Conditions: Immune Thrombocytopenia
Keywords: ITP
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 60
Healthy volunteers: no

Brief summary:
Evaluate the safety and tolerability of avatrombopag given for 90 days after stopping treatment with eltrombopag or romiplostim.

Detailed description:
This Phase 4, prospective, multi-center, open-label study will evaluate safety, platelet count, and subject reported medication satisfaction in adult subjects with chronic ITP after switching to avatrombopag from eltrombopag or romiplostim. At least 100 subjects will be enrolled, 50 (±10) who have received eltrombopag and 50 (±10) who have received romiplostim for at least 90 days prior to study entry.

Arms:
arm 1: Avatrombopag 20 mg oral tablet formulation for 90 days

Interventions: intervention 1: Avatrombopag Oral Tablet
Intervention descriptions: intervention 1: Avatrombopag 20 mg given daily for 90 days. Initial dose and dose adjustments will be determined by the physician along with the Doptelet prescribing information

Protocol document:
Prot_000.pdf: 
TITLE PAGE
CLINICAL STUDY PROTOCOL
Prospective, Multi-center, Open-label Study Measuring Safety and 
Treatment Satisfaction in Adult Subjects with Chronic Immune 
Thrombocytopenia (ITP) after Switching to Avatrombopag from 
Eltrombopag or Romiplostim 
 
Investigational Product: Avatrombopag oral tablet
Protocol Number: AVA-ITP-401
NCT Number: 04638829 
Sponsor: 
Sobi, Inc. (formerly Dova Pharmaceuticals, Inc.) 
77 Fourth Ave, 3rd Floor
Waltham, MA 02451 
United States
 
Version Number: 2.0
Date: 28 January 2022
Replaces: Version 1.0 / 24 August 2020
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Sobi, Inc. except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Sobi, Inc. 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 Sobi, Inc. and 
that it may not be further disclosed to third parties. 


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SIGNATURE PAGE
STUDY TITLE: Prospective, Multi-center, Open-label Study Measuring Safety and 
Treatment Satisfaction in Adult Subjects with Chronic Immune Thrombocytopenia (ITP) 
after Switching to Avatrombopag from Eltrombopag or Romiplostim 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
 
Signature 
 
 
 
 
 
 
 
Date
 
 
Vice President, Global Drug Development 
Sobi, Inc. 
31 January 2022


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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 Sobi, Inc. 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 Sobi, Inc. 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 Sobi, Inc. 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 Institutional Review Board/Ethics Committee 
Regulations, and International Council for Harmonisation (ICH) Guidelines for Good Clinical 
Practices. 
 
 
 
 
 
 
______________________________________________  
____________________
Investigator’s Signature 
 
 
 
 
 
Date
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
 


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SYNOPSIS
TITLE: Prospective, Multi-center, Open-label Study Measuring Safety and Treatment 
Satisfaction in Adult Subjects with Chronic Immune Thrombocytopenia (ITP) after Switching to 
Avatrombopag from Eltrombopag or Romiplostim
PROTOCOL NUMBER: AVA-ITP-401 
PROTOCOL VERSION/DATE: V2.0/28 January 2022
PRODUCT: Avatrombopag oral tablet
PHASE: 4
RATIONALE AND BACKGROUND: Chronic ITP is an autoimmune disorder characterized by 
low platelet counts and the risk of bleeding complications. The clinical management of ITP 
depends on its severity and the bleeding risk.  Treatment is considered when platelet counts fall 
below 30 to 50×109/L with a goal to maintain platelet counts in a target range of 50 to 150-
200×109/L, so patients can live relatively active lives with a manageable bleeding risk.  The 
standard of care after a failure of 1st line therapy includes the initiation of a thrombopoietin
receptor agonist (TPO-RA) (Provan, 2019).  Three TPO-RAs (eltrombopag [Promacta®], 
romiplostim [Nplate®], and avatrombopag [DOPTELET®]) are currently approved in the United 
States (US) for the treatment of thrombocytopenia in adult patients with chronic ITP who have 
had an insufficient response to a previous treatment.  
Avatrombopag (DOPTELET) was approved in June 2019 for the treatment of thrombocytopenia 
in adult patients with chronic ITP who have had an insufficient response to a previous treatment. 
It is an orally administered small molecule that mimics the biological effects of thrombopoietin
(TPO) vitro and in vivo. In clinical trials, avatrombopag increased platelet counts within 3-5 days 
and maintained them in the target range (50 to 150×109/L) with chronic dosing (Jurczak, 2018).
Further, it has an exposure-adjusted safety profile generally comparable to placebo, no boxed 
safety warning for hepatotoxicity, and is recommended to be taken with food. 
Eltrombopag is taken orally, however, the tablets must be taken on an empty stomach or with a 
low calcium meal and 2 hours before or 4 hours after any antacids, dairy products, or mineral 
supplements containing polyvalent cations. Romiplostim requires a weekly subcutaneous injection 
which is typically administered by the patient’s healthcare provider.  
The US Prescribing Information (USPI) for eltrombopag, romiplostim, and avatrombopag 
recommends using the lowest dose needed to achieve and maintain a platelet count 50×109/L, as 
necessary, to reduce the risk of bleeding in patients with ITP. Dose adjustment guidelines in the 
USPI are based on platelet count response and should not exceed a dose of 75 mg once daily, 
10 µg/kg once weekly, and 40 mg once daily for eltrombopag, romiplostim, and avatrombopag, 
respectively; the goal of dose adjustments should not be to normalize platelet counts. Additionally, 
the USPI recommends discontinuation of the TPO-RA if the platelet count does not increase to a 
level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum 
dose.  


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Observational studies have shown that switching to an alternate TPO-RA may be beneficial if 
there was an insufficient response to treatment with the initial TPO-RA, which may be due to 
refractoriness to the previous treatment or non-compliance with the treatment regimen (Kuter,
2015).  Although there are now 3 TPO-RA options for adult patients with ITP, data on clinical 
outcomes, treatment responses, and patient reported outcomes among patients who switch TPO-
RAs for the treatment of ITP are limited. 
The purpose of this Phase 4 prospective study is to evaluate safety, platelet count, and subject 
reported treatment satisfaction after receiving avatrombopag for 90 days following treatment with 
either eltrombopag or romiplostim.  The initial dose and dose adjustments of avatrombopag will 
be determined by the Investigator, per the DOPTELET USPI.  There is no protocol-required 
washout period between treatment with TPO-RAs, however avatrombopag should not be 
administered on the same day as another TPO-RA. The start and stop dates of all prior and 
concomitant medications should be recorded in the electronic case report form (eCRF). 
The Treatment Satisfaction Questionnaire for Medication (TSQM) Version 1.4 is a validated 14-
item questionnaire designed as a general measure of treatment satisfaction with medication.  In 
order to capture subject reported outcomes after switching from eltrombopag or romiplostim to 
avatrombopag, the TSQM will be administered at Baseline (before the first dose of 
avatrombopag), Day 30, and Day 90.  
STUDY OBJECTIVES:
Primary Objective: Characterize the safety and tolerability of avatrombopag given for 90 days 
after stopping treatment with eltrombopag or romiplostim.  
Secondary Objectives: 
 Evaluate the change in subject reported outcomes from Baseline after switching to 
avatrombopag from eltrombopag or romiplostim. 
 Evaluate the platelet counts after switching to avatrombopag from eltrombopag or 
romiplostim. 
STUDY ENDPOINTS:
Primary Endpoint: Occurrence of adverse events (AEs) and serious adverse events (SAEs).  
Secondary Endpoints:
 Change from Baseline in each of the 4 domains of the TSQM Version 1.4 (e.g., 
convenience, global satisfaction, effectiveness, and side effects) to Day 90 or End of 
Study.
 Proportion of subjects who have a platelet count between 50×109/L to 200×109/L at 
Day 15, Day 30, Day 60, and Day 90. 


