Clinical trial NCT03326843
Conditions: Thrombocytopenia
Keywords: low platelet count ITP
Sponsor: Sobi, Inc.
Start date: 2018-03-26; Completion date: 2019-02-25
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 3b open-label, multicenter study to evaluate the safety and efficacy of avatrombopag in subjects with thrombocytopenia scheduled for operations to critical sites or operations with a high risk of bleeding.

Detailed description:
Subjects will receive oral avatrombopag once daily for 5 days beginning on Day 1, followed by a wait period prior to the procedure, which will occur on Day 10 to 13. The Follow-up Period will include 2 visits; 7 days post-procedure and 30 days after last dose.

Arms: arm 1: Open-label: oral avatrombopag
Interventions: intervention 1: Avatrombopag 60 mg
Intervention descriptions: intervention 1: Oral avatrombopag administered once daily for 5 days prior to procedure.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
An Open-Label Study to Evaluate the Efficacy and Safety of 
Avatrombopag for the Treatment of Subjects with 
Thrombocytopenia Scheduled for a Surgical Procedure 
Investigational Product: Avatrombopag tablets 
Protocol Number: AVA-PST-320 
 
 
Sponsor: 
Dova Pharmaceuticals 
240 Leigh Farm Road, Suite 245 
Durham, NC  27707 
United States 
Telephone: 919-748-5975 
Fax: 919-748-5976 
 
 
Version Number: 3.0 / Amendment 2 
Date: 17 September 2018 
Replaces: Version 2.0 / 09 April 2018 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Dova Pharmaceuticals except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical study for Dova Pharmaceuticals. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board and study personnel directly involved with conducting this protocol. Persons to whom the 
information is disclosed must be informed that the information is confidential and proprietary to 
Dova Pharmaceuticals and that it may not be further disclosed to third parties. 




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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Dova Pharmaceuticals to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study procedures. I will 
let them know that this information is confidential and proprietary to Dova Pharmaceuticals and 
that it may not be further disclosed to third parties. I understand that the study may be terminated 
or enrollment suspended at any time by Dova Pharmaceuticals with or without cause, or by me if 
it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board Regulations, and ICH Guidelines for Good Clinical Practices. 
______________________________________________ 
____________________ 
Investigator’s Signature 
Date 
______________________________________________ 
Investigator’s Printed Name 


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SYNOPSIS 
TITLE: An Open-Label Study to Evaluate the Efficacy and Safety of Avatrombopag for the 
Treatment of Subjects with Thrombocytopenia Scheduled for a Surgical Procedure 
PROTOCOL NUMBER: AVA-PST-320 
INVESTIGATIONAL PRODUCT: Oral avatrombopag 
PHASE: 3b 
INDICATION: Treatment of thrombocytopenia in subjects scheduled for operations to critical 
sites (eg, eye surgery, neurosurgery) or operations with a high risk of bleeding (eg, major 
abdominal surgery) 
OBJECTIVES: 
The primary objective of this study is to evaluate the efficacy of avatrombopag in increasing 
platelet counts in subjects with thrombocytopenia scheduled for operations to critical sites or 
operations with a high risk of bleeding. 
The secondary objectives of this study are the following: 
•
To evaluate the safety of avatrombopag in subjects with thrombocytopenia scheduled for 
operations to critical sites or operations with a high risk of bleeding,
•
To evaluate the effect of avatrombopag on the need for transfusions in subjects with 
thrombocytopenia scheduled for operations to critical sites or operations with a high risk of 
bleeding, and
•
To evaluate the effect of avatrombopag on bleeding in subjects with thrombocytopenia
scheduled for operations to critical sites or operations with a high risk of bleeding.
POPULATION: 
The population for this study is subjects ≥18 years of age at the time of informed consent who are 
scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or operations with 
a high risk of bleeding (eg, major abdominal surgery), OR, in the opinion of the Investigator, 
would otherwise require a pre-operative platelet transfusion to prevent bleeding. Subjects without 
chronic liver disease must have a mean baseline platelet count between 50 × 109/L and <100 × 
109/L, measured on 2 separate occasions, with neither platelet count ≥100 × 109/L. Subjects with 
chronic liver disease (CLD) must have a mean baseline platelet count between 50 × 109/L and <75 
× 109/L, measured on 2 separate occasions, with neither platelet count ≥75 × 109/L. 


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STUDY DESIGN AND DURATION: 
This is a Phase 3b open-label, multicenter study of the efficacy and safety of oral avatrombopag 
for the treatment of subjects with thrombocytopenia scheduled for a surgical procedure. Eligible 
subjects scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or 
operations with a high risk of bleeding (eg, major abdominal surgery) will be enrolled into the 
study and receive avatrombopag.  
Mean baseline platelet count in subjects without CLD must be between 50 × 109/L and <100 × 
109/L and between 50 × 109/L and <75 × 109/L in subjects with CLD. Platelet counts must be 
measured on 2 separate occasions, and must be performed at least 1 day apart with neither platelet 
count ≥100 × 109/L in subjects without CLD and ≥75 × 109/L in subjects with CLD. One standard 
of care platelet count measurement may be used if collected within 14 days of Baseline and the 
mean of these 2 platelet counts (mean baseline platelet count) will be used for entry criteria. 
Subjects will receive 60 mg oral avatrombopag once daily for 5 days beginning on Day 1, followed 
by a wait period prior to the procedure, which will occur on Day 10 (+3 days). The platelet 
response data will be reviewed after approximately 25% and 50% of subjects have been enrolled 
in the study. If required, the dose may be adjusted for subsequent subjects based on insufficient 
increase in platelet counts on Procedure Day. If a higher dose is considered necessary, subjects 
will receive 80 mg oral avatrombopag once daily for 5 days beginning on Day 1, followed by a 
wait period prior to the procedure, which will occur on Day 10 (+3 days).  
The Follow-up Period will include 2 visits, which will occur at approximately 7 days (+3 days) 
post-procedure and 30 days (±3 days) after the last dose of study drug.  
The total study duration will be approximately 5 to 7 weeks. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Subjects will receive 60 mg oral avatrombopag once daily for 5 days. If required, the dose may be 
adjusted for subsequent subjects based on insufficient increase in platelet counts on 
Procedure Day. If a higher dose is considered necessary, subjects will receive 80 mg oral 
avatrombopag once daily for 5 days. 
EFFICACY VARIABLES: 
The primary efficacy endpoint is the proportion of subjects achieving a platelet count of 
≥100 × 109/L on Procedure Day, when measured prior to a platelet transfusion (if any). 
The secondary efficacy endpoints include the following: 
•
Change in platelet count from baseline to Procedure Day,
•
Proportion of subjects without platelet transfusion and any other treatment for bleeding after 
the Baseline Visit and up to 7 days following Procedure Day,
•
Proportion of subjects without platelet transfusion after the Baseline Visit and up to 7 days
following Procedure Day, and
•
Proportion of subjects without bleeding after the Baseline Visit and up to 7 days following 
Procedure Day.


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SAFETY VARIABLES: 
Safety variables will include adverse events, physical examination findings, clinical laboratory 
parameters, and vital signs.  
STATISTICAL ANALYSES: 
Efficacy Analysis 
All primary and secondary efficacy endpoints will be analyzed using the Full Analysis Set (FAS). 
The Per-Protocol Analysis Set (PPS) will be used only for sensitivity analysis of the primary and 
secondary efficacy endpoints. 
Primary Efficacy Analysis: The primary efficacy endpoint is the proportion of subjects achieving 
a platelet count of ≥100 × 109/L on Procedure Day, when measured prior to a platelet transfusion 
(if any). Subjects with missing information due to early withdrawal or other reasons are considered 
as having a platelet count <100 × 109/L in the analysis; that is, missing values are considered as 
non-responders. The primary endpoint will be estimated from a binomial distribution, with 95% 
confidence interval (CI) of the proportion calculated. The study will be claimed successful if the 
lower boundary of the 2-sided 95% CI is above the 0.65. The primary analysis will be performed 
on the FAS and repeated on the PPS.  
Secondary Efficacy Analysis 
The following secondary efficacy endpoints will be summarized and analyzed in the same manner 
as the primary efficacy endpoint: 
•
Proportion of subjects without platelet transfusion and any other treatment for bleeding after 
the Baseline Visit and up to 7 days following Procedure Day,
•
Proportion of subjects without platelet transfusion after the Baseline Visit and up to 7 days
following Procedure Day, and
•
Proportion of subjects without bleeding after the Baseline Visit and up to 7 days following 
Procedure Day.
Change in platelet count from baseline to Procedure Day for avatrombopag will be calculated for 
each subject and summarized descriptively. The mean (95% CI) and median (range) will be 
provided.  
Additional efficacy analyses will be performed if deemed necessary. The details of the analyses 
will be described in the Statistical Analysis Plan that will be finalized prior to database lock. 
Safety and tolerability will be assessed by examining the incidence of adverse events, physical 
examination findings, clinical laboratory parameters, and vital signs over time using the Safety 
Analysis Set. 


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SAMPLE SIZE DETERMINATION: 
It is estimated from pharmacokinetic/pharmacodynamic modeling that the proportion of subjects 
treated with avatrombopag expected to achieve a platelet count of ≥100 × 109/L on Procedure Day, 
when measured prior to platelet transfusion (if any), is approximately 85%. Assuming the true 
response rate is 0.8 and the desired lower boundary of the 2-sided 95% CI is at least 0.65, 
60 enrolled subjects will provide greater than 90% power.  If the decision is made to increase the 
dose of study drug at one of the interim reviews of the data based on the pre-defined boundaries, 
up to an additional 30 subjects may be enrolled in the study for a maximum sample size of 
90 subjects.    
SITES: Approximately 30 sites in the United States 
SPONSOR: 
Dova Pharmaceuticals 
240 Leigh Farm Road, Suite 245 
Durham, NC 27707 
United States  
Telephone: 919-748-5975 
Fax: 919-748-5976 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents ............................................................................................................................ 8 
List of Tables ................................................................................................................................ 12 
List of Abbreviations and Definition of Terms............................................................................. 13 
1 Introduction and Background Information ............................................................................. 14 
1.1 
Thrombocytopenia ........................................................................................................ 14 
1.2 
Avatrombopag ............................................................................................................... 14 
1.3 
Nonclinical Studies ....................................................................................................... 15 
1.4 
Clinical Studies ............................................................................................................. 15 
1.4.1 Phase 1 Studies .................................................................................................. 15 
1.4.2 Phase 2 Studies .................................................................................................. 16 
1.4.3 Phase 3 Studies .................................................................................................. 17 
1.5 
Rationale ........................................................................................................................ 18 
1.6 
Risk/Benefit ................................................................................................................... 19 
2 Study Objectives ..................................................................................................................... 20 
2.1 
Primary Objective ......................................................................................................... 20 
2.2 
Secondary Objectives .................................................................................................... 20 
3 Study Description.................................................................................................................... 21 
3.1 
Summary of Study Design ............................................................................................ 21 
3.2 
Study Indication ............................................................................................................ 21 
4 Selection and Withdrawal of Subjects .................................................................................... 22 
4.1 
Inclusion Criteria ........................................................................................................... 22 
4.2 
Exclusion Criteria .......................................................................................................... 22 
4.3 
Withdrawal Criteria ....................................................................................................... 24 
4.3.1 Subjects with Study Drug Interruption or Discontinuation ............................... 24 
5 Study Treatments .................................................................................................................... 25 
5.1 
Treatment Groups .......................................................................................................... 25 
5.2 
Rationale for Dosing ..................................................................................................... 25 


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5.3 
Randomization and Blinding ......................................................................................... 25 
5.4 
Breaking the Blind ........................................................................................................ 25 
5.5 
Drug Supplies ................................................................................................................ 26 
5.5.1 Formulation and Packaging ............................................................................... 26 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 26 
5.5.3 Study Drug Administration ............................................................................... 26 
5.5.4 Treatment Compliance ...................................................................................... 26 
5.5.5 Storage and Accountability ............................................................................... 26 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 26 
5.6.1 Excluded Medications and/or Procedures ......................................................... 26 
5.6.2 Documentation of Concomitant Medication Use .............................................. 27 
6 Study Procedures .................................................................................................................... 28 
6.1 
Informed Consent .......................................................................................................... 28 
6.2 
Screening ....................................................................................................................... 28 
6.2.1 Visit 1 – Screening Visit (optional) ................................................................... 28 
6.2.2 Visit 2 - Baseline Visit ...................................................................................... 28 
6.3 
Treatment Period ........................................................................................................... 29 
6.3.1 Visit 3 ................................................................................................................ 29 
6.4 
Visit 4 - Procedure Day ................................................................................................. 30 
6.5 
Follow-Up Period .......................................................................................................... 30 
6.5.1 Visit 5 ................................................................................................................ 30 
6.5.2 Visit 6 ................................................................................................................ 31 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................... 31 
7 Efficacy Assessments.............................................................................................................. 33 
8 Safety Assessments ................................................................................................................. 34 
8.1 
Adverse Events .............................................................................................................. 34 
8.1.1 Adverse (Drug) Reaction .................................................................................. 34 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 34 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 35 
8.2 
Serious Adverse Events ................................................................................................. 36 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 37 
8.4 
Pregnancy Reporting ..................................................................................................... 37 


