocytopenia in patients 
with chronic liver disease, prior to an elective procedure.
For more detailed information regarding effects in humans, please refer to the Investigator
Brochure.
7.1.2.4
Common Serious Adverse Events Expected to Occur in the Study Population Even in 
the Absence of Study Drug Exposure
Thrombotic/thromboembolic complications may occur in patients with chronic liver disease.  
Portal vein thrombosis (PVT) is of particular concern in chronic liver disease patients who are 
prone this type of thrombosis and is often associated with poor portal vein flow.  The presence of 
thrombocytopenia can increase the potential for bleeding, which results in an elevated morbidity 
and mortality risk in patients with liver disease.  In cirrhotic patients undergoing abdominal 
surgery, bleeding accounts for up to 60% of all causes of death.  Thrombocytopenic patients 
often require multiple platelet transfusions, which can be associated with complications such as 
systemic infections, iron overload, and platelet refractoriness.4
7.2
STUDY RATIONALE
The current study will evaluate avatrombopag in the treatment of thrombocytopenia associated 
with liver disease prior to an elective procedure to reduce the need for platelet transfusions or 
any rescue procedure for bleeding due to procedural and postprocedural bleeding complications
Dose selection has been carefully focused on seeking to maintain an appropriate risk: benefit 
ratio in this patient population, removing the requirement for platelet transfusion, or any rescue 
procedure for bleeding, while minimizing the risk of thromboembolic events. The selected 
doses, based on modeling and simulation of the E5501-G000-202 study data, are aimed at 
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achieving sufficient efficacy (eliminating the need for platelet transfusion) while specifically 
limiting the proportion of subjects achieving platelet counts >200 × 109/L to less than 2%. The 
current study design employs a dosing regimen, according to baseline platelet count, that is 
anticipated to lead to a similar rise in platelet counts irrespective of baseline platelet count.  
Subjects will be enrolled into 2 cohorts according to mean baseline platelet count (<40 × 109/L 
or from 40 to <50 × 109/L) and dosed with 60 mg avatrombopag versus placebo for subjects with 
platelet count <40 × 109/L and 40 mg avatrombopag versus placebo for subjects with platelet 
count from 40 to <50 × 109/L. 
This is 1 of 2 duplicate global pivotal studies that will overlap geographically to ensure that 
minor differences in clinical practices between regions will be balanced across the studies.
7.2.1
Risk Mitigation
Patients with liver disease have a significant risk of thromboembolic and bleeding events. As 
platelet counts decline, cirrhotic patients tend to become more susceptible to bleeding following 
an inciting event such as trauma, rather than spontaneous bleeding as seen in other 
thrombocytopenic conditions such as ITP. 
This apparent discrepancy is mainly due to 
coagulation abnormalities seen in patients with cirrhosis.5,6
Despite an apparent ‘balance’ 
between pro- and anti-coagulation factors in plasma, the coagulation system in the cirrhotic 
patient is associated with an increased tendency towards thrombosis, regardless of observed 
prolonged conventional coagulation test times, such as prothrombin time, activated partial 
thromboplastin time, and INR. 
As a result, especially in patients with thrombocytopenia 
associated with liver disease, excessive elevations in platelet counts may potentially trigger 
thrombotic/thromboembolic events in the background of known coagulation abnormalities.
Perhaps, the most significant thrombotic event seen in patients with thrombocytopenia associated 
with liver disease is PVT.
Portal vein thrombosis in the general population is a rare event. However, it is a relatively 
common complication in patients with liver cirrhosis (4% - 15%)7, with frequencies increasing 
with the degree of cirrhosis and a prevalence as high as approximately 30% in candidates for 
liver transplantation. Although even complete occlusion of the portal vein may not result in 
overt clinical manifestations, due to rapid development of collateral veins bypassing the 
thrombosed segment, patients can experience acute and chronic onset of a variety of clinical 
symptoms.
These include increased variceal bleeding, refractory ascites and abdominal pain, 
presumably from small bowel ischemia or infarction due to the involvement of the superior 
mesenteric vein.8  Furthermore, the occurrence of PVT is known to increase the risk of mortality 
both prior to and post liver transplantation.9 Eltrombopag, a currently marketed TPO-receptor 
agonist for the treatment of ITP, has been reported to have been associated with the occurrence 
of PVT in patients with chronic liver disease and thrombocytopenia.10  In the ELtrombopag 
EValuated for its Ability to overcome Thrombocytopenia and Enable procedures (ELEVATE)
study, aimed at decreasing the requirement for platelet transfusion prior to elective procedures, 
there was an imbalance in the incidence of PVT and mesenteric thrombosis between the active 
and placebo arms.10  In addition to very high and prolonged elevations in platelet counts (26% of 
eltrombopag-treated subjects reached >200 × 109/Land 5% reached >400 × 109/L); 6 (4%)
subjects in the eltrombopag arm and 1 (1%) in the placebo arm experienced a thrombotic event 
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of the portal venous system, leading to early termination of the study.11,12  In the current Phase 3 
program, avatrombopag doses and treatment duration have been selected so that platelet count 
elevations are transient and not excessive, with the projected percentage of subjects who reach 
>200 × 109/L limited to <2%. During this study, if a potential PVT is suspected, subjects will 
undergo confirmation of diagnosis and appropriate treatment as per local guidelines.
Development of PVT is recognized as a multifactorial complication, which involves both 
inherited and acquired thrombotic risk factors.  One of the strongest risk factors predisposing 
patients to the development of a PVT may be a reduced flow in the portal vein. Literature and 
meeting reports indicate that a portal vein flow rate of 10 to 15 cm/second is a good predictor of 
future risk for PVT.11 Doppler sonography, which is routinely used in patients with liver disease, 
can be used to assess portal vein flow rates and guidelines have been developed that can reduce 
interobserver variability in measuring flow rates to low levels.14  Therefore, in the Phase 3 
program, portal vein flow rate will be performed during the Screening Period, to pre-identify and 
exclude subjects with low portal flow.  In addition, subjects with a history of arterial or venous 
thrombosis and subjects with current evidence of thrombosis will be excluded.  For subjects 
whose preprocedural platelet count is >200 × 109/L on the Procedure Day, the elective procedure
may be delayed at the discretion of the investigator until platelet counts are below 200 × 109/L.  
All subjects whose platelet count exceeds 200 × 109/L on the Procedure Day will be required to 
have a Doppler assessment following the procedure.  For any subjects where the presence of a 
PVT is suspected, confirmation of diagnosis, via computerized tomography (CT) scan or 
magnetic resonance imaging (MRI), should be performed and treatment for PVT initiated per 
local guidelines.  As part of the protocol, guidance on use of Doppler sonography for assessment 
of portal flow will be included in Appendix 3.
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8
STUDY OBJECTIVES
8.1
PRIMARY OBJECTIVE
The primary objective of the study is to confirm that avatrombopag (60 mg avatrombopag for 
subjects with platelet count <40 × 109/L and 40 mg avatrombopag for subjects with platelet 
count from 40 to <50 × 109/L) is superior to placebo in removing the need for platelet 
transfusions or any rescue procedure for bleeding after randomization and up to 7 days following
an elective procedure in subjects with chronic liver disease who have thrombocytopenia.
8.2
SECONDARY OBJECTIVES
The secondary objectives of the study are:  (revised per Amendment 04)

To confirm that avatrombopag is superior to placebo in achieving a platelet count of 
≥50 x 109/L on Procedure Day in the proposed target population

To confirm that avatrombopag is superior to placebo in elevating platelet counts from 
baseline on Procedure Day in the proposed target population

To evaluate the safety of avatrombopag in the proposed target population
8.3
EXPLORATORY OBJECTIVES
The exploratory objectives of the study are:

To characterize the pharmacokinetics and the relationship between avatrombopag plasma 
concentrations and platelet count using the population approach

To characterize platelet count changes from baseline, the extent of platelet transfusion 
use, evaluate the incidence of bleeding events, and assess the severity of any bleeding 
events (revised per Amendment 04)

To assess the health economic impact associated with minimizing the need for platelet 
transfusions and any rescue procedure for bleeding associated with an elective procedure
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9
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN
This
is a Phase 3, global, multicenter,
randomized, double-blind, placebo-controlled, 
parallel-group study using avatrombopag to treat adults with thrombocytopenia associated with 
liver disease prior to an elective procedure.  Subjects will be enrolled into 2 cohorts according to 
mean baseline platelet count and, within each baseline platelet count cohort, will be further
stratified by risk of bleeding associated with the elective procedure (low, moderate or high) and
hepatocellular carcinoma (HCC) status (Yes or No). Neither baseline platelet count cohort will 
comprise greater than 55% of the total number of subjects enrolled into the study. The estimated 
study duration to enroll and complete all subjects is approximately 20 months. 
Within the lower baseline platelet count cohort (<40 × 109/L) and each stratum, subjects will be 
randomized by an interactive voice and web response system (IxRS) in a 2:1 ratio to receive 
avatrombopag or placebo as follows:

60 mg avatrombopag on Days 1 to 5 (Group A: avatrombopag, lower baseline platelet 
count)

Matching placebo on Days 1 to 5 (Group B: placebo, lower baseline platelet count)
Within the higher baseline platelet count cohort (from 40 to <50 × 109/L) and each stratum, 
subjects will be randomized in a 2:1 ratio to receive avatrombopag or placebo as follows: 

40 mg avatrombopag on Days 1 to 5 (Group C: avatrombopag, higher baseline platelet 
count)

Matching placebo on Days 1 to 5 (Group D: placebo, higher baseline platelet count)
Platelet counts must be measured on 2 separate occasions, during the Screening Period and at 
Baseline, and must be performed at least 1 day apart with neither platelet count >60 × 109/L.  
The mean of these 2 platelet counts (mean baseline platelet count <50 × 109/L) will be used for 
entry criteria.  
The elective procedure must be scheduled to be performed within 10 to 13 days of first dose of 
study drug and after Visit 4 assessments have been performed.
This study will consist of 3 phases: Prerandomization, Randomization, and a Follow-up Phase.  
The Prerandomization Phase consists of a Screening Period that will take place from Day -14 
through Day -1.
The Randomization Phase includes the Baseline Period, Treatment Period, and Procedure Day 
(5 to 8 days after last dose of study drug, [Study Day 10 to 13]).  During the Baseline Period, 
subjects who have met all entry criteria, provided signed informed consent, and been randomized 
will be instructed to take study drug on Days 1 to 5.  
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The elective procedure for those subjects whose preprocedural platelet count is >200 × 109/L on 
Visit 4 (Procedure Day) may be delayed at the discretion of the investigator until platelet counts 
are below 200 × 109/L.  All subjects whose platelet count exceeds 200 × 109/L will be required to 
have a Doppler assessment at Visit 5.  For any subjects where the presence of a PVT is 
suspected, confirmation of diagnosis, via CT scan or MRI, should be performed and treatment 
for PVT initiated per local guidelines.
The Follow-up Phase encompasses 2 visits: 7 days postprocedure day and 30 days after receiving 
the last dose of study drug.   
An independent Data Safety Monitoring Board (DSMB) will be established to monitor the 
ongoing safety data.
The end of the study will be the date of the clinical database lock (ie, when all study data are 
collected and data validation is completed).
An overview of the study design is presented in Figure 1.  
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Figure 1
Study Design 
PLT=platelet count; R = randomization
Platelet counts must be measured on 2 separate occasions, during the Screening Period and at Baseline, and must be performed at least 1 day apart with neither
platelet count >60 × 109/L.  The mean of these 2 platelet counts (mean baseline platelet count <50 × 109/L) will be used for entry criteria and determination of 
baseline platelet count.
a:
Visit 3 occurs on Day 4 (±1 day) during the Treatment Period.    
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9.1.1
Prerandomization Phase
The Prerandomization Phase consists of a Screening Period that will last up to 14 days.
9.1.1.1
Screening Period (Visit 1)
Screening will occur between Day -14 and Day -1.  
The purpose of the Screening Period is to obtain informed consent and to establish protocol 
eligibility.  Subjects must have a diagnosis of thrombocytopenia associated with liver disease and 
be scheduled to undergo an elective procedure.  Only subjects who, in the opinion of the 
investigator, are expected to require platelet transfusion to address a risk of bleeding associated 
with the procedure will be recruited into this study. 
Informed consent will be obtained after the study has been fully explained to each subject and 
before the conduct of any screening procedures or assessments.  Procedures to be followed when 
obtaining informed consent are detailed in Section 5.3.
After providing informed consent, all subjects will undergo screening assessments to ensure that 
they meet all of the inclusion and none of the exclusion criteria, as described in Section 9.3.1 and 
Section 9.3.2.  Screening assessments and timing are shown in Section 9.5.2.1 (Table 5).
During this phase, the type and schedule of the elective procedure will be confirmed.  
The Screening Disposition case report form (CRF) page must be completed to indicate whether 
the subject is eligible to participate in the study and to provide reasons for screen failure, if 
applicable.
Rescreen of subjects will only be allowed under the following circumstances:

Scheduled procedure is cancelled or delayed

Platelet count inclusion criteria is not met as platelet count tends to fluctuate

Unable to complete the Screening Period due to administrative, logistical issues

Previously screen failed due to criteria no longer in the protocol (added per Amendment 
01)
Repeat of screening laboratory evaluations are allowed in cases where abnormal result(s) are 
noted during the Screening Period that are believed to be related to a potential laboratory error 
or a transient and/or reversible condition  (eg, clumped platelets or hemolyzed sample for
complete blood count).  Results of the repeated assessment must be available before 
randomization.  If additional blood samples are sent to the central laboratory during the 
Screening Period, eligibility must be assessed based on the most recent laboratory values.  The 
2 most recent values will be used to determine the mean platelet count value for entry criteria 
and for assignment to the low or high baseline platelet count cohort.
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9.1.2
Randomization Phase
The duration of the Randomization Phase will be 10 to 13 days and will include 3 periods:  
Baseline, Treatment, and Procedure Day. Subjects whose screening assessments and evaluations 
are completed and reviewed by the principal investigator and who continue to meet all of the 
inclusion and none of the exclusion criteria will enter the Randomization Phase. 
9.1.2.1
Baseline Period (Visit 2)
The Baseline Period will occur on Study Day 1. Subjects who meet all the inclusion criteria and 
none of the exclusion criteria, (Sections 9.3.1 and 9.3.2) will be randomized and begin the 
Treatment Period.
Baseline assessments are shown in Section 9.5.2.1 (Table 5).
Platelet counts must be measured on 2 separate occasions, during the Screening Period and at 
Baseline, and must be performed at least 1 day apart with neither platelet count >60 × 109/L.  
The mean of these 2 platelet counts (mean baseline platelet count <50 × 109/L) will be used for 
entry criteria.
Upon confirmation of eligibility, subjects will be enrolled into 2 cohorts according to mean 
baseline platelet count (<40 × 109/L or from 40 to <50 × 109/L).  Within each cohort, subjects 
will be further stratified by risk of bleeding associated with the elective procedure (low, 
moderate or high) and presence of HCC (Yes or No). Neither baseline platelet count cohort will 
comprise greater than 55% of the total number of subjects enrolled into the study.  
Within the lower baseline platelet count cohort (<40 × 109/L) and each stratum, subjects will be
randomized in a 2:1 ratio to receive avatrombopag or placebo as follows: 

Group A (avatrombopag, lower baseline platelet count):  60 mg avatrombopag 
(3 × 20-mg tablets) once daily on Days 1 through 5 

Group B (placebo, lower baseline platelet count):  placebo (3 × 20-mg matching placebo 
tablets) once daily on Days 1 through 5
Within the higher baseline platelet count cohort (from 40 to <50 × 109/L) and each stratum, 
subjects will be randomized in a 2:1 ratio to receive avatrombopag or placebo as follows: 

Group C (avatrombopag, higher baseline platelet count): 40 mg
avatrombopag 
(2 × 20-mg tablets) once daily on Days 1 through 5

Group D (placebo, higher baseline platelet count): placebo (2 × 20-mg matching placebo 
tablets) once daily on Days 1 through 5
Subjects will receive a dosing diary in which they are to record the dates and times of their study 
drug doses.
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9.1.2.2
Treatment Period (Visit 3)
During the Treatment Period, subjects will take avatrombopag (60 or 40 mg) or placebo daily 
from Days 1 to 5.  There will be a visit on Day 4 (±1 day) (Visit 3).  Subjects are to record the 
dates and times of their study drug doses in the dosing diary. 
Assessments to be conducted are shown in Section 9.5.2.1 (Table 5).
9.1.2.3
Procedure Day (Visit 4)
This will occur 5 to 8 days after the last dose of study drug (on Study Day 10 to 13). 
All Procedure Day assessments are to be completed prior to the procedure and include 
assessments shown in Section 9.5.2.1 (Table 5).
In addition, all subjects are required to return study drug and the dosing diary at this visit.
The elective procedure for those subjects whose preprocedural platelet count is >200 × 109/L on 
Visit 4 (Procedure Day) may be delayed at the discretion of the investigator until platelet counts 
are below 200 × 109/L.  All subjects whose platelet count exceeds 200 × 109/L will be required to 
have a Doppler assessment at Visit 5.  For any subjects where the presence of a PVT is 
suspected, confirmation of diagnosis, via CT scan or MRI, should be performed and treatment 
for PVT initiated per local guidelines.  
Permitted procedures and the risk of bleeding associated with each procedure are listed in 
Table 1.  It is planned that no fewer than 10% of subjects will be enrolled into the high risk 
group and no more than 60% of subjects in the low-risk group.  
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Table 1
Permitted Procedures and the Risk of Bleeding Associated with Each Procedure
(revised per Amendment 02)
Risk of Bleeding 
Associated with 
Procedure
Procedure
Low risk 
Paracentesis
Thoracentesis
Gastrointestinal endoscopy with or without plans for biopsy, 
colonoscopy, polypectomy, or variceal banding 
Moderate risk 
Liver biopsy
Bronchoscopy with or without plans for biopsy
Ethanol ablation therapy  or chemoembolization for HCC
High risk 
Vascular catheterization (including right side procedures in subjects 
with pulmonary hypertension)
Transjugular intrahepatic portosystemic shunt
Dental procedures
Renal biopsy
Biliary interventions
Nephrostomy tube placement
Radiofrequency ablation
Laparoscopic interventions
Level of risk based on KOL input and Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis RB, et al. for 
the Standards of Practice Committee with Cardiovascular and Interventional Radiological Society of Europe 
(CIRSE) Endorsement.  Consensus Guidelines for Periprocedural Management of Coagulation Status and 
Hemostasis Risk in Percutaneous Image-guided Interventions (2009)15
Subjects who have an International Normalization Ratio (INR) >1.6 should be treated with fresh 
frozen plasma (FFP) or other appropriate therapies, where indicated, as per local guidelines and 
practices. 
The following are considered as rescue procedures when used specifically for bleeding:

Platelet transfusion

FFP

Cryoprecipitate

Vitamin K (phytonadione)

Desmopressin

Recombinant activated factor VII

Aminocaproic acid

Tranexanic acid (added per Amendment 01)