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STUDY DESIGN AND DURATION: This Phase 4, prospective, multi-center, open-label study 
will evaluate safety, platelet count, and subject reported medication satisfaction in adult subjects 
with chronic ITP after switching to avatrombopag from eltrombopag or romiplostim.  At least 
100 subjects will be enrolled, 50 (±10) who have received eltrombopag and 50 (±10) who have 
received romiplostim for at least 90 days prior to study entry. 
The initial dose and dose adjustments of avatrombopag will be determined by the Investigator in 
conjunction with the DOPTELET USPI.  There is no protocol-required washout period between 
treatment with TPO-RAs, however avatrombopag should not be administered on the same day as 
another TPO-RA. The start and stop dates of all prior and concomitant medications should be 
recorded in the eCRF.
Safety will be evaluated throughout the study.  Bleeding severity will be captured using the World 
Health Organization (WHO) Bleeding Scale at each visit. Platelet counts will be collected per 
protocol at Baseline, Day 15, Day 30, Day 60 and Day 90, however, all other platelet counts 
collected per the subject’s standard of care while they are enrolled in the study should be recorded 
in the eCRF.  The TSQM will be administered prior to the first dose of avatrombopag (at Baseline), 
at Day 30, and at Day 90 or at the time of early termination from the study.  Compliance with the 
Investigator prescribed avatrombopag dosing regimen will be captured via a subject reported 
Dosing Diary which should be evaluated by the study team during each visit to the clinic, per the 
subject’s standard of care.    
Subjects may be screened within 28 days of the Baseline Visit, however, the Screening Visit may 
be combined with the Baseline Visit.  The duration of subject participation and collection of 
clinical data will be a minimum of 90 days from the Screening Visit/Visit 1 to Day 90.  The only 
protocol-required visits during the study are the Baseline Visit, Day 15, Day 30, Day 60, and the 
Day 90 or Early Termination Visit.  
If a subject is early terminated, the early termination assessments should be completed prior to 
discharge from the study.  
STUDY POPULATION: 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate:  
1. Subject is willing and able to provide written informed consent. 
2. Male or female aged 18 years of age at the Screening Visit/Visit 1. 
3. Subject has been undergoing treatment for primary ITP with eltrombopag or romiplostim 
for at least 90 days prior to the Screening Visit/Visit 1.  
4. Subject has had a previous response (at any time) to either eltrombopag or romiplostim, 
defined as at least 2 platelet counts 50×109/L.  
5. Subject is willing and able to comply with all aspects of the protocol, including completing 
the self-administered TSQM. 


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Exclusion Criteria
Subjects who meet any of the following criteria will not be eligible to participate: 
1. Subject is currently receiving chemotherapy or radiation for any form of cancer. 
2. Subject with conditions that are likely to prevent them from accurately and reliably 
completing study assessments, including evidence of moderate to severe dementia, and/or 
severe and progressive medical illness, as determined by the Investigator.
3. Any previous avatrombopag use.  
4. Previous participation in this study; a subject may not re-enroll after prior discontinuation 
or completion.  
5. Enrollment in another clinical study with any investigational drug or device within 30 days 
of Baseline (or 5 half-lives, whichever is longer); however, participation in observational 
studies within the previous 30 days is permitted. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: Subjects will receive the 
avatrombopag 20 mg oral tablet formulation for up to 90 days while enrolled in the study. 
Avatrombopag dosage will be determined by the Investigator, based on platelet count, in 
conjunction with the DOPTELET USPI.  
STATISTICAL/DATA ANALYSES: 
Analysis Populations 
The analyses and summaries of demographic and Baseline characteristics, safety assessments, and 
subject reported outcomes will be provided for the All Enrolled Population which is defined as all 
subjects who receive at least 1 dose of study drug.   
Analysis of Safety
AEs, SAEs, and Adverse Events of Special Interest (AESIs) will be summarized for all enrolled 
subjects using counts and percentages. Treatment-emergent AEs and SAEs will be summarized 
overall, by system organ class, and by preferred term. AESIs will be summarized by event type 
(thromboembolic events and bleeding events). In addition, treatment-emergent AEs will be 
summarized by severity and by relationship to study drug.
Bleeding events reported during the study will be summarized by their WHO grade. 
Analysis of Platelet Count 
Platelet count assessed at Baseline, Day 15, Day 30, Day 60, and Day 90 will be summarized 
descriptively for all enrolled subjects.  Graphic presentations of platelet count over time will be 
provided. 
The proportion of subjects who have a platelet count 50×109/L to 200×109/L will be tabulated 
using count and percentage for Baseline, Day 15, Day 30, Day 60, and Day 90. 


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Analysis of TSQM
Descriptive statistics will be summarized for each domain score and each visit. The change from 
Baseline and percent change in each mean domain score will also be summarized descriptively. 
The primary interest in the TSQM assessment is the convenience domain score. The hypothesis is 
that switching from a prior TPO-RA treatment (eltrombopag or romiplostim) to avatrombopag 
results in an improvement in the convenience domain score. Change from Baseline to Day 90 (or 
End of Study) in the convenience domain score will be tested using paired t-tests, by prior TPO-
RA treatment (eltrombopag vs romiplostim) and overall.  
SAMPLE SIZE DETERMINATION: 
Assuming the mean TSQM convenience scores at Baseline and at the end of study are 74 and 82, 
respectively,  with a standard deviation (SD) of 19, 50 subjects will provide 83% power to detect 
a change from Baseline of 8 at a 2-sided significance level of 0.05 based on a paired t-test. The 
total sample size will be 100 subjects which includes approximately 50 subjects with a prior 
treatment of eltrombopag and approximately 50 subjects with a prior treatment of romiplostim. 
SITES: Approximately 20 centers in the US. 
SPONSOR:
Sobi, Inc.  (Sobi) 
77 Fourth Ave, 3rd Floor Waltham, MA 02451 United States  


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TABLE OF CONTENTS
Title Page ........................................................................................................................................ 1
Signature Page ................................................................................................................................ 2
Investigator Agreement................................................................................................................... 3
Synopsis .......................................................................................................................................... 4
Table of Contents............................................................................................................................ 9
List of Tables ................................................................................................................................ 12
List of Figures............................................................................................................................... 12
List of Abbreviations and Definition of Terms............................................................................. 13
1
Introduction and Background Information ............................................................................. 14
1.1 
Thrombocytopenia ........................................................................................................ 14
1.2 
Immune Thrombocytopenia .......................................................................................... 14
1.3 
Avatrombopag............................................................................................................... 15
1.4 
Study Rationale ............................................................................................................. 16
2
Study Objectives..................................................................................................................... 17
2.1 
Primary Objective ......................................................................................................... 17
2.2 
Secondary Objectives.................................................................................................... 17
3
Study Endpoints ...................................................................................................................... 18
3.1 
Primary Endpoint .......................................................................................................... 18
3.2 
Secondary Endpoints..................................................................................................... 18
4
Study Description.................................................................................................................... 19
4.1
Summary of Study Design ............................................................................................ 19
5
Selection and Early Termination of Subjects.......................................................................... 20
5.1 
Inclusion Criteria........................................................................................................... 20
5.2 
Exclusion Criteria.......................................................................................................... 20
5.3 
Subject and Study Discontinuation ............................................................................... 20
5.3.1
Screen Failures .................................................................................................. 21
5.3.2
Early Termination ............................................................................................. 21
6
Study Treatment ...................................................................................................................... 22
6.1 
Randomization and Blinding ......................................................................................... 22
6.2 
Avatrombopag Supplies ................................................................................................ 22