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8.5 
Expedited Reporting ...................................................................................................... 38 
8.6 
Clinical Laboratory Evaluations .................................................................................... 38 
8.7 
Vital Signs ..................................................................................................................... 38 
8.8 
Physical Examinations .................................................................................................. 38 
8.9 
Demographic and Medical History ............................................................................... 38 
9 Statistics .................................................................................................................................. 39 
9.1 
Analysis Populations ..................................................................................................... 39 
9.2 
Statistical Methods ........................................................................................................ 39 
9.2.1 Analysis of Efficacy .......................................................................................... 39 
9.2.1.1 Primary efficacy analysis .................................................................... 39 
9.2.1.2 Secondary efficacy analysis ................................................................ 39 
9.2.1.3 Other efficacy analysis ........................................................................ 39 
9.2.2 Analysis of Safety ............................................................................................. 40 
9.2.3 Interim Analysis ................................................................................................ 40 
9.2.4 Sample Size Determination ............................................................................... 40 
10 Data Management and Record Keeping ................................................................................. 41 
10.1 Data Management ......................................................................................................... 41 
10.1.1 Data Handling ................................................................................................... 41 
10.1.2 Computer Systems ............................................................................................. 41 
10.1.3 Data Entry ......................................................................................................... 41 
10.1.4 Medical Information Coding ............................................................................. 41 
10.1.5 Data Validation ................................................................................................. 41 
10.2 Record Keeping ............................................................................................................. 42 
11 Investigator Requirements and Quality Control ..................................................................... 43 
11.1 Ethical Conduct of the Study ........................................................................................ 43 
11.2 Institutional Review Board ............................................................................................ 43 
11.3 Informed Consent .......................................................................................................... 43 
11.4 Study Monitoring Requirements ................................................................................... 43 
11.5 Disclosure of Data ......................................................................................................... 44 
11.6 Retention of Records ..................................................................................................... 44 
11.7 Publication Policy ......................................................................................................... 44 
11.8 Financial Disclosure ...................................................................................................... 45 


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12 Study Administrative Information .......................................................................................... 46 
12.1 Protocol Amendments ................................................................................................... 46 
12.2 Address List ................................................................................................................... 46 
12.2.1 Sponsor 46 
12.2.2 Contract Research Organization ........................................................................ 46 
12.2.3 Drug Safety ....................................................................................................... 46 
12.2.4 Biological Specimens ........................................................................................ 46 
13 References ............................................................................................................................... 47 
Appendix A:  Schedule of Procedures .......................................................................................... 48 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 50 
Appendix C:  Cytochrome P450 Inducers and Inhibitors ............................................................. 51 
Appendix D:  International Society on Thrombosis and Haemostasis Bleeding Definitions ....... 52 
Appendix E: Protocol Amendments ............................................................................................. 54 


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LIST OF TABLES 
Table 1 
Schedule of Procedures ............................................................................................... 48 
Table 2 
CYP450 Inducers ........................................................................................................ 51 
Table 3 
Non-Surgical International Society on Thrombosis and Haemostasis Bleeding 
Definition .................................................................................................................... 52 
Table 4 
Surgical International Society on Thrombosis and Haemostasis Bleeding Definition 53 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
21 CFR 
Title 21 of the Code of Federal Regulations 
β-hCG 
BCLC 
Beta-human chorionic gonadotropin 
Barcelona Clinic Liver Cancer 
CI 
Confidence interval 
CLD 
Chronic Liver Disease 
CRA 
Clinical Research Associate 
CYP 
Cytochrome P450 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FAS 
Full Analysis Set 
GCP 
HCC 
Good Clinical Practice 
Hepatocellular Carcinoma 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISTH 
International Society on Thrombosis and Haemostasis 
ITP 
Idiopathic thrombocytopenic purpura 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Analysis Set 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
TPO 
Thrombopoietin 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Thrombocytopenia 
Platelets are an important component of blood that function to maintain normal hemostasis. In the 
case of vessel injuries, platelets immediately control bleeding by adhesion, activation, and 
aggregation, thereby forming a stable clot in conjunction with blood coagulation factors. 
Thrombopoietin (TPO), the principal physiologic regulator of platelet production, is produced 
constitutively in the liver, circulates in the bloodstream, and is delivered to the bone marrow, where 
it stimulates the early development of multiple hematopoietic lineages and megakaryocytopoiesis. 
Bone marrow production of platelets is directly affected by TPO levels.  
The circulating platelet count in blood is determined by the rates of platelet production and platelet 
destruction. In healthy individuals, the average lifespan of platelets is 7 to 10 days, after which 
they are destroyed and replaced with newly-generated platelets. A normal blood platelet count 
ranges from 150 × 109/L to 450 × 109/L, and patients who have less than 150 × 109/L have the 
condition known as thrombocytopenia. Thrombocytopenia is a potentially serious condition that 
is characterized by a deficiency of platelets in the circulatory system that is associated with an 
increased risk of bleeding. Thrombocytopenia can result from decreased platelet production in the 
bone marrow, increased platelet destruction in the blood (such as from auto-antibodies) or 
sequestration of platelets in the spleen. 
There are no approved pharmaceutical options to treat thrombocytopenia in patients prior to 
undergoing surgery. Treatment decisions are guided by platelet count measurements, clinical 
guidelines, and healthcare providers’ clinical judgment regarding the risk of bleeding for each 
category of procedure. Patients with thrombocytopenia are commonly administered platelet 
transfusions immediately prior to surgery in order to proactively mitigate the risk of bleeding.  The 
extent of the bleeding risk relates to the degree of thrombocytopenia and other coexisting 
coagulopathies as well as the type of scheduled procedure. 
Platelet transfusions are effective, but associated with substantial risks. Approximately 30% of 
platelet transfusions are associated with serious complications including febrile and allergic 
reactions, circulatory overload, acute pulmonary injury, and bacterial or viral infections.1 In the 
15% to 25% of patients who require repeated platelet transfusions, the platelet response may 
become inadequate due to human leukocyte antigen alloimmunization.2  
Additionally, like all blood products, platelets are a limited clinical commodity, and even more so 
because of their very limited shelf life (approximately 5 days). Approximately 9 million units of 
platelets are transfused each year in the United States,2 of which 40% are transfused in the surgical 
settings.3   
1.2 
Avatrombopag  
Avatrombopag maleate (previously known as AKR-501 monomaleate, YM477 monomaleate, and 
YM-301477 monomaleate) is an orally administered TPO receptor agonist that mimics the 
biologic effects of TPO in vitro and in vivo. Thrombopoietin exerts its effect on 
megakaryocytopoiesis and thrombocytopoiesis through binding and activation of the TPO 
receptor, which is expressed on hematopoietic stem cells, cells of the megakaryocytic lineage, and 
platelets. Avatrombopag activates the human TPO receptor by binding to a different site on the 


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TPO receptor, but it is still capable of stimulating signal transduction and mimicking the biologic 
effects of TPO, resulting in a measured increase in platelet counts.  
1.3 
Nonclinical Studies 
The toxicity of avatrombopag has been extensively evaluated in single- and repeated-dose oral 
toxicity studies in mice, rats, dogs, and cynomolgus monkeys (for up to 13 weeks in mice, 
26 weeks in rats, 4 weeks in dogs, and 52 weeks in cynomolgus monkeys). The genotoxicity of 
avatrombopag was evaluated in vitro and in vivo.  Two-year carcinogenicity studies have been 
conducted in mice and rats.  Reproductive and developmental toxicity was evaluated by 
conducting male and female fertility studies in rats, embryo-fetal development toxicity studies in 
rats and rabbits, pre- and postnatal development studies in rats, and a juvenile dose range-finding 
study in rats.  The potential for dermal and eye irritation in rabbits, dermal sensitization in guinea 
pigs, and phototoxicity in pigmented rats was also evaluated.  Nonclinical studies have indicated 
that avatrombopag was well tolerated and data suggest that avatrombopag is a promising candidate 
for use in the treatment of thrombocytopenia of diverse etiologies, including the treatment of 
thrombocytopenia in subjects scheduled for operations to critical sites or operations with a high 
risk of bleeding. 
Additional details are available in the avatrombopag Investigator’s Brochure.4 
1.4 
Clinical Studies 
Avatrombopag has been studied in humans in both single- and multiple-dose Phase 1, dose-rising, 
safety, and tolerability studies and in Phase 2 and Phase 3 efficacy and safety studies. A total of 
1365 subjects have been randomized across the 24 completed studies in the avatrombopag clinical 
development plan.  The total safety database for avatrombopag includes 1143 subjects in the 
completed clinical studies.  This includes 559 healthy volunteers, 394 subjects with 
thrombocytopenia associated with chronic liver disease prior to scheduled surgical or diagnostic 
procedures, 62 subjects with chronic hepatitis C virus related thrombocytopenia to enable initiation 
and maintenance of antiviral treatment, and 128 subjects with chronic idiopathic thrombocytopenic 
purpura (ITP).    
Based on these data, avatrombopag (DOPTELET®) was approved by FDA in May 2018 for the 
treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to 
undergo a procedure. 
1.4.1 
Phase 1 Studies 
The clinical pharmacology program was designed to establish the pharmacokinetic (PK) profile of 
avatrombopag, the determination of the elimination pathways, the investigation of potential 
clinically important drug-drug interactions, the effects of both intrinsic and extrinsic factors on 
PK, and the relationship between PK and pharmacodynamic (PD) effects related to clinical 
efficacy.  In 15 completed Phase 1 studies involving 559 healthy volunteers exposed to 
avatrombopag, the most common adverse event occurring in 5% or more of subjects treated with 
avatrombopag was headache. 
Additional details are available in the avatrombopag Investigator’s Brochure. 


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1.4.2 
Phase 2 Studies 
In 64 ITP patients who were randomized in a double-blind, placebo-controlled, Phase 2 efficacy 
and safety study (501-CL-003), avatrombopag demonstrated superior efficacy compared with 
placebo as measured by platelet response on Day 28. This response was dose-related. 
Avatrombopag continued to be effective after an additional 6 months of treatment as measured by 
durable and overall platelet response rates in 53 subjects who continued into a 6-month rollover 
study (501-CL-004). Durable platelet response was defined as subjects who had at least 75% of 
their measured platelet count values at response level during the last 14 weeks of the 24-week 
treatment period and did not receive rescue therapy during the study. All subjects needed to have 
at least 3 platelet count assessments in the last 14 weeks of Study 501-CL-004. Overall response 
rate was defined as the proportion of subjects who achieved either a durable response or a transient 
response (transient response was defined as subjects whose platelet counts were at a response level 
at 2 or more consecutive analysis windows during the 24-week treatment period of 
Study 501-CL-004, without having achieved a durable response). 
In the combined 501-CL-003 and 501-CL-004 studies, the most common treatment-emergent 
adverse events (TEAEs), occurring in 5% or more of subjects treated with avatrombopag were (by 
decreasing order of frequency) fatigue, headache, epistaxis, contusion, arthralgia, diarrhea, 
thrombocytopenia, gingival bleeding, back pain, edema peripheral, petechiae, platelet count 
increased, vomiting, dyspnea, nausea, upper respiratory tract infection, pain in extremity, 
ecchymosis, 
cough, 
insomnia, 
dizziness, 
pharyngolaryngeal 
pain, 
hyperlipidemia, 
nasopharyngitis, and platelet count decreased. Most TEAEs were Grade 1 or 2, transient, and 
completely resolved. 
A total of 130 subjects with thrombocytopenia associated with chronic liver disease who were 
scheduled to undergo elective surgical or diagnostic procedures were enrolled in a Phase 2, 
randomized, placebo-controlled, double-blind, parallel-group study (E5501-G000-202). The 
subjects were split into 2 cohorts and received either avatrombopag (Cohort A: first generation 
formulation; Cohort B: second generation formulation) or placebo. The primary analysis of the 
responder rate in the overall combined avatrombopag group was statistically significant compared 
with the overall combined placebo group. A similar statistical significance was again noted when 
the data were adjusted for the etiology of liver disease by Cochran-Mantel-Haenszel test. Within 
Cohort B, the response rate in platelet counts by Day 08 increased significantly in subjects 
receiving treatment with avatrombopag compared with placebo. In addition, a statistically 
significant reduction was achieved in the proportion of subjects receiving platelet transfusion 
before elective invasive procedures in Cohort B compared with placebo. The most commonly 
reported TEAEs, occurring in 5% or more of subjects treated with avatrombopag were (by 
decreasing order of frequency) nausea, fatigue, headache, portal hypertensive gastropathy, 
diarrhea, dizziness, muscle spasms, procedural pain, varices esophageal, vomiting, abdominal pain 
upper, and edema peripheral. 
Study E5501-G000-203 was a Phase 2 multicenter, multinational, randomized, placebo-controlled, 
double-blind, parallel group study to demonstrate the efficacy of once-daily dosing with 
avatrombopag compared with placebo in subjects with chronic hepatitis C virus related 
thrombocytopenia who are potential candidates for antiviral treatment. Prior to the initiation of 
antiviral therapy, the most commonly reported TEAEs (≥5% of subjects) in the combined 
avatrombopag group were nausea and fatigue. The most commonly reported TEAEs (≥5% of 
subjects) during the Core Study and Extension Phase included anemia, neutropenia, nausea, 