Whole blood transfusion

Packed red cell transfusion
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
Surgical intervention or interventional radiology
9.1.3
Follow-up Phase (Visits 5 and 6)
Upon completion of the Procedure Day period, all subjects will enter the Follow-up Phase 
comprised of 2 visits: 7 days postprocedure Day and Day 35.
Assessments and timing are shown in Section 9.5.2.1 (Table 5).
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUPS
The current study will evaluate avatrombopag in the treatment of thrombocytopenia associated 
with liver disease prior to an elective procedure to reduce the need for platelet transfusions or 
any rescue procedure for bleeding due to procedural and postprocedural bleeding complications.  
The study design employs a dosing regimen, according to baseline platelet count, that is 
anticipated to lead to a similar rise in platelet counts irrespective of baseline platelet count.  
Subjects will be enrolled into 2 cohorts according to mean baseline platelet count (<40 × 109/L 
or from 40 to <50 × 109/L) and dosed with 60 mg avatrombopag versus placebo for subjects with 
platelet count <40 × 109/L and 40 mg avatrombopag versus placebo for subjects with platelet 
count from 40 to <50 × 109/L.  Within each cohort, subjects will be further stratified by risk of 
bleeding associated with the elective procedure (low, moderate, or high) and HCC status.  From 
previous studies, it is anticipated that the 2 baseline platelet count cohorts (<40 × 109/L and from 
40 to <50× 109/L) will be equally represented. However, neither baseline platelet count cohort 
will be permitted to comprise greater than 55% of the total number of subjects enrolled into the 
study.  
The clinical primary endpoint is based on reducing the need for platelet transfusions or any 
rescue procedure for bleeding due to procedural and postprocedural bleeding complications.  A 
similar primary endpoint has already been used for eltrombopag, another TPO agonist.  Based on 
the clinical grounds and the available literature, the primary endpoint of “proportion of subjects 
who do not require a platelet transfusion or any rescue procedure for bleeding after 
randomization and up to 7 days following an elective procedure,” is considered to be clinically 
relevant.
The secondary and exploratory endpoints surrounding World Health Organization (WHO)
bleeding scores and BARC bleeding scale in the current study are also clinically relevant, as 
bleeding is considered a complication of thrombocytopenia that can lead to increased morbidity, 
mortality, and use of medical resources. 
Information obtained from these secondary and 
exploratory endpoints can provide important information regarding bleeding scores and 
associated medical interventions in patients with thrombocytopenia associated with liver disease 
and thrombocytopenia.  
An independent DSMB will be established to monitor the ongoing safety data.
If there are 
excessive serious adverse events (SAE) in a dose arm, further subject enrollment to that dose arm 
may be suspended at the discretion of the DSMB. The study will continue to its end with the 
remaining dose until follow-up is completed for all enrolled subjects.
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Randomization will be used in this study to avoid bias in the assignment of subjects to treatment, 
to increase the likelihood that known and unknown subject attributes (eg, demographics and 
baseline characteristics) are balanced across treatment groups, and to ensure the validity of 
statistical comparisons across treatment groups.  Blinding to treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints.
It is envisaged that 2 global pivotal studies will overlap geographically to ensure that minor 
differences in clinical practices between regions will be balanced across both studies.
9.3
SELECTION OF STUDY POPULATION
Approximately 200 subjects with thrombocytopenia associated with liver disease who are 
scheduled to undergo an elective surgical or diagnostic procedure will be randomized at 
approximately 80 to 100 sites in regions that may include Asia/Pacific, Europe, Middle East, 
Africa, Latin America, and North America. (revised per Amendment 04) Only subjects who, in 
the opinion of the investigator, are expected to require platelet transfusion to address a risk of 
bleeding associated with the procedure will be recruited into this study. Subjects who do not 
meet all of the inclusion criteria or who meet any of the exclusion criteria will not be eligible to 
receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Subjects ≥18 years of age at Screening with chronic liver disease
2. Subjects who have a mean baseline platelet count of <50 × 109/L. Platelet counts must be 
measured on 2 separate occasions, during the Screening Period and at Baseline, and must be 
performed at least 1 day apart with neither platelet count >60 × 109/L.  The mean of these 2
platelet counts (mean baseline platelet count) will be used for entry criteria and for 
assignment to the low or high baseline platelet count cohort.
3. Subjects scheduled to undergo a permitted elective procedure and who, in the opinion of the 
investigator, will otherwise require a platelet transfusion to address a risk of bleeding 
associated with the procedure unless there is a clinically significant increase in platelet
count from baseline (revised per Amendments 02 and 03)
4. Model For End-stage Liver Disease (MELD) score ≤24 at Screening
5. If taking inhibitors of P glycoprotein (P-gp), except for verapamil, dose must be stable for 
7 days prior to Screening (see Appendix 2 for the list of P-gp Inhibitors)
6. Provide written informed consent
7. Willing and able to comply with all aspects of the protocol
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9.3.2
Exclusion Criteria
(revised per Amendment 02)
Subjects who meet any of the following criteria will be excluded from this study:
1. Any history of arterial or venous thrombosis, including partial or complete thrombosis
2. Evidence of thrombosis (partial or complete) in the main portal vein, portal vein branches, 
or any part of the splenic mesenteric system at Screening
3. Portal vein blood flow velocity rate <10 cm/second at Screening
4. Hepatic encephalopathy that cannot be effectively treated
5. Subjects with HCC and Barcelona Clinic Liver Cancer (BCLC) staging classification C 
or D
6. Platelet transfusion or receipt of blood products containing platelets within 7 days of 
Screening. However packed red blood cells are permitted
7. Heparin, warfarin, nonsteroidal anti-inflammatory drugs (NSAID), aspirin, verapamil, and 
antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) 
within 7 days of Screening
8. Use of erythropoietin stimulating agents within 7 days of Screening
9. Interferon (IFN) use within 14 days of Screening
10. Estrogen-containing hormonal contraceptive or hormone replacement therapy use within 
30 days of Screening
11. Active infection requiring systemic antibiotic therapy within 7 days of Screening.  
However, prophylactic use of antibiotics is permitted.
12. Alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence within 
6 months of the study start (unless participating in a controlled rehabilitation program) or 
acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the 
study start
13. Elective procedure performed prior to Visit 4 (Procedure Day)
14. Known to be human immunodeficiency virus (HIV) positive
15. Any clinically significant acute or active bleeding (gastrointestinal, central nervous system, 
etc.)
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16. Known history of any primary hematologic disorder (eg, ITP, myelodysplastic syndrome, 
etc.)
17. Known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden; 
prothrombin  G20210A; ATIII deficiency etc.) (revised per Amendment 01)
18. Subjects with a history of significant cardiovascular disease (eg, congestive heart failure 
New York Heart Association Grade III/IV, arrhythmia known to increase the risk of 
thromboembolic events [eg, atrial fibrillation], coronary artery stent placement, angioplasty, 
and coronary artery bypass graft [CABG])
19. Females of childbearing potential who have had unprotected sexual intercourse within 
30 days before study entry and who do not agree to use a highly effective method of 
contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as 
condom 
plus 
diaphragm 
with 
spermicide], 
a 
progesterone-only 
contraceptive 
implant/injection, or have a vasectomized partner with confirmed azoospermia) throughout 
the entire study period and for 30 days after study drug discontinuation.  If currently 
abstinent, the subject must agree to use a double-barrier method as described above if she 
becomes sexually active during the study period or for 30 days after study drug 
discontinuation. All females will be considered to be of childbearing potential unless they 
are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age 
group and without other known or suspected cause) or have been sterilized surgically 
(ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 1 month before 
dosing.
20. Females who are lactating or pregnant at Screening or Baseline (as documented by a 
positive serum beta-human chorionic gonadotropin [β-hCG] test with a minimum 
sensitivity 25 IU/L or equivalent units of β-hCG).  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before the 
first dose of study drug.
21. Post liver transplant subjects
22. Any subject who has previously received avatrombopag
23. Hypersensitivity to avatrombopag maleate or any of its excipients
24. Hemoglobin levels ≤8.0 or ≥18.0 g/dL for men and >15 for women at Screening, with 
hematocrit ≥54% for men and ≥45% for women
25. Current malignancy including solid tumors and hematologic malignancies (except HCC)
26. Any history of concomitant medical condition that, in the opinion of the investigator(s), 
would compromise the subject’s ability to safely complete the study
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27. Currently enrolled in another clinical trial with any investigational drug or device within 
30 days of Screening
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  The subject may stop study drug or withdraw from the study at any time for any reason.  
A subject who discontinues study treatment, but does not withdraw consent, should be followed 
for subsequent protocol-specified visits and procedures.
In these subjects, the Visit 4 (Procedure Day) assessments for the study will be performed as an 
end of study visit as outlined in Section 9.5.2.1 (Table 5), with the exception of the elective 
procedure, which may take place outside the study.  The primary reason for discontinuation and 
all other reason(s) contributing to the subject’s discontinuation from study drug should be 
collected on the Subject Disposition CRF page.
These subjects will also be required to complete a follow-up visit, Visit 6 (Day 35) assessments, 
which will be conducted approximately 30 days after the last dose of study drug.
9.4
TREATMENTS
In this study, the test drug is avatrombopag.  The study drugs are avatrombopag, expressed as the 
amount of free base, and placebo. 
9.4.1
Treatments Administered
Subjects will be instructed to take avatrombopag 20-mg tablets or matching placebo orally, once 
daily, with a meal, as follows:

Group A (avatrombopag, lower baseline platelet count):  60 mg avatrombopag 
(3 × 20-mg tablets) once daily on Days 1 through 5

Group B (placebo, lower baseline platelet count):  placebo (3 × 20-mg matching placebo 
tablets) once daily on Days 1 through 5

Group C (avatrombopag, higher baseline platelet count):  40 mg avatrombopag  
(2 × 20-mg tablets) once daily on Days 1 through 5 

Group D (placebo, higher baseline platelet count):  placebo (2 × 20-mg matching placebo 
tablets) once daily on Days 1 through 5
On Day 4 (Visit 3), subjects will take their study medication after the predose PK sample has 
been taken.
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9.4.2
Identity of Investigational Products
Avatrombopag and matching placebo will be supplied by the sponsor in labeled containers.  The 
product release certificates for avatrombopag will be included in the clinical study report for this 
study.
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study drug will consist of avatrombopag or corresponding matching placebo.
9.4.2.1
Generic and Chemical Name
●
Test drug code:
E5501
●
Generic name:
avatrombopag maleate
●
Chemical name:
1-(3-Chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-
cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-
carboxylic acid maleate
9.4.2.2
Comparator Drug
The comparator drug is matching placebo, which will be provided as matching 20-mg tablets.
9.4.2.3
Labeling for Study Drugs
Study drugs (ie, avatrombopag and placebo) will be labeled in accordance with text that is in full 
regulatory compliance with each participating country and is translated into the required 
languages for each of those countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range.  The investigator or designee is responsible for ensuring that 
the temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be enrolled into 2 cohorts according to mean baseline platelet count (<40 × 109/L 
or from 40 to <50 × 109/L), with neither baseline platelet count cohort comprising greater than 
55% of the total number of subjects enrolled into the study. Within each cohort, subjects will be 
further stratified centrally by risk of bleeding associated with the elective procedure (low, 
moderate, or high) and HCC status (Yes or No), in order to ensure balance between treatments 
within each cohort and each further stratum.  Within each cohort and each further stratum, 
subjects will be assigned in a 2:1 ratio to receive avatrombopag or placebo once a day for 5 days 
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based on a computer-generated randomization scheme using permuted-block randomization.  It 
is planned that no fewer than 10% of subjects will be enrolled into the high risk group and no 
more than 60% of subjects in the low-risk group.  The randomization scheme and identification 
for each subject will be kept strictly confidential before the database lock and final unblinding, 
and will be included in the final clinical study report for this study.
Approximately 200 subjects who meet all the eligibility requirements will be randomized.  
(revised per Amendment 04)
Randomization will be performed centrally by an IxRS.  The IxRS or clinical supply vendor will 
generate the randomized study drug identification numbers.  After successful completion of 
Visit 1, the investigator or designee will call or access via web the IxRS to register the subject 
information and the IxRS will assign each subject a unique 6-digit randomization number at 
Visit 2.  
9.4.4
Selection of Doses in the Study
Dose selection has been carefully focused on seeking to maintain an appropriate risk:benefit ratio 
balance in this patient population, removing the requirement for platelet transfusion, or any 
rescue procedure for bleeding, while minimizing the risk of thromboembolic events.  The 
selected doses, based on modeling and simulation of the E5501-G000-202 study data, are aimed 
at achieving sufficient efficacy (eliminating the need for platelet transfusion) while specifically 
limiting the proportion of subjects achieving platelet counts >200 × 109/L to less than 2%.
The current study design employs a dosing regimen according to baseline platelet count that is 
anticipated to lead to a similar overall rise in platelet counts irrespective of baseline platelet 
count.  
9.4.5
Selection and Timing of Dose for Each Subject
Subjects will be instructed to take avatrombopag 20-mg tablets or matching placebo orally, once 
daily, with a meal.  On Day 4 (Visit 3), subjects will take their study medication after the predose 
PK sample has been taken.
9.4.6
Blinding
During the study, subjects and all personnel involved with the conduct and interpretation of the 
study, including investigators, site personnel, and sponsor staff will be blinded to the treatment 
codes.  Randomization data will be kept strictly confidential, filed securely by an appropriate 
group with the sponsor and accessible only to authorized persons (eg, Eisai Global Safety) until 
the time of unblinding, per SOP.
A master list of all treatments and the subject numbers associated with them will be maintained 
in a sealed envelope by the IxRS vendor, and the sponsor.  In the event that emergency 
conditions require knowledge of the study treatment given, the blind may be broken via the code 
breaker facility within the IxRS.  Emergency procedures for revealing drug codes are given in 
Section 9.5.4.5.  
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A subject’s treatment should only be unblinded when knowledge of the treatment is essential for 
further management of the subject.  A subject whose treatment is unblinded will not receive any 
further study medication.  If possible, before breaking the blind, the investigator should consult 
with the sponsor to ascertain the necessity of breaking the code.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the subject 
during the study and used by the subject within 30 days before Visit 1 will be recorded on the 
Prior & Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  The 
investigator will record on the Adverse Event CRF any AE for which the concomitant 
medication/therapy was administered.  If the concomitant medication/therapy is being 
administered for a medical condition present at the time of entry into the study, the investigator 
will record the medical condition on the Medical History and Current Medical Condition CRF.
9.4.7.1
Permitted Prior Therapy
Subjects who have taken IFN previously, but who have discontinued use for at least 14 days 
before Screening, are eligible for this study. Subjects who have taken erythropoietin-stimulating 
agents, but who have discontinued use for at least 7 days before Screening, are eligible for this 
study.  Subjects who have taken heparin, warfarin, NSAIDs, aspirin, verapamil, or antiplatelet 
therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban), but who have 
discontinued use for at least 7 days before Screening, are eligible for this study.  Subjects who 
are taking inhibitors of P-gp (excluding verapamil) and are on a stable dose for at least 7 days 
before Screening are eligible for this study.  Subjects who have received platelet transfusion or 
blood products containing platelets, but who have had their last treatment at least 7 days prior to 
Screening, are eligible for this study; however packed red blood cells are permitted throughout.
9.4.7.2
Permitted Concomitant Therapy
Subjects should be instructed to contact site personnel before starting any new medications or 
treatments.  Medications or treatments not specified as prohibited (see below) are permitted 
during the study.  
All prescription drugs, herbal products, nutritional supplements (including vitamins), and over 
the counter medications are to be recorded, as well as any changes in concomitant medications, 
including dose, after Visit 1 and while the subject is in the study. Stable doses of inhibitors of 
P-gp are permitted during the study. The dose of these medications should remain unchanged 
until the first postprocedure visit (Visit 5).  Please refer to Appendix 2 for a list of P-gp 
inhibitors.
Subjects may receive therapy if clinically indicated as rescue therapy for bleeding.  
9.4.7.3
Prohibited Concomitant Therapy
Erythropoietin stimulating agents are prohibited throughout the study. Interferon use is 
prohibited during the study; however, at the investigator’s discretion, subjects may restart IFN 
therapy if clinically indicated during the Follow-up Phase (ie, after Visit 4 [Procedure Day]).
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Eltrombopag, romiplostim, heparin, warfarin, NSAIDs, aspirin, verapamil, estrogen, and 
antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) are 
prohibited. (revised per Amendment 02)  Aspirin, for antiplatelet therapy, can be prescribed at 
the discretion of the investigator in subjects in which the platelet count rises and who are 
believed to have an increased risk of thrombosis.  In subjects where use of aspirin is 
contraindicated, an alternate antiplatelet therapy such as a platelet adenosine diphosphate 
receptor inhibitor (eg, clopidogrel) can be prescribed.  It should be noted that clopidogrel should 
be used with due consideration in subjects with liver disease.  Lack of activation due to liver 
disease could lead to a reduction in activation of the prodrug.  In addition, as clopidogrel is 
activated by the CYP system, care is required when administering clopidogrel to subjects with 
liver disease and co-administering clopidogrel with agents that are substrates or inhibitors of 
CYP.
9.4.8
Treatment Compliance
Subjects will receive a dosing diary in which they are to record the dates and times of their study 
drug doses.
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates will review treatment compliance during site visits and at the completion of 
the study.
9.4.9
Drug Supplies and Accountability
The investigator and the study staff will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping) following the sponsor’s instructions and adherence 
to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not enrolled 
in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study drugs, 
dispensing of study drugs to the subject, collection and reconciliation of unused study drugs that 
are either returned by the subjects or shipped to site but not dispensed to subjects, and return of 
reconciled study drugs to the sponsor or (where applicable) destruction of reconciled study drugs 
at the site.  This includes, but may not be limited to:  (a) documentation of receipt of study drugs, 
(b) study drugs dispensing/return reconciliation log, (c) study drugs accountability log, (d) all 
shipping service receipts, (e) documentation of returns to the sponsor, and (f) certificates of 
destruction for any destruction of study drugs that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs and inventory records must be made available, upon request, for inspection by a 
designated representative of the sponsor or a representative of a health authority (eg, Food and 
Drug Administration, Medicines and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs and empty and partially empty containers from used study drugs are to be 
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returned to the investigator by the subject and together with unused study drugs that were 
shipped to the site but not dispensed to subjects are to be returned to the sponsor’s designated 
central or local depot(s) during the study or at the conclusion of the study, unless provision is 
made by the sponsor for destruction of study drugs and containers at the site.  Destruction at the 
site will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and reconciliation 
procedures by the site’s personnel and documentation procedures by the sponsor’s personnel, 
study drugs that are to be returned to the sponsor’s designated central or local depot(s) must be 
boxed and sealed and shipped back to the central or local depot(s) following all local regulatory 
requirements.  In some regions, study drugs may be removed from the site and hand delivered to 
the central or local depot by sponsor representatives.  Where study drugs are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
STUDY ASSESSMENTS
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth, age, sex, race, and ethnicity.
9.5.1.2
Baseline Assessments
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All significant medical and surgical history must be noted in the Medical History and 
Current Medical Conditions CRF.
Physical examinations (both comprehensive and targeted) will be performed as designated on the 
Schedule of Procedures/Assessments (Table 5).  A comprehensive physical examination will 
include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), 
abdomen, limbs, skin, and neurologic examination.  A urogenital examination will only be 
required in the presence of clinical symptoms related to this region.  A targeted physical 
examination will include evaluations of the heart and lungs, abdomen, and limbs.  Examinations 
of other regions will only be required in the presence of clinical symptoms related to this region. 
Documentation of the physical examination will be included in the source documentation at the 
site.  Significant findings at the Screening Visit will be recorded on the Medical History and 
Current Medical Conditions CRF.  Changes from screening physical examination findings that 
meet the definition of an AE will be recorded on the Adverse Events CRF.
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CONFIRMATION OF ELECTIVE PROCEDURE
Elective procedure(s) will be recorded at the Screening Visit.
CHILD–TURCOTTE-PUGH (CTP) SCORE
The subject’s Child–Turcotte-Pugh (CTP) score will be calculated based on the screening 
laboratory values and physical examination.  
MODEL FOR END-STAGE LIVER DISEASE (MELD) SCORE
The subject’s MELD score (based on serum bilirubin, serum creatinine, and INR for 
prothrombin time at Screening) will be calculated.  The MELD score must be ≤24 for inclusion 
into the study.  
BARCELONA-CLINIC LIVER CANCER (BCLC) STAGE
For subjects with HCC, the BCLC stage will be collected at Screening.
The BCLC staging 
classification must be 0, A, or B for inclusion in the study. Therefore, HCC subjects with a 
staging classification of C or D will be excluded from the study as these subjects have a higher 
risk of developing a PVT complication.  The BCLC staging classification guides treatment, 
particularly in early tumors. The BCLC staging system links tumoral stage with a treatment 
strategy, and is aimed at incorporating prognosis estimation and potential treatment 
advancements in 1 unified proposal, with Stage 0 and additional stages ranging from A to D. 
The system may be applied to most subjects with HCC, although individual cases might warrant 
special consideration.16
DOPPLER SONOGRAPHY WITH FLOW RATE
Subjects will be screened for evidence of PVT, including portal vein flow rate, using Doppler 
sonography before study entry.  All subjects whose platelet count exceeds 200 x 109/L will be 
required to have a Doppler assessment at Visit 5.  Three main portal vein blood flow velocity 
measurements, lasting no less than 4 seconds, will be recorded, and the mean of the 3 values 
recorded as the final reading.  Subjects will be required to have a main portal vein blood flow 
velocity rate of ≥10 cm/second at Screening to be eligible for the study.  The Doppler 
sonography and flow rate assessment can be completed at any time during the Screening Period 
with results available prior to randomization.
Guidelines have been developed to reduce inter-observer variability in measuring flow rates14 to 
ensure uniformity of flow rate measurements.  Every effort should be made to have the same 
sonography operator at the study site perform all ultrasound evaluations throughout the study.  
Please refer to Appendix 3 for additional information.
9.5.1.3
Efficacy Assessments
The timing of assessments is described in the Schedule of Assessments/Procedures (Table 5).  
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NUMBER OF PLATELET TRANSFUSIONS
The incidence of platelet transfusions will be monitored by the investigator (or appropriately 
delegated study site personnel) from randomization.  The number of transfusions administered (if 
used), along with date and start/stop times, will be specified and recorded in the CRF. In order 
to minimize missing data for the primary endpoint, “Not Done” (or “Not Applicable”) will be 
collected on the CRF to indicate subjects who did not receive a platelet transfusion.
ANY RESCUE PROCEDURE FOR BLEEDING
Any rescue procedure for bleeding will be monitored by the investigator (or appropriately 
delegated study site personnel) from randomization onwards.
Any rescue procedure for 
bleeding, including number of transfusions administered (if used), along with start and end 
dates/times, will be recorded.  In order to minimize missing data for the primary endpoint, “Not 
Done” (or “Not Applicable”) will be collected on the CRF to indicate subjects who did not 
receive rescue therapy.
The following are considered as rescue procedures when used specifically for bleeding:

Platelet transfusion

FFP

Cryoprecipitate

Vitamin K (phytonadione)

Desmopressin

Recombinant activated factor VII

Aminocaproic acid

Tranexanic acid (added per Amendment 01)

Whole blood transfusion

Packed red cell transfusion

Surgical intervention or interventional radiology
PLATELET COUNTS
Platelet count by local laboratory will be measured in all subjects at Screening (Days -14 to -1) 
and at Baseline (Day 1), then on the Procedure Day (Day 10), 7 days postprocedure and Day 35.  
Screening and Baseline platelet counts must be measured at least 1 day apart with neither platelet 
count >60 × 109/L for eligibility.
The mean of these 2 platelet counts (mean baseline platelet 
count <50 × 109/L) will be used for entry criteria.
BLEEDING EVENTS
All bleeding events will be assessed by the investigator (or appropriately delegated study site 
personnel) from randomization utilizing the WHO bleeding score (Table 2) and the Bleeding 
Academic Research Consortium (BARC) bleeding scale (Table 3).
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Table 2
WHO Bleeding Score Categories
Bleeding Grade
Description
Grade 0
No bleeding
Grade 1
Petechial bleeding
Grade 2
Mild blood loss (clinically significant)
Grade 3
Gross blood loss, requires transfusion (severe)
Grade 4
Debilitating blood loss, retinal or cerebral associated with fatality
Table 3
BARC Bleeding Scale Categories
Bleeding Type
Description
Type 0
No bleeding
Type 1
Minor bleeding (not requiring medical attention) 
Type 2
Mild blood loss (clinically significant - requiring evaluation or 
intervention)
Type 3a
Overt bleeding plus hemoglobin drop 3 to < 5 g/dL, requires transfusion
Type 3b
Overt bleeding plus hemoglobin drop ≥ 5 g/dL, requires IV vasoactive 
agents
Type 3c
Intracranial hemorrhage, intraocular bleed compromising vision
Type 4
Coronary artery bypass graft-related bleeding (CABG)a
Type 5a
Probable fatal bleeding; no autopsy or imaging confirmation
Type 5b
Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation
a: CABG is not a permitted procedure (see Section 9.3.2)
BARC bleeding scale based on Standardized bleeding definitions for cardiovascular clinical trials: a consensus 
report from the Bleeding Academic Research Consortium. (2011) 17
9.5.1.4
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic 
Assessments
PHARMACOKINETIC ASSESSMENTS
The pharmacokinetics of avatrombopag and effects of covariates will be assessed using 
population modeling.  A total of 3 blood samples for PK analysis will be collected. One sample
will be collected on Day 1 between 2 to 6 hours postdose. Two samples will be collected on
Day 4 (±1 day):  a predose sample within 2 hours prior to dosing and a second sample between 
2 to 6 hours postdose.  
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Please refer to the Laboratory Manual for a description of collection, handling, and shipping 
procedures for PK samples.
Plasma samples will be assayed for avatrombopag concentrations using a validated liquid 
chromatography-tandem mass spectrometry method with a lower limit of quantification of 
1.00 ng/mL.
Blood will also be drawn where possible at the first report of an SAE or severe unexpected AE 
and at its resolution.
PHARMACODYNAMIC ASSESSMENTS
Platelet count by local laboratory will be measured in all subjects at least 1 day apart at 
Screening (Days -14 to -1) and Baseline (Day 1), then on the Procedure Day (Day 10), 7 days 
postprocedure, and Day 35.
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS
The relationship between avatrombopag plasma concentrations and platelet count will be 
evaluated using population PK/pharmacodynamic (PD) modeling.  Effects of covariates on the 
PD parameters will be evaluated.  
PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0 grades (for both increasing and 
decreasing severity), and SAEs including platelet transfusion-related complications; regular 
monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital 
signs and electrocardiograms (ECG); the performance of physical examinations; and Doppler 
sonography as detailed in Table 5.
An independent DSMB will be established in order to ensure the safety of the subjects.  
ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is avatrombopag
The criteria for identifying AEs are:
●
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product
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●
Any new disease or exacerbation of an existing disease
●
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
●
Recurrence of an intermittent medical condition (eg, headache) not present at 
pretreatment (Baseline)
●
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not.
A laboratory result should be considered by the investigator to be an AE if it:
●
Results in the withdrawal of study drug
●
Results in withholding of study drug pending some investigational outcome
●
Results in an intervention, based on medical evaluation (eg, potassium supplement for 
hypokalemia)
●
Results in any out of range laboratory value that in the investigator’s judgment fulfills the 
definitions of an AE with regard to the subject’s medical profile
●
Increases in severity compared with baseline by ≥2 CTCAE grades (see Appendix 1 for 
CTCAE v 4.0), with the exception of lymphocytes, albumin, cholesterol, glucose, and 
phosphate. For these tests, any change of ≥2 grades will be evaluated by the investigator 
to determine if it is of clinical significance and, if so, will be considered an AE.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit. Serious AEs will be collected for 30 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event CRF. 
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE.  Medical and scientific judgment should be exercised in 
deciding whether an isolated laboratory abnormality should be classified as an AE.  
Abnormal ECG (QTc, corrected for heart rate) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc interval 
is >450 ms and there is an increase of >60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
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All AEs must be followed for 30 days after the subject’s last dose, or until resolution, whichever 
comes first.  
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
ASSESSING SEVERITY OF ADVERSE EVENTS
Adverse events will be graded on a 5-point scale according to CTCAE v4.018 as follows:
Grade 1 = 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2 = 
Moderate: minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living
Grade 3 = 
Severe or medically significant but not immediately life threatening hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities 
of daily living
Grade 4 = 
Life-threatening consequences: urgent intervention indicated
Grade 5 = 
Death related to AE
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing severity).  
All AEs reported using CTCAE classification and graded as 4 or 5 are to be considered serious.
The criteria for assessing severity are different from those used for seriousness (see Serious 
Adverse Events and Other Events of Interest for the definition of an SAE).
ASSESSING RELATIONSHIP TO STUDY TREATMENT
Items to be considered when assessing the relationship of an AE to the study treatment are:
●
Temporal relationship of the onset of the event to the initiation of the study treatment
●
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
●
Whether the event is known to be associated with the study treatment or with other 
similar treatments
●
The presence of risk factors in the study subject known to increase the occurrence of the 
event
●
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
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CLASSIFICATION OF CAUSALITY
Not Related
A causal relationship between the study treatment and the AE is not a reasonable 
possibility.
Related
A causal relationship between the study treatment and the AE is a reasonable 
possibility.  The investigator must further qualify the degree of certainty as 
“possible” or “probable.”
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
A SAE is any untoward medical occurrence that at any dose:
●
Results in death
●
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)
●
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Results in persistent or significant disability/incapacity
●
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent 1 of the outcomes in the definition of SAE listed above 
should also be considered SAEs.  Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication 
error; 
any 
treatment-emergent 
significant 
laboratory 
abnormality;
recurrence 
of 
thrombocytopenia (defined as a platelet count of <10 × 109/L and 10 × 109/L less than baseline 
count within 30 days of discontinuation); thromboembolic events; bleeding events (WHO 
Grade 2 to 4); and platelet transfusion-related complications. These events of interest are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of the 
above criteria.  All AEs associated with events of interest are to be reported on the CRF whether 
or not they meet the criteria for SAEs.  All liver transplantations are to be captured as SAEs.
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The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(ie, there is no untoward medical occurrence) associated with the hospitalization:
●
Hospitalizations for respite care 
●
Planned hospitalizations required by the protocol
●
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration).  
●
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
●
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug plasma concentration should be 
drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 4.  The Schedule of Procedures/Assessments (Table 5) shows the visits and 
time points at which blood for clinical laboratory tests and urine for urinalysis will be collected 
in the study.
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Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Complete Blood Count
hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (basophils, eosinophils, lymphocytes, monocytes, total 
neutrophils [segmented and bands])
Coagulation panel
prothrombin time, activated partial thromboplastin time, international 
normalized ratio
Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin, gamma-glutamyl 
transpeptidase
Renal function parameters
blood urea nitrogen, creatinine
Other
albumin, calcium, cholesterol, creatine phosphokinase with 
fractionation,  globulin, glucose, lactate dehydrogenase, phosphorus, 
total protein, triglycerides, uric acid
Urinalysis
bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, 
pH, protein, RBCs, specific gravity, WBCs
Protocol specified
human immunodeficiency virus serology, serum thrombopoietin
Females only
serum beta-human chorionic gonadotropin pregnancy tests, urine 
pregnancy tests
Platelet function tests a
eg, p-selectin and integrin IIbβ3 with and without an agonist. The 
following agonists will be used: 0.5 μM ADP, 20 μM ADP, 1.5 μM 
TRAP, or 20 μM TRAP
(eg, platelet aggregation with an agonist. ADP will be used as the 
agonist) (revised per Amendment 02)
ADP = adenosine diphosphate, RBC = red blood cell, TRAP = thrombin receptor agonist peptide, WBC = white 
blood cell
a: Performed only at selected sites 
Clinical laboratory tests during the study will be performed by the designated central laboratory.  
All blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  When a hematology test is required, 2 blood samples will 
be collected: 1 for central laboratory analysis and 1 for local laboratory analysis. Investigators 
will utilize the platelet count result received from the local laboratory hematology test analysis to 
qualify subject’s entry into the study, and also for clinical assessments.
Only platelet count data from local laboratories, including the date and clock time of collection 
of the sample, will be collected and entered into the CRF for analysis. All other hematological 
parameters will be collected and loaded into the database for analysis according to results 
derived from the designated central laboratory.
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A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Adverse Events and Other Events of Interest) and the CRF Completion Guidelines.  In these 
instances, the AE corresponding to the laboratory abnormality will be recorded on the Adverse 
Event CRF.
For laboratory abnormalities meeting the criteria of SAEs (see Serious Adverse Events and Other 
Events of Interest), the site must fax or email the SAE report including the laboratory report (as 
regionally required) to the sponsor using the SAE form (see Reporting of Serious Adverse 
Events [Section 9.5.4.1]).
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats per 
minute], respiration rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated on the Schedule of Procedures/Assessments (Table 5) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been sitting 
for 5 minutes.  Preferably, all blood pressure measurements will be performed on the same arm
and by the same person. 
PHYSICAL EXAMINATIONS
Physical 
examinations 
will 
be 
performed 
as 
designated 
on 
the 
Schedule 
of 
Procedures/Assessments (Table 5).  Documentation of the physical examination will be included 
in the source documentation at the site.  Only changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events CRF.
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated on the Schedule of Procedures/Assessments 
(Table 5).  Subjects must be in the supine position for a period of 5 minutes before the ECG.  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see Adverse 
Events and Other Events of Interest) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Serious Adverse Events and Other 
Events of Interest), the site must fax or email the SAE report including the ECG report to the 
sponsor using the SAE form (see Reporting of Serious Adverse Events [Section 9.5.4.1]).
OTHER SAFETY ASSESSMENTS
DOPPLER SONOGRAPHY 
Subjects will be screened for evidence of PVT and portal vein flow rate using Doppler 
sonography at Screening.  Only subjects whose preprocedural platelet count is >200 × 109/L on 
Visit 4 (Procedure Day) will be required to have a Doppler assessment at Visit 5.  For any 
subjects where the presence of a PVT is suspected, confirmation of diagnosis, via CT scan or 
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MRI, should be performed and treatment for PVT initiated per local guidelines.  Please refer to 
Appendix 3 for additional information.
VIRAL TESTS
A blood sample will be taken to test for HIV antibodies at Screening.
PREGNANCY TEST
At the Screening Visit, a serum β-hCG test will be performed for females of childbearing 
potential or who have been amenorrheic for less than 12 months.  All females will be considered 
to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive 
amenorrhea in the appropriate age group and without other known or suspected cause) or have 
been sterilized surgically (ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at 
least 1 month before dosing. A urine β-hCG test will be performed at other time points during 
the study, as specified in the Schedule of Procedures/Assessments (Table 5).
PLATELET FUNCTION
At selected sites, blood samples will be collected on Day 1 (Visit 2) before dosing (Baseline), on 
Day 4 (Visit 3), and on the Procedure Day (Day 10) for platelet function assessment.  Platelet 
function will be assessed using specified flow cytometric markers or platelet aggregometry at 
selected sites (Table 4).  Flow cytometry will be performed at Visits 2, 3, and 4.  Platelet 
aggregometory will be conducted on Day -14 to 1 (Visit 1 or 2) before dosing and on the 
Procedure Day (Day 10).   (revised per Amendment 02)
9.5.1.6
Other Assessments
HEALTH ECONOMIC ASSESSMENTS
Health economic parameters will be collected at each visit (as appropriate). Health care resource 
utilization, including any rescue treatment, procedure, and laboratory test for bleeding including 
the number of transfused platelet units, the supply from which the transfused platelet units were 
procured including whole blood platelets from a random donor pool (if known) with or without 
leukocyte depletion, as an apheresis product (as platelets alone) from a single donor and/or 
autologous blood donation, number of hospital days, number of intensive care bed-days, number 
of outpatient visits to the hospital’s outpatient department, the clinic, the physician’s office, 
home health care or other place of service, and health care resource utilization related to other 
transfusion-related complications during all scheduled and unscheduled visits will be collected in 
the CRF.
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 5 presents the schedule of procedures/assessments for the study.
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Table 5
Schedule of Procedures/Assessments in Study E5501-G000-310
Phase
Prerandomization
Randomization
Follow-Up
Period
Screening
Baseline
Treatment
Procedure Day 
Visit 
1
2
3
4a, b
5
6c
Day
Days -14 to -1
Day 1
Day 4 
(±1 day)
Day 10
(+3 days)
7 Days 
Postprocedure
(+3 days)
Day 35
(+3 days)
Procedures/Assessments 
Subject informed consent 
X 
Inclusion/Exclusion criteria
X 
X
Demographics
X
Medical history 
X 
CTP and MELD Scores
X 
BCLC graded
X
Prior/concomitant medications 
X 
X 
X
X
X
X
Health care resource use
X
X
X
X
X
Adverse events 
X 
X 
X 
X
X
X
Physical examinatione
X 
X
X
X
Vital signs (including height, weight)
X f
X
X
X
X
ECG (12-lead)
X 
X 
X
X
Hematology (including platelet count by 
local laboratory)g
Xh
Xh
X
X
X
X
Coagulation
X 
X
X 
Serum chemistry, liver function tests, CPK 
with fractionation, urinalysisi
X 
X
X 
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Table 5
Schedule of Procedures/Assessments in Study E5501-G000-310
continued
Phase
Prerandomization
Randomization
Follow-Up
Period
Screening
Baseline
Treatment
Procedure Day
Postprocedure
Visit 
1
2
3
4 a,b,c
5
6d
Day
Days -14 to -1
Day 1
Day 4 
(±1 day)
Day 10
(+3 days)
7 Days 
Postprocedure
(+3 days)
Day 35
(+3 days)
HIV serology
X
Pregnancy testingj
X
X 
X
X
Doppler sonography
Xk
Xl
Assessment of platelet transfusionm
X
X
X
X
Assessment of any rescue procedure for 
bleedingn
X
X
X
X
Serum TPO  
X
X
X
Platelet function testso
X
X
X
Randomization
X
PK blood sampling
Xp
Xp,q
Study drug dosingr,s
X
X
Dispense dosing diaryt
X
Retrieve/review dosing diary
X
X
Collect study drug, if applicable 
X
Bleeding assessment (WHO and BARC)
X
X
X
X
X
BARC = Bleeding Academic Research Consortium; BCLC = Barcelona Clinic Liver Cancer; CPK = creatine phosphokinase; CTP = Child-
Turcotte-Pugh; ECG = electrocardiogram; HIV = human immunodeficiency virus; MELD = Model For End-stage Liver Disease; PK = 
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Table 5
Schedule of Procedures/Assessments in Study E5501-G000-310
pharmacokinetics; TPO = thrombopoietin; WHO = World Health Organization
a:
Subjects will undergo their elective procedure within 5 to 8 days of their last dose of study drug (ie, Study Day 10 to13), and after completing
the Procedure Day assessments. 
b:
Visit 4 (Procedure Day) assessments will also occur when any subject has been withdrawn or discontinued early from the study for any reason.
c:
Visit 6 (Day 35) assessments will also occur when any subject has been withdrawn or discontinued early from the study for any reason.
d:
BCLC grade is only for subjects with hepatocellular carcinoma.
e:
Comprehensive physical examination at Screening and targeted physical examination at all subsequent visits.
f:
Height will be recorded at Screening (Visit 1) only.
g:
Hematology must be taken prior to any platelet transfusion
h:
Independent platelet counts performed by a local laboratory at Screening and Baseline must be at least 1 day apart with neither platelet count 
>60 × 109/L.  The mean of these 2 platelet counts (mean baseline platelet count) must be <50 x 109/L (as per Inclusion Criterion #2), to be 
eligible to participate in the study.        
i:
Complete urinalysis will be performed at Screening and dipstick analysis at all subsequent visits.  If urine dipstick is abnormal, a complete 
urinalysis will be required.  After the Screening measurement, fractionation will only be analyzed by the central laboratory in the event CPK 
level is abnormal.
j:
For females of childbearing potential or who have been amenorrheic for less than 12 months.  Serum beta-human chorionic gonadotropin 
pregnancy testing will be performed at Screening (Visit 1).  Urine pregnancy testing will be performed at Visits 2, 4, and 6.
k:
Portal vein flow velocity will be assessed at this visit. Subjects will be required to have a main portal vein blood flow velocity rate of 
≥10 cm/second at Screening to be eligible for the study.  
Three main portal vein blood flow velocity measurements, lasting no less than 4 seconds, will be recorded, and the mean of the 3 values 
recorded as the final reading.  
The Doppler sonography and flow rate assessment can be completed at any time during the Screening Period with results available prior to 
randomization.
l:
Only subjects whose preprocedural platelet count exceeds 200 × 109/L will be required to have a Doppler assessment at Visit 5.  For any 
subjects where the presence of a portal vein thrombosis (PVT) is suspected, confirmation of diagnosis via computerized tomography scan or 
magnetic resonance imaging, should be performed and treatment for PVT initiated per local guidelines.
m: Number of transfusions administered (if used), along with start and end dates/times, will be recorded.
n:
Any rescue procedure for bleeding, including number of transfusions administered (if used), along with start and end dates/times, will be 
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Table 5
Schedule of Procedures/Assessments in Study E5501-G000-310
recorded.
o:
Platelet function tests will be performed at selected sites. Flow cytometry will be performed at Visits 2, 3, and 4.  Platelet aggregometory will 
be performed on Day -14 to 1 (Visit 1 or 2) before dosing and on the Procedure Day (Day 10) (revised per Amendment 02).
p:
On Visit 2 (Day 1), 1 PK sample will be collected between 2 to 6 hours after dosing.
q:
On Visit 3 (Day 4 ±1), 2 PK samples will be collected:  predose (within 2 hours prior to dosing) and between 2 to 6 hours after dosing.
r:
Subjects will be randomized to receive placebo or avatrombopag as follows:
Group A (avatrombopag, lower baseline platelet count):  60 mg avatrombopag (3 × 20-mg tablets) once daily on Days 1 through 5
Group B (placebo, lower baseline platelet count):  placebo (3 × 20-mg matching placebo tablets) once daily on Days 1 through 5
Group C (avatrombopag, higher baseline platelet count):  40 mg avatrombopag (2 × 20-mg tablets) once daily on Days 1 through 5
Group D (placebo, higher baseline platelet count):  placebo (2 × 20-mg matching placebo tablets) once daily on Days 1 through 5
s:
All doses of study drug will be taken with a meal.
t:
Subjects will receive a dosing diary in which they are to record the dates and times of their study drug doses.
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9.5.3
Appropriateness of Measurements
All clinical assessments, including platelet counts, are standard measurements commonly used in 
studies of subjects with thrombocytopenia associated with liver disease.
The safety assessments to be performed in this study, including but not limited to hematology 
analyses, blood chemistry tests, urinalysis, physical examinations, ECGs, Doppler sonography, 
vital signs, and assessment of AEs, are standard evaluations to ensure subject safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no later 
than 24 hours from when the investigator becomes aware of the event.
Deaths and life-threatening events should be reported immediately by telephone.  The
immediate report should be followed up within 24 hours by emailing or faxing the 
completed SAE form.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for 30 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to the 
study treatment should be reported to the sponsor regardless of the length of time that has passed 
since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor to 
be filed in the sponsor’s Trial Master File.
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9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or within 
30 days of last study treatment, or any exposure to study drug through breastfeeding during study 
treatment or within 30 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.  The Pregnancy Report 
Form must be used for reporting.  All pregnancies must be followed to outcome.  The outcome 
of the pregnancy must be reported as soon as possible but no later than 1 business day from the 
date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Other Events of Interest
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, MISUSE,
ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  Overdose,
misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with the
protocol
Abuse
Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study drug use 
or subject harm while the study drug is in the control of site personnel or the
subject.  
All AEs associated with an overdose should be captured on the Adverse Event CRF.  Adverse 
events associated with overdose, misuse, abuse, or medication error should be reported using the 
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procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1) even if the AEs do 
not meet serious criteria.  Abuse is always to be captured as an AE.  If the AE associated with an 
overdose, misuse, abuse, or medication error does not meet serious criteria, it must still be 
reported using the SAE form and in an expedited manner but should be noted as nonserious on 
the SAE form and the Adverse Event CRF.
REPORTING OF SIGNIFICANT LABORATORY ABNORMALITY
Any significant treatment-emergent laboratory abnormality observed during the clinical study 
should be entered on the Adverse Event CRF and reported using the procedures detailed in 
Reporting of Serious Adverse Events (Section 9.5.4.1), even if the laboratory abnormality does 
not meet serious criteria.  If the significant laboratory abnormality does not meet serious criteria, 
it must still be reported using the SAE form and in an expedited manner but should be noted as 
nonserious on the SAE form and the Adverse Event CRF.
A laboratory result should be considered a treatment-emergent significant abnormality if the 
result:
●
Is within normal limits at baseline and has increased in severity to meet the sponsor’s 
grading criteria for laboratory values of Grade 3 or above
●
Is outside normal limits at baseline and increases in severity to the sponsor’s grading 
criteria for laboratory values of Grade 4 or above.  These abnormalities are automatically
considered to be serious, with the exception of expected and reproducible hematologic 
abnormalities.
●
Is otherwise considered by the investigator to meet serious criteria as defined in 
Section 9.5.1.5 (Serious Adverse Events and Other Events of Interest)
Significant laboratory abnormalities should not be listed as separate AEs or SAEs if they are 
considered to be part of the clinical syndrome that is being reported as an AE or SAE. 
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (ie, recurrence of thrombocytopenia [defined as a platelet count of 
<10 × 109/L and 10 × 109/L less than baseline count within 30 days of discontinuation]); 
thromboembolic events; bleeding events (WHO Grade 2 to 4); and platelet transfusion-related 
complications should be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event does not meet serious criteria, it must still be 
reported using the SAE form and in an expedited manner but should be noted as nonserious on 
the SAE form and the Adverse Event CRF.  All liver transplantations will be captured as SAEs.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within specific 
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time frames).  For this reason, it is imperative that sites provide complete SAE information in the 
manner described above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code for 
an individual subject.  In all such cases, the AE necessitating the emergency blind break will be 
handled as an SAE in accordance with the procedures indicated above.  Any broken code will be 
clearly justified and documented.  The medical monitor must be notified immediately of the 
blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All suspected 
unexpected serious adverse reactions will be reported, as required, to the CAs of all involved 
European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures the Visit 4 
(Procedure Day) assessments for the study will be performed as an end of study visit.
The investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and provide appropriate medical treatment and other necessary measures for the 
subject.  A subject who has ceased to return for visits will be followed up by mail, phone, or 
other means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms.  This 
information will be recorded in the CRF.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, withdrawal of 
consent, pregnancy, study terminated by sponsor, or administrative/other.  In addition to the 
primary reason, the subject may indicate 1 or more of secondary reasons for discontinuation.  
Study disposition information will be collected on the Subject Disposition CRF.
A subject removed from the study for any reason may not be replaced.
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9.5.6
Abuse or Diversion of Study Drug
Not applicable
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to receive 
medical care by another physician.  At each visit, the investigator will ask the subject whether 
he/she has received medical care by another physician since the last visit or is planning to do so 
in the future.  When the subject is going to receive medical care by another physician, the 
investigator, with the consent of the subject, will inform the other physician that the subject is 
participating in the clinical study.
9.6
DATA QUALITY ASSURANCE
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.  Site audits will be made 
periodically by the sponsor’s or the CRO’s qualified compliance auditing team, which is an 
independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator must sign the completed CRF to attest to its 
accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in any 
form to third parties without written permission from Eisai, except for authorized representatives 
of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
STATISTICAL METHODS
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released for unblinding.  However, unblinded safety analyses for 
review by a DSMB will be conducted by an independent statistical group prior to database lock.  
Statistical analyses will be performed using SAS® software or other validated statistical software 
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as required.  Details of the planned statistical analyses are outlined below; further details will be 
included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before the unblinded interim 
safety analyses, final database lock and treatment unblinding, and will be included in the clinical 
study report.  An interim statistical analysis plan, describing the safety analyses planned for the 
purposes of review by the DSMB, will also be produced.
9.7.1.1
Study Endpoints
PRIMARY ENDPOINTS
The primary efficacy endpoint is the proportion of subjects who do not require a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure.
SECONDARY ENDPOINTS
The secondary efficacy endpoints are:

Proportion of responders defined as subjects who achieve platelet counts of ≥50 × 109/L 
on Procedure Day (ie, prior to receiving a platelet transfusion or undergoing the elective 
procedure)

Change from baseline in platelet count on Procedure Day (ie, prior to receiving a platelet 
transfusion or undergoing the elective procedure)
(revised per Amendment 04)
EXPLORATORY ENDPOINTS
The exploratory endpoints are:

Platelet count and change from baseline in platelet count at each visit

Proportion of subjects who achieve platelet count of ≥50 × 109/L, ≥75 × 109/L, or 
≥200 × 109/L at each visit

Number of platelet units used per platelet transfusion episode

Severity of bleeding events assessed by WHO bleeding score and BARC bleeding scale

Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 
7 days following an elective procedure (revised per Amendment 04)

Health economics assessed by resource use
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9.7.1.2
Definitions of Analysis Sets
Full Analysis Set (FAS):  The FAS is the group of randomized subjects.  The FAS will be 
analyzed “as randomized”.
Per Protocol Set (PP):  The PP Set is the group of all randomized subjects who receive 
protocol-assigned study drug and do not meet any of the following criteria:

Subjects who have any major protocol violations (major inclusion/exclusion violations or 
other major protocol violations that impact the evaluation of efficacy)

Subjects who use a prohibited concomitant medication that affects the assessment of 
study endpoints

Subjects who are noncompliant in terms of study medication
A comprehensive list of subjects to be excluded from the PP will be agreed upon by the study 
team prior to database lock.  The PP will be analyzed “as randomized”.
Safety Analysis Set:  The Safety Analysis Set is the group of subjects who receive at least 1 dose 
of study drug and have at least 1 postdose safety assessment.  This set will be analyzed “as 
treated.”
PK Analysis Set:  The PK Analysis Set is the group of randomized subjects who receive at least 
1 dose of avatrombopag and have at least 1 quantifiable avatrombopag concentration with a 
documented dosing history.
PK/PD Analysis Set:  The PK/PD Analysis Set is the group of randomized subjects who receive 
at least 1 dose of avatrombopag, have at least 1 quantifiable avatrombopag concentration, and at 
least 1 platelet count, with a documented dosing history.
9.7.1.3
Subject Disposition
Subject disposition will be summarized by treatment group for the FAS and Safety Analysis set. 
The number (percentage) of subjects who completed or discontinued prematurely from the study 
and their reason for discontinuation will be summarized by treatment group.  In addition, the 
number of subjects screened and the number and percentage of subjects who failed screening and 
the reasons for screen failure will be summarized, based on data recorded on the Screening 
Disposition CRF.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis set will be 
summarized for each treatment group using descriptive statistics or frequency count.  Continuous 
demographic and baseline variables include age, weight, height, body mass index, MELD score, 
CTP score, and baseline platelet count; categorical variables include sex, race, ethnicity group, 
baseline platelet count stratification level, risk of bleeding associated with the elective procedure, 
and HCC status.  
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9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded using the WHO Drug 
Dictionary.  The number and percentage of subjects who took prior and concomitant medications 
will be summarized for the Safety Analysis set by treatment group, Anatomical Therapeutic 
Chemical class (indicating therapeutic class) and WHO Drug Dictionary preferred term.  Prior 
medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 30 days after the subject’s last dose.  
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary population for the efficacy analyses, while the PP will be 
used as a supportive analysis.  All analyses of platelet counts will be based on local laboratory 
results.
PRIMARY EFFICACY ANALYSIS
The primary efficacy variable is the proportion of subjects who do not require a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure.
The null hypothesis is that the proportion of subjects not requiring a platelet transfusion or any 
rescue procedure for bleeding after randomization and up to 7 days following an elective 
procedure is the same between the avatrombopag and placebo treatment groups.  The 
corresponding alternative hypothesis is that the proportion of subjects not requiring a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure is not the same between avatrombopag and placebo. This hypothesis will 
be tested separately within each baseline platelet cohort.
The proportion of subjects not requiring a platelet transfusion or any rescue procedure for 
bleeding will be tested between the individual avatrombopag treatment group (40 or 60 mg) and 
matching placebo within each baseline platelet count cohort (<40 × 109/L or from 40 to 
<50 × 109/L), each at a significance level of α=0.05, using the generalized Cochran Mantel 
Haenszel (CMH) test adjusting for risk of bleeding associated with the elective procedure (low, 
moderate, or high based on Amendment 02 categorization).  

For subjects with platelet count <40 x 109/L at baseline, the treatment comparison will be 
carried out between the 60 mg avatrombopag treatment group versus matching placebo.

For subjects with platelet count from 40 to <50 × 109/L at baseline, the treatment 
comparison will be carried out between the 40 mg avatrombopag treatment group versus 
matching placebo.
This study will be considered as positive if statistical significance is achieved for the primary 
efficacy endpoint for both baseline platelet count cohorts.
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The 95% confidence interval (CI) for the proportion of subjects not requiring a platelet 
transfusion or any rescue procedure for bleeding will be calculated for each treatment group 
within each baseline platelet count cohort.  In addition, the 95% CI for the difference between 
avatrombopag and matching placebo will be provided within each baseline platelet count cohort.
Since the HCC status is included in the randomization stratification for safety purposes only, not 
for efficacy consideration, HCC will not be included in the CMH model for the primary efficacy 
analysis.
Subjects with missing information about the primary efficacy outcome due to early withdrawal 
or other reasons will be considered as having received a transfusion for the primary analysis.
The following analyses will be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based 
on the PP analysis set. 

Observed case: The same primary efficacy analyses described above will be repeated 
based on observed data.  Subjects with missing information about the primary efficacy 
outcome will be excluded from this analysis.

Fisher’s exact Test: The same primary efficacy analyses described above will be carried 
out using Fisher’s exact test.

Modified primary efficacy endpoint: Proportion of subjects who do not require a platelet 
transfusion after randomization and up to 7 days following an elective procedure.  This 
efficacy endpoint will be analyzed using the same approach as primary efficacy analysis 
using FAS. 
Additional sensitivity analyses may also be explored, if deemed appropriate.
SECONDARY EFFICACY ANALYSES
There are 2 secondary efficacy endpoints in this study:  (revised per Amendment 04)

Proportion of responders defined as subjects who achieve target platelet counts of 
≥50 × 109/L on Procedure Day (prior to receiving a platelet transfusion or undergoing the 
elective procedure)

Change from baseline in platelet count on Procedure Day (prior to receiving a platelet 
transfusion or undergoing the elective procedure)
The analysis of the secondary efficacy variables as defined above will proceed following a 
sequential gatekeeping testing procedure with the multiplicity adjustment to  control the Type I 
error rate at significance level α=0.05.  
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The proportion of subjects who achieve platelet counts of ≥50 × 109/L on the Procedure Day will 
be analyzed first.  The proportion of subjects with platelet counts of ≥50 × 109/L on the 
Procedure Day will be tested between the individual avatrombopag treatment group (40 or 
60 mg) and matching placebo separately within each baseline platelet count cohort (<40 × 109/L 
or from 40 to <50 × 109/L), each at a significance level of α=0.05, using the generalized CMH 
test adjusting for risk of bleeding associated with the elective procedure (low, moderate, or high
based on Amendment 02 categorization). 
The second secondary efficacy variable, change from baseline in platelet count on the Procedure 
Day, will be analyzed only if the test for the first secondary efficacy variable is statistically 
significant for both baseline platelet count cohorts.  The change from baseline in platelet count 
will be analyzed using the Wilcoxon rank sum test separately within each baseline platelet count 
cohort (<40 × 109/L or from 40 to <50 × 109/L), each at a significance level of α=0.05.  (revised 
per Amendment 04)
EXPLORATORY EFFICACY ANALYSES
The following efficacy variables are considered exploratory:

Platelet count and change from baseline in platelet count at each visit

Proportion of subjects who achieve platelet count of ≥50 × 109/L, ≥75 × 109/L, or 
≥200 × 109/L at each visit

Number of platelet units used per platelet transfusion episode

Severity of bleeding events assessed by WHO bleeding score and BARC bleeding scale

Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 
7 days following an elective procedure (revised per Amendment 04)
In general, the continuous variables will be analyzed within an analysis of covariance framework
or Wilcoxon rank sum test, as appropriate.  Categorical variables will be analyzed using CMH, 
Chi-square or Fisher's exact test.  Additional analysis may be performed as needed using 
appropriate statistical methodologies as specified in the SAP. 
Subgroup analyses will be performed on the primary efficacy variable, including age group 
(<65 and ≥65 years old); sex (male and female); race (white, black, asian and other); geographic 
region; bleeding risk associated with the elective procedure (low, moderate, or high based on 
Amendment 02 categorization); MELD score (<10, 10-14, and >14); and CTP grade (A, B, and 
C).  Additional subgroups may be explored, if deemed appropriate.
No adjustment for multiplicity is planned for exploratory, subgroup and sensitivity analyses.
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9.7.1.7
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic Analyses
PHARMACOKINETIC ANALYSES
Plasma concentration versus time data will be listed. 
The data will be analyzed using a 
population PK approach to estimate population PK parameters and the effect of covariates on the 
PK parameters will be evaluated. 
For the population PK analysis, data from this study will be pooled with PK data from two
Phase 2 studies in subjects with thrombocytopenia associated with liver disease, including 
hepatitis C, and possibly with data from Phase 1 studies.
The population PK analysis will be performed to characterize the PK of avatrombopag in 
subjects with thrombocytopenia associated with liver disease, and to screen for potential 
covariates with any significant and clinically relevant effects on avatrombopag PK.  The PK 
model will be parameterized for absorption rate constant, apparent clearance, and apparent 
volume of distribution.  Derived exposure parameters will be area under the concentration-time 
curve and maximum plasma concentration.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
The relationship between avatrombopag concentration and platelet count will be analyzed using 
a population PK/PD approach to estimate population PD parameters and the effect of covariates 
on the PD parameters will be evaluated. 
For the PK/PD modeling, data from this study will be pooled with PK/PD data from two Phase 2 
studies in subjects with thrombocytopenia associated with liver disease, including hepatitis C, 
and possibly with data from Phase 1 studies.
The population PK and PK/PD analyses will be detailed in a separate analysis plan.
PHARMACOGENOMIC/PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety assessment will be 
summarized for overall and within each baseline platelet count cohort as appropriate.  Safety 
assessments including AEs, laboratory tests, vital signs, and ECG will be summarized by 
treatment groups using descriptive statistics (mean, standard deviation, median, minimum and 
maximum) or frequency count as appropriate.  No hypothesis testing will be performed for safety 
assessment.
Study Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
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EXTENT OF EXPOSURE
The extent of exposure to study drug will be characterized by duration of exposure (in days) for 
each treatment group.
Duration of exposure will be defined as the number of days between the date the subject received 
the first dose of study drug and the date the subject received the last dose of study drug.  
Duration of exposure will be summarized using descriptive statistics by treatment group.  In 
addition, the duration of exposure will be categorized and will be summarized using frequency 
count by treatment group.
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 15.1 or higher) lower level 
term closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary system 
organ class (SOC) are also captured in the database.
A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
30 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
●
Reemerges during treatment (up to 30 days after the last dose of study drug), having been 
present at pretreatment (Baseline) but stopped before the last dose of study drug plus 
30 days, or 
●
Worsens in severity during treatment (up to 30 days after the last dose of study drug) 
relative to the pretreatment state, when the AE is continuous.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
Treatment-emergent AEs will be summarized by treatment group.  The following summaries will 
be reported for TEAEs:
●
Incidence of TEAEs by SOC and PT 
●
Incidence of treatment-related TEAEs by SOC and PT
●
Incidence of TEAEs by SOC, PT, and CTCAE Grade
●
Incidence of TEAEs by SOC, PT, and relationship to treatment.
A subject will be counted only once within a SOC and PT, even if the subject experienced more 
than 1 TEAE within a specific SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs:
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●
Incidence of treatment-emergent SAEs by SOC and PT 
●
Incidence of treatment-related treatment-emergent SAEs by SOC and PT
●
Incidence of treatment-emergent SAEs by SOC, PT, and relationship to treatment
In addition, subjects with TEAEs, treatment-related TEAEs leading to discontinuation from 
study treatment, and AEs of special interest for this study (including recurrence of 
thrombocytopenia, thromboembolic events and bleeding events [WHO Grade 2 to 4]) will also 
be summarized for each treatment group.
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  With 
the exception of urinalysis, platelet function tests, and platelet count (which is considered as an 
efficacy parameter), for all quantitative parameters listed in Section 9.5.1.5 Safety Assessments 
(Laboratory Measurements), the actual value and the change from baseline to Procedure Day and 
to the end of the Follow-up Phase will be summarized by treatment group using descriptive 
statistics.  Analysis of changes from baseline will be based on the number of subjects with both 
nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Shifts from baseline (LNH) to Procedure Day and to the end of the Follow-up Phase will 
be presented for each laboratory parameter.  Similar shift tables from baseline (LNH) to the 
highest/lowest postbaseline LNH classification will also be provided.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used to 
identify subjects with treatment-emergent markedly abnormal laboratory values (TEMAV). 
Except for phosphate, a TEMAV is defined as a postbaseline value with an increase from 
baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a postbaseline value 
with an increase from baseline to a grade of 3 or higher.  The number and percentage of subjects 
with TEMAVs will be presented by treatment group; each subject may be counted once in the 
laboratory parameter high and in the laboratory parameter low categories, as applicable.  
Markedly abnormal laboratory values will be flagged in the subject data listings.
VITAL SIGNS
Descriptive statistics for vital sign parameters (i.e. diastolic and systolic blood pressure, pulse, 
respiration rate, body temperature, and weight) and changes from baseline will be presented by 
visit and treatment group.
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
and treatment group.  ECG interpretation (categorized as normal; abnormal, not clinically 
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significant; and abnormal, clinically significant) will be presented by visit and treatment group
using frequency count.
OTHER SAFETY ANALYSES
Results from Doppler sonography and platelet function tests will be presented.
9.7.1.9
Other Analyses
HEALTH ECONOMIC ANALYSES
The health outcome economics, as measured by healthcare resources utilization, will be 
summarized by item and by treatment group. The categorical variables will be tested using 
CMH, Chi-squared or Fisher's exact test, while continuous variables may be analyzed by t-test or 
Wilcoxon rank sum test as appropriate.
Details of these analyses will be provided in a separate analysis plan.
9.7.2
Determination of Sample Size
The proposed sample size is based on comparisons of the primary efficacy variable, with the 
response rate defined as the proportion of subjects who do not require a platelet transfusion or 
any rescue procedure for bleeding after randomization and up to 7 days following an elective 
procedure.  Based on clinical opinion and the published results of a similar compound in adults 
with thrombocytopenia associated with liver disease (ELEVATE study),10 the response rate in 
the placebo group is assumed to be 18%.  With each baseline platelet count cohort, a sample size 
of 100 randomized subjects, 67 subjects for avatrombopag and 33 subjects for placebo, will have 
greater than 90% power to detect an absolute difference of 35% between the avatrombopag 
response rate and the placebo response rate assuming 18% response rate for placebo using 
Fisher’s Exact tests with a 2-sided α=0.05.  (revised per Amendment 04)  The hypothesized 
treatment group difference is based on platelet count changes found in the Phase 2 study (E5501-
G000-202) and dose-response modeling using data from that study and others in the project 
development.  Based on the baseline data in the Phase 2 study and assuming these are projected 
to be similar for this study, it is anticipated that this study will enroll roughly half of the total 
number of subjects in each of the 2 baseline platelet count cohorts to make the total sample size 
of 200 randomized subjects, 133 subjects for avatrombopag and 67 subjects for placebo.  
(revised per Amendment 04)
9.7.3
Interim Analysis
No interim efficacy analysis is planned, and therefore no adjustment of the P-value for the final 
efficacy analysis is needed.  However, to protect subjects’ safety, an independent DSMB will be 
established to monitor the ongoing safety data. Some of the safety parameters that DSMB will 
review will include variables that are also being assessed in this study for efficacy (eg, platelet 
count to ensure there are not too many subjects with a platelet count that exceeds 200 × 109/L 
and bleeding).  The DSMB interim safety analysis will be performed by an independent 
statistician and governed by an external DSMB.  To maintain the blinding and integrity of the 
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study, procedures will be implemented to ensure the DSMB and independent statistician have 
sole access to unblinded interim safety data.
Full details of the DSMB procedures, including primary responsibilities of the DSMB, its
relationship with other study components, its membership, and its purpose and timings of its 
meetings, will be documented in a DSMB Charter.  These details will also include procedures to 
ensure confidentiality and proper communication, the guidelines to be implemented by the 
DSMB, and an outline of the content of the closed reports (unblinded) and open reports (blinded) 
that will be provided to the DSMB.  
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be described in the SAP.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will 
be documented and described in the clinical study report.
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10 REFERENCE LIST
1. Slichter SJ.  Evidence-based platelet transfusion guidelines.  Hematology.  Am Soc 
Hematol Educ Program.  2007:172-8.
2. Schiffer C, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, et al. 
Platelet transfusion for patients with cancer: Clinical Practice Guidelines of the American 
Society of Clinical Oncology. J Clin Oncol. 2001;19:1519-38.
3. Kuter DJ.  Thrombopoietin: biology and potential clinical applications.  In: McCrae KR, 
editor.  Thrombocytopenia.  New York: Taylor & Francis Group; 2006.  p. 17-53.
4. Poordad F, Theodore D, Sullivan J, Grotzinger K. Evaluating medical resource utilization 
and costs associated with thrombocytopenia in chronic liver disease patients.  J Med 
Econ.  2012;15(1):112-24.
5. Tripodi A, Primignani M, Chantarangkul V, Dell’era A, Clerici M, De Franchis R, et al.
An imbalance of pro- vs. anti-coagulation factors in plasma from patients with cirrhosis.
Gastroenterol. 2009;137:2105-11.
6. Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, et al. 
Hemostasis and thrombosis in patients with liver disease: the ups and downs.  J Hepatol. 
2010;53:362-71.
7. Ponziani FR, Zocco MA, Campanale C, Rinninella E, Tortora A, Di Maurizio L, et al. 
Portal vein thrombosis: insights into physiopathology, diagnosis and treatment. World J 
Gastroenterol. 2010;16(2):143-55.
8. Fimognari FL, Violi F. Portal vein thrombosis in liver cirrhosis.
Intern Emerg Med. 
2008;3:213-8.
9. Englesbe MJ, Kubus J, Muhammad W, Sonnenday CJ, Welling T, Punch JD. Portal vein 
thrombosis and survival in patients with cirrhosis. Liver Trans. 2010;16:83-90.
10. Afdhal NH, Giannini EG, Tayyab G, Mohsin A, Lee JW, Andriulli A, et al. Eltrombopag 
before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 
2012;367:716-24.
11. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedical
Products/ucm211796.htm
12. http://clinicaltrials.gov/ct2/show/results/NCT00678587?term=promacta+elevate&rank=1
&sect=Xa015#outcome4
13. Zocco MA, Di Stasio E, De Cristofaro R, Novi M, Ainora ME, Ponziani F, et al. 
Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring 
system and portal vein thrombosis development. J Hepatol. 2009;51:682-9.
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14. Sabba C, Merkel C, Zoli M, Ferraioli G, Gaiani S, Sacerdoti D, et al. Interobserver and 
interequipment variability of echo-doppler examination of the portal vein: effect of a 
cooperative training program. Hepatol. 1995;21:428-33.
15. Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis RB, et al. for the 
Standards of Practice Committee with Cardiovascular and Interventional Radiological 
Society of Europe (CIRSE) Endorsement. Consensus guidelines for periprocedural 
management of coagulation status and hemostasis risk in percutaneous image-guided 
interventions. J Vasc Interv Radiol 2009; 20:S240–9.
16. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma.  Lancet. 2003;362:1907-17.
17. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized 
bleeding definitions for cardiovascular clinical trials: a consensus report from the 
Bleeding Academic Research Consortium. Circulation. 2011;123:2736-47.
18. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES)
11.1 CHANGES TO THE PROTOCOL
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the sponsor before implementation.  Amendments specifically affecting the 
safety of subjects, the scope of the investigation, or the scientific quality of the study require 
submission to health or regulatory authorities as well as additional approval by the applicable 
IRBs/IECs of all investigational sites.  These requirements should in no way prevent any 
immediate action from being taken by the investigator, or by the sponsor, in the interest of 
preserving the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to eliminate 
an immediate hazard to the subjects, the sponsor’s medical monitor and the IRB/IEC for the site 
must be notified immediately.  The sponsor must notify the health or regulatory authority as 
required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local regulations.  
In these cases, the sponsor may be required to send a letter to the IRB/IEC and the CA detailing 
such changes.
11.2 ADHERENCE TO THE PROTOCOL
The investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5).
11.3 MONITORING PROCEDURES
The CRO’s CRA will maintain contact with the investigator and designated staff by telephone, 
letter, or email between study visits.  Monitoring visits to each site will be conducted by the 
assigned CRA as described in the monitoring plan.  The investigator will allow the CRA to 
inspect the clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the local 
auditing agency and IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following:
●
Clinic, office, or hospital charts
●
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
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●
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, CT scans, MRIs, radioactive images, ECGs, rhythm strips, 
electroencephalograms, polysomnographs, pulmonary function tests, aggregation tracing
at selected sites) regardless of how these images are stored, including microfiche and 
photographic negatives (revised per Amendment 02)  
●
Pain, quality of life, or medical history questionnaires completed by subjects
●
Records of telephone contacts
●
Diaries or evaluation checklists
●
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
●
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
●
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
●
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4 RECORDING OF DATA
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except when a 
section of the CRF itself is used as the source document.  Any correction to entries made on the 
CRF must be documented in a valid audit trail where the correction is dated, the individual 
making the correct is identified, the reason for the change is stated, and the original data are not 
obscured.  Only data required by the protocol for the purposes of the study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor and 
retain a copy of the CRFs.
Data will be recorded electronically (See Section 9.6.1).
11.5 IDENTIFICATION OF SOURCE DATA
All data to be recorded on the CRF must reflect the corresponding source documents.
11.6 RETENTION OF RECORDS
The circumstances of completion or termination of the study notwithstanding, the investigator is 
responsible for retaining all study documents, including but not limited to the protocol, copies of 
CRFs, the Investigator's Brochure, and regulatory agency registration documents (eg, Form FDA 
1572, ICFs, and IRB/IEC correspondence).  In addition, the sponsor will send a list of treatment 
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codes by study subject to the investigator after the clinical database for this study has been 
locked.  The site should plan to retain study documents, as directed by the sponsor, for at least 
2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 3 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records.
11.7 AUDITING PROCEDURES AND INSPECTION
In addition to the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s SOPs 
to evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform the sponsor immediately.
11.8 HANDLING OF STUDY DRUG
All study drug will be supplied to the principal investigator (or a designated pharmacist) by the 
sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and 
stored according to the conditions specified on the drug labels.  The investigator (or a designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the study drug 
in a drug accountability ledger, a copy of which must be given to the sponsor at the end of the 
study.  An accurate record of the date and amount of study drug dispensed to each subject must 
be available for inspection at any time.  The CRA will visit the site and review these documents 
along with all other study conduct documents at appropriate intervals once study drug has been 
received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA.
11.9 PUBLICATION OF RESULTS
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant to 
the terms and conditions set forth in the executed Clinical Trial Agreement between the 
sponsor/CRO and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either at the date of the commencement of the study or 
generated during the study.
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The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10DISCLOSURE AND CONFIDENTIALITY
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and will not be 
disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of the sponsor.  No data collected as part of 
this study will be used in any written work, including publications, without the written consent of 
the sponsor.  These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Trial Agreement 
executed between the sponsor/CRO and the institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11DISCONTINUATION OF STUDY
The sponsor reserves the right to discontinue the study for medical reasons or any other reason at 
any time.  If a study is prematurely terminated or suspended, the sponsor will promptly inform 
the investigators/institutions and regulatory authorities of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC will also be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so dictate.  If 
the investigator terminates or suspends a study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform the sponsor and the IRB/IEC and provide the sponsor and the IRB/IEC 
with a detailed written explanation of the termination or suspension.  Study records must be 
retained as noted above.
11.12SUBJECT INSURANCE AND INDEMNITY
The sponsor will provide insurance for any subjects participating in the study in accordance with 
all applicable laws and regulations.
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12 APPENDICES
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Appendix 1
Sponsor’s Grading for Laboratory Values
(revised per Amendment 02)
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
< LLN – 10.0 g/dL
< LLN – 100 g/L
< LLN – 6.2 mmol/L
< 10.0 – 8.0 g/dL
< 100 – 80 g/L
< 6.2 – 4.9 mmol/L 
< 8.0 g/dL
< 80 g/L
< 4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
< LLN – 3.0 x 109/L
< LLN – 3000/mm3
< 3.0 – 2.0 x 109/L
< 3000 – 2000/mm3
< 2.0 – 1.0 x 109/L
< 2000 – 1000/mm3
< 1.0 x 109/L
< 1000/mm3 
Lymphocytes 
< LLN – 800/mm3 
< LLN – 0.8 x 109/L
< 800 – 500/mm3
< 0.8 – 0.5 x 109/L
< 500 – 200/mm3
< 0.5 – 0.2 x 109/L
< 200/mm3
< 0.2 x 109/L
Neutrophils 
< LLN – 1.5 x 109/L
< LLN – 1500/mm3
< 1.5 – 1.0 x 109/L
< 1500 – 1000/mm3
< 1.0 – 0.5 x 109/L
< 1000 – 500/mm3 
< 0.5 x 109/L
< 500/mm3 
Platelets
< LLN – 75.0 x 109/L
< LLN – 75,000/mm3
< 75.0 – 50.0 x 109/L
< 75,000 – 50,000/mm3
< 50.0 – 25.0 x 109/L
< 50,000 – 25,000/mm3
< 25.0 x 109/L
< 25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
< LLN – 3 g/dL
< LLN – 30 g/L
< 3 – 2 g/dL
< 30 – 20 g/L
< 2 g/dL
< 20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
ALT
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
AST
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Bicarbonate, serum-low 
< LLN – 16 mmol/L
< 16 – 11 mmol/L
<11 – 8 mmol/L
< 8 mmol/L 
Bilirubin (hyperbilirubinemia)
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN
> 3.0 – 10.0 x ULN 
> 10.0 x ULN
Calcium, serum-low (hypocalcemia) 
< LLN – 8.0 mg/dL
< LLN – 2.0 mmol/L
< 8.0 – 7.0 mg/dL
< 2.0 – 1.75 mmol/L
< 7.0 – 6.0 mg/dL
< 1.75 – 1.5 mmol/L
< 6.0 mg/dL
< 1.5 mmol/L
Calcium, serum-high (hypercalcemia)
> ULN – 11.5 mg/dL
> ULN – 2.9 mmol/L
> 11.5 – 12.5 mg/dL
> 2.9 – 3.1 mmol/L
> 12.5 – 13.5 mg/dL
> 3.1 – 3.4 mmol/L
> 13.5 mg/dL
> 3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
> ULN – 300 mg/dL
> ULN – 7.75 mmol/L 
> 300 – 400 mg/dL
> 7.75 – 10.34 mmol/L 
> 400 – 500 mg/dL
> 10.34 – 12.92 mmol/L 
> 500 mg/dL
> 12.92 mmol/L 
Creatinine
> ULN – 1.5 x ULN
> 1.5 – 3.0 x ULN
> 3.0 – 6.0 x ULN
> 6.0 x ULN
GGT (γ-Glutamyl transpeptidase) 
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
> ULN – 160 mg/dL
> ULN – 8.9 mmol/L 
Fasting glucose value:
> 160 – 250 mg/dL
> 8.9 – 13.9 mmol/L 
Fasting glucose value:
> 250 – 500 mg/dL;
> 13.9 – 27.8 mmol/L;
hospitalization indicated
Fasting glucose value:
> 500 mg/dL;
> 27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
< LLN – 55 mg/dL
< LLN – 3.0 mmol/L
< 55 – 40 mg/dL
< 3.0 – 2.2 mmol/L
< 40 – 30 mg/dL
< 2.2 – 1.7 mmol/L
< 30 mg/dL
< 1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
< LLN – 2.5 mg/dL
< LLN – 0.8 mmol/L
< 2.5 – 2.0 mg/dL
< 0.8 – 0.6 mmol/L
< 2.0 – 1.0 mg/dL
< 0.6 – 0.3 mmol/L
< 1.0 mg/dL
< 0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
> ULN – 5.5 mmol/L 
> 5.5 – 6.0 mmol/L
> 6.0 – 7.0 mmol/L
hospitalization indicated
> 7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
< LLN – 3.0 mmol/L
< LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
< 3.0 – 2.5 mmol/L
hospitalization indicated
< 2.5 mmol/L
life-threatening 
consequences
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Sodium, serum-high (hypernatremia)
> ULN – 150 mmol/L
> 150 – 155 mmol/L
> 155 – 160 mmol/L
hospitalization indicated
> 160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
< LLN – 130 mmol/L
N/A
< 130 – 120 mmol/L
< 120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
> 300 – 500 mg/dL
> 3.42 – 5.7 mmol/L 
> 500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
> 1000 mg/dL
> 11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
> ULN – 10 mg/dL 
≤ 0.59 mmol/L without 
physiologic 
consequences 
N/A
> ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
> 10 mg/dL
> 0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, 
WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
List of P-glycoprotein Inhibitors
Inhibitor
Therapeutic Class
amiodarone 
Antiarrhythmics 
azithromycin 
Antibiotics 
captopril 
ACE Inhibitors 
carvedilol 
α/β Adrenergic Antagonists 
clarithromycin 
Antibiotics 
conivaptan 
Diuretics 
cremophor 
RH40 Transporter Modulators
cyclosporine
Immunosuppressive
diltiazem 
Calcium Channel Blockers 
dronedarone
Antiarrhythmics 
elacridar (GF120918) 
Transporter Modulators 
erythromycin 
Antibiotics 
felodipine 
Calcium Channel Blockers 
ginkgo
Herbal Medications
indinavir and ritonavir
Protease Inhibitors
itraconazole 
Antifungals 
ketoconazole
Antifungal
lopinavir and ritonavir 
Protease Inhibitors 
mibefradil 
Calcium Channel Blockers 
milk thistle 
Herbal Medications
nifedipine 
Calcium Channel Blockers 
nitrendipine 
Calcium Channel Blockers 
quinidine 
Antiarrhythmics 
ranolazine 
Cardiovascular Drugs 
ritonavir 
Protease Inhibitors 
talinolol 
α/β Adrenergic Antagonists 
telaprevir 
Antivirals
telmisartan
Angiotensin II Inhibitors 
tipranavir/ritonavir
Protease Inhibitors
tolvaptan
Vasopressin Antagonist
valspodar (PSC 833) 
Transporter Modulators 
verapamil 
Calcium Channel Blockers 
Source:  University of Washington Drug Drug Interaction database (except for cyclosporine and ketoconazole) 
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Appendix 3
Guidelines for Doppler Sonography Measurements
The key to collecting relevant ultrasound data is consistency.  The following measures are 
adopted to minimize the variability of data obtained. 
Minimize subject variability:

The subject should be fasting for at least 4 hours prior to the Doppler sonography
o
Rationale: Portal vein flow rate increases after food intake

The subject should be in the supine position for at least 15 minutes prior to the Doppler 
sonography
o
Rationale: Posture has an impact on portal vein flow rate. Standardizing posture 
across study sites can minimize variability

The subject should be instructed to take a full inspiration and hold his/her breath for a 
few seconds during portal vein flow measurement
o
Rationale: Measuring portal vein flow rate at the same point in the respiratory 
cycle can minimize variability
Minimize operator variability:
In order to minimize operator variability, the following instructions are provided:

When possible, the same trained sonography operator will perform all of the Doppler 
sonography testing on all subjects at the study site throughout the study. 

The portal vein should be scanned longitudinally 

Sample volume should be positioned in the center of the vessel, in the tract underneath 
the hepatic artery, covering 50% of the vessel diameter

The Doppler angle should be 55º or just below

Pulse repetition frequency should be 4 kHz; the high pass filter should be adjusted to 
100 Hz

The Doppler and B-mode tracings should be recorded simultaneously

The average portal blood maximum velocity should be obtained by manual tracing of the 
upper limit of the Doppler waveforms

The Doppler waveform calculation should be obtained by covering 2 cardiac cycles 
between 3 arterial wall artifacts
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
Portal vein diameter should be measured from the inner anterior to the inner posterior 
wall
Three main portal vein blood flow velocity measurements, lasting no less than 4 seconds, will be 
recorded, and the mean of the 3 values recorded as the final reading.  
Minimize equipment variability:
Different equipment may furnish different results due to interequipment variability.  Therefore, 
the sponsor recommends that the same Doppler equipment should be used at the study site 
throughout the study. 
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E5501-G000-310
Study Protocol Title:
A Randomized, Global, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of 
Once-daily Oral Avatrombopag for the Treatment of Adults with 
Thrombocytopenia Associated with Liver Disease Prior to an
Elective Procedure
Investigational Product
Name:
E5501/avatrombopag maleate
IND Number:
76,680
EudraCT Number:
2013-000965-34
SIGNATURES (revised per Amendment 02)
Authors:
Eisai Inc.
Date
Eisai Ltd.
Date
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E5501-G000-310
Study Protocol Title:
A 
Randomized, 
Global, 
Double-blind, 
Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of Once-
daily Oral Avatrombopag for the Treatment of Adults with 
Thrombocytopenia Associated with Liver Disease Prior to an 
Elective Procedure
Investigational Product
Name:
E5501/avatrombopag maleate
IND Number:
76,680
EudraCT Number:
2013-000965-34
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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SAP_001.pdf: 
Clinical Study Report 
E5501-G000-310 
 
16.1.9 
Documentation of Statistical Methods 
The final approved Statistical Analysis Plan and other statistical documents, as applicable, for 
this study are provided in the following pages. 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E5501-G000-310 
Study Protocol 
Title: 
A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group 
Study to Evaluate the Efficacy and Safety of Once-daily Oral 
Avatrombopag for the Treatment of Adults with Thrombocytopenia 
Associated with Liver Disease Prior to an Elective Procedure 
Date: 
Feb. 16, 2017 
Version: 
Final 3.0 
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SIGNATURE PAGE 
Author: 
Eisai Inc. 
 
 
[electronic signature in EDGE]  
Signature 
Date:  ______________ 
 
Approval 
Project Statistician: 
 
 
 
Biostatistics Head of Neuroscience and 
General Medicine PCU: 
 
 Eisai Inc. 
 
 
 
 
 
[electronic signature in EDGE] 
Signature 
 
Date: ________________ 
 
 
 
 
 
 
 
[electronic signature in EDGE] 
Signature 
Date: ________________ 
Study Director: 
 
Eisai Ltd. 
 
 
 
[electronic signature in EDGE] 
Signature 
Date: ________________ 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS 
3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5 
3 
INTRODUCTION 
6 
3.1 
Study Objectives 
6 
3.1.1 
Primary Objective(s) 
6 
3.1.2 
Secondary Objective(s) 
6 
3.1.3 
Exploratory Objective(s) 
6 
3.2 
Overall Study Design and Plan 
7 
4 
DETERMINATION OF SAMPLE SIZE 
10 
5 
STATISTICAL METHODS 
11 
5.1 
Study Endpoints 
11 
5.1.1 
Primary Endpoint(s) 
11 
5.1.2 
Secondary Endpoint(s) 
11 
5.1.3 
Exploratory Endpoint(s) 
11 
5.2 
Study Subjects 
12 
5.2.1 
Definitions of Analysis Sets 
12 
5.2.2 
Subject Disposition 
12 
5.2.3 
Protocol Deviations 
13 
5.2.4 
Demographic and Other Baseline Characteristics 
13 
5.2.5 
Prior and Concomitant Therapy 
14 
5.2.6 
Treatment Compliance 
14 
5.3 
Data Analysis General Considerations 
14 
5.3.1 
Pooling of Centers 
14 
5.3.2 
Adjustments for Covariates 
14 
5.3.3 
Multiple Comparisons/Multiplicity 
15 
5.3.4 
Examination of Subgroups 
15 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
15 
5.3.6 
Other Considerations 
15 
5.4 
Efficacy Analyses 
16 
5.4.1 
Primary Efficacy Analyses 
16 
5.4.1.1 
Sensitivity Analysis 
17 
5.4.1.2 
Subgroup Analysis 
17 
5.4.2 
Secondary Efficacy Analyses 
18 
5.4.2.1 
Proportion of subjects achieved platelet counts of ≥50 × 
109/L on the Procedure Day 
18 
5.4.2.2 
Change from baseline in platelet count on the Procedure 
Day 
18 
5.4.3 
Other Efficacy Analyses 
19 
5.4.3.1 
Platelet count and change from baseline in platelet 
count at each visit 
19 
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5.4.3.2 
Proportion of responders defined as subjects who 
achieve platelet counts of ≥50 × 109/L, ≥75 × 109/L, or 
≥200 × 109/L at each visit 
19 
5.4.3.3 
Number of platelet units used per platelet transfusion 
episode 
19 
5.4.3.4 
Severity of bleeding event assessed by WHO bleeding 
score and BARC bleeding scale 
19 
5.4.3.5 
Proportion of subjects with a WHO bleeding score ≥2 
after randomization and up to 7 days following an 
elective procedure 
19 
5.5 
Pharmacokinetic , Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses 
20 
5.5.1 
Pharmacokinetic Analyses 
20 
5.5.2 
Pharmacodynamic Analyses 
20 
5.5.3 
Pharmacogenomic/Pharmacogenetic Analyses 
20 
5.6 
Safety Analyses 
20 
5.6.1 
Extent of Exposure 
20 
5.6.2 
Adverse Events 
20 
5.6.3 
Laboratory Values 
22 
5.6.4 
Vital Signs 
22 
5.6.5 
Electrocardiograms 
22 
5.6.6 
Other Safety Analyses 
23 
5.6.6.1 
Adverse Events of Special Interest 
23 
5.6.6.2 
Doppler Sonography 
23 
5.6.6.3 
Platelet Function Test 
23 
5.7 
Other Analyses 
24 
5.7.1 
Health Outcome Economics Analyses 
24 
5.8 
Exploratory Analyses 
24 
5.9 
Extension Phase Analyses 
24 
6 
INTERIM ANALYSES 
24 
7 
CHANGES IN THE PLANNED ANALYSES 
24 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
25 
8.1 
Visit Window 
25 
8.2 
Missing Data Handling 
26 
9 
PROGRAMMING SPECIFICATIONS 
26 
10 
STATISTICAL SOFTWARE 
26 
11 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
27 
12 
REFERENCES 
27 
13 
APPENDICES 
28 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results 
28 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ANOVA 
analysis of variance 
ATC 
anatomical therapeutic class 
BARC 
Bleeding Academic Research Consortium 
BCLC 
Barcelona-Clinic Liver Cancer 
BMI 
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CTCAE  
common terminology criteria for adverse events 
CTP 
Child-Turcotte-Pugh 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
FAS 
full analysis set 
HCC 
hepatocellular carcinoma 
LNH 
low/normal/high 
INR 
international normalized ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-stage Liver Disease 
NI 
non-inferiority 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
per protocol analysis set 
PT 
preferred term 
QTcB 
corrected QT interval by Bazett’s formula  
QTcF 
corrected QT interval by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation  
SI 
Système International 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TLG 
tables, listings, and graphs 
WHO  
World Health Organization  
WHO DD 
World Health Organization Drug Dictionary 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Eisai Protocol E5501-G000-310 
(Version 7.0), Amendment 4.  
This document is prepared based on the study protocol (dated December 2, 2016).  Reader is 
referred to the final study protocol, the case report form (CRF), general CRF completion 
guidelines for details of study design, conduct and data collection. 
3.1 
STUDY OBJECTIVES 
3.1.1 
Primary Objective(s) 
The primary objective of the study is to confirm that avatrombopag (60 mg avatrombopag for 
subjects with platelet count <40 × 109/L and 40 mg avatrombopag for subjects with platelet 
count from 40 to <50 × 109/L) is superior to placebo in removing the need for platelet 
transfusions or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure in chronic liver disease patients who have thrombocytopenia. 
3.1.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
• To confirm that avatrombopag is superior to placebo in achieving a platelet count of 
≥50 x 109/L on Procedure Day in the proposed target population 
• To confirm that avatrombopag is superior to placebo in elevating platelet counts from 
baseline on Procedure Day in the proposed target population 
• To evaluate the safety of avatrombopag in the proposed target population 
3.1.3 
Exploratory Objective(s) 
The exploratory objectives of the study are: 
• To characterize the pharmacokinetics (PK) and the relationship between avatrombopag 
plasma concentrations and platelet count using the population approach 
• To characterize platelet count changes from baseline, the extent of platelet transfusion 
use, evaluate the incidence of bleeding events, and assess the severity of any bleeding 
events 
• To evaluate the health economic impact associated with minimizing the need for platelet 
transfusions and any rescue procedure for bleeding associated with an elective procedure 
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3.2 
OVERALL STUDY DESIGN AND PLAN 
E5501-G000-310 is a Phase 3, global, multicenter, randomized, double-blind, placebo-
controlled, parallel group study using avatrombopag to treat adults with thrombocytopenia 
associated with liver disease prior to an elective procedure.   
Subjects meeting all entry criteria will be enrolled into 2 cohorts according to mean baseline 
platelet count (<40 × 109/L or from 40 to <50 × 109/L).  Within each cohort, subjects will be 
further stratified by the risk of bleeding associated with the elective procedure (low, moderate or 
high) and hepatocellular carcinoma (HCC) status (Yes or No).  From previous studies, it is 
anticipated that the 2 baseline platelet count cohorts (<40 × 109/L and from 40 to <50× 109/L) 
will be equally represented.  However, neither baseline platelet count cohort will be permitted to 
comprise greater than 55% of the total number of subjects enrolled into the study.   
Permitted procedures and the risk of bleeding associated with each procedure are listed in 
Table 1.  It is planned that no fewer than 10% of subjects will be enrolled into the high risk 
group and no more than 60% of subjects in the low-risk group. 
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Table 1 
Permitted Procedures and the Risk of Bleeding Associated with Each 
Procedure 
Risk of Bleeding 
Associated 
with 
Procedure 
Procedure 
Low risk  
Paracentesis 
Thoracentesis 
Gastrointestinal endoscopy with or without plans for biopsy, 
colonoscopy, polypectomy, or variceal banding  
Moderate risk  
Liver biopsy 
Bronchoscopy with or without plans for biopsy 
Ethanol ablation therapy or chemoembolization for HCC 
High risk  
Vascular catheterization (including right side procedures in subjects 
with pulmonary hypertension) 
Transjugular intrahepatic portosystemic shunt  
Dental procedures 
Renal biopsy 
Biliary interventions 
Nephrostomy tube placement 
Radiofrequency ablation 
Laparoscopic interventions 
Level of risk based on key opinion leader (KOL) input and Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis 
RB, et al. for the Standards of Practice Committee with Cardiovascular and Interventional Radiological Society of Europe 
(CIRSE) Endorsement. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in 
percutaneous image-guided interventions. J Vasc Interv Radiol 2009; 20:S240–9. 
 
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Within the lower baseline platelet count cohort (<40× 109/L) and each stratum, subjects will be 
randomized in a 2:1 ratio to receive avatrombopag or matching placebo as follows: 
• 60 mg avatrombopag on Days 1 to 5 (Group A) 
• Matching placebo on Days 1 to 5 (Group B) 
Within the higher baseline platelet count cohort (from 40 to <50 × 109/L) and each stratum, 
subjects will be randomized in a 2:1 ratio to receive avatrombopag or matching placebo as 
follows:  
• 40 mg avatrombopag on Days 1 to 5 (Group C) 
• Matching placebo on Days 1 to 5 (Group D) 
Platelet counts must be measured on 2 separate occasions, during the Screening Period and at 
Baseline, and must be performed at least one day apart with neither platelet count >60 × 109/L.  
The average of these 2 platelet counts will be used for entry criteria (the mean baseline platelet 
count of <50 × 109/L).  The elective surgical or diagnostic procedure is scheduled to be 
performed within 10 to 13 days of first dose of study drug. 
This study will consist of 3 phases: Prerandomization, Randomization, and Follow-up Phases.   
The Prerandomization Phase consists of a Screening Period (Visit 1) that will take place from 
Day -14 through Day -1.  During this period, the type and schedule of the elective procedure will 
be confirmed. 
The Randomization Phase includes the Baseline Period, Treatment Period, and Procedure Day.  
During the Baseline Period (Visit 2), subjects who have met all entry criteria, provided signed 
informed consent, and been randomized will be instructed to take study drug during the 
Treatment Period on Days 1 to 5.  During the Treatment Period, subjects will come in for PK 
samplings on Day 4 (Visit 3). The elective procedure will be performed 5 to 8 days after last 
dose of study drug (Study Day 10 to 13) after all assessments on Visit 4 (Procedure Day) have 
been performed. The elective procedure for those subjects whose preprocedural platelet count is 
>200 × 109/L on Visit 4 may be delayed at the discretion of the investigator until platelet counts 
are below 200 × 109/L.  All subjects whose platelet count exceeds 200 × 109/L will be required to 
have a Doppler assessment at Visit 5.   
The Follow-up Phase encompasses 2 visits: 7 days post Procedure Day (Visit 5) and 30 days 
after receiving the last dose of study drug (Visit 6).    
An overview of the study design is presented in Figure 1 
 
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Figure 1 
Study Design  
PLT = platelet count; R = randomization 
Platelet counts must be measured on 2 separate occasions, during the Screening Period and at Baseline, and must be 
performed at least one day apart with neither platelet count >60 × 109/L.  The mean of these 2 platelet counts (mean 
baseline platelet count <50 × 109/L) will be used for entry criteria and determination of baseline platelet count. 
a:  Visit 3 occurs on Day 4 (±1 day) during the Treatment Period.   
 