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6.3 
Avatrombopag Dosage and Administration .................................................................. 22
6.4
Receipt of Supplies........................................................................................................ 22
6.5 
Avatrombopag Storage Conditions ............................................................................... 22
6.6 
Compliance.................................................................................................................... 22
6.7 
Avatrombopag Accountability ...................................................................................... 23
6.8
Avatrombopag Handling and Returns........................................................................... 23
7
Study Procedures .................................................................................................................... 24
7.1 
Informed Consent.......................................................................................................... 24
7.2
Screening Visit (Visit 1)................................................................................................ 24
7.3
Baseline Visit (Visit 2/Day 1) ....................................................................................... 25
7.4 
Treatment Period (through Day 90) .............................................................................. 26
7.4.1
Day 15 (±2 Days)/Visit 3 .................................................................................. 26
7.4.2
Day 30 (±2 Days)/Visit 4 .................................................................................. 26
7.4.3
Day 60 (±2 Days)/Visit 5 .................................................................................. 27
7.4.4
Standard-of-Care Clinic Visits.......................................................................... 27
7.4.5
Day 90 (±2 Days)/End of Study/Early Termination Visit/Visit 6 ..................... 28
7.5 
Early Termination Visit ................................................................................................. 28
8
Study Assessments .................................................................................................................. 29
8.1 
Treatment Satisfaction Questionnaire for Medication (TSQM).................................... 29
8.2 
Laboratory Examinations .............................................................................................. 29
8.2.1
Platelet Count (Local Lab) ................................................................................ 29
8.3
World Health Organization Bleeding Scale.................................................................. 29
9
Safety Assessments................................................................................................................. 30
9.1 
Adverse Events.............................................................................................................. 30
9.1.1
Additional Safety Information .......................................................................... 30
9.1.2
Assessment of Adverse Events by the Investigator .......................................... 31
9.2 
Serious Adverse Events................................................................................................. 33
9.3 
Method of Detecting Adverse Events and Serious Adverse Events ............................. 33
9.4 
Serious Adverse Event Reporting 
Procedures for Investigators ................................ 34
9.4.1
Initial Reports.................................................................................................... 34
9.4.2
Follow-up Reports ............................................................................................. 34
9.5 
Adverse Events of Special Interest................................................................................ 34


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9.6 
Pregnancy Reporting ..................................................................................................... 35
9.7
Regulatory Reporting Requirements for Serious Adverse Events ................................ 35
10 Statistics.................................................................................................................................. 36
10.1 Analysis Populations..................................................................................................... 36
10.2 Statistical Methods ........................................................................................................ 36
10.2.1 Analysis of Safety ............................................................................................. 36
10.2.2 Analysis of Platelet Count................................................................................. 36
10.2.3 Analysis of the Treatment Satisfaction Questionnaire for Medication ............. 36
10.2.4 Sample Size Determination............................................................................... 37
11 Data Management and Record Keeping ................................................................................. 38
11.1 Data Management ......................................................................................................... 38
11.1.1 Data Handling ................................................................................................... 38
11.1.2 Computer Systems............................................................................................. 38
11.1.3 Data Entry ......................................................................................................... 38
11.1.4 Medical Information Coding ............................................................................. 38
11.1.5 Data Validation ................................................................................................. 38
11.2 Record Keeping............................................................................................................. 38
12 Investigator Requirements and Quality Control ..................................................................... 39
12.1 Ethical Conduct of the Study ........................................................................................ 39
12.2 Institutional Review Board ............................................................................................ 39
12.3 Protocol Amendments................................................................................................... 39
12.4 Informed Consent.......................................................................................................... 39
12.5 Study Monitoring Requirements ................................................................................... 40
12.6 Disclosure of Data......................................................................................................... 40
12.7 Retention of Records..................................................................................................... 41
12.8 Publication Policy ......................................................................................................... 41
12.9 Financial Disclosure ...................................................................................................... 41
12.10 Insurance and Indemnity ............................................................................................... 41
13 References............................................................................................................................... 42
Appendix A:  Schedule of Events ................................................................................................. 43
Appendix B:  WHO Bleeding Scale ............................................................................................. 45
Appendix C: Protocol Amendments ............................................................................................. 46


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LIST OF TABLES
Table 1
Adverse Events with a Frequency 10% in Subjects with Chronic ITP Treated with 
DOPTELET – Pooled Data from Clinical Trialsa ....................................................... 16
Table 2
AVA-ITP-401 Schedule of Events ............................................................................. 43
LIST OF FIGURES 
Figure 1 
AVA-ITP-401 Study Schematic ................................................................................. 19


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
21 CFR
Title 21 of the Code of Federal Regulations 
AE
Adverse event
AESI
Adverse event of special interest
CLD
Chronic liver disease
CRA
Clinical research associate
eCRF
Electronic case report form 
EDC
Electronic data capture 
FDA
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH
International Council for Harmonisation
IRB 
Institutional Review Board
ITP
Immune thrombocytopenia 
SAE
Serious adverse event 
SD 
Standard deviation 
SUSAR
Suspected unexpected serious adverse reaction 
TPO
Thrombopoietin
TPO-RA
Thrombopoietin receptor agonist 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
US 
United States 
USPI 
United States Prescribing Information
WHO
World Health Organization


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1
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Thrombocytopenia 
Platelets originate from megakaryocytes in the bone marrow and are an important component of 
blood that function to maintain normal hemostasis by helping to control bleeding through 
aggregating and inducing clot formation in conjunction with blood coagulation factors.  In healthy 
individuals, the average lifespan of platelets is 7 to 10 days, after which they are destroyed and 
replaced with newly generated platelets from the bone marrow.  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, which is associated with easy or excessive bruising and 
mild to severe or potentially fatal bleeding.
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 leading to 
megakaryocytopoiesis.  This results in the production of new platelets by the bone marrow, a 
process which is directly correlated with plasma TPO levels.
The circulating platelet count in the blood is determined by the rates of platelet production and 
platelet destruction.  Thrombocytopenia can result from decreased platelet production in the bone 
marrow, increased platelet destruction in the blood (such as from autoantibodies), sequestration of 
platelets in the spleen, and/or the dilution of platelets following multiple blood transfusions.  There 
are numerous disease states which cause thrombocytopenia, including immune thrombocytopenia 
(ITP), chronic liver disease (CLD), and chemotherapy-induced thrombocytopenia (CIT). 
1.2
Immune Thrombocytopenia 
ITP is an autoimmune disorder characterized by low platelet counts caused by a combination of 
both impaired platelet production and increased peripheral platelet destruction.  It has an incidence 
of as many as 5 out of every 100,000 people and may be either a primary condition or secondary 
to other causes, such as bacterial or viral infections.  The 2019 International Consensus Report on 
the Investigation and Management of ITP (Provan, 2019) and the American Society of 
Hematology Guidelines for ITP (Neunert, 2019) define ITP in 3 distinct subsets in accordance 
with disease duration, which includes:  
 Newly Diagnosed ITP: within 3 months of the diagnosis
 Persistent ITP: within 3 to 12 months of the diagnosis
 Chronic ITP: more than 1 year after the diagnosis 
Clinical management of ITP depends primarily on its severity, with initial therapy being indicated 
when platelet counts fall below 30 to 50×109/L with a goal to maintain platelet counts between 50 
to 200×109/L to reduce the risk of concurrent bleeding symptoms or impact on health-related 
quality of life (Neunert, 2019; Provan, 2019).  The clinical goal of treatment for ITP is not to 
normalize platelet counts, but to increase platelet counts to a level that enables patients to live 
relatively normal and active lives with a manageable risk of bleeding. For the treatment of newly 
diagnosed ITP in patients who have non-life-threatening bleeding, agents that decrease platelet 
destruction (e.g., corticosteroids or immunoglobulins) are recommended as 1st line treatment.  
These medications have variable and transient efficacy and significant toxicities.   