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fatigue, pruritus, leukopenia, chills, insomnia, headache, rash, diarrhea, influenza like illness, 
cough, pyrexia, asthenia, vomiting, irritability, abdominal pain, ascites, injection site erythema, 
edema peripheral, epistaxis, abdominal pain upper, depression, lymphopenia, dyspepsia, 
hemorrhoids, nasopharyngitis, upper respiratory tract infection, hyperuricemia, dizziness, 
dyspnea, and dyspnea exertional. The majority of these commonly reported TEAEs occurred after 
the initiation of antiviral treatment, and are consistent with what is expected in patients receiving 
antiviral therapy with interferon, ribavirin, and/or telaprevir. 
In Study E5501-J081-204, a Phase 2, randomized, placebo-controlled, double-blind, 
parallel-group study, a total of 39 Japanese subjects with thrombocytopenia associated with 
chronic liver disease were randomly assigned to a study group and received the placebo or 
avatrombopag. The primary analysis of the responder rate (a responder was defined as subjects 
with a platelet count ≥50 × 109/L and showed at least 20 × 109/L increase from baseline, at Visit 4 
[Days 10 to 13]) in the avatrombopag 40 mg and 60 mg groups was statistically significant 
compared with the placebo group. The most commonly reported TEAEs (≥5% of subjects) in the 
avatrombopag group were, by decreasing order of frequency, post procedural complication, 
post-embolisation syndrome, diarrhea, blood glucose increased, hemorrhage subcutaneous, 
constipation, and nasopharyngitis. 
1.4.3 
Phase 3 Studies 
Four Phase 3 efficacy and safety studies (E5501-G000-302, E5501- G000-305, E5501-G000-310, 
and E5501-G000-311) were completed. 
In Study E5501-G000-302, a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study with an open-label extension (OLE) phase treating thrombocytopenia in 
adults with chronic ITP, subjects received oral avatrombopag or matching placebo, with a starting 
dose of 20 mg once daily avatrombopag, followed with dose titration up to a maximum dose of 
40 mg or down to a minimum dose of 5 mg. The OLE included once daily, oral dosing with a 
starting dose of 20 mg avatrombopag once daily, followed with dose titration (5, 10, 20, 30, or 
40 mg doses). The primary efficacy endpoint was highly statistically significant favoring 
avatrombopag (p<0.0001) compared with placebo.  The median of the cumulative number of 
weeks with platelet count ≥50 × 109/L during the 6-month treatment was 12.4 weeks for 
avatrombopag and 0 weeks for placebo. The most commonly reported TEAEs (≥5% of subjects) 
in the avatrombopag group in the Core Study were headache, contusion, upper respiratory tract 
infection, arthralgia, epistaxis, fatigue, gingival bleeding, petechiae, back pain, insomnia, mouth 
hemorrhage, nasopharyngitis, nausea, anemia, blood gastrin increased, cough, hypertension, 
influenza, thrombocytopenia, and vomiting. In the combined Core Study and Extension Phase in 
the avatrombopag group (n = 47), the most commonly reported TEAEs (≥5% of subjects) 
presented were contusion, headache, upper respiratory tract infection, thrombocytopenia, 
epistaxis, gingival bleeding, fatigue, petechiae, pharyngitis, arthralgia, hypertension, 
nasopharyngitis, back pain, influenza, mouth hemorrhage, cough, insomnia, nausea, pain in 
extremity, and urinary tract infection. 
In Study E5501-G000-305, a multicenter, randomized, double-blind, active-controlled, 
parallel-group study with an OLE phase in adults with chronic ITP, subjects received oral 
avatrombopag at 5, 10, 20, 30, or 40 mg, with a starting dose of avatrombopag 20 mg, followed 
with dose titration down to 5 mg or up to 40 mg. A total of 23 subjects were randomized into the 
study prior to the premature termination of the study due to slow enrollment. The most commonly 


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reported TEAEs in the avatrombopag group in the Core Study were dizziness, headache, insomnia, 
musculoskeletal pain, and nausea, (3 [25.0%] subjects each). During the combined Core Study and 
Extension Phase, the most commonly reported TEAEs were fatigue and headache 
(5 [29.4%] subjects each) and dizziness, insomnia, and nasopharyngitis (4 [23.5%] subjects each). 
Two (16.7%) subjects in the avatrombopag group had serious adverse events (SAEs) during the 
Core Study. The event of ITP was not considered by the Investigator to be related to treatment. 
The events of portal vein thrombosis and thrombophlebitis septic were considered by the 
Investigator to be possibly related to study drug. 
Studies E5501-G000-310 and E5501-G000-311 enrolled adults with chronic liver disease and 
severe thrombocytopenia (mean baseline platelet count <50 × 109/L), scheduled to undergo 
invasive procedures.  Cohorts were defined based on baseline platelet count (Cohort 1, <40 × 109/L 
or Cohort 2, 40 to <50 × 109/L), and patients were randomized 2:1 to once-daily oral avatrombopag 
(60 mg for Cohort 1, 40 mg for Cohort 2) or placebo for 5 days with the procedure scheduled 5 to 
8 days after their last dose. 
The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion or 
any bleeding rescue procedure up to 7 days post-procedure.  Secondary endpoints assessed the 
proportion of patients achieving the target platelet count (≥50 × 109/L), change in platelet count 
from baseline to Procedure Day, and safety. 
Study 
310 
randomized 
231 
patients 
to 
1 
of 
2 
possible 
cohorts: 
Cohort 
1 
(90 avatrombopag/48 placebo) or Cohort 2 (59 avatrombopag/34 placebo). Patients had a median 
age of 57 years with 68% of patients being male and a baseline median platelet count of 38 × 109/L. 
The chronic liver disease etiology of patients was 14% alcohol, 62% viral hepatitis, and 23% other. 
Study 
311 
randomized 
204 
patients 
to 
1 
of 
2 
possible 
cohorts: 
Cohort 
1 
(70 avatrombopag/43 placebo) or Cohort 2 (58 avatrombopag/33 placebo). Patients had a median 
age of 59 years with 62% of patients being male and a baseline median platelet of 39 × 109/L. The 
chronic liver disease etiology of patients was 15% alcohol, 53% viral hepatitis, and 33% other. 
Significantly greater proportions of avatrombopag-treated patients across all cohorts did not 
require platelet transfusion or bleeding rescue procedures compared with placebo: 
Study 310: Cohort 1, 66% versus 23%; Cohort 2, 88% versus 38%; each p<0.0001; 
Study 311: Cohort 1, 69% versus 35%, p=0.0006; Cohort 2, 89% versus 33%, p<0.0001.  
Avatrombopag was also superior to placebo for both secondary endpoints, increasing mean platelet 
counts on Procedure Day to 64 × 109/L in Cohort 1 and 85 × 109/L in Cohort 2.  The most common 
TEAEs were pyrexia, abdominal pain, nausea, and headache, which were similar for placebo and 
avatrombopag arms in both studies.  Most TEAEs were mild to moderate in severity; however, 
1 thrombotic TEAE occurred in Cohort 2 (40 mg avatrombopag) in Study 311. The studies 
concluded avatrombopag given over 5 days significantly reduced the need for platelet transfusions 
or rescue procedures for bleeding, and it was well tolerated with a safety profile similar to placebo.   
1.5 
Rationale 
Avatrombopag is being developed to potentially address the unmet medical need of 
thrombocytopenia in subjects scheduled for operations to critical sites or operations with a high 
risk of bleeding complications. The study aims to evaluate the efficacy of avatrombopag in 
increasing platelet counts. The safety of avatrombopag will also be assessed through monitoring 
of adverse events, physical examination findings, clinical laboratory parameters, and vital signs. 


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Data to date suggest that avatrombopag is a promising candidate for use in the treatment of 
thrombocytopenia of diverse etiologies. 
1.6 
Risk/Benefit 
The current treatment for thrombocytopenia in subjects scheduled for operations at critical sites or 
that have a high risk of bleeding is a platelet transfusion immediately prior to the therapeutic 
procedure in order to proactively mitigate the risk of bleeding. While the risks of single platelet 
transfusions are generally considered acceptable, they are only transiently effective at increasing 
platelet counts, and are associated with important patient risks that can have significant health and 
economic consequences. In addition to the potential risks of transfusion reactions and infections, 
which in rare cases can be fatal, the development of anti-platelet antibodies and the resultant 
refractoriness to subsequent platelet transfusions are of particular importance. Given that 
avatrombopag stimulates the body’s own megakaryocytes to produce platelets, there is no risk for 
infection, and no immune response and thus no risk of refractoriness. This has important 
implications in preserving the utilization of platelets for emergent or future needs of the patient, 
which may not be available if they become refractory. 
Given these considerations, a safe thrombopoietic agent that can lessen or eliminate the need for 
platelet transfusions and provide options for the treatment of moderate thrombocytopenia would 
provide an important public health benefit. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of avatrombopag in increasing 
platelet counts in subjects with thrombocytopenia scheduled for operations to critical sites or 
operations with a high risk of bleeding. 
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
• To evaluate the safety of avatrombopag in subjects with thrombocytopenia scheduled for 
operations to critical sites or operations with a high risk of bleeding,  
• To evaluate the effect of avatrombopag on the need for transfusions in subjects with 
thrombocytopenia scheduled for operations to critical sites or operations with a high risk of 
bleeding, and 
• To evaluate the effect of avatrombopag on bleeding in subjects with thrombocytopenia 
scheduled for operations to critical sites or operations with a high risk of bleeding. 
 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 3b open-label, multicenter study of the efficacy and safety of oral avatrombopag 
for the treatment of subjects with thrombocytopenia scheduled for a surgical procedure. Eligible 
subjects scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or 
operations with a high risk of bleeding (eg, major abdominal surgery) will be enrolled into the 
study and receive avatrombopag.  
Mean baseline platelet count in subjects without CLD must be between 50 × 109/L and <100 × 
109/L and between 50 × 109/L and <75 × 109/L in subjects with CLD. Platelet counts must be 
measured on 2 separate occasions, and must be performed at least 1 day apart with neither platelet 
count ≥100 × 109/L in subjects without CLD and ≥75 × 109/L in subjects with CLD. One standard 
of care platelet count measurement may be used if collected within 14 days of Baseline and the 
mean of these 2 platelet counts (mean baseline platelet count) will be used for entry criteria. 
Subjects will receive 60 mg oral avatrombopag once daily for 5 days beginning on Day 1, followed 
by a wait period prior to the procedure, which will occur on Day 10 (+3 days). The platelet response 
data will be reviewed after approximately 25% and 50% of subjects have been enrolled in the 
study. If required, the dose may be adjusted for subsequent subjects based on insufficient increase 
in platelet counts on Procedure Day. If a higher dose is considered necessary, subjects will receive 
80 mg oral avatrombopag once daily for 5 days beginning on Day 1, followed by a wait period 
prior to the procedure, which will occur on Day 10 (+3 days).  
The Follow-up Period will include 2 visits, which will occur at approximately 7 days (+3 days) 
post-procedure and 30 days (±3 days) after the last dose of study drug.  
The total study duration will be approximately 5 to 7 weeks. 
3.2 
Study Indication 
The indication for this study is the treatment of thrombocytopenia in subjects scheduled for 
operations to critical sites (eg, eye surgery, neurosurgery) or operations with a high risk of bleeding 
(eg, major abdominal surgery). 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
Local laboratories will be used to determine eligibility; however, for study analysis and reporting 
purposes, only values determined at a central laboratory will be used with the exception of platelet 
count. Local laboratories may be used if immediate results are clinically needed. 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Subject is ≥18 years of age at the time of informed consent; 
2. Subject has a mean baseline platelet count between: 
a. 50 × 109/L and <100 × 109/L in subjects without a diagnosis of chronic liver disease.  
or 
b. 50 × 109/L and <75 × 109/L in subjects with diagnosed chronic liver disease.  
Platelet counts must be measured on 2 separate occasions, and must be performed at least 1 day 
apart with neither platelet count ≥100 × 109/L in subjects without CLD and ≥75 × 109/L in 
subjects with CLD. One standard of care platelet count measurement may be used if collected 
within 14 days of Baseline and the mean of these 2 platelet counts (mean baseline platelet 
count) will be used for entry criteria; 
3. Subject is scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or 
operations with a high risk of bleeding (eg, major abdominal surgery), OR, in the opinion of 
the Investigator, would otherwise require a pre-operative platelet transfusion to prevent 
bleeding; 
4. Female subjects of childbearing potential must 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]; hormonal contraceptive given orally, by injection, 
or by implant; or has 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; 
Note: All female subjects are considered to be of childbearing potential unless they are 
postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group and 
without another known or suspected cause) or has been sterilized surgically (ie, bilateral tubal 
ligation, hysterectomy, or bilateral oophorectomy) at least 1 month before dosing. 
5. Subject is willing and able to comply with all aspects of the protocol; and 
6. Subject (or legally authorized representative) must provide written informed consent. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Subject has a history of arterial or venous thrombosis within the previous 6 months of Baseline; 
2. Known portal vein blood flow velocity rate <10 cm/second or previous occurrence of a portal 
vein thrombosis within 6 months of Baseline; 