4 
DETERMINATION OF SAMPLE SIZE 
The proposed sample size was based on comparisons of the primary efficacy variable, with the 
response rate defined as the proportion of subjects who do not require a platelet transfusion or 
any rescue procedure for bleeding after randomization and up to 7 days following an elective 
procedure.  Based on clinical opinion and the published results of a similar compound in adults 
with thrombocytopenia associated with liver disease (ELtrombopag EValuated for its Ability to 
overcome Thrombocytopenia and Enable procedures [ELEVATE] study [Afdahl, 2012])2, the 
response rate in the placebo group is assumed to be 18%.  Within each baseline platelet count 
cohort, a sample size of 100 randomized subjects, 67 subjects for avatrombopag and 33 subjects 
for placebo, would have greater than 90% power to detect an absolute difference of 35% between 
the avatrombopag response rate and the placebo response rate assuming 18% response rate for 
placebo using Fisher’s Exact tests with a 2-sided α=0.05.  The hypothesized treatment group 
difference was based on platelet count changes found in the Phase 2 study (E5501-G000-202) 
and dose-response modeling using data from that study and others in the project development.  
Based on the baseline data in the Phase 2 study and assuming these were projected to be similar 
for this study, it was anticipated that this study would enroll roughly half of the total number of 
subjects in each of the 2 baseline platelet count cohorts to make the total sample size of 200 
randomized subjects, 133 subjects for avatrombopag and 67 subjects for placebo. 
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5 
STATISTICAL METHODS 
Descriptive statistics will be reported for continuous variables using mean, standard deviation 
(SD), median, minimum and maximum.  Categorical variables will be summarized using 
frequency count as number (percentage) of subjects.  Graphical displays of the data might be 
presented where appropriate to aid interpretation. 
5.1 
STUDY ENDPOINTS 
5.1.1 
Primary Endpoint(s) 
The primary efficacy endpoint is the proportion of subjects who do not require a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure. 
5.1.2 
Secondary Endpoint(s) 
The secondary efficacy endpoints are: 
• Proportion of responders defined as subjects who achieve platelet counts of ≥50 × 109/L 
on Procedure Day (i.e., prior to receiving a platelet transfusion or undergoing the elective 
procedure) 
• Change from baseline in platelet count on Procedure Day (i.e., prior to receiving a 
platelet transfusion or undergoing the elective procedure)  
5.1.3 
Exploratory Endpoint(s)  
The exploratory endpoints are: 
• Platelet count and change from baseline in platelet count at each visit 
• Proportion of responders defined as subjects who achieve platelet counts of ≥50 × 109/L, 
≥75 × 109/L, or ≥200 × 109/L at each visit 
• Number of platelet units used per platelet transfusion episode 
• Severity of bleeding event assessed by WHO bleeding score and Bleeding Academic 
Research Consortium (BARC) bleeding scale 
• Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 7 
days following an elective procedure 
• Health economics assessed by resource use 
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5.2 
STUDY SUBJECTS 
5.2.1 
Definitions of Analysis Sets 
Full Analysis Set (FAS):  The FAS is the group of all subjects who are randomized into the 
study.  
Per Protocol Analysis Set (PP):  The PP is the group of all randomized subjects who receive 
protocol-assigned study drug and do not meet any of the following criteria: 
• Baseline platelet count of >50 × 109/L   
• Subjects who were enrolled in the study despite not being planned for transfusion even in 
the event of no significant increase of platelet count 
• Taking prohibited prior medications or prior transfusion 
• Presence of significant bleeding at baseline  
• Did not have a protocol permitted procedure on Day 8 - 15 
• Received dose different from the intended dose  
• Received <80% of the total dose or received >40% of total dose without food 
• No elective procedures or elective procedure outside day 8-15 
• Subject received platelet transfusion before knowing V4 platelet count 
• Subject refused platelet transfusion 
 
Subjects who met any of the criteria listed above will be excluded from the PP due to possible 
introduction of bias.   
Safety Analysis Set:  The Safety Analysis Set is the group of subjects who receive at least one 
dose of study drug and have at least one post dose safety assessment.   
The number (percentage) of subjects in each analysis set will be summarized by treatment groups 
using descriptive statistics.  The summaries for FAS and PP will be based on subjects “as 
randomized”.  The summary for Safety Analysis Set will be based on subjects “as treated”. 
5.2.2 
Subject Disposition 
Subject disposition will be summarized by treatment group for FAS and the Safety Analysis Set.  
The number (percentage) of subjects who completed or discontinued prematurely from the study 
and their reason for discontinuation will be summarized by treatment group.  In addition, the 
number of subjects screened and the number and percentage of subjects who failed screening and 
the reasons for screen failure will be summarized, based on data recorded on the Screening 
Disposition CRF.   
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5.2.3 
Protocol Deviations 
Major protocol deviations will be identified, reviewed and documented by the clinical team prior 
to database lock/treatment unblinding.  All protocol deviations will be categorized according to 
standard classifications including the following: 
 
• Violations of inclusion/exclusion criteria 
• Noncompliance with protocol procedures/assessments 
• Noncompliance of drug dosage 
• Use of prohibited treatments 
 
All significant protocol deviations will be listed, and summarized by category and by treatment 
group.   
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the FAS and Safety Analysis set will be 
summarized for each treatment group and overall using descriptive statistics or frequency count.  
Continuous demographic variables include age, weight, height and body mass index (BMI); 
categorical variables include age group (<65, and ≥65 years old), sex, ethnicity, race, region and 
country.  The following baseline disease characteristics will also be summarized: 
• Baseline platelet count and its category (<40 × 109/L and 40 to <50 × 109/L) 
• Bleeding risk associated with the elective procedure (low, moderate and high based on 
Amendment 02 categorization) and the type of elective procedure 
• HCC status (yes and no) and Barcelona-Clinic Liver Cancer (BCLC) stage (0, A, B, C 
and D) 
• Model for End-stage Liver Disease  (MELD) score 
• Child-Turcotte-Pugh (CTP) score and CTP grade (A, B and C) 
• Baseline international normalized ratio (INR) and its category (≤1.6 and >1.6) 
• Portal vein flow rate as per Doppler Sonography assessment 
• Creatinine clearance and disease etiology.  
MEDICAL HISTORY 
All medical histories as documented by the Investigator will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).   
The number (percentage) of subjects reporting a history of any medical condition will be 
summarized by System Organ Class (SOC), preferred term for each treatment group and overall 
based on FAS.   
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5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded on the CRF will be coded using the WHO Drug 
Dictionary (WHO DD).   
Prior medications are defined as medications that stop prior to the first dose of study drug.  
Concomitant medications are defined as medications that (1) start before the first dose of study 
drug and are continuing at the time of the first dose of study drug, or (2) start on or after the date 
of the first dose of study drug, up to 30 days after the last dose of study drug. 
The number (percentage) of subjects who take prior and concomitant medications will be 
summarized using the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical 
(ATC) Classification, and WHO DD preferred term.  In addition, the number (percentage) of 
subjects who take the concomitant medications associated with elective procedures will also be 
summarized using the Safety Analysis Set by treatment group, ATC Classification, and WHO 
DD preferred term. 
If a subject takes the same medications for the same class level or drug name, the subject will be 
counted only once for that class level or drug name. 
5.2.6 
Treatment Compliance 
Treatment compliance is defined as follows: 
 
Total number of tablets dispensed – total number of  tablets returned 
Total number of tablets subject should have taken  
Treatment compliance will be summarized using descriptive statistics by treatment group based 
on FAS and Safety Analysis Set.  Treatment compliance will also be summarized by treatment 
group using the categories <80%, ≥80% to ≤100%, >100% to ≤120%, and >120%. 
5.3 
DATA ANALYSIS GENERAL CONSIDERATIONS 
The FAS will be used as the primary population for all efficacy analyses, while the PP will be 
used in supportive analyses of the primary efficacy endpoint and Safety analysis set will be used 
for all safety analyses.  Unless stated otherwise, all efficacy analyses will be performed at α=0.05 
significance level and only descriptive statistics or frequency count will be generated for safety 
analyses without any hypothesis testing. 
5.3.1 
Pooling of Centers  
This study is a multicenter international study with an estimated 100 centers participating in the 
study.  Due to small expected number of subjects in each center, all analyses will be performed 
with all centers pooled across the study unless stated otherwise.  Consistency of results across 
geographic regions will be examined as specified in the respective sections in this document. 
5.3.2 
Adjustments for Covariates 
The primary efficacy endpoint, the proportion of subjects without platelet transfusion or any 
rescue procedure for bleeding, and the first secondary efficacy endpoint, proportion of subjects 
with platelet count ≥50 × 109/L on Procedure Day, will be analysed separately within each 
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baseline platelet count cohort (<40 × 109/L or from 40 to <50 × 109/L) using the Cochran-
Mantel-Haenszel (CMH) test adjusting for the risk of bleeding associated with the elective 
procedure (low, moderate, or high based on Amendment 02 categorization).  Since the HCC 
status is included in the randomization stratification for safety purposes only, not for efficacy 
consideration, HCC will not be included in the CMH model for the primary efficacy analysis. 
5.3.3 
Multiple Comparisons/Multiplicity 
The primary efficacy endpoint will be tested between the individual avatrombopag treatment 
group (40 or 60 mg) and matching placebo within each baseline platelet count cohort 
(<40 × 109/L or from 40 to <50 × 109/L), each at a significance level of α=0.05.  The primary 
efficacy endpoint is considered positive only if the tests are statistically significant for both 
baseline platelet count cohorts to control the family-wise Type I error rate at a significance level 
of α=0.05. 
A sequential gatekeeping testing procedure will be used for the secondary efficacy endpoints to 
control the family-wise Type I error rate at a significance level of α=0.05. The secondary 
efficacy endpoints will be analyzed if the primary efficacy endpoint is statistically significant for 
both baseline platelet count cohorts.  The first secondary efficacy endpoint is tested first within 
each baseline platelet count cohort, each at a significance level of α=0.05.  Only if the first 
secondary efficacy endpoint is statistically significant for both baseline platelet count cohorts, 
the analysis of second secondary efficacy endpoint will proceed within each baseline platelet 
count cohort, each at a significance level of α=0.05.  No alpha adjustment is planned for other 
efficacy endpoints. 
5.3.4 
Examination of Subgroups 
Subgroup analysis of primary efficacy endpoint will be performed using age group (<65 and ≥65 
years old), sex (male and female), race (white, black, Asian, and other), geographic region, 
bleeding risk associated with  procedure (low, moderate, and high based on Amendment 02 
categorization), MELD score (<10, 10-14, and >14), and CTP grade (A, B, and C).  Additional 
subgroup analysis may also be explored, if deemed appropriate. 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
Unless stated otherwise, missing values will be considered as non-responders in responder 
analyses for all efficacy analyses; observed data will be used in other type of efficacy analyses.  
Details can be found in Sections 5.4, Efficacy Analyses.   
All safety analyses will be performed based on the observed data only. 
5.3.6 
Other Considerations 
None 
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5.4 
EFFICACY ANALYSES 
The FAS will be used as the primary population for the efficacy analyses, while the PP will be 
used as a supportive analysis.  All analyses of platelet counts will be based on local laboratory 
results. 
5.4.1 
Primary Efficacy Analyses 
The primary efficacy variable is the proportion of subjects who do not require a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure. 
The null hypothesis is that the proportion of subjects not requiring a platelet transfusion or any 
rescue procedure for bleeding after randomization and up to 7 days following an elective 
procedure is the same between the avatrombopag and placebo treatment groups.  The 
corresponding alternative hypothesis is that the proportion of subjects not requiring a platelet 
transfusion or any rescue procedure for bleeding after randomization and up to 7 days following 
an elective procedure is not the same between avatrombopag and placebo.  This hypothesis will 
be tested separately with each baseline platelet count cohort.   
The proportion of subjects not requiring a platelet transfusion or any rescue procedure for 
bleeding will be tested between the individual avatrombopag treatment group (40 or 60mg) and 
matching placebo within each baseline platelet count cohort (<40 × 109/L or from 40 to 
<50 × 109/L), each at a significance level of α=0.05 using the generalized Cochran Mantel 
Haenszel (CMH) test adjusting for the risk of bleeding associated with the elective procedure 
(low, moderate, or high based on Amendment 02 categorization). 
• For subjects with platelet count <40 × 109/L at baseline, the treatment comparison will be 
carried out between the 60 mg avatrombopag treatment group (Group A) versus matching 
placebo (Group B). 
• For subjects with platelet count from 40 to <50 × 109/L at baseline, the treatment 
comparison will be carried out between the 40 mg avatrombopag treatment group (Group 
C) versus matching placebo (Group D). 
This study will be considered as positive if statistical significance is achieved for primary 
efficacy endpoints for both baseline platelet count cohorts. 
 
The 95% CI for the proportion of subjects not requiring a platelet transfusion or any rescue 
procedure for bleeding will be calculated for each treatment group within each baseline platelet 
count cohort.  In addition, the 95% CI for the difference between avatrombopag and matching 
placebo will also be provided within each baseline platelet count cohort using normal 
approximation method. 
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Since the HCC status is included in the randomization stratification for safety purposes only, not 
for efficacy consideration, HCC will not be included in the CMH model for the primary efficacy 
analysis. 
Subjects with missing information about the primary efficacy outcome due to early withdrawal 
or other reasons will be considered as having received a transfusion for the primary analysis. 
5.4.1.1 
Sensitivity Analysis 
The following analyses will be considered as sensitivity analyses: 
• PP analysis: The same primary efficacy analyses described in Section 5.4.1 will be 
repeated based on the PP analysis set.  
• Observed case: The same primary efficacy analyses described in Section 5.4.1 will be 
repeated based on observed data.  Subjects with missing information about the primary 
efficacy outcome will be excluded from this analysis. 
• Fisher’s exact Test: The same primary efficacy analyses described in Section 5.4.1 will 
be carried out using Fisher’s exact test. 
• Modified primary efficacy endpoint: Proportion of subjects who do not require a platelet 
transfusion after randomization and up to 7 days following an elective procedure.  This 
efficacy endpoint will be analyzed using the same approach as primary efficacy analysis 
using FAS 
Additional sensitivity analyses may also be explored, if deemed appropriate. 
5.4.1.2 
Subgroup Analysis 
The primary efficacy variable described in Section 5.4.1 will be summarized by each subgroup 
listed below.  
• age group (<65 and ≥65 years old) 
• sex (male and female) 
• race (white, black, Asian and other) 
• geographic region 
• bleeding risk associated with the elective procedure (low, moderate and high based on 
Amendment 02 categorization) 
• MELD score (<10, 10-14, and >14) 
• CTP grade (A, B, and C) 
• Disease etiology (alcoholic liver disease, chronic viral disease, nonalcoholic 
steatohepatitis, other) 
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Additional subgroups may also be explored, if deemed appropriate. 
5.4.2 
Secondary Efficacy Analyses 
There are 2 secondary efficacy endpoints in this study: 
• Proportion of responders, defined as subjects who achieve target platelet counts of ≥50 × 
109/L on Procedure Day (prior to receiving a platelet transfusion or undergoing the 
elective procedure)  
• Change from baseline in platelet count on Procedure Day (prior to receiving a platelet 
transfusion or undergoing the elective procedure) 
The analysis of the secondary efficacy variables, as defined above, will proceed following a 
sequential gatekeeping testing procedure to control the family-wise Type I error rate at a 
significance level of α=0.05.   
5.4.2.1 
Proportion of subjects achieved platelet counts of ≥50 × 109/L on the Procedure Day 
The proportion of subjects who achieve platelet counts of ≥50 × 109/L on the Procedure Day will 
be analyzed first.   
The proportion of subjects with platelet counts of ≥50 × 109/L on the Procedure Day will be 
tested between the individual avatrombopag treatment group (40 or 60mg) and matching placebo 
separately within each baseline platelet count cohort (<40 × 109/L or from 40 to <50 × 109/L), 
each  at a significance level of α=0.05 using the generalized CMH test adjusting for the risk of 
bleeding associated with the elective procedure (low, moderate, or high based on Amendment 02 
categorization).    
The 95% CI for the proportion of subjects with platelet counts of ≥50 × 109/L on the Procedure 
Day will be calculated for each treatment group within each baseline platelet count cohort.  In 
addition, the 95% CI for the difference between avatrombopag and placebo will also be provided 
within each baseline platelet count cohort using normal approximation method. 
Subjects with missing platelet count on Procedure Day will be considered as not achieving the 
platelet count of ≥50 × 109/L for this analysis. 
5.4.2.2 
Change from baseline in platelet count on the Procedure Day 
The second secondary efficacy variable, change from baseline in platelet count on the Procedure 
Day, will be analyzed only if the first secondary efficacy variable is statistically significant for 
both baseline platelet count cohorts.   
The change from baseline in platelet count on Procedure Day will be analyzed using the 
Wilcoxon rank sum test separately within each baseline platelet count cohort (<40 × 109/L or 
from 40 to <50 × 109/L), each at a significance level of α=0.05. The treatment difference 
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between avatrombopag and placebo will be provided within each baseline platelet count cohort 
using Hodges-Lehmann estimation along with associated asymptotic (Moses) 95% CIs. 
Last observation carried forward will be used for subjects with missing platelet count on 
Procedure Day for this analysis. 
5.4.3 
Other Efficacy Analyses 
The following efficacy analyses are for exploratory purpose only.      
5.4.3.1 
Platelet count and change from baseline in platelet count at each visit 
Platelet count and change from baseline in platelet count will be compared between individual 
avatrombopag (40 or 60mg) and matching placebo separately within each baseline platelet count 
cohort at a significance level of α=0.05, using the Wilcoxon rank sum test based on observed 
data.  Missing values will not be imputed. 
5.4.3.2 
Proportion of responders defined as subjects who achieve platelet counts of 
≥50 × 109/L, ≥75 × 109/L, or ≥200 × 109/L at each visit 
The number and percentage of responders will be summarized by treatment group within each 
baseline platelet count cohort at each visit.  Missing values will not be imputed. 
5.4.3.3 
Number of platelet units used per platelet transfusion episode 
The average number of platelet units used per platelet transfusion episode will be summarized by 
treatment group within each baseline platelet count cohort using descriptive statistics for subjects 
require platelet transfusion.  
5.4.3.4 
Severity of bleeding event assessed by WHO bleeding score and BARC bleeding 
scale 
The number and percentages of subjects with bleeding events will be summarized by the highest 
bleeding score and by treatment group within each baseline platelet count cohort, separately for 
WHO bleeding score and BARC bleeding scale.  
5.4.3.5 
Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 
7 days following an elective procedure 
Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 7 days 
following an elective procedure, will be summarized by treatment group within each baseline 
cohort, and by overall treatment groups, regardless of the baseline platelet count cohorts. 
A 2-sided 95% CI will be constructed by baseline cohort, and for the overall treatment difference 
(avatrombopag minus placebo) using normal approximation method for the proportion of 
subjects with the qualified WHO bleeding score. 
Subjects with missing WHO bleeding score will be considered as having a WHO bleeding score 
≥2 in this analysis. 
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5.5 
PHARMACOKINETIC , PHARMACODYNAMIC, AND 
PHARMACOGENOMIC/PHARMACOGENETIC ANALYSES 
Population pharmacokinetic (PK) and  pharmacokinetic/pharmacodynamic (PK/PD) analysis are 
specified in the protocol but will not be discussed in this SAP.  Separate analysis plan(s) for 
these analyses will be developed and finalized before the database lock. 
5.5.1 
Pharmacokinetic Analyses 
Not Applicable. 
5.5.2 
Pharmacodynamic Analyses 
Not Applicable. 
5.5.3 
Pharmacogenomic/Pharmacogenetic Analyses 
Not Applicable. 
5.6 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set.  Unless specified, all safety 
assessments will be summarized both overall (regardless of baseline platelet count) and within 
each baseline platelet count cohort. Safety data, presented by treatment group, will be 
summarized on an “as treated” basis using descriptive statistics or frequency count.   
Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.  Unless 
specified otherwise, the baseline value will be defined as the most recent value reported prior to 
the first dose of study drug. 
5.6.1 
Extent of Exposure 
The extent of exposure to study drug will be characterized by duration of exposure (in days) for 
each treatment group.   
Duration of exposure will be defined as the number of days between the date the subject received 
the first dose of study drug and the date the subject received the last dose of study drug, 
inclusive.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized, and will be summarized using 
frequency count by treatment group. 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 15.1 or higher) lower level 
term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) will also be captured in the database. 
A treatment-emergent AE (TEAE) is defined as an AE that 
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• Emerged during treatment (up to 30 days after the last dose of study drug), having been 
absent at pretreatment (Baseline) or  
• Reemerged during treatment (up to 30 days after the last dose of study drug), having been 
present at pretreatment (Baseline) but stopped before the last dose of study drug plus 30 
days, or 
• Worsened in severity during treatment (up to 30 days after the last dose of study drug) 
relative to the pretreatment state, when the AE was continuous. 
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
An overview table of TEAE, including number of subjects with TEAEs, treatment-emergent 
serious adverse events (SAEs), deaths, severe TEAEs, study drug related TEAEs, TEAEs leading 
to study drug withdrawal will be provided.  In addition, the following summaries will be 
produced: 
• Incidence of TEAEs by SOC and PT  
• Incidence of treatment-related TEAEs by SOC and PT 
• Incidence of procedure-related TEAEs by SOC and PT 
• Incidence of TEAEs after procedure (with an onset date on or after Procedure Day) by 
SOC and PT 
• Incidence of TEAEs related to platelet transfusion complications by SOC and PT 
• Incidence of TEAEs by SOC, PT, and common terminology criteria for adverse events 
(CTCAE) grade 
• Incidence of treatment-related TEAEs by SOC, PT, and CTCAE grade 
• Incidence of TEAEs by SOC, PT, and relationship to treatment 
If a subject experiences more than one TEAE within a preferred term, the subject will be counted 
only once in the calculation of incidence of TEAE within that preferred term.  Similarly, if a 
subject experiences more than one TEAE within a SOC, the subject will be counted only once in 
the calculation of incidence of TEAE within that SOC.  If a subject experiences more than one 
TEAE within a preferred term (or SOC), the occurrence with the highest CTCAE grade will be 
used in the calculation of the incidence of TEAE within that preferred term (SOC) by CTCAE 
grade.  If a subject experiences more than one TEAE within a preferred term (or SOC), the 
occurrence considered most closely related to study drug will be used in the calculation of the 
incidence of TEAE with that preferred term (SOC) by relationship (given by investigator). 
The following summaries will also be presented for the treatment-emergent SAEs: 
• Incidence of treatment-emergent SAEs by SOC and PT  
• Incidence of treatment-related treatment-emergent SAEs by SOC and PT  
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• Incidence of treatment-emergent SAEs by SOC, PT, and relationship to treatment. 
In addition, number (percentage) of subjects with TEAEs and treatment-related TEAEs leading 
to discontinuation from study treatment will also be summarized by MedDRA SOC, PT for each 
treatment group. 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
With the exception of urinalysis, platelet function tests and platelet count (which is considered as 
an efficacy parameter),for all quantitative parameters listed in protocol Section 9.5.1.5 Safety 
Assessments (Laboratory Measurements), the actual value and the change from baseline will be 
summarized by visit and treatment group using descriptive statistics.  Analysis of changes from 
baseline will be based on the number of subjects with both nonmissing baseline and relevant 
postbaseline results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value is below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Shifts from baseline (LNH) to Procedure Day and to the end of the Follow-up Phase will 
be presented for each laboratory parameter.  Similar shift tables from baseline (LNH) to the 
highest/lowest postbaseline LNH classification will also be provided.  A subject will be counted 
once in highest LNH classification and once in the lowest LNH classification. 
 