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After the failure of a 1st line therapy, 2nd line treatment options approved in the United States (US) 
for the treatment of thrombocytopenia in adult patients with chronic ITP who have had an 
insufficient response to a previous treatment include the TPO receptor agonists (TPO-RAs) 
avatrombopag (DOPTELET®), eltrombopag (Promacta®), and romiplostim (Nplate®).   
The US Prescribing Information (USPI) for avatrombopag, eltrombopag, and romiplostim 
recommends using the lowest dose needed to achieve and maintain a platelet count 50×109/L, as 
necessary, to reduce the risk of bleeding in patients with ITP. Dose adjustment guidelines in the 
USPIs of TPO-RAs are based on platelet count response and should not exceed a dose of 40 mg 
once daily, 75 mg once daily, or 10 µg/kg once weekly for avatrombopag, eltrombopag, and 
romiplostim, respectively; the goal of dose adjustments should not be to normalize platelet counts.  
Additionally, each of the 3 USPIs recommend discontinuation of the TPO-RA if the platelet count 
does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of 
therapy at the maximum dose.  
Avatrombopag is an oral agent which is taken with any type of food.  Although eltrombopag is 
also taken orally, the tablets must be taken with a meal low in calcium ( 50 mg) and 2 hours before 
or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing >50 mg calcium 
[e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables]), or supplements 
containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc, 
which may be challenging for patients.  Romiplostim requires weekly subcutaneous injections 
which are typically performed by the patient’s healthcare provider (Promacta USPI; Nplate USPI; 
Neunert, 2019; Provan, 2019).  
Observational studies have shown that switching to an alternate TPO-RA may be beneficial if the 
patient had an insufficient response to treatment with the initial TPO-RA, which may be due to 
refractoriness to the previous treatment or non-compliance with the treatment regimen (Kuter, 
2015).  Data also suggests that switching to an alternate TPO-RA in order to improve convenience 
in patients who are responding to their current TPO-RA therapy may yield continued efficacy 
(Kuter, 2015).  Although there are now 3 approved TPO-RA options for adult patients with ITP, 
data on clinical outcomes, treatment responses, and patient reported outcomes among patients who 
switch TPO-RAs for the treatment of ITP are limited.  
1.3 
Avatrombopag 
Avatrombopag maleate is an orally administered, small molecule TPO-receptor (c-Mpl) agonist
that mimics the biologic effects of TPO in vitro and in vivo, resulting in a measured increase in 
platelet counts.  Like other TPO receptor agonists, avatrombopag activates the human TPO 
receptor, but binds to a different site on the receptor than endogenous TPO.
After binding, 
avatrombopag stimulates signal transduction and mimics the biologic effects of TPO, which in 
turn increases platelet counts.  Given its basic mechanism of action, by directly stimulating the 
normal production of new platelets by the bone marrow, avatrombopag has the potential to be 
useful for the treatment of thrombocytopenia of any etiology across a variety of indications and 
patient populations when used in both acute and chronic dosing regimens.
Avatrombopag has been approved by the US Food and Drug Administration (FDA) for the 
treatment of thrombocytopenia in adult patients with CLD who are scheduled to undergo a 
procedure and for the treatment of adult patients with chronic ITP who have had an insufficient 
response to a previous treatment (DOPTELET USPI).


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Exposure to avatrombopag across the clinical development program includes chronic and acute 
dosing from a range of 1 to 100 mg. The total safety subject population from completed studies 
includes more than 1200 subjects who received avatrombopag and had at least 1 safety assessment.  
In the Phase 2 and 3 studies conducted in adults with ITP, avatrombopag was administered to 128 
subjects for a median duration of 7 months and a maximum duration of 2.3 years.  The primary 
efficacy endpoint in the pivotal Phase 3 ITP study (E5501-G000-302 [Study 302]) the Cumulative 
Number of Weeks with a 
9/L during 6 months of treatment in the absence of 
rescue therapy, was a median of 12.4 weeks for avatrombopag versus 0 weeks for placebo 
(p<0.0001).  The most common (
%) adverse events (AEs) in placebo and avatrombopag-
treated subjects from the Phase 2 and 3 ITP studies (pooled data) are presented in Table 1. 
Table 1 
Adverse Events with a Frequency 10% in Subjects with Chronic ITP Treated 
with DOPTELET – Pooled Data from Clinical Trialsa 
Adverse Event
DOPTELET
(N=128)
Placebo
(N=22)
Headache
31%
14%
Fatigue 
28%
9%
Contusion
26%
18%
Epistaxis 
19%
18%
Upper Respiratory Tract Infection 
15%
5%
Arthralgia
13%
0%
Gingival Bleeding
13%
0%
Petechiae
11%
9%
Nasopharyngitis
10%
0%
a: DOPTELET USPI 
1.4
Study Rationale
The purpose of this Phase 4 prospective study is to evaluate safety, platelet count, and subject
reported treatment satisfaction after receiving avatrombopag for 90 days following at least 90 days
of treatment with either eltrombopag or romiplostim.  
The study will enroll at least 100 adult subjects which will include 50 (±10) subjects who were 
treated with eltrombopag and 50 (±10)  subjects who were treated with romiplostim.  Participating 
subjects must have a diagnosis of chronic ITP and have had a previous response (defined as at 
least 2 platelet counts 50×109/L) to either eltrombopag or romiplostim.  Once enrolled in the 
study, subjects will be started on avatrombopag at a dose determined to be appropriate by the 
Investigator in conjunction with the DOPTELET USPI.  
Safety will be collected throughout the 90-day study period.  Platelet counts will be collected per 
protocol at Baseline, Day 15, Day 30, Day 60, and at Day 90.  No additional platelet counts are 
required, however, all platelet counts collected per the subject’s standard of care during the study 
period should be recorded in the electronic case report form (eCRF).  
The Treatment Satisfaction Questionnaire for Medication (TSQM) Version 1.4 is a validated 14-
item questionnaire designed as a general measure of treatment satisfaction with medication.  In 
order to capture subject reported outcomes after switching from eltrombopag or romiplostim to 
avatrombopag, the TSQM will be administered at Baseline (before the first dose of avatrombopag), 
Day 30, and Day 90.


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2
STUDY OBJECTIVES
2.1 
Primary Objective
Characterize the safety and tolerability of avatrombopag given for 90 days after stopping treatment 
with eltrombopag or romiplostim. 
2.2
Secondary Objectives 
 Evaluate the change in subject reported outcomes from Baseline after switching to 
avatrombopag from eltrombopag or romiplostim. 
 Evaluate platelet counts after switching to avatrombopag from eltrombopag or 
romiplostim. 
 


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3
STUDY ENDPOINTS 
3.1
Primary Endpoint
Occurrence of AEs and serious adverse events (SAEs). 
3.2
Secondary Endpoints
 Change from Baseline in each of the 4 domains of the TSQM Version 1.4 (e.g., 
convenience, global satisfaction, effectiveness, and side effects) to Day 90 or End of 
Study.
 Proportion of subjects who have a platelet count between 50×109/L to 200×109/L at 
Day 15, Day 30, Day 60, and Day 90.
 