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3. Subject plans to have a platelet transfusion or plans to receive blood products containing 
platelets within 7 days of the Baseline Visit; however, packed red blood cells are permitted; 
4. Subject is unable to temporarily withhold anticoagulant or antiplatelet therapy per local 
standard of care prior to the operation (low dose aspirin may be continued); 
5. Use of erythropoietin-stimulating agents within 7 days of the Baseline Visit; 
6. Use of moderate or strong inducers of cytochrome P450 (CYP) 2C9 or CYP3A4/5 from 7 days 
prior to Baseline through the end of the dosing regimen (see Appendix C); 
7. Current use of a thrombopoietin receptor agonist (eg, eltrombopag or romiplostim); 
8. Subject has an active infection requiring systemic antibiotic therapy within 7 days of the 
Baseline Visit; however, prophylactic use of antibiotics is permitted; 
9. Subject with alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence 
within 6 months of the Baseline Visit (unless participating in a controlled rehabilitation 
program) or alcoholic hepatitis within 6 months of the Screening Visit;  
10. Subject has a surgery between the Baseline Visit and Visit 4 (Procedure Day); 
11. Subject is known to be human immunodeficiency virus positive; 
12. Subject has any clinically significant bleeding at the Baseline Visit;  
13. Subject has a known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden, 
prothrombin G20210A, ATIII deficiency, etc.);  
14. Subject has a recent history (within the previous 6 months) of significant cardiovascular 
disease (eg, exacerbation of congestive heart failure, arrhythmia known to increase the risk of 
thromboembolic events [eg, atrial fibrillation], coronary or peripheral artery stent placement 
or angioplasty, and coronary or peripheral artery bypass graft); 
15. Female subjects who are lactating or pregnant at the Baseline Visit (as documented by a 
positive serum beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity 
of 25 IU/L or equivalent units of β-hCG) or are planning to become pregnant during the study; 
16. Subject has a hypersensitivity to avatrombopag or any of its excipients; 
17. Subject has hemoglobin levels ≤8.0 g/dL or ≥18.0 g/dL for males and >15 g/dL for females at 
the Baseline Visit, with hematocrit ≥54% for males and ≥45% for females;  
18. Subject has prothrombin time/international normalized ratio and activated partial 
thromboplastin time outside 80% to 120% of the normal range; 
19. Subject with a current malignancy including solid tumors and hematologic malignancies whose 
thrombocytopenia may be attributed to chemotherapy;  
20. Hepatic encephalopathy that cannot be effectively treated; 
21. Subjects with hepatocellular carcinoma (HCC) and Barcelona Clinic Liver Cancer (BCLC) 
staging classification C or D; 
22. Subject has any history of a concomitant medical condition that, in the opinion of the 
Investigator, would compromise the subject’s ability to safely complete the study; or 


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23. Subject is currently enrolled in another clinical study with any investigational drug or device 
within 30 days of the Baseline Visit; however, participation in observational studies is 
permitted. 
4.3 
Withdrawal Criteria 
Participation of a subject in this clinical study may be discontinued for any of the following 
reasons: 
• The subject withdraws consent or requests discontinuation from the study for any reason; 
• Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol; 
• Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the subject; 
• Pregnancy; 
• Requirement of prohibited concomitant medication; 
• Subject failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by the Sponsor or the regulatory authority. 
If a subject withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
Visit 6 (Day 35 [±3 days]). The reason for subject withdrawal must be documented in the electronic 
case report form (eCRF). 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
Subjects withdrawn prior to receiving a dose of study drug may be replaced as needed to meet the 
enrollment objectives of the study.  
4.3.1 
Subjects with Study Drug Interruption or Discontinuation 
The Investigator should contact the Medical Monitor with any questions regarding how to handle 
a study drug discontinuation. 
Subjects who discontinue study drug will be followed for the entire study duration through the 
Follow-up Period, and all procedures should be followed according to the protocol. 
If a subject discontinues study drug due to an adverse event, the Investigator will attempt to follow 
the event until it has resolved or stabilized. 
If a subject misses a dose of study drug, temporarily interrupts treatments (whether due to an 
adverse event or other reason), the Investigator should contact the Medical Monitor regarding how 
to handle treatment re-initiation or if permanent study drug discontinuation is required. 
 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
This is a Phase 3b open-label, single-arm, multicenter study of the efficacy and safety of oral 
avatrombopag for the treatment of subjects with thrombocytopenia scheduled for a surgical 
procedure. Eligible subjects scheduled to undergo operations to critical sites (eye surgery, 
neurosurgery) or operations with a high risk of bleeding (eg, major abdominal surgery) will be 
enrolled into the study and receive avatrombopag.  
Subjects will receive 60 mg oral avatrombopag once daily for 5 days beginning on Day 1, followed 
by a wait period prior to the procedure, which will occur on Day 10 (+3 days). 
At the Screening or Baseline Visit, site personnel will contact the interactive response technology 
(IRT) to register the subject. A subject identification number will be used to identify the subject 
throughout the study and will be entered on all documentation. A subject identification number 
will not be assigned to more than 1 subject. If a subject is not eligible to receive treatment, or if a 
subject discontinues from the study, the subject identification number cannot be assigned to 
another subject. The IRT will be used throughout the study.  
5.2 
Rationale for Dosing 
A PK/PD model was developed to simulate platelet response to avatrombopag administration in 
order to select a dose regimen for this study. Using data from healthy volunteers and patients with 
chronic liver disease, the PK/PD model evaluated the relationship of avatrombopag concentrations 
to increases in platelet counts. Simulations were performed assuming the baseline platelet count 
ranged between 50 and <100 × 109/L with a requirement to increase the platelet count to levels 
≥100 × 109/L prior to the procedure. Simulations suggested that 60 mg avatrombopag administered 
once daily for 5 days with the procedure scheduled 5 to 8 days after the last dose of study drug 
would result in approximately 85% of subjects having platelet counts that exceed 100 × 109/L. 
Simulations were also performed for subjects with CLD. In order to limit the number of subjects 
with a platelet count >200 × 109/L after treatment yet still have the majority of subjects with a 
platelet count ≥100 × 109/L on the day of surgery, subjects with CLD must have a platelet count 
between 50 and <75 × 109/L at Baseline. 
To ensure the accuracy of the predictions, platelet response data will be reviewed by the Sponsor 
and Medical Monitor, and if necessary, the Investigators participating in the study, after the 
enrollment of 25% and 50% of subjects to determine if the dose for subsequent subjects enrolled 
in the study should be increased to 80 mg once daily for 5 days. 
5.3 
Randomization and Blinding 
This is an open-label, single-arm study; therefore, no randomization or blinding will occur.  
5.4 
Breaking the Blind 
Not applicable. 


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5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
Avatrombopag will be provided as film-coated tablets with each tablet containing 20 mg of 
avatrombopag maleate and the following excipients: lactose monohydrate, colloidal silicon 
dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, and Opadry II 85F42244. 
Study drug will be packaged in blister packages.  
5.5.2 
Study Drug Preparation and Dispensing 
Study drug will be provided to subjects in blister packages. The Investigator or designee will 
provide subjects with sufficient study drug to complete the 5-day regimen. 
5.5.3 
Study Drug Administration 
Subjects will receive 60 mg oral avatrombopag once daily for 5 days beginning on Day 1, followed 
by a wait period prior to the procedure, which will occur on Day 10 (+3 days).  
For study site visits during the Treatment Period, study drug may be administered at the site or the 
subject may self-dose. Subjects will self-dose at all other times and be instructed to take study drug 
with food.  
The number of tablets to be taken will be as follows: 
• 60 mg: three 20 mg tablets, or 
• 80 mg: four 20 mg tablets (if needed).  
5.5.4 
Treatment Compliance 
Compliance with study drug administration will be assessed by counting returned study drug 
packages and any unused study drug. Study drug compliance will be recorded on the drug 
accountability log. 
5.5.5 
Storage and Accountability 
Avatrombopag tablets should be stored at controlled room temperature (20 to 25°C/68 to 77°F) 
and in the containers provided.  
Records will be maintained indicating the receipt and dispensation of all study drug supplies. At 
the conclusion of the study, any unused study drug will be returned to the Sponsor or the Sponsor’s 
designee. If no supply remains, this will be indicated in the Drug Accountability Log.  
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
The following medications and/or procedures are excluded: 
• Platelet transfusion or receipt of blood products containing platelets within 7 days of the 
Baseline Visit; however, packed red blood cells are permitted; 


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• Use of anticoagulant or antiplatelet therapy (other than low dose aspirin) onVisit 4 (Procedure 
Day) 
• Use of erythropoietin-stimulating agents within 7 days of the Baseline Visit; 
• Use of moderate or strong inducers of CYP2C9 or CYP3A4/5 from 7 days prior to Baseline 
through the end of the dosing regimen (see Appendix C); 
• Use of thrombopoietin receptor agonists (eg, eltrombopag or romiplostim); 
• Use of systemic antibiotic therapy within 7 days of the Baseline Visit; however, prophylactic 
use of antibiotics is permitted; 
• A surgery between the Baseline Visit and Visit 4 (Procedure Day); and 
• Currently enrolled in another clinical study with any investigational drug or device within 
30 days of the Baseline Visit; however, participation in observational studies is permitted. 
5.6.2 
Documentation of Concomitant Medication Use 
All concomitant medications (including concurrent therapies and concurrent procedures) will be 
documented as indicated in Appendix A. Dose, indication for administration, and dates of 
medication administration will also be captured in source documents and on the appropriate eCRF. 


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6 
STUDY PROCEDURES 
A schedule of procedures in tabular format is provided in Table 1 in Appendix A.  
Local laboratories will be used to determine eligibility; however, for study analysis and reporting 
purposes, only values determined at a central laboratory will be used with the exception of platelet 
count. Local laboratories may be used if immediate results are clinically needed.  
Two platelet counts collected on different days must be used to calculate the mean baseline platelet 
count to determine eligibility as described in Inclusion Criterion #2. If a platelet count obtained 
per standard of care within 14 days of Baseline (Visit 2) is not available, a platelet count must be 
obtained at Screening (Visit 1) and then repeated at Baseline (Visit 2) to confirm eligibility.  If an 
eligible platelet count obtained per standard of care is available from this time period, Visit 1 is 
not required and all Screening and Baseline procedures can be performed at Visit 2. 
6.1 
Informed Consent 
Prior to conducting any study-related activities, written informed consent must be signed and dated 
by the subject (or legally authorized representative). See Section 11.3 for additional information 
on informed consent. 
6.2 
Screening 
6.2.1 
 Visit 1 – Screening Visit (optional)  
If an eligible platelet count obtained per standard of care within 14 days of the Baseline visit is 
available, this visit is not required and study procedures may commence as described for Visit 2. 
The following procedures will be performed at the Screening Visit at Visit 1 (Day -14 to Day -1): 
• Obtain informed consent prior to screening procedures; 
• Obtain demographics and medical history (including etiology of thrombocytopenia); 
• Collect blood samples for the following assessments: 
o Platelet count (local and central laboratories),  
• Contact IRT to register the subject in the study. 
6.2.2 
Visit 2 - Baseline Visit 
The following procedures will be performed prior to study drug administration at the Baseline 
Visit at Visit 2 (Day 1): 
• Obtain informed consent prior to screening procedures, if Visit 1 not performed; 
• Conduct eligibility assessment based on inclusion/exclusion criteria;  
• Obtain demographics and medical history (including etiology of thrombocytopenia), if Visit 1 
not performed; 
• Collect procedure-related information; 
• Record concomitant medications; 
• Assess adverse events; 


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• Perform physical examination; 
• Record vital signs (includes weight, body temperature, blood pressure, and pulse rate); 
• Record an eligible platelet count collected within the previous 14 days, if available; Collect 
blood samples for the following assessments (-1 Day permitted): 
o Hematology (local and central laboratories),  
o Platelet count (local and central laboratories); 
o Coagulation (local and central laboratories); 
o Serum chemistry (central laboratory only); and 
o Pregnancy test for female subjects of childbearing potential only (serum or urine); 
• Contact IRT;  
• Dispense study drug; and 
• Administer or self-dose study drug. 
6.3 
Treatment Period  
Subjects will receive 60 mg oral avatrombopag once daily for 5 days. For study site visits during 
the Treatment Period, study drug may be administered at the site or the subject may self-dose. 
Subjects will self-dose at all other times and be instructed to take study drug with food. The 
Investigator or designee will provide subjects with sufficient study drug to complete the 5-day 
regimen. 
6.3.1 
Visit 3 
The following procedures will be performed at Visit 3 (Day 5 [-2 days]): 
• Record concomitant medications, 
• Assess adverse events, 
• Collect blood samples for the following assessments: 
o Hematology (central laboratory only), 
o Platelet count (local and central laboratories), and 
o Coagulation (central laboratory only), 
• Assess whether subject required any rescue procedure for bleeding, 
• If any bleeding, perform ISTH non-surgical bleeding assessment (see Appendix D), 
• Contact IRT, and 
• Administer or self-dose study drug. 