The Sponsor’s Grading for Laboratory Values (see Appendix 1) presents the criteria that will be 
used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAV).  Except for phosphate, a TEMAV is defined as a postbaseline value with an increase 
from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a postbaseline 
value with an increase from baseline to a grade of 3 or higher. When displaying the incidence of 
TEMAVs, each subject will be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable. 
5.6.4 
Vital Signs 
For each vital signs parameters (diastolic and systolic blood pressure, pulse, respiration rate, 
temperature and weight), the actual value and changes from baseline will be summarized by visit 
and treatment group using descriptive statistics.  Analysis of changes from baseline will be based 
on the number of subjects with both nonmissing baseline and relevant postbaseline results.  
5.6.5 
Electrocardiograms 
For each electrocardiogram (ECG) parameter (including PR interval, RR interval, QRS interval, 
QT interval, QTcB interval, QTcF interval and heart rate), the actual value and change from 
baseline will be summarized by visit and treatment group using descriptive statistics.  ECG 
interpretation (categorized as normal and abnormal) will be summarized using frequency count 
at each visit by treatment group. 
Maximum postbaseline QTcB and QTcF will also be tabulated by treatment group as follows: 
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• Number and percentage of subjects in the borderline (430-450 msec), abnormal category 
(> 450 msec), and highly abnormal (>500 msec) during the treatment, and 
• Number and percentage of subjects with an increment of 30-60 msec and > 60 msec from 
the baseline visit. 
QT will be corrected primarily using Fridericia’s formula (QTcF) and also using Bazett’s 
formula (QTcB) defined as:  
• QTcF is the heart rate corrected QT interval by Fridericia’s formula: QTcF = QT/(RR)0.33  
• QTcB is the heart rate corrected QT interval by Bazett’s formula: QTcB = QT/(RR)0.5. 
5.6.6 
Other Safety Analyses 
5.6.6.1 
Adverse Events of Special Interest 
The incidence of treatment-emergent adverse events and treatment-related, treatment-emergent 
adverse events of special interest will be summarized by treatment group. 
Adverse events of special interest include: 
• Recurrence of thrombocytopenia (platelet count of <10 × 109/L and 10 × 109/L less than 
baseline count within 30 days of discontinuation) 
• Thromboembolic events 
• Bleeding events (WHO Grade 2 to 4) 
Recurrence of thrombocytopenia events include the adverse events with MedDRA preferred term 
belonging to 2nd level Standardized MedDRA Query (SMQ) ‘Haematopoietic thrombocytopenia’ 
and with ‘Event of Special Interest per Protocol Definition’ checked as ‘Yes’ on the AE CRF 
page. 
Thromboembolic events include the adverse events with MedDRA preferred term belonging to 
SMQ ‘Embolic and thrombotic events’. 
Bleeding events (WHO Grade 2 to 4) include the adverse events with MedDRA preferred term 
belonging to 2nd level SMQ ‘Haemorrhage terms (excl laboratory terms)’ and with WHO 
Bleeding Scale score 2 to 4. 
Additionally the incidence of treatment-emergent adverse events and treatment-related, 
treatment-emergent adverse events for thromboembolic events will be summarized by treatment 
group and by HCC status. 
5.6.6.2 
Doppler Sonography 
The results from Doppler Sonography will be presented in the listings only. 
5.6.6.3 
Platelet Function Test 
For each parameter of platelet function assessed via flow cytometric markers, the actual value 
and changes from baseline will be summarized by visit and treatment group using descriptive 
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statistics.  Analysis of changes from baseline will be based on the number of subjects with both 
nonmissing baseline and relevant postbaseline results. 
Only listings will be provided for platelet function assessed using platelet aggregometry. 
5.7 
OTHER ANALYSES 
5.7.1 
Health Outcome Economics Analyses 
Health outcome economics data will be listed in the subject data listings only.  
5.8 
EXPLORATORY ANALYSES 
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriately titled/labeled as exploratory and will be clearly distinguished 
from planned analyses when results are reported in the Clinical Study Report. 
5.9 
EXTENSION PHASE ANALYSES 
Not applicable. 
6 
INTERIM ANALYSES 
No interim efficacy analysis is planned for this study, and therefore no adjustment of the P-value 
for the final efficacy analysis is needed.  However, to protect subjects’ safety, an independent 
DSMB will be established to monitor the ongoing safety data in unblinded manner.  To maintain 
the blinding of DSMB members on the efficacy data, no platelet transfusion data, by-subject 
listing on platelet count, and by-visit summary on platelet count and change from baseline in 
platelet count will be sent to DSMB.  The only information DSMB will receive on platelet count 
is the percentage of subjects with extreme values (eg, exceeds 200 x 109/L) for safety reason.  
The DSMB safety interim analysis will be performed by an independent statistician and 
governed by an external DSMB.  To maintain the blinding and integrity of the study, procedures 
will be implemented to ensure the DSMB and independent statistician have sole access to 
unblinded interim safety data. 
Full details of the DSMB procedures including primary responsibilities of the DSMB, its 
relationship with other study components, its membership, and the purpose and timings of its 
meetings will be documented in a DSMB charter.  These details will also include procedures to 
ensure confidentiality and proper communication, the guidelines to be implemented by the 
DSMB, and an outline of the content of the closed reports (unblinded) and open reports (blinded) 
that will be provided to the DSMB. 
7 
CHANGES IN THE PLANNED ANALYSES 
SAP version (Final 3.0) is updated based on Protocol Amendment 04 with the following 
changes:  
• Sections 3.1.2, 3.1.3, 5.1.2, 5.1.3, 5.3.3.1, 5.4.2, 5.4.2.3, 5.4.3 and 5.4.3.5:  Efficacy 
endpoint “Proportion of subjects with a WHO bleeding score ≥2 after randomization and 
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up to 7 days following an elective procedure” is moved from secondary to exploratory 
endpoint to match the protocol amendment 4.  These sections have been updated to 
reflect this change.   
• Section 4: Sample size is reduced from 300 to 200.  This section has been updated to 
match the protocol amendment 4.   
• Section 5.4.2.2: Calculation of 95% CI for change from baseline in platelet count on 
Procedure Day for each treatment group within each baseline platelet count cohort has 
been removed to ensure consistency with the study objectives. 
• Section 5.7.1: This section is updated to reflect that only listings will be provided for the 
Health Economics Assessment. 
• Section 5.2.1: Per-Protocol exclusion criteria are finalized. 
 
SAP version (Final 2.0) was updated based on Protocol Amendment 02 with the following 
changes:  
• Section 3.2 table 1, and sections 5.2.4, 5.3.2, 5.3.4, 5.4.1, 5.4.1.2 and 5.4.2.1: 
Categorization of risk of bleeding is updated to match protocol amendment 02  
• Section 5.6.6.3: Listing of platelet function test assessed using platelet aggregometry has 
been added.  
• Section 13.1: "Fasting Glucose value" has been added to the criteria for determining 
grade 3 and 4 in the lab grading table. 
 
SAP version (Final 2.0) was also updated from version Final 1.0 to ensure consistency with the 
eCRF/protocol as follows:  
• Section 5.6.5:  ECG interpretation category is updated.  
• Section 5.2.4: Baseline summaries of creatinine clearance and disease etiology, and 
subgroup analysis by disease etiology have been added. 
8 
 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
VISIT WINDOW 
Study Day 1 is defined as the date of the first dose of study drug.  The analysis visits defined 
below will be used in the by-visit summaries:  
Visit  
Target Visit 
Date 
Visit Window  
Analysis Visit 
Visit 2 
(Baseline)  
Study Day 1 
Less or equal to Study Day 
1 
Last visit on or before Study 
Day 1 
Visit 3  
Study Day 4 
Study Day 2 to 7 
Closest visit to Study Day 4 
Visit 4 
Study Day 
Subjects with procedure: 
Subjects with platelet 
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Visit  
Target Visit 
Date 
Visit Window  
Analysis Visit 
(Procedure 
Day) 
10 to 13 
Study Day 8 to actual 
procedure day 
Subjects without procedure: 
Study Day 8 to 13 
transfusion:  last visit before 
transfusion  
Subjects with procedure but 
without transfusion: last visit 
before procedure 
Subjects without platelet 
transfusion or procedure: closest 
visit to Study Day 10 
Visit 5  
7 Days post 
procedure 
Subjects with procedure: 1 
to 10 days post actual 
procedure day  
Subjects without procedure: 
Study Day 14 to 20 
Subjects with procedure: visit 
closest to 7 days post actual 
procedure day  
Subjects without procedure: 
closest visit to Study Day 17 
Visit 6  
Study Day 
35   
Subjects with procedure: 
Greater or equal to actual 
procedure day +11 days 
Subject without procedure: 
Greater or equal to Study 
Day 21  
Closest visit to Study Day 35 
 
8.2 
MISSING DATA HANDLING 
For the responder analysis of primary and secondary efficacy endpoints, subjects without the 
required platelet transfusion data or platelet count data will be considered as non-responders.  
For other efficacy analyses, unless specified otherwise, observed data will be used without 
missing data imputation.  Details can be found in Sections 5.4, Efficacy Analyses. 
Safety data will be analyzed using observed data with no imputation for missing values. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 
STATISTICAL SOFTWARE 
All data analyses will be performed by Eisai Inc. or designee. Statistical analyses and summaries 
will be performed using SAS® or other validated statistical software as required.   
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11 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
The study TLG shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and graphs in detail. 
12 
REFERENCES 
1. Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis RB, et al. for the Standards 
of Practice Committee with Cardiovascular and Interventional Radiological Society of 
Europe (CIRSE) Endorsement. Consensus Guidelines for Periprocedural Management of 
Coagulation Status and Hemostasis Risk in Percutaneous Image-guided Interventions. J Vasc 
Interv Radiol 2009; 20:S240–S249. 
2. Afdhal NH, Giannini EG, Tayyab G, Mohsin A, Lee JW, Andriulli A, Jeffers L, et al. 
Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia.  N Engl J 
Med. 2012;367:716-724. 
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13 
APPENDICES 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results  
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
< LLN – 10.0 g/dL 
< LLN – 100 g/L 
< LLN – 6.2 mmol/L 
< 10.0 – 8.0 g/dL 
< 100 – 80 g/L 
< 6.2 – 4.9 mmol/L  
< 8.0 g/dL 
< 80 g/L 
< 4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
< LLN – 3.0 x 109/L 
< LLN – 3000/mm3  
< 3.0 – 2.0 x 109/L 
< 3000 – 2000/mm3  
< 2.0 – 1.0 x 109/L 
< 2000 – 1000/mm3  
< 1.0 x 109/L 
< 1000/mm3  
Lymphocytes  
< LLN – 800/mm3  
< LLN – 0.8 x 109/L 
< 800 – 500/mm3 
< 0.8 – 0.5 x 109/L 
< 500 – 200/mm3  
< 0.5 – 0.2 x 109/L 
< 200/mm3 
< 0.2 x 109/L 
Neutrophils  
< LLN – 1.5 x 109/L 
< LLN – 1500/mm3  
< 1.5 – 1.0 x 109/L 
< 1500 – 1000/mm3 
< 1.0 – 0.5 x 109/L 
< 1000 – 500/mm3  
< 0.5 x 109/L 
< 500/mm3  
Platelets 
< LLN – 75.0 x 109/L 
< LLN – 75,000/mm3  
< 75.0 – 50.0 x 109/L 
< 75,000 – 50,000/mm3  
< 50.0 – 25.0 x 109/L 
< 50,000 – 25,000/mm3 
< 25.0 x 109/L 
< 25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
< LLN – 3 g/dL 
< LLN – 30 g/L 
< 3 – 2 g/dL 
< 30 – 20 g/L 
< 2 g/dL 
< 20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
ALT 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
AST 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
Bicarbonate, serum-low  
< LLN – 16 mmol/L 
< 16 – 11 mmol/L 
<11 – 8 mmol/L 
< 8 mmol/L  
Bilirubin (hyperbilirubinemia) 
> ULN – 1.5 x ULN  
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x ULN  
> 10.0 x ULN 
Calcium, serum-low (hypocalcemia)  
< LLN – 8.0 mg/dL 
< LLN – 2.0 mmol/L 
< 8.0 – 7.0 mg/dL 
< 2.0 – 1.75 mmol/L 
< 7.0 – 6.0 mg/dL 
< 1.75 – 1.5 mmol/L 
< 6.0 mg/dL 
< 1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
> ULN – 11.5 mg/dL 
> ULN – 2.9 mmol/L 
> 11.5 – 12.5 mg/dL 
> 2.9 – 3.1 mmol/L 
> 12.5 – 13.5 mg/dL 
> 3.1 – 3.4 mmol/L 
> 13.5 mg/dL 
> 3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
> ULN – 300 mg/dL 
> ULN – 7.75 mmol/L  
> 300 – 400 mg/dL 
> 7.75 – 10.34 mmol/L  
> 400 – 500 mg/dL 
> 10.34 – 12.92 mmol/L  
> 500 mg/dL 
> 12.92 mmol/L  
Creatinine 
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN 
> 3.0 – 6.0 x ULN 
> 6.0 x ULN 
GGT (γ-Glutamyl transpeptidase)  
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
> ULN – 160 mg/dL 
> ULN – 8.9 mmol/L  
Fasting glucose value: 
> 160 – 250 mg/dL 
> 8.9 – 13.9 mmol/L  
Fasting glucose value: 
> 250 – 500 mg/dL; 
> 13.9 – 27.8 mmol/L; 
hospitalization indicated 
Fasting glucose value: 
> 500 mg/dL; 
> 27.8 mmol/L; 
life-threatening 
consequences  
Glucose, serum-low (hypoglycemia) 
< LLN – 55 mg/dL 
< LLN – 3.0 mmol/L 
< 55 – 40 mg/dL 
< 3.0 – 2.2 mmol/L 
< 40 – 30 mg/dL 
< 2.2 – 1.7 mmol/L 
< 30 mg/dL 
< 1.7 mmol/L 
life-threatening 
consequences; 
seizures 
Phosphate, serum-low 
(hypophosphatemia)  
< LLN – 2.5 mg/dL 
< LLN – 0.8 mmol/L 
< 2.5 – 2.0 mg/dL 
< 0.8 – 0.6 mmol/L 
< 2.0 – 1.0 mg/dL 
< 0.6 – 0.3 mmol/L 
< 1.0 mg/dL 
< 0.3 mmol/L 
life-threatening 
consequences 
Potassium, serum-high (hyperkalemia) > ULN – 5.5 mmol/L  
> 5.5 – 6.0 mmol/L 
> 6.0 – 7.0 mmol/L 
hospitalization indicated 
> 7.0 mmol/L 
life-threatening 
consequences 
Potassium, serum-low (hypokalemia)  
< LLN – 3.0 mmol/L 
< LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated 
< 3.0 – 2.5 mmol/L 
hospitalization indicated 
< 2.5 mmol/L 
life-threatening 
consequences 
Sodium, serum-high (hypernatremia) 
> ULN – 150 mmol/L 
> 150 – 155 mmol/L 
> 155 – 160 mmol/L 
hospitalization indicated 
> 160 mmol/L 
life-threatening 
consequences 
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Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium, serum-low (hyponatremia) 
< LLN – 130 mmol/L 
N/A 
< 130 – 120 mmol/L 
< 120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
> 300 – 500 mg/dL 
> 3.42 – 5.7 mmol/L  
> 500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
> 1000 mg/dL 
> 11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
> ULN – 10 mg/dL  
≤ 0.59 mmol/L without 
physiologic 
consequences  
N/A 
> ULN – 10 mg/dL  
≤ 0.59 mmol/L with 
physiologic 
consequences  
> 10 mg/dL 
> 0.59 mmol/L  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010). 
 
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