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4
STUDY DESCRIPTION 
4.1
Summary of Study Design 
This Phase 4, prospective, multi-center, open-label study will evaluate safety, platelet count, and 
subject reported medication satisfaction in adult subjects with chronic ITP after switching to 
avatrombopag from eltrombopag or romiplostim.  At least 100 subjects will be enrolled, 50 (±10) 
who have received eltrombopag and 50 (±10) who have received romiplostim for at least 90 days 
prior to study entry. An overview of the study design is provided in Figure 1. 
The initial dose and dose adjustments of avatrombopag will be determined by the Investigator in 
conjunction with the DOPTELET USPI.  There is no protocol-required washout period between 
treatment with TPO-RAs, however avatrombopag should not be administered on the same day as 
another TPO-RA. The start and stop dates of all prior and concomitant medications should be 
recorded in the eCRF. 
Safety will be evaluated throughout the study.  Platelet counts will be collected per protocol at 
Baseline, Day 15, Day 30, Day 60, and Day 90, however, all other platelet counts collected per the 
subject’s standard of care while they are enrolled in the study should be recorded in the eCRF.  
The TSQM will be administered prior to the first dose of avatrombopag (at Baseline), at Day 30, 
and at Day 90 or at the time of early termination from the study. Compliance with the Investigator 
prescribed avatrombopag dosing regimen will be captured via a subject reported Dosing Diary 
which should be evaluated by the study team during each visit to the clinic, per the subject’s 
standard of care.    
Subjects may be screened within 28 days of the Baseline Visit/Visit 2, however, the Screening 
Visit/Visit 1 may be combined with the Baseline Visit/Visit 2.  The duration of subject 
participation and collection of clinical data will be a minimum of 90 days from the Screening
Visit/Visit 1 to Day 90.  The only protocol-required clinic visits during the study are the Baseline 
Visit/Visit 2, Day 15, Day 30, Day 60, and the Day 90 or Early Termination Visit.   
If a subject is early terminated, the early termination assessments should be completed prior to 
discharge from the study. 
Figure 1 AVA-ITP-401 Study Schematic 


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5
SELECTION AND EARLY TERMINATION OF SUBJECTS
5.1
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate:  
1. Subject is willing and able to provide written informed consent.  
2. Male or female aged 18 years of age at the Screening Visit/Visit 1.
3. Subject has been undergoing treatment for primary ITP with eltrombopag or romiplostim 
for at least 90 days prior to the Screening Visit/Visit 1. 
4. Subject has had a previous response (at any time) to either eltrombopag or romiplostim, 
defined as at least 2 platelet counts 50×109/L.  
5. Subject is willing and able to comply with all aspects of the protocol, including completing 
the self-administered TSQM. 
5.2
Exclusion Criteria
Subjects who meet any of the following criteria will not be eligible to participate:  
1. Subject is currently receiving chemotherapy or radiation for any form of cancer. 
2. Subject with conditions that are likely to prevent them from accurately and reliably 
completing study assessments, including evidence of moderate to severe dementia, and/or 
severe and progressive medical illness, as determined by the Investigator.
3. Any previous avatrombopag use. 
4. Previous participation in this study; a subject may not re-enroll after prior discontinuation 
or completion.  
5. Enrollment in another clinical study with any investigational drug or device within 30 days 
of Baseline (or 5 half-lives, whichever is longer); however, participation in observational 
studies within the previous 30 days is permitted. 
5.3 
Subject and Study Discontinuation
A subject can withdraw from the study, at any time, and for any reason. The standard of care for 
the subject will not be affected in any way. 
If a subject withdraws prematurely from the study, study staff should make every effort to collect
the full panel of data scheduled for the Day 90/Early Termination Visit.  
The reason for early termination must be documented in the eCRF. Terminated subjects will not 
be replaced.  


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5.3.1
Screen Failures 
Subjects who sign and date the informed consent form (ICF) but who fail to meet all the inclusion 
criteria or meet any exclusion criteria are defined as a screen failure.  
The following data will be recorded in the eCRF for screen failed subjects:  
 ICF signature date 
 Demographic information 
 AEs that occur after signing the ICF 
 Reason for screen failure (e.g., inclusion/exclusion criteria that was not met, etc.)
Subjects may be re-screened with prior approval from the Sponsor.  
5.3.2
Early Termination 
A subject may be early terminated for any of the following reasons:  
 Subject wishes to withdraw consent for any reason. 
 Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol.  
 Subject failed to meet inclusion/exclusion criterion.
 Occurrence of any medical condition 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 AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition which indicates to the Investigator that continued participation in 
the study is not in the best interest of the subject. 
 Investigator discretion.
 Sponsor request.
 Termination of the study by the Sponsor or a regulatory agency. 
If a subject is early terminated from the study, the Early Termination procedures (Section 7.4.5) 
should be performed.  Subjects early terminated from the study will not be replaced, regardless of 
the reason for early termination.  
 
 


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6
STUDY TREATMENT
Avatrombopag doses will be determined by the treating physician in conjunction with the 
FDA-approved package insert.
6.1
Randomization and Blinding
All subjects enrolled in this study will receive open-label avatrombopag.  Therefore, no 
randomization or blinding is required. 
6.2
Avatrombopag Supplies
A sufficient supply of commercially available avatrombopag will be provided to the clinical site. 
Avatrombopag will be provided as film-coated tablets, with each tablet containing avatrombopag 
maleate (equivalent to 20 mg avatrombopag) and excipients.   
6.3 
Avatrombopag Dosage and Administration 
Avatrombopag doses will be determined by the treating physician in conjunction with the 
FDA-approved DOPTELET USPI.  
At the Baseline Visit/Visit 2, the clinical site will dispense the number of avatrombopag tablets 
required for dosing each subject at the discretion of the Investigator, per the subject’s standard of 
care.  
6.4
Receipt of Supplies
Upon receipt of the avatrombopag supplies, the pharmacist, or designee, will visually inspect the 
shipment and verify drug information, quantity, and condition of the avatrombopag received. 
6.5 
Avatrombopag Storage Conditions 
Avatrombopag should be stored in a secure location, in its original packaging, at a controlled room 
temperature of 20°C to 25°C (68°F to 77°F) and protected from light and moisture. Excursions are 
permitted to 15°C  to 30°C (59°F to 86°F). The storage location must be a locked room with limited 
access, available to appropriate study personnel only.  
6.6
Compliance  
Compliance with the Investigator-prescribed avatrombopag dosing regimen will be evaluated
through the study drug accountability eCRF page and the completion of a Dosing Diary by the 
subject.   
The first dose of avatrombopag will be taken while the subject is at the site during the Baseline 
Visit/Visit 2.  During this visit, subjects will be provided with instructions on appropriate at-home 
avatrombopag administration.  When taking avatrombopag at home, subjects should record the 
date and time of each dose in the provided Dosing Diary. 
 


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6.7
Avatrombopag Accountability
The Sponsor will provide the Investigators with a sufficient amount of avatrombopag to begin 
enrollment for this study.  Sites will be responsible for ordering additional avatrombopag as 
needed, once subjects have been enrolled, via a website (detailed instructions will be provided). It 
is the responsibility of the Investigator to ensure that a current record of inventory/drug 
accountability is maintained.  Inventory records must be readily available for inspection by the 
study Clinical Research Associate (CRA), the Sponsor (or designee), or regulatory authorities.  
6.8
Avatrombopag Handling and Returns 
Upon completion or termination of the study, and upon written authorization from the Sponsor, or 
its designee, unused and/or partially used avatrombopag should be returned or destroyed at the 
investigational site.  If avatrombopag will be destroyed by the study site, it is the Investigator’s 
responsibility to ensure that the Sponsor or its designee has provided written authorization for 
proper disposal of avatrombopag, and that appropriate records of the disposal are documented and 
maintained. No unused avatrombopag may be disposed of until fully accounted for by the Sponsor, 
or designee.  