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6.4 
Visit 4 - Procedure Day 
The following procedures will be performed pre-operatively on Procedure Day at Visit 4 (Day 10 
[+3 days]): 
• Record vital signs (includes weight, body temperature, blood pressure, and pulse rate); 
• Collect blood samples for the following assessments: 
o Hematology (central laboratory only), 
o Platelet count (local and central laboratories),  
o Coagulation (central laboratory only), and 
o Serum chemistry (central laboratory only);  
• Record whether subject required a platelet transfusion; 
• If any bleeding, perform ISTH non-surgical bleeding assessment (see Appendix D); 
• Contact IRT; and 
• Collect study drug package and any unused study drug. 
The following procedures will be performed post-operatively on Procedure Day at Visit 4 (Day 10 
[+3 days]): 
• Record concomitant medications, 
• Record adverse events, 
• Record whether subject required any rescue procedure for bleeding, and 
• If any bleeding, perform ISTH surgical bleeding assessment (see Appendix D). 
6.5 
Follow-Up Period 
6.5.1 
Visit 5 
The following procedures will be performed at Visit 5 (7 days post-procedure [+3 days]): 
• Record concomitant medications; 
• Assess adverse events; 
• Perform physical examination; 
• Record vital signs (includes weight, body temperature, blood pressure, and pulse rate); 
• Collect blood samples for the following assessments: 
o Hematology (central laboratory only), 
o Platelet count (local and central laboratories),  
o Coagulation (central laboratory only), and 
o Serum chemistry (central laboratory only); 
• Assess whether subject required a platelet transfusion; 


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• Assess whether subject required any rescue procedure for bleeding;  
• If any bleeding, perform ISTH surgical and non-surgical bleeding assessment (see Appendix 
D); and 
• Contact IRT. 
6.5.2 
Visit 6  
The following procedures will be performed at Visit 6 (Day 35 [±3 days]): 
• Record concomitant medications; 
• Assess adverse events; 
• Perform physical examination; 
• Record vital signs (includes weight, body temperature, blood pressure, and pulse rate); 
• Collect blood samples for the following assessments: 
o Hematology (central laboratory only), 
o Platelet count (local and central laboratories),  
o Coagulation (central laboratory only), and 
o Serum chemistry (central laboratory only); 
• Perform pregnancy test for female subjects of childbearing potential only (serum or urine);  
• Assess whether subject required a platelet transfusion; 
• Assess whether subject required any rescue procedure for bleeding; 
• If any bleeding, perform ISTH surgical and non-surgical bleeding assessment (see Appendix 
D); and 
• Contact IRT. 
6.6 
Early Termination Visit and Withdrawal Procedures 
For subjects who are withdrawn from the study prior to completion, all Visit 6 procedures will be 
performed at an Early Termination Visit. These procedures include the following:  
• Record concomitant medications; 
• Assess adverse events; 
• Perform physical examination; 
• Record vital signs (includes weight, body temperature, blood pressure, and pulse rate); 
• Collect blood samples for the following assessments: 
o Hematology (central laboratory only), 
o Platelet count (local and central laboratories),  


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o Coagulation (central laboratory only), and 
o Serum chemistry (central laboratory only);  
• Perform pregnancy test for female subjects of childbearing potential only (serum or urine);  
• Assess whether subject required a platelet transfusion; 
• Assess whether subject required any rescue procedure for bleeding; 
• If any bleeding, perform ISTH surgical and/or non-surgical bleeding assessment (see Appendix 
D); and 
Note: For an Early Termination Visit where a subject withdraws from the study prior to surgery 
on Procedure Day, the non-surgical ISTH bleeding definitions will be used. If a subject 
withdraws after surgery on Procedure Day, both the non-surgical and surgical ISTH bleeding 
definitions will be used. 
• Contact IRT. 


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7 
EFFICACY ASSESSMENTS 
The primary efficacy endpoint is the proportion of subjects achieving a platelet count of 
≥100 × 109/L on Procedure Day, when measured prior to a platelet transfusion (if any). 
The secondary efficacy endpoints include the following: 
• Change in platelet count from baseline to Procedure Day, 
• Proportion of subjects without platelet transfusion and any other treatment for bleeding after 
the Baseline Visit and up to 7 days following Procedure Day,  
• Proportion of subjects without platelet transfusion after the Baseline Visit and up to 7 days 
following Procedure Day, and 
• Proportion of subjects without bleeding after the Baseline Visit and up to 7 days following 
Procedure Day. 
Blood samples to assess platelet count will be collected as indicated in Appendix A. Local 
laboratories will be used to determine eligibility; however, for study analysis and reporting 
purposes, only values determined at a central laboratory will be used with the exception of platelet 
count. Local laboratories may be used if immediate results are clinically needed.  
Whether a subject requires a platelet transfusion will be determined by the Investigator or treating 
physician. Transfusion may be deemed necessary if the platelet count is below the target value of 
≥100 × 109/L or at the discretion of the Investigator or treating physician.  
Bleeding will be evaluated by the Investigator using the non-surgical and surgical ISTH bleeding 
definitions described in Appendix D. The non-surgical ISTH bleeding definitions (Table 3) will 
be used when evaluating subjects prior to surgery on Procedure Day, and the surgical ISTH 
bleeding definitions (Table 4) will be used when evaluating subjects after surgery on Procedure 
Day. Both the non-surgical and surgical ISTH bleeding definitions will be used to evaluate subjects 
during the Follow-up Period. For an Early Termination Visit where a subject withdraws from the 
study prior to surgery on Procedure Day, the non-surgical ISTH bleeding definitions will be used. 
If a subject withdraws after surgery on Procedure Day, both the non-surgical and surgical ISTH 
bleeding definitions will be used. 


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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product, which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and/or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product, whether or not related to the investigational medicinal product. All adverse 
events, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of informed consent until study participation is complete. Subjects 
should be instructed to report any adverse event that they experience to the Investigator. 
Investigators should make an assessment for adverse events at each visit and record the event on 
the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at the Baseline Visit should not be reported as an adverse 
event unless the medical condition or signs or symptoms present at baseline change in severity or 
seriousness at any time during the study. In this case, it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination findings that are detected during 
the study or are present at the Baseline Visit and significantly worsen during the study should be 
reported as adverse events. The Investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. Clinically significant abnormal laboratory values occurring during the 
clinical study will be followed until repeat tests return to normal, stabilize, or are no longer 
clinically significant. Any abnormal test that is determined to be an error does not require reporting 
as an adverse event. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e. the relationship cannot be ruled out. 
8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  


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8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
•
The temporal sequence from study drug administration-
o The event should occur after the study drug is given. The length of time from study drug
exposure to event should be evaluated in the clinical context of the event. 
•
Underlying, concomitant, intercurrent diseases-
o Each report should be evaluated in the context of the natural history and course of the
disease being treated and any other disease the subject may have. 
•
Concomitant drug-
o The other drugs the subject is taking or the treatment the subject receives should be
examined to determine whether any of them might be recognized to cause the event in 
question. 
•
Known response pattern for this class of study drug-
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a
class effect. 


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•
Exposure to physical and/or mental stresses-
o The exposure to stress might induce adverse changes in the recipient and provide a logical
and better explanation for the event. 
•
The pharmacology and PK of the study drug-
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion)
of the study drug should be considered. 
8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
•
Death,
•
A life-threatening adverse event,
o
NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view of
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of
death. It does not include an event that, had it occurred in a more severe form, might have
caused death.
•
Requires hospitalization or prolongation of existing hospitalizations,
o
NOTE: Any hospital admission with at least 1 overnight stay will be considered an
inpatient hospitalization. An emergency room visit without hospital admission will not be
recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled
or planned before signing of informed consent. However, unexpected complications and/or
prolongation of hospitalization that occur during elective surgery should be recorded as
adverse events and assessed for seriousness. Admission to the hospital for social or
situational reasons (ie, no place to stay, live too far away to come for hospital visits) will
not be considered inpatient hospitalizations. Hospitalization due to expected recovery time
for the planned procedure will not be counted as an SAE.
•
A persistent or significant disability/incapacity or substantial disruption of the ability to
conduct normal life functions,
•
A congenital anomaly/birth defect, or
•
An important medical event.
o
NOTE: Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered an SAE when, based upon appropriate medical
judgment, they may jeopardize the subject and may require medical or surgical intervention
to prevent one of the outcomes listed above. Examples of such medical events include
allergic bronchospasm requiring intensive treatment in an emergency room or at home,
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the
development of drug dependency.


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8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported within 24 hours of the knowledge of the occurrence 
(this refers to any adverse event that meets any of the aforementioned serious criteria). All SAEs 
that the Investigator considers related to study drug occurring after the 30-day Follow-up Period 
must be reported to the Sponsor. 
To report the SAE, complete the appropriate form for the study. It is very important that the 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 appropriate SAE follow-up 
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 Institutional Review Board (IRB) 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. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study File. 
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the appropriate 
form for the study and submit any supporting documentation (eg, subject discharge summary or 
autopsy reports) via fax or e-mail.  
8.4 
Pregnancy Reporting 
If the subject becomes pregnant during the study or within 30 days of discontinuing study drug, 
the Investigator should report the pregnancy within 24 hours of being notified. Safety will then 
forward the appropriate form to the Investigator for completion.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The subject should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify Safety. 
At the completion of the pregnancy, the Investigator will document the outcome of the pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), 
the Investigator should follow the procedures for reporting an SAE. 


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8.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the FDA, and in any case no later 
than 7 days after knowledge by the Sponsor of such a case, and that relevant follow-up information 
will subsequently be communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all Investigators as required. 
8.6 
Clinical Laboratory Evaluations 
Clinical safety laboratory assessments will include serum chemistry, hematology, and coagulation 
and will be obtained as indicated in Appendix A. See Appendix B for a complete list of analytes. 
Local laboratories will be used to determine eligibility; however, for study analysis and reporting 
purposes, only values determined at a central laboratory will be used with the exception of platelet 
count. Local laboratories may be used if immediate results are clinically needed.  
8.7 
Vital Signs 
Vital sign measurements will include height (at the Baseline Visit only), weight, body temperature, 
blood pressure, and pulse rate and will be measured after resting for 5 minutes as indicated in 
Appendix A. 
8.8 
Physical Examinations 
Physical examinations will consist of the following at a minimum: chest, lungs, heart, and 
abdomen.. Physical examinations will be performed as indicated in Appendix A.  
8.9 
Demographic and Medical History 
Demographic information (date of birth, gender, race, and ethnic group) and relevant medical 
history will be recorded at the Screening or Baseline Visit.  


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9 
STATISTICS 
9.1 
Analysis Populations 
Full Analysis Set (FAS): The FAS will include all enrolled subjects who receive at least 1 dose of 
avatrombopag. 
Per-Protocol Analysis Set (PPS): The PPS will include the subset of subjects from the FAS who 
are treated according to the protocol without any major deviations. A full list of major protocol 
deviations will be finalized prior to database lock. 
Safety Analysis Set: The Safety Analysis Set will include all subjects who receive at least 1 dose 
of avatrombopag. 
9.2 
Statistical Methods 
9.2.1 
Analysis of Efficacy 
All primary and secondary efficacy endpoints will be analyzed using the FAS. The PPS will be 
used only for sensitivity analysis of the primary and secondary efficacy endpoints. 
9.2.1.1 
Primary efficacy analysis 
The primary efficacy endpoint is the proportion of subjects achieving a platelet count of 
≥100 × 109/L on Procedure Day, when measured prior to a platelet transfusion (if any). Subjects 
with missing information due to early withdrawal or other reasons are considered as having a 
platelet count <100 × 109/L in the analysis; that is, missing values are considered as 
non-responders. The primary endpoint will be estimated from a binomial distribution, with 
95% confidence interval (CI) of the proportion calculated. The study will be claimed successful if 
the lower boundary of the 2-sided 95% CI is above the 0.65. The primary analysis will be 
performed on the FAS and repeated on the PPS.  
9.2.1.2 
Secondary efficacy analysis 
The following secondary efficacy endpoints will be summarized and analyzed in the same manner 
as the primary efficacy endpoint: 
•
Proportion of subjects without platelet transfusion and any other treatment for bleeding after
the Baseline Visit and up to 7 days following Procedure Day,
•
Proportion of subjects without platelet transfusion after the Baseline Visit and up to 7 days
following Procedure Day, and
•
Proportion of subjects without bleeding after the Baseline Visit and up to 7 days following
Procedure Day.
Change in platelet count from baseline to Procedure Day for avatrombopag will be calculated for 
each subject and summarized descriptively. The mean (95% CI) and median (range) will be 
provided.  
9.2.1.3 
Other efficacy analysis 
Additional efficacy analyses will be performed if deemed necessary. The details of the analyses 
will be described in the Statistical Analysis Plan that will be finalized prior to database lock. 