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7
STUDY PROCEDURES
The only protocol-mandated visits are the Screening Visit/Visit 1, the Baseline Visit/Visit 2 (which 
may be combined with the Screening Visit/Visit 1), Day 15, Day 30, Day 60, and the Day 90/Early 
Termination Visit.  
Data will be collected from information routinely recorded in a subject’s medical record and from 
laboratory data. Except for the Screening Visit/Visit 1, Baseline Visit/Visit 2, Day 15, Day 30, 
Day 60, and Day 90/Early Termination Visit, no visits, examinations, laboratory tests, or 
procedures are mandated or recommended as part of this study.  All platelet counts collected per 
the subject’s standard of care while the subject is enrolled in the study should be recorded in the 
eCRF.  
A schedule of events in tabular format is provided in Table 2 in Appendix A. 
7.1 
Informed Consent 
Prior to conducting any study-related data collection, informed consent must be signed and dated 
by the subject. See Section 12.4 for additional information on informed consent. 
7.2 
Screening Visit (Visit 1) 
The Screening Visit/Visit 1 must be completed within 28 days of the Baseline Visit/Visit 2, 
however, this visit may also be combined with the Baseline Visit/Visit 2. 
The following procedures should be performed at the Screening Visit/Visit 1.  
 Collect signed and dated informed consent prior to any other study procedures.  
 Review of inclusion/exclusion criteria (Section 5) to confirm study eligibility. 
 Record subject demographic information including race/ethnicity, date of birth and gender.  
 Record ITP history that is available in the subject’s medical record, including: 
o Date of ITP diagnosis.  
o Number of platelet transfusions in the previous 1 year, including date of last platelet 
transfusion.  
o Number of previous hospitalizations for ITP.  
o Number of previous significant bleeding events (e.g., blood loss 1/2 cup).  
o
Most recent dose level and duration of previous treatments with eltrombopag and/or
romiplostim, including qualifying eltrombopag/romiplostim treatment over the 90 
days prior to study entry.   
o Other previous treatments for ITP, including duration.   
o History of splenectomy (yes/no). 
o History of thromboembolic events.  
 Record the reason for switching to avatrombopag from eltrombopag or romiplostim.


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 Record subject-reported responses to brief questions (to be provided) regarding the prior 
administration of eltrombopag or romiplostim. 
 Record any data on Additional Safety Information (Section 9.1.1) or (AESIs) (Section 9.5) 
that have occurred since the subject signed the ICF.  
 Record any AEs that have occurred since the subject signed the ICF. 
Record any concomitant medication use, including concomitant ITP medications. 
Instruct subject on when to return for the Baseline Visit/Visit 2 if the Screening Visit/Visit 
1 will not be combined with the Baseline Visit/Visit 2. 
7.3
Baseline Visit (Visit 2/Day 1) 
The Baseline Visit/Visit 2 must be completed within 28 days of the Screening Visit/Visit 1 but 
may also be combined with the Screening Visit/Visit 1.  If the Baseline Visit/Visit 2 will be 
combined with the Screening Visit/Visit 1, ensure all procedures listed under Section 7.2 are 
completed. 
The following procedures should be performed at the Baseline Visit/Visit 2.  
 Review of inclusion/exclusion criteria (Section 5) to confirm continued study eligibility.
 Administer the TSQM Version 1.4 to the subject prior to any other study procedures. 
 Perform World Health Organization (WHO) Bleeding Scale Assessment (Appendix B).  
The Investigator should ask the subject the following question: “Have you had any bleeding 
or bruising within the last 7 days?”. This assessment should be completed after the TSQM 
has been completed, but prior to other visit assessments.  
 Record any changes in ITP history, including changes in:  
o Number of platelet transfusions in the previous 1 year, including date of last platelet 
transfusion.  
o Number of previous hospitalizations for ITP.  
o Number of previous significant bleeding events (e.g., blood loss 1/2 cup).  
o Most recent dose level and duration of previous treatments with eltrombopag and/or 
romiplostim, including qualifying eltrombopag/romiplostim treatment over the 90 
days prior to study entry.   
o Other previous treatments for ITP, including duration.   
o History of splenectomy (yes/no). 
o History of thromboembolic events.  
 Record the reason for switching to avatrombopag from eltrombopag or romiplostim.  
 Record the date of the last dose of eltrombopag or romiplostim. 
 Collect and record platelet count (local lab).  
 Determine appropriate dose of avatrombopag, based on instructions in the USPI.  


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 Administer first dose of avatrombopag, on a full stomach, while the subject is in the clinic
and record the date/time of the first dose on the eCRF and on the Dosing Diary. 
 Provide instructions to the subject for proper at-home administration of avatrombopag, 
including completion of the Dosing Diary.  
 Dispense avatrombopag and the Dosing Diary to the subject. 
Record any data on Additional Safety Information (Section 9.1.1) or AESIs (Section 9.5) 
that have occurred since the subject signed the ICF.  
Record any AEs that have occurred since the subject signed the ICF. 
Record any concomitant medication use, including concomitant ITP medications. 
Instruct subject on when to return for the Day 15 Visit. 
7.4
Treatment Period (through Day 90)
7.4.1 
Day 15 (±2 Days)/Visit 3 
Perform WHO Bleeding Scale Assessment (Appendix B).  The Investigator should ask the 
subject the following question: “Have you had any bleeding or bruising since I saw you 
last?”. This assessment should be completed prior to other visit assessments.  
 Collect and record platelet count (local lab).  
Record the occurrence of any platelet transfusion (including the number of units). 
Record whether the subject required any rescue procedure for bleeding. 
Review subject Dosing Diary and record any deviations from prescribed dosing regimen 
in the eCRF.  
Record any changes in avatrombopag dose and dose frequency. 
 Dispense additional avatrombopag to the subject, as needed. 
Record any data on Additional Safety Information (Section 9.1.1) or AESIs (Section 9.5) 
that have occurred.  
 Record any AEs. 
 Record any concomitant medication use, including concomitant ITP medications.  
 Instruct subject on when to return for the Day 30 Visit.  
7.4.2 
Day 30 (±2 Days)/Visit 4 
 Administer TSQM Version 1.4 to the subject.  
 Perform WHO Bleeding Scale Assessment (Appendix B).  The Investigator should ask the 
subject the following question: “Have you had any bleeding or bruising since I saw you 
last?”. This assessment should be completed prior to other visit assessments.  
 Collect and record platelet count (local lab).  


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 Record the occurrence of any platelet transfusion (including the number of units).
Record whether the subject required any rescue procedure for bleeding. 
Review subject Dosing Diary and record any deviations from prescribed dosing regimen 
in the eCRF. 
Record any changes in avatrombopag dose and dose frequency. 
Dispense additional avatrombopag to the subject, as needed.
Record any data on Additional Safety Information (Section 9.1.1) or AESIs (Section 9.5) 
that have occurred. 
Record any AEs.
 Record any concomitant medication use, including concomitant ITP medications.  
 Instruct subject on when to return for the Day 60 visit.  
7.4.3 
Day 60 (±2 Days)/Visit 5 
 Perform WHO Bleeding Scale Assessment (Appendix B).  The Investigator should ask the 
subject the following question: “Have you had any bleeding or bruising since I saw you 
last?”. This assessment should be completed prior to other visit assessments.  
 Collect and record platelet count (local lab). 
 Record the occurrence of any platelet transfusion (including the number of units).  
 Record whether the subject required any rescue procedure for bleeding.  
 Review subject Dosing Diary and record any deviations from prescribed dosing regimen 
in the eCRF.  
 Record any changes in avatrombopag dose and dose frequency. 
 Dispense additional avatrombopag to the subject, as needed. 
Record any data on Additional Safety Information (Section 9.1.1) or AESIs (Section 9.5) 
that have occurred. 
Record any AEs.
Record any concomitant medication use, including concomitant ITP medications. 
Instruct subject on when to return for the Day 90/End of Study Visit. 
7.4.4
Standard-of-Care Clinic Visits
If the subject has a clinic visit or laboratory assessment of platelet count that is separate from the 
protocol-required visits described in Section 7.2 through Section 7.4.3, the following data (if 
available and collected per the subject’s standard-of-care) should be recorded in the eCRF. 
WHO Bleeding Scale Assessment, if collected per the subject’s standard-of-care.
Record any platelet counts that are collected, per the subject’s standard of care, while 
enrolled in the study. 