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9.2.2 
Analysis of Safety 
Safety and tolerability will be assessed by examining the incidence of adverse events, physical 
examination findings, clinical laboratory parameters, and vital signs over time using the Safety 
Analysis Set. 
9.2.3 
Interim Analysis 
Two interim data reviews are planned to assess study design assumptions and adjust study drug 
dose regimen if necessary.  
The first interim data review will be conducted when approximately 25% of subjects 
(approximately 15 subjects) have been enrolled. For the primary efficacy endpoint, if fewer than 
10 responders out of 15 enrolled subjects are observed (the probability of observing 
<10 responders out of 15 enrolled subjects is 0.0611 if the true response rate is 0.8), the 
avatrombopag dose increase (to 80 mg) will be considered for the subsequent enrolled subjects. 
Otherwise, the study will continue as planned until the second interim data review. 
In the event that the avatrombopag dose was not adjusted after the first interim data review, the 
second interim data review will be conducted when approximately 50% of subjects (approximately 
30 subjects) have been enrolled. If fewer than 21 responders out of 30 enrolled subjects are 
observed (the probability of observing <21 responders out of 30 enrolled subjects is 0.0611 if the 
true response rate is 0.8), the avatrombopag dose increase (to 80 mg) will be considered for the 
subsequent enrolled subjects. Otherwise, the study will continue as planned until the completion 
of the study.  
Details of the planned interim analyses will be provided in the Interim Analysis Plan. 
9.2.4 
Sample Size Determination 
It is estimated from PK/PD modeling that the proportion of subjects treated with avatrombopag 
expected to achieve a platelet count of ≥100 × 109/L on Procedure Day, when measured prior to 
platelet transfusion (if any), is approximately 85%. Assuming the true response rate is 0.8 and the 
desired lower boundary of the 2-sided 95% CI is at least 0.65, 60 enrolled subjects will provide 
greater than 90% power.  If the decision is made to increase the dose of study drug at one of the 
interim reviews of the data based on the pre-defined boundaries, up to an additional 30 subjects 
may be enrolled in the study for a maximum sample size of 90 subjects.    


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associate (CRA) 
on an ongoing basis and during monitoring visits. The CRAs will verify data recorded in the 
electronic data capture (EDC) system with source documents. All corrections or changes made to 
any study data must be appropriately tracked in an audit trail in the EDC system. An eCRF will be 
considered complete when all missing, incorrect, and/or inconsistent data has been accounted for 
and reconciliation between other databases (eg, safety, IRT) is complete. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR) Part 11 and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
•
Medical Dictionary for Regulatory Activities for medical history and adverse events, and
•
World Health Organization Drug Dictionary for prior and concomitant medications.
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 


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10.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
11.2 
Institutional Review Board 
The IRB will review all appropriate study documentation in order to safeguard the rights, safety, 
and well-being of subjects. The study will only be conducted at sites where IRB approval has been 
obtained. The protocol, Investigator’s Brochure, Informed Consent Form (ICF), advertisements (if 
applicable), written information given to the subjects, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council on Harmonisation (ICH) require that approval be 
obtained from an IRB prior to participation of subjects in research studies. Prior to study onset, the 
protocol, any protocol amendments, ICFs, advertisements to be used for subject recruitment, and 
any other written information regarding this study to be provided to a subject or subject’s legal 
guardian must be approved by the IRB. 
No drug will be released to the site until written IRB authorization has been received by the 
Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study subject (or legally authorized representative) is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation and must ensure that the subject has been informed of his/her rights to privacy. The 
Investigator will obtain written informed consent from each subject (or legally authorized 
representative) before any study-specific activity is performed and should document in the source 
documentation that consent was obtained prior to enrollment in the study. The original signed copy 
of the ICF must be maintained by the Investigator and is subject to inspection by a representative 
of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. A copy of the 
signed ICF will be given to the subject (or legally authorized representative). 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any subject in this study, the Sponsor or their designee will review with the 


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Investigator and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs 
and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, forms for 
SAEs, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 




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13 
REFERENCES 
1. McCullough J. Current issues with platelet transfusion in patients with cancer. Semin
Hematol. 2000;37(2 Suppl 4):3-10.
2. Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer:
clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol.
2001;19(5):1519-1538.
3. Kuter DJ. Thrombopoietin: biology and potential clinical applications. In: McCrae KR, eds.
Thrombocytopenia. New York, New York: Taylor & Francis Group; 2006.
4. Avatrombopag maleate Global Investigator’s Brochure, v12, April 2016.


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APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 1 
Schedule of Procedures 
Period 
Screening 
Treatment 
Procedure Day 
Follow-Up 
Visit 
1 
(optional) 
2 
(Baseline Visit) 
3 
4 
5 
6 
(ET Visit) 
Day 
Day -14 to -1 
Day 1 [1] 
Day 5 
Day 10 [2] 
7 Days 
Post-Procedure 
Day 35 
Window 
(-2 days) 
(+3 days) 
(+3 days) 
(±3 days) 
Procedures 
Subject informed consent 
X 
X [11] 
Inclusion/exclusion criteria 
X 
Demographics 
X 
X [11] 
Medical history [10] 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Physical examination [3] 
X 
X 
X 
X 
Vital signs [4] 
X 
X 
X 
X 
Hematology 
X [5] 
X 
X 
X 
X 
Platelet count [5] 
X 
X 
X 
X 
X 
X 
Coagulation 
X [5] 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
Pregnancy testing [6] 
X [7] 
X [7] 
Assessment of platelet transfusion 
X 
X 
X 
Assessment of any rescue procedure for bleeding 
X 
X 
X 
X 
Procedure-related information (type, risk, etc.) 
X 
Contact IRT 
X 
X 
X 
X 
X 
X 
Dispense study drug [8] 
X 
Study drug dosing [8] 
X 
X 
Bleeding assessment (ISTH) [9] 
X 
X 
X 
X 
Collect study drug 
X 
Note: Prior to conducting any study-related activities, written informed consent must be signed and dated by the subject. Local laboratories will be used to determine eligibility; 
however, for study analysis and reporting purposes, only values determined at a central laboratory will be used with the exception of platelet count. Local laboratories may be used 
if immediate results are clinically needed. 
1.
All assessments will be performed prior to study drug dosing.


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2.
The following procedures will be performed pre-operatively on Procedure Day: vital signs, hematology, platelet count, coagulation, serum chemistry, record whether subject
required a platelet transfusion, ISTH non-surgical bleeding assessment (if any bleeding), contact IRT, and collect study drug. The following procedures will be performed
post-operatively on Procedure Day: concomitant medications, adverse events, record any rescue procedure for bleeding, and ISTH surgical bleeding assessment (if any
bleeding). 
3.
Physical examinations will consist of the following at a minimum: chest, lungs, heart, and abdomen.
4.
Vital sign measurements will include height (at the Baseline Visit only), weight, body temperature, blood pressure, and pulse rate and will be measured after resting for
5 minutes.
5.
Local and central laboratories. Baseline hematology, platelet count and coagulation laboratories may be collected up to one day prior to the Baseline visit (Visit 2).
6.
For female subjects of childbearing potential only. A serum or urine pregnancy test will be performed at the Baseline Visit prior to study drug administration.
7.
Either a serum or urine pregnancy test may be used.
8.
Subjects will receive 60 mg oral avatrombopag once daily for 5 days beginning on Day 1. For study site visits during the Treatment Period, study drug may be administered at
the site or the subject may self-dose. Subjects will self-dose at all other times and be instructed to take study drug with food. The Investigator or designee will provide subjects
with sufficient study drug to complete the 5-day regimen.
9.
Bleeding will be evaluated, if present, by the Investigator using the non-surgical and surgical ISTH bleeding definitions described in Appendix D. The non-surgical ISTH
bleeding definitions (Table 3) will be used when evaluating subjects prior to surgery on Procedure Day, and the surgical ISTH bleeding definitions (Table 4) will be used
when evaluating subjects after surgery on Procedure Day. Both the non-surgical and surgical ISTH bleeding definitions will be used to evaluate subjects during the Follow-up
Period. For an Early Termination Visit where a subject withdraws from the study prior to surgery on Procedure Day, the non-surgical ISTH bleeding definitions will be used.
If a subject withdraws after surgery on Procedure Day, both the non-surgical and surgical ISTH bleeding definitions will be used.
10. Document etiology of thrombocytopenia.
11. If Visit 1 not performed
ET = Early Termination; IRT = Interactive Response Technology; ISTH = International Society on Thrombosis and Haemostasis.


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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphorus 
Lactate dehydrogenase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
1. Manual microscopic review is performed only if white blood cell count
and/or differential values are out of reference range.
Coagulation 
Prothrombin time 
Activated partial thromboplastin time 
International normalized ratio 
Pregnancy Test 
Beta-human chorionic gonadotropin 


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APPENDIX C:  CYTOCHROME P450 INDUCERS AND INHIBITORS 
Table 2 
CYP450 Inducers 
 
Strong 
Moderate 
CYP2C9 inducers 
NA 
Aprepitant, carbamazepine, enzalutamide, 
rifampin, ritonavir 
CYP3A4 inducers 
Carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s wort 
Bosentan, efavirenz, etravirine, modafinil 
CYP = cytochrome P450; NA = not applicable. 
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm
#inVivo 


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APPENDIX D:  INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS BLEEDING 
DEFINITIONS 
Table 3 
Non-Surgical International Society on Thrombosis and Haemostasis Bleeding Definition 
Major bleeding 
Defined as overt bleeding with 1 or more of the following: 
•
Associated with a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more;
•
Leads to a transfusion of 2 or more units of packed red blood cells or whole blood;
•
Occurs in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment
syndrome, retroperitoneal; and/or
•
Contributes to death.
Non-major 
clinically relevant 
bleeding  
Defined as overt bleeding not meeting the criteria for major bleeding, but associated with medical intervention, unscheduled contact 
with a physician (visit or telephone call), (temporary) cessation of study treatment, or associated with any other discomfort, such as 
pain or impairment of daily activities. Examples of such bleeding include: 
•
Any bleeding compromising hemodynamics;
•
Any bleeding leading to hospitalization;
•
Epistaxis if it lasts for >5 minutes, if it is repetitive (ie, ≥2 episodes of true bleeding, [ie, not spots on a handkerchief] within
24 hours), or if it leads to an intervention (packing, electrocoagulation, etc);
•
Gingival bleeding if it occurs spontaneously (ie, unrelated to tooth brushing or eating) or lasts >5 minutes;
•
Hematuria if it is macroscopic and either spontaneous or lasts >24 hours after instrumentation (eg, catheter placement or surgery)
of the urogenital tract;
•
Macroscopic gastrointestinal hemorrhage (at least 1 episode of melena/hematemesis, if clinically apparent, and hemoccult positive
rectal blood loss, if more than a few spots on toilet paper);
•
Hemoptysis, if more than a few speckles in the sputum and not occurring within the context of a pulmonary embolism;
•
Intramuscular hematoma;
•
Subcutaneous (skin) hematoma if the size is >25 cm2 or >100 cm2 if provoked; and/or
•
Any other bleeding type that is considered to have clinical consequences for a subject.
Minor bleeding 
Defined as all other overt bleeding episodes not meeting the criteria for major or clinically relevant non-major bleeding. 
Sources: Schulman S, Angeras D, Bergqvist B, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb 
Haemost. 2010;8:202-204 and Tangelder M, Nwachuku C, Jaff M, et al. A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in 
patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention. J Endovasc Ther. 2015; 
22(2)261-268.  


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Table 4 
Surgical International Society on Thrombosis and Haemostasis Bleeding Definition 
Major bleeding 
•
Fatal bleeding;
•
Bleeding that is symptomatic and occurs in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal,
pericardial, in a non-operated joint, or intramuscular with compartment syndrome, assessed in consultation with the surgeon;
•
Extrasurgical site bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or
more units of whole blood or red cells, with temporal association within 24 to 48 hours to the bleeding;
•
Surgical site bleeding that requires a second intervention – open, arthroscopic, endovascular – or a hemarthrosis of sufficient size
as to interfere with rehabilitation by delaying mobilization or delayed wound healing, resulting in prolonged hospitalization or a
deep wound infection; and
•
Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability, as assessed by
the surgeon. There should be an associate fall in hemoglobin level of at least 20 g/L (1.24 mmol/L), or transfusion, indicated by
the bleeding, of at least 2 units of whole blood or red cells, with temporal association within 24 hours to the bleeding.
Minor bleeding 
Defined as all other overt bleeding episodes not meeting the criteria for major bleeding. 
Sources: Schulman S, Angeras D, Bergqvist B, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb 
Haemost. 2010;8:202-204 and Tangelder M, Nwachuku C, Jaff M, et al. A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in 
patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention. J Endovasc Ther. 2015; 
22(2)261-268.  


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APPENDIX E: Protocol Amendments 
Amendment #2 – 17 September 2018 
Rationale for Amendment 
Amendment 2 has been introduced to clarify certain inclusion and exclusion criteria and to allow 
for a single Baseline visit (Visit 2) prior to study drug administration. The Screening visit (Visit 
1) has been modified to an optional visit, required only if a subject does not have an eligible platelet
count collected per standard of care within 14 days of Baseline which can be used to determine
eligibility. If an eligible platelet count is available from this time period, this may serve as one of
the 2 required platelet counts to determine the mean baseline platelet count for inclusion criterion
#2.
Due to varying local platelet count thresholds, the specification of a 100×109/L target after platelet 
transfusion has been removed. Inclusion criterion #3 has been clarified to include subjects 
scheduled to undergo operations to critical sites or with a high risk of bleeding, OR if, in the 
opinion of the Investigator, a pre-operative platelet transfusion would otherwise be required. 
Exclusion criteria #1 and #14 have been clarified to exclude only a recent history, defined as the 
previous 6 months, of thrombotic events or significant cardiovascular events.  Exclusion #4 has 
been clarified to require subjects to be able to temporarily withhold antiplatelet or anticoagulant 
medications pre-operatively per local standard of care, with low dose aspirin excepted. 
Certain study procedures have also been removed or clarified.  The ISTH bleeding assessments 
are to be performed only if bleeding occurs; the requirement to perform a physical exam on 
Procedure Day has been removed; the scope of physical exams will now only require chest, lungs, 
heart, and abdomen at a minimum.  
Summary of Significant Changes in Amendment 2 
•
Inclusion criterion #2 has be modified to allow for an eligible platelet count obtained per
standard of care within 14 days of Baseline to be used as 1 of the 2 required in order to
calculate the mean baseline platelet count to determine eligibility
•
Inclusion criterion #3 has been clarified to include subjects scheduled to undergo
operations to critical sites or with a high risk of bleeding, OR if, in the opinion of the
Investigator, a pre-operative platelet transfusion would otherwise be required
•
Exclusion criteria #1 and #14 have been clarified to exclude only a recent history of
thrombotic or significant cardiovascular events
•
Visit 1 is now optional, required only for subjects without an eligible pre-existing platelet
count; all screening and baseline procedures can be performed at Visit 2
The following presents changes made by this amendment.  New/revised text is presented in bold 
italics; deleted text is identified by strikethrough. Typographic corrections, including grammatical 
and punctuation errors, are not shown. 


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SYNOPSIS 
POPULATION: 
The population for this study is subjects ≥18 years of age at the time of informed consent who are 
scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or operations with 
a high risk of bleeding (eg, major abdominal surgery) who OR, in the opinion of the Investigator, 
would otherwise require a pre-operative platelet transfusion aiming for a platelet count of at least 
100 × 109/L to prevent bleeding. Subjects without chronic liver disease must have a mean baseline 
platelet count between 50 × 109/L and <100 × 109/L, measured on 2 separate occasions (the 
Screening Visit and the Baseline Visit), with neither platelet count ≥100 × 109/L. Subjects with 
chronic liver disease (CLD) must have a mean baseline platelet count between 50 × 109/L and <75 
× 109/L, measured on 2 separate occasions (the Screening Visit and the Baseline Visit), with 
neither platelet count ≥75 × 109/L. 
STUDY DESIGN AND DURATION:  
Subjects must be screened prior to the Baseline Visit. Mean baseline platelet count in subjects 
without CLD must be between 50 × 109/L and <100 × 109/L and between 50 × 109/L and <75 × 
109/L in subjects with CLD. Platelet counts must be measured on 2 separate occasions (the 
Screening Visit and the Baseline Visit), and must be performed at least 1 day apart with neither 
platelet count ≥100 × 109/L in subjects without CLD and ≥75 × 109/L in subjects with CLD. One 
standard of care platelet count measurement may be used if collected within 14 days of Baseline 
and the mean of these 2 platelet counts (mean baseline platelet count) will be used for entry 
criteria. 
1.4 Clinical Studies 
Based on these data, avatrombopag (DOPTELET®) was approved by FDA in May 2018 for the 
treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to 
undergo a procedure. 
3.1 Summary of Study Design 
Subjects must be screened prior to the Baseline Visit. Mean baseline platelet count in subjects 
without CLD must be between 50 × 109/L and <100 × 109/L and between 50 × 109/L and <75 × 
109/L in subjects with CLD. Platelet counts must be measured on 2 separate occasions (the 
Screening Visit and the Baseline Visit), and must be performed at least 1 day apart with neither 
platelet count ≥100 × 109/L in subjects without CLD and ≥75 × 109/L in subjects with CLD. One 
standard of care platelet count measurement may be used if collected within 14 days of Baseline 
and the mean of these 2 platelet counts (mean baseline platelet count) will be used for entry 
criteria. 
4.1 Inclusion Criteria 
2. Subject has a mean baseline platelet count between: 
a.  50 × 109/L and <100 × 109/L in subjects without a diagnosis of chronic liver disease.  
or 
b. 50 × 109/L and <75 × 109/L in subjects with diagnosed chronic liver disease.  


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Platelet counts must be measured on 2 separate occasions (the Screening Visit and the Baseline 
Visit), and must be performed at least 1 day apart with neither platelet count ≥100 × 109/L in 
subjects without CLD and ≥75 × 109/L in subjects with CLD. The mean of these 2 platelet 
counts (mean baseline platelet count) will be used for entry criteria; 
3. Subject is scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or
operations with a high risk of bleeding (eg, major abdominal surgery), and OR, in the opinion
of the Investigator, would otherwise require a pre-operative platelet transfusion aiming for a 
platelet count of at least 100 x 109/L to prevent bleeding; 
6. Subject (or legally authorized representative) must provide written informed consent.
4.2 Exclusion Criteria
1. Subject has a history of arterial or venous thrombosis within the previous 6 months of
Baseline;
2. Known portal vein blood flow velocity rate <10 cm/second or previous occurrence of a portal
vein thrombosis within 6 months of screening Baseline
3. Subject plans to have a platelet transfusion or plans to receive blood products containing
platelets within 7 days of the Screening Baseline Visit; however, packed red blood cells are
permitted;
4. Subject is unable to temporarily withhold use of anticoagulant or antiplatelet therapy within
7 days of the Screening Visit per local standard of care prior to the operation (low dose
aspirin may be continued);
5. Use of erythropoietin-stimulating agents within 7 days of the Screening Baseline Visit;
6. Use of moderate or strong inducers of cytochrome P450 (CYP) 2C9 or CYP3A4/5 from 7 days
prior to Screening Baseline through the end of the dosing regimen (see Appendix C);
8. Subject has an active infection requiring systemic antibiotic therapy within 7 days of the
Screening Baseline Visit; however, prophylactic use of antibiotics is permitted;
9. Subject with alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence
within 6 months of the Screening Baseline Visit (unless participating in a controlled
rehabilitation program) or alcoholic hepatitis within 6 months of the Screening Visit;
10. Subject has a surgery between the Screening Baseline Visit and Visit 4 (Procedure Day);
12. Subject has any clinically significant bleeding at the Screening Baseline Visit;
14. Subject has a recent history (within the previous 6 months) of significant cardiovascular
disease (eg, exacerbation of congestive heart failure New York Heart Association Grade
III/IV, arrhythmia known to increase the risk of thromboembolic events [eg, atrial fibrillation],
coronary or peripheral artery stent placement or angioplasty, and coronary or peripheral artery
bypass graft);
15. Female subjects who are lactating or pregnant at the Screening Visit or the Baseline Visit (as
documented by a positive serum beta-human chorionic gonadotropin [β-hCG] test with a
minimum sensitivity of 25 IU/L or equivalent units of β-hCG) or are planning to become
pregnant during the study;


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17. Subject has hemoglobin levels ≤8.0 g/dL or ≥18.0 g/dL for males and >15 g/dL for females at
the Screening Baseline Visit, with hematocrit ≥54% for males and ≥45% for females;
19. Subject with a current malignancy including solid tumors and hematologic malignancies whose
thrombocytopenia may be attributed to chemotherapy during the study;
23. Subject is currently enrolled in another clinical study with any investigational drug or device
within 30 days of the Screening Baseline Visit; however, participation in observational studies
is permitted.
5.1 Treatment Groups 
At the Screening or Baseline Visit, site personnel will contact the interactive response technology 
(IRT) to register the subject. 
5.6.1 Excluded Medications and/or Procedures 
The following medications and/or procedures are excluded: 
•
Platelet transfusion or receipt of blood products containing platelets within 7 days of the
Screening Baseline Visit; however, packed red blood cells are permitted;
•
Use of anticoagulant or antiplatelet therapy (other than low dose aspirin) on between 7 days
prior to the Screening Visit and Visit 4 (Procedure Day)
•
Use of erythropoietin-stimulating agents within 7 days of the Screening Baseline Visit;
•
Use of moderate or strong inducers of CYP2C9 or CYP3A4/5 from 7 days prior to Screening
Baseline through the end of the dosing regimen (see Appendix C);
•
Use of systemic antibiotic therapy within 7 days of the Screening Baseline Visit; however,
prophylactic use of antibiotics is permitted;
•
A surgery between the Screening Baseline Visit and Visit 4 (Procedure Day); and
•
Currently enrolled in another clinical study with any investigational drug or device within
30 days of the Screening Baseline Visit; however, participation in observational studies is
permitted.
6. STUDY PROCEDURES
Two platelet counts collected on different days must be used to calculate the mean baseline 
platelet count to determine eligibility as described in Inclusion Criterion #2. If a platelet count 
obtained per standard of care within 14 days of Baseline (Visit 2) is not available, a platelet 
count must be obtained at Screening (Visit 1) and then repeated at Baseline (Visit 2) to confirm 
eligibility.  If an eligible platelet count obtained per standard of care is available from this time 
period, Visit 1 is not required and all Screening and Baseline procedures can be performed at 
Visit 2. 
6.1 Informed Consent 
Prior to conducting any study-related activities, written informed consent must be signed and dated 
by the subject (or legally authorized representative). See Section 11.3 for additional information 
on informed consent. 


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6.2 Screening 
6.2.1 Visit 1 – Screening Visit (optional) 
If an eligible platelet count obtained per standard of care within 14 days of the Baseline visit is 
available, this visit is not required and study procedures may commence as described for Visit 
2. The following procedures will be performed at the Screening Visit at Visit 1 (Day -14 to Day -
1):
•
Conduct eligibility assessment based on inclusion/exclusion criteria;
•
Record concomitant medications;
•
Assess adverse events;
•
Perform physical examination;
•
Record vital signs (includes height, weight, body temperature, blood pressure, and pulse rate);
•
Collect blood samples for the following assessments:
o
Hematology (local and central laboratories),
o
Platelet count (local and central laboratories),
o
Serum chemistry (central laboratory only), and
o
Serum pregnancy test for female subjects of childbearing potential only (central laboratory
only);
•
Collect procedure-related information; and
6.2.2 Visit 2 - Baseline Visit 
The following procedures will be performed prior to study drug administration at the Baseline 
Visit at Visit 2 (Day 1): 
•
Obtain informed consent prior to screening procedures, if Visit 1 not performed;
•
Conduct eligibility assessment based on inclusion/exclusion criteria;
•
Obtain demographics and medical history (including etiology of thrombocytopenia), if Visit
1 not performed;
•
Collect procedure-related information;
•
Record concomitant medications;
•
Assess adverse events;
•
Perform physical examination;
•
Record vital signs (includes weight, body temperature, blood pressure, and pulse rate);
•
Record an eligible platelet count collected within the previous 14 days, if available;
•
Collect blood samples for the following assessments (-1 Day permitted):
o
Hematology (local and central laboratories),


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o
Platelet count (local and central laboratories);
o
Coagulation (local and central laboratories);
o
Serum chemistry (central laboratory only); and
o
Pregnancy test for female subjects of childbearing potential only (serum or urine);
•
Perform pregnancy test for female subjects of childbearing potential only (serum or urine);
•
Assess whether subject required any rescue procedures for bleeding;
•
Perform International Society on Thrombosis and Haemostasis (ISTH) non-surgical bleeding
assessment (see Appendix D);
•
Contact IRT;
6.3.1 Visit 3 
•
If any bleeding, perform ISTH non-surgical bleeding assessment (see Appendix D),
6.4 Visit 4 - Procedure Day 
The following procedures will be performed pre-operatively on Procedure Day at Visit 4 (Day 10 
[+3 days]): 
•
Perform physical examination
•
Assess Record whether subject required a platelet transfusion;
•
If any bleeding, perform ISTH non-surgical bleeding assessment (see Appendix D);
The following procedures will be performed post-operatively on Procedure Day at Visit 4 (Day 10 
[+3 days]): 
•
Assess Record adverse events,
•
Assess Record whether subject required any rescue procedure for bleeding, and
•
If any bleeding, perform ISTH surgical bleeding assessment (see Appendix D).
6.5 Follow-Up Period 
6.5.1 Visit 5 
The following procedures will be performed at Visit 5 (7 days post-procedure [+3 days]): 
•
If any bleeding, perform ISTH surgical and non-surgical bleeding assessment (see Appendix
D); and
6.5.2 Visit 6  
The following procedures will be performed at Visit 6 (Day 35 [±3 days]): 
•
If any bleeding, perform ISTH surgical and non-surgical bleeding assessment (see Appendix
D); and


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6.6 Early Termination Visit and Withdrawal Procedures 
For subjects who are withdrawn from the study prior to completion, all Visit 6 procedures will be 
performed at an Early Termination Visit. These procedures include the following:  
•
If any bleeding, perform ISTH surgical and/or non-surgical bleeding assessment (see
Appendix D); and
8.1 Adverse Events 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of informed consent until study participation is complete. Subjects 
should be instructed to report any adverse event that they experience to the Investigator. Beginning 
with the Screening Visit, Investigators should make an assessment for adverse events at each visit 
and record the event on the appropriate adverse event eCRF. 
Any medical condition already present at the Screening Baseline Visit should not be reported as 
an adverse event unless the medical condition or signs or symptoms present at baseline change in 
severity or seriousness at any time during the study. In this case, it should be reported as an adverse 
event. 
Clinically significant abnormal laboratory or other examination findings that are detected during 
the study or are present at the Screening Baseline Visit and significantly worsen during the study 
should be reported as adverse events. The Investigator will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an adverse event. 
8.7 Vital Signs 
Vital sign measurements will include height (at the Screening Baseline Visit only), weight, body 
temperature, blood pressure, and pulse rate and will be measured after resting for 5 minutes as 
indicated in Appendix A. 
8.8 Physical Examination 
Physical examinations will consist of the following at a minimum: general appearance, head and 
neck, eyes and ears, nose and throat, chest, lungs, heart, and abdomen extremities and joints, lymph 
nodes, skin, and neurology. Physical examinations will be performed as indicated in Appendix A. 
8.9 Demographic and Medical History 
Demographic information (date of birth, gender, race, and ethnic group) and relevant medical 
history will be recorded at the Screening or Baseline Visit.  
11.3 Informed Consent 
The Investigator must ensure that each study subject (or legally authorized representative) is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation and must ensure that the subject has been informed of his/her rights to privacy. The 
Investigator will obtain written informed consent from each subject (or legally authorized 
representative) before any study-specific activity is performed and should document in the source 