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 Record the occurrence of any platelet transfusion (including the number of units).  
Record whether the subject required any rescue procedure for bleeding. 
Record any changes in avatrombopag dose and dose frequency. 
Dispense additional avatrombopag to the subject, as needed.
Record any data on Additional Safety Information (Section 9.1.1) or AESIs (Section 9.5) 
that have occurred. 
Record any AEs.
Record any concomitant medication use, including concomitant ITP medications. 
7.4.5
Day 90 (±2 Days)/End of Study/Early Termination Visit/Visit 6
The following procedures should be performed during the Day 90/End of Study/Early Termination 
Visit. 
Administer TSQM Version 1.4 to the subject. 
Perform WHO Bleeding Scale Assessment (Appendix B).  The Investigator should ask the 
subject the following question: “Have you had any bleeding or bruising since I saw you 
last?”. This assessment should be completed after the TSQM but prior to other visit 
assessments.  
Collect and record platelet count (local lab).  
 Record the occurrence of any platelet transfusion (including the number of units).  
 Record whether the subject required any rescue procedure for bleeding.  
 Record final avatrombopag dose and dose frequency on the eCRF.  
 Review Dosing Diary, record any deviations from prescribe dosing regimen, and collect 
from the subject.  
 Record any data on Additional Safety Information (Section 9.1.1) or AESIs (Section 9.5) 
that have occurred.  
 Record any AEs. 
 Record any concomitant medication use, including concomitant ITP medications.  
 Discharge subject from the study.  
7.5 
Early Termination Visit  
All subjects who are early terminated from the study prior to the Day 90/End of Study Visit should 
complete the Day 90/End of Study Visit assessments in Section 7.4.5. 
 


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8
STUDY ASSESSMENTS
8.1
Treatment Satisfaction Questionnaire for Medication (TSQM) 
The TSQM is a 14-item, validated, self-administered patient reported outcome (PRO) 
questionnaire that is used to assess treatment satisfaction by analyzing the following 4 domains: 
effectiveness, side effects, convenience, and global satisfaction (Atkinson, 2004).   
The TSQM will be administered to the subject at the Baseline Visit/Visit 2, at Day 30, and at the 
Day 90/End of Study/Early Termination Visit prior to any study procedures.  
8.2 
Laboratory Examinations 
8.2.1 
Platelet Count (Local Lab) 
Local laboratory platelet counts will be collected per protocol at the Baseline Visit/Visit 2, Day 
15, Day 30, Day 60 and at the Day 90/End of Study/Early Termination Visit. All other platelet 
counts collected per the subject’s standard of care while they are enrolled in the study should be 
recorded in the eCRF.   
8.3 
World Health Organization Bleeding Scale 
Beginning with the Baseline Visit/Visit 2, the Investigator should assess bleeding using the WHO 
Bleeding Scale (Appendix B) according to verbal response.  
During the Baseline Visit/Visit 2, the following question should be asked: “Have you experienced 
any bruising or bleeding within the last 7 days?”.   
At each subsequent visit, the following question should be asked: “Have you experienced any 
bruising or bleeding since I saw you last?”.  
This assessment should be completed after the TSQM at the Baseline, Day 30, and the Day 90 
Visits.  
 


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9
SAFETY ASSESSMENTS
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or an SAE and remain responsible for following 
up on AEs that are serious, considered related to study procedures, or that caused the subject to 
discontinue avatrombopag. 
9.1
Adverse Events 
An AE 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 AE 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. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
AEs will be monitored and documented from the time of informed consent until study participation 
is complete. Subjects should be instructed to report any AE that they experience to the Investigator. 
Beginning with the informed consent signature, Investigators should make an assessment for AEs 
at each visit and record the event on the appropriate AE eCRF. Events associated with disease 
progression should not be reported as AEs or SAEs. However, if in the Investigator’s opinion the 
disease progression is manifesting in an unusual or uncharacteristic manner, the associated events 
should be reported as AEs/SAEs, as appropriate. 
Wherever possible, a specific disease or syndrome (i.e., diagnosis) 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 AE on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an AE, not the procedure.  
Any medical condition already present at Screening should not be reported as an AE unless the 
medical condition or signs or symptoms present at Screening change in severity, frequency or 
seriousness at any time during the study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination findings that are detected during 
the study or are present at Screening and significantly worsen during the study should be reported 
as AEs. The Investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal finding 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 AE. 
9.1.1 
Additional Safety Information 
In addition to AEs, there are safety-related situations in which other information must be collected, 
regardless of whether or not there is an associated AE. These include: 
 Use during pregnancy (i.e., drug exposure to a fetus in utero). 
 Exposure to a drug during breast-feeding/lactation. 


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 Overdose (whether intentional, accidental or prescribed; whether symptomatic or not). 
o An overdose is defined as the administration of a quantity of a medicinal product 
given per administration or cumulatively which is above the maximum recommended 
dose according to the authorized product information.  When applying this definition,
clinical judgment should always be applied. 
 Drug abuse or misuse. 
 Medication errors (including dispensing errors, accidental exposure, maladministration, 
etc.). 
 Unapproved or off-label use (i.e., intentional medical use of a product not in conjunction 
with the authorized product information). 
 Withdrawal reactions/rebound effects. 
 Unusual exacerbation of existing disease. 
 Suspected use of counterfeit/falsified medicines/tampering.
 Drug-drug/drug-food interactions.
Occupational exposure (as a result of one’s professional or non-professional occupation).
Unexpected or unintended benefit/effect. 
 Actual or potential transmission via a medicinal product of an infectious agent.
If these above events occur and are serious (see Section 9.2), they should be reported using the 
SAE Report Form within 24 hours by fax or email. If non-serious, the events should be reported 
in the eCRF. 
9.1.2 
Assessment of Adverse Events by the Investigator
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to avatrombopag using the categories 
of yes or no. 
9.1.2.1 
Severity Assessment 
 Mild – A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of 
daily living. 
 Moderate – A type of AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
 Severe – A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   


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9.1.2.2 
Causality Assessment 
The relationship of an AE to the administration of avatrombopag is to be assessed according to the 
following definitions: 
 No (unrelated, not related, no relation) – The time course between the administration of 
avatrombopag and the occurrence or worsening of the AE rules out a causal relationship 
and another cause (concomitant drugs, therapies, complications, etc.) is suspected.
 Yes (related) – The time course between the administration of avatrombopag and the 
occurrence or worsening of the AE is consistent with a causal relationship and no other 
cause (concomitant drugs, therapies, complications, etc.) can be identified. 
o The definition implies a reasonable possibility of a causal relationship between the 
event and avatrombopag.  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 avatrombopag administration- 
o The event should occur after avatrombopag is given. The length of time from 
avatrombopag 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(s)- 
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 medication- 
o Clinical and/or preclinical data may indicate whether a particular response is likely 
to be a class effect. 
 Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the subject and provide a 
logical and better explanation for the event. 
 The pharmacology and PK of avatrombopag- 
o The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of avatrombopag should be considered. 