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documentation that consent was obtained prior to enrollment in the study. The original signed copy 
of the ICF must be maintained by the Investigator and is subject to inspection by a representative 
of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. A copy of the 
signed ICF will be given to the subject (or legally authorized representative) 
Table 1 
Schedule of Procedures 
Period 
Screening 
Treatment 
Procedure 
Day 
Follow-Up 
Visit 
1 
(optional) 
2 
(Baseline 
Visit) 
3 
4 
5 
6 
(ET 
Visit) 
Day 
Day -14 
to -1 
Day 1 [1] 
Day 5 
Day 10 [2] 
7 Days 
Post-Procedure 
Day 35 
Window 
(-2 days) 
(+3 days) 
(+3 days) 
(±3 days) 
Procedures 
Subject informed consent 
X 
X [11] 
Inclusion/exclusion criteria 
X 
X 
Demographics 
X 
X [11] 
Medical history [10] 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Physical examination [3] 
X 
X 
X 
X 
X 
Vital signs [4] 
X 
X 
X 
X 
X 
Hematology 
X[5] 
X [5] 
X 
X 
X 
X 
Platelet count [5] 
X 
X 
X 
X 
X 
X 
Coagulation 
X[5] 
X [5] 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
Pregnancy testing [6] 
X 
X [7] 
X [7] 
Assessment of platelet 
transfusion 
X 
X 
X 
Assessment of any rescue 
procedure for bleeding 
X 
X 
X 
X 
X 
Procedure-related 
information (type, risk, etc.) 
X 
X 
Contact IRT 
X 
X 
X 
X 
X 
X 
Dispense study drug [8] 
X 
Study drug dosing [8] 
X 
X 
Bleeding assessment (ISTH) 
[9] 
X 
X 
X 
X 
X 
Collect study drug 
X 
Note: Prior to conducting any study-related activities, written informed consent must be signed and dated by the subject. Local 
laboratories will be used to determine eligibility; however, for study analysis and reporting purposes, only values determined at a 
central laboratory will be used with the exception of platelet count. Local laboratories may be used if immediate results are 
clinically needed. 
1.
All assessments will be performed prior to study drug dosing.
2.
The following procedures will be performed pre-operatively on Procedure Day: physical examination, vital signs,
hematology, platelet count, coagulation, serum chemistry, assess record whether subject required a platelet transfusion,
ISTH non-surgical bleeding assessment (if any bleeding), contact IRT, and collect study drug. The following procedures
will be performed post-operatively on Procedure Day: concomitant medications, adverse events, assess record any rescue
procedure for bleeding, and ISTH surgical bleeding assessment (if any bleeding).
3.
Physical examinations will consist of the following at a minimum: general appearance, head and neck, eye and ears, nose
and throat, chest, lungs, heart, and abdomen extremities and joints, lymph nodes, skin, and neurology.
4.
Vital sign measurements will include height (at the Screening Baseline Visit only), weight, body temperature, blood
pressure, and pulse rate and will be measured after resting for 5 minutes.


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Version 3.0 / Amendment 2, 17 September 2018 
62 
5.
Local and central laboratories. Baseline hematology, platelet count and coagulation laboratories may be collected up to one
day prior to the Baseline visit (Visit 2).
6.
For female subjects of childbearing potential only. A serum or urine pregnancy test will be performed at the Screening
Baseline Visit At the Baseline Visit, the pregnancy test will be performed prior to study drug administration.
7.
Either a serum or urine pregnancy test may be used.
8.
Subjects will receive 60 mg oral avatrombopag once daily for 5 days beginning on Day 1. For study site visits during the
Treatment Period, study drug may be administered at the site or the subject may self-dose. Subjects will self-dose at all other
times and be instructed to take study drug with food. The Investigator or designee will provide subjects with sufficient study
drug to complete the 5-day regimen.
9.
Bleeding will be evaluated, if present, by the Investigator using the non-surgical and surgical ISTH bleeding definitions
described in Appendix D. The non-surgical ISTH bleeding definitions (Table 3) will be used when evaluating subjects prior
to surgery on Procedure Day, and the surgical ISTH bleeding definitions (Table 4) will be used when evaluating subjects
after surgery on Procedure Day. Both the non-surgical and surgical ISTH bleeding definitions will be used to evaluate
subjects during the Follow-up Period. For an Early Termination Visit where a subject withdraws from the study prior to
surgery on Procedure Day, the non-surgical ISTH bleeding definitions will be used. If a subject withdraws after surgery on
Procedure Day, both the non-surgical and surgical ISTH bleeding definitions will be used.
10. Document etiology of thrombocytopenia.
11. If Visit 1 not performed
ET = Early Termination; IRT = Interactive Response Technology; ISTH = International Society on Thrombosis and Haemostasis.


Dova Pharmaceuticals 
Clinical Study Protocol AVA-PST-320 
Confidential & Proprietary 
 
Version 3.0 / Amendment 2, 17 September 2018 
63 
Amendment #1 – 09 April 2018 
Rationale for Amendment 
Amendment 1 has been introduced to include patients with thrombocytopenia due to chronic liver 
disease.  In the original protocol, exclusion criterion #2 excluded patients whose thrombocytopenia 
was due to chronic liver disease as an appropriate dosing regimen had not yet been established for 
these patients.  PK/PD modeling efforts have since been completed to evaluate the predicted 
platelet responses in patients with chronic liver disease who would require a platelet count >100 × 
109/L for a surgical procedure. Several different daily doses and platelet count cutoffs were 
evaluated to balance efficacy (achieving a platelet count >100 × 109/L) and safety concerns 
(minimizing the number of patients with a platelet count >200 × 109/L). By limiting the baseline 
platelet count for patients with chronic liver disease to between 50 × 109/L and <75 × 109/L, a 60 
mg × 5 days dosing regimen is predicted to achieve platelet counts above 100 × 109/L but below 
200 × 109/L for the majority of patients. 
Chronic liver disease patients with additional risk factors for thrombosis are excluded for safety 
reasons. Additional exclusion criteria have been added to exclude patients with a history of portal 
vein thrombosis in the previous 6 months, known portal vein blood flow velocity rate <10 cm/sec, 
hepatic encephalopathy which cannot be effectively treated, and hepatocellular carcinoma (BCLC 
staging classification C or D).  
Exclusion criterion #7 (use of dual moderate inhibitors of CYP2C9 and CYP3A4/5) has been 
removed based upon the minimal pharmacodynamic impact of this interaction during short-term 
administration of avatrombopag. An additional exclusion criterion has been added excluding 
current use of another thrombopoietin receptor agonist for safety reasons and to decrease the 
potential for confounding of the primary endpoint. 
Summary of Significant Changes in Amendment 1 
•
Patients with thrombocytopenia due to chronic liver disease can now be enrolled, with a
lower baseline platelet count between 50 × 109/L and <75 × 109/L
•
Three additional exclusion criteria, related to chronic liver disease, have been added
•
Use of dual moderate inhibitors of CYP2C9 and CYP3A4/5 (eg, fluconazole) are now
allowed
•
Current use of other thrombopoietin receptor agonists (eg, eltrombopag and romiplostim)
is excluded
The following presents changes made by this amendment.  New/revised text is presented in bold 
italics; deleted text is identified by strikethrough. Typographic corrections, including grammatical 
and punctuation errors, are not shown. 
SYNOPSIS 
POPULATION: 


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Clinical Study Protocol AVA-PST-320 
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Version 3.0 / Amendment 2, 17 September 2018 
64 
The population for this study is subjects ≥18 years of age at the time of informed consent who are 
scheduled to undergo operations to critical sites (eg, eye surgery, neurosurgery) or operations with 
a high risk of bleeding (eg, major abdominal surgery) who, in the opinion of the Investigator, 
would otherwise require a platelet transfusion aiming for a platelet count of at least 100 × 109/L to 
prevent bleeding. Subjects without chronic liver disease must have a mean baseline platelet count 
between 50 × 109/L and <100 × 109/L, measured on 2 separate occasions (the Screening Visit and 
the Baseline Visit), with neither platelet count ≥100 × 109/L. Subjects with chronic liver disease 
(CLD) must have a mean baseline platelet count between 50 × 109/L and <75 × 109/L, measured 
on 2 separate occasions (the Screening Visit and the Baseline Visit), with neither platelet count 
≥75 × 109/L. 
STUDY DESIGN AND DURATION: 
Subjects must be screened prior to the Baseline Visit. Mean baseline platelet count in subjects 
without CLD must be between 50 × 109/L and <100 × 109/L; between 50 × 109/L and <75 × 109/L 
in subjects with CLD. Platelet counts must be measured on 2 separate occasions (the Screening 
Visit and the Baseline Visit), and must be performed at least 1 day apart with neither platelet count 
≥100 × 109/L in subjects without CLD and ≥75 × 109/L in subjects with CLD. The mean of these 
2 platelet counts (mean baseline platelet count) will be used for entry criteria. 
3.1 Summary of Study Design 
Subjects must be screened prior to the Baseline Visit. Mean baseline platelet count in subjects 
without CLD must be between 50 × 109/L and <100 × 109/L; between 50 × 109/L and <75 × 109/L 
in subjects with CLD. Platelet counts must be measured on 2 separate occasions (the Screening 
Visit and the Baseline Visit), and must be performed at least 1 day apart with neither platelet count 
≥100 × 109/L in subjects without CLD and ≥75 × 109/L in subjects with CLD. The mean of these 
2 platelet counts (mean baseline platelet count) will be used for entry criteria. 
4.1 Inclusion Criteria 
24. Subject has a mean baseline platelet count between:
a.
50 × 109/L and <100 × 109/L in subjects without a diagnosis of chronic liver disease.
or
b. 50 × 109/L and <75 × 109/L in subjects with diagnosed chronic liver disease.
Platelet counts must be measured on 2 separate occasions (the Screening Visit and the Baseline 
Visit), and must be performed at least 1 day apart with neither platelet count ≥100 × 109/L in 
subjects without CLD and ≥75 × 109/L in subjects with CLD. The mean of these 2 platelet 
counts (mean baseline platelet count) will be used for entry criteria; 


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Clinical Study Protocol AVA-PST-320 
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Version 3.0 / Amendment 2, 17 September 2018 
65 
4.2 Exclusion Criteria 
2. Subject has a diagnosis of thrombocytopenia due to chronic liver disease
25. Known portal vein blood flow velocity rate <10 cm/second or previous occurrence of a portal
vein thrombosis within 6 months of screening
6. Use of moderate or strong inducers of cytochrome P450 (CYP) 2C9 or CYP3A4/5 from 7 days
prior to Screening through the end of the dosing regimen (see Appendix C);
7. Use of dual moderate inhibitors of CYP2C9 and CYP3A4/5 (ie, fluconazole);
7. Current use of a thrombopoietin receptor agonist (eg, eltrombopag or romiplostim);
8. Subject with a current malignancy including solid tumors and hematologic malignancies
undergoing or planned for treatment whose thrombocytopenia may be attributed to
chemotherapy during the study;
9. Hepatic encephalopathy that cannot be effectively treated;
10. Subjects with hepatocellular carcinoma (HCC) and Barcelona Clinic Liver Cancer (BCLC)
staging classification C or D
5.2 Rationale for Dosing 
A PK/PD model was developed to simulate platelet response to avatrombopag administration in 
order to select a dose regimen for this study. Using data from healthy volunteers and patients with 
chronic liver disease, the PK/PD model evaluated the relationship of avatrombopag concentrations 
to increases in platelet counts. Simulations were performed assuming the baseline platelet count 
ranged between 50 and <100 × 109/L with a requirement to increase the platelet count to levels 
≥100 × 109/L prior to the procedure. Simulations suggested that 60 mg avatrombopag administered 
once daily for 5 days with the procedure scheduled 5 to 8 days after the last dose of study drug 
would result in approximately 85% of subjects having platelet counts that exceed 100 × 109/L. 
Simulations were also performed for subjects with CLD. In order to limit the number of subjects 
with a platelet count >200 × 109/L after treatment yet still have the majority of subjects with a 
platelet count ≥100 × 109/L on the day of surgery, subjects with CLD must have a platelet count 
between 50 and <75 × 109/L at Baseline. 
5.6.1 Excluded Medications and/or Procedures 
•
Use of anticoagulant or antiplatelet therapy within between 7 days of prior to the
Screening Visit and Visit 4 (Procedure Day)
•
Use of moderate or strong inducers of cytochrome P450 (CYP) 2C9 or CYP3A4/5 from
7 days prior to Screening through the end of the dosing regimen (see Appendix C);
•
Use of dual moderate inhibitors of CYP2C9 and CYP3A4/5 (ie, fluconazole);



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