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9.2
Serious Adverse Events
An AE 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 AE, 
o NOTE: An AE 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 will be considered an inpatient hospitalization, even if 
admitted and discharged on the same day. 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 AEs and assessed for seriousness. Admission to 
the hospital for social or situational reasons (i.e., 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. 
9.3 
Method of Detecting Adverse Events and Serious Adverse Events 
AEs will be reported by the subject (or, when appropriate, by a healthcare provider, caregiver or 
surrogate). Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 


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9.4
Serious Adverse Event Reporting  Procedures for Investigators
9.4.1
Initial Reports 
All SAEs, regardless of causal assessment, occurring from the time of informed consent until 
discharge from the study at Day 90 must be reported to the Sponsor as directed on the SAE 
reporting form within 24 hours of the knowledge of the occurrence (this refers to any AE that 
meets any of the aforementioned serious criteria). All SAEs that the Investigator considers causally 
related to avatrombopag occurring after discharge from the study must be reported to the Sponsor. 
To report the SAE, complete the appropriate form for the study and submit to the Sponsor or 
designee as instructed on the form. 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. 
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.
After discharge from the study, if the Investigator becomes aware of an SAE which, per the 
Investigator, is attributable to avatrombopag treatment, the event should be reported to the Sponsor 
within 24 hours of awareness.  
The detailed contact information for reporting of SAEs is provided in the Investigator Study File. 
9.4.2
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), the subject 
is lost to follow-up, or the subject dies.
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. 
Within 24 hours of receipt of follow-up information, the Investigator must update the appropriate 
form for the study and submit any supporting documentation (e.g., subject discharge summary or 
autopsy reports) via fax or e-mail.  
9.5 
Adverse Events of Special Interest 
The Investigator will monitor each subject for clinical and laboratory evidence for pre-defined 
AESIs throughout their participation in this study.  The purpose for specifying these AESI is to 
enable further characterization of the clinical course and management of these events.  An AESI 
may or may not be the consequence of treatment with avatrombopag.
The AESIs defined in this protocol include:
 Thromboembolic events (any thrombotic or embolic event, whether arterial or venous) 
 Bleeding events (any clinically significant blood loss [e.g., WHO Grade 2 or higher]). 


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These events will be recorded on the AE eCRF page. The Investigator will assess and record any 
additional information on the AESI in detail on a SAE form (whether or not the event meets 
seriousness criteria in Section 9.2), to be submitted within 24 hours of awareness of the event. 
During the course of the study, additional AESIs may be identified by the Sponsor.   
9.6 
Pregnancy Reporting 
If a subject becomes pregnant during the study, the Investigator should report the pregnancy using 
the Pregnancy Report Form within 24 hours of being notified. Monitoring of the subject should 
continue until conclusion of the pregnancy, which may involve follow-up after the subject’s 
involvement in the study has ended. Abnormal pregnancy outcomes (e.g., spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
9.7 
Regulatory Reporting Requirements for Serious Adverse Events 
Regulatory reporting requirements for SAEs include:  
 Prompt notification by the Investigator to the Sponsor, or designee, of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study intervention under clinical investigation are met.  
 The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor, or designee, will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB, and Investigators.  
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy.  These 
safety reports will be forwarded to Investigators as necessary.  
 An Investigator who receives an Investigator safety report describing a SUSAR or other 
specific safety information (e.g., summary or listing of SUSARs) from the Sponsor will 
review the report, file it, and will notify the IRB, if appropriate, according to local 
requirements.  


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10
STATISTICS 
This section outlines the statistical methodology used for the safety, platelet count, and TSQM 
assessments. The detailed analyses will be provided in the Statistical Analysis Plan that will be 
finalized before the database lock.   
10.1 
Analysis Populations 
The analyses and summaries of demographic and Baseline characteristics, safety assessments, and 
subject reported outcomes will be provided for the All Enrolled Population which is defined as all 
subjects who receive at least 1 dose of study drug.    
10.2 
Statistical Methods 
10.2.1 
Analysis of Safety 
AEs, SAEs, and AESIs will be summarized for all enrolled subjects using counts and percentages. 
Treatment-emergent AEs and SAEs will be summarized overall, by system organ class, and by 
preferred term. AESIs will be summarized by event type (thromboembolic events and bleeding 
events). In addition, treatment-emergent AEs will be summarized by severity and by relationship 
to study drug. 
Bleeding events reported during the study will be summarized by WHO grade. 
10.2.2 
Analysis of Platelet Count 
Platelet count assessed at Baseline, Day 15, Day 30, Day 60, and Day 90 will be summarized 
descriptively for all enrolled subjects.  Graphic presentations of platelet count over time will be 
provided. 
The proportion of subjects who have a platelet count 50×109/L and 200×109/L will be tabulated 
using count and percentage for Baseline, Day 15, Day 30, Day 60, and Day 90.
10.2.3 
Analysis of the Treatment Satisfaction Questionnaire for Medication
Domain scores of effectiveness, side effects, convenience, and global satisfaction will be computed 
according to the TSQM manual, Version 1.4. Each domain score ranges from 0 to 100, and a higher 
score indicates a better outcome. Descriptive statistics will be summarized for each domain score 
and each visit. The change from Baseline and percent change in each mean domain score will be 
summarized descriptively. 
The primary interest in the TSQM assessment is the convenience domain score. The hypothesis is 
that switching from a prior TPO-RA treatment (e.g., eltrombopag or romiplostim) to avatrombopag 
results in an improvement in the convenience domain score. Change from Baseline to Day 90 (or 
End of Study) in the convenience domain score will be tested using paired t-tests, by prior TPO-
RA treatment (eltrombopag vs romiplostim) and overall.
Additional analyses on platelet count and TSQM may be conducted as appropriate. 
 
 


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10.2.4 
Sample Size Determination
The primary interest in assessing the TSQM in this study is the convenience domain score. An 
observational, retrospective study conducted in 2011 and supported by GlaxoSmithKline showed 
that the mean convenience score for eltrombopag-treated and romiplostim-treated subjects were 
76.11 and 62.12, respectively. Study E5501-G000-302, a 6-month, randomized, placebo-
controlled study in chronic ITP patients, showed that the mean TSQM convenience score assessed 
at Week 12 and at the End of Study for avatrombopag-treated patients was approximately 85 with 
a standard deviation (SD) which ranged from 12.2 – 14.8. Likewise, E5501-G000-305, a 6-month, 
randomized, active-control study in chronic ITP patients, showed that the mean TSQM 
convenience score assessed at the End of Study was 78.9 (SD = 15.4) for avatrombopag-treated 
patients and 68.2 (SD = 21.0) for eltrombopag-treated patients.   
Assuming a mean TSQM convenience score at Baseline and at the End of Study of 74 and 82, 
respectively, with a SD of 19, 50 subjects will provide 83% power to detect a change from Baseline 
of 8 at a 2-sided significance level of 0.05 based on a paired t-test. The total sample size will be 
100 subjects; approximately 50 subjects who received prior treatment with eltrombopag and 
approximately 50 subjects who recieved prior treatment with romiplostim.     
 


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11
DATA MANAGEMENT AND RECORD KEEPING 
11.1
Data Management
11.1.1 
Data Handling
Data will be recorded at the site on eCRFs and reviewed by the Sponsor or designee during 
monitoring visits/calls. All corrections or changes made to any study data must be appropriately 
tracked in an audit trail in the Electronic Data Capture (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 (e.g., safety) is complete. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
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 username 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. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities (MedDRA) for medical history and AEs, and 
 WHO Drug Dictionary for prior and concomitant medications. 
11.1.5 
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. 
11.2 
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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12
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
12.1
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol and all regulatory requirements, in 
accordance with Good Clinical Practice (GCP), including International Council for Harmonisation 
(ICH) guidelines, and in general conformity with the most recent version of the Declaration of 
Helsinki. Sobi Quality Assurance or designee may verify adherence to these practices and 
procedures through audit and inspection. 
12.2 
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, 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. 
The Investigator is obligated to keep the IRB informed of any unanticipated problems. This may 
include notification to the IRB of Investigational New Drug (IND) Safety Reports. 
Federal regulations and ICH guidelines 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, or advertisements to be used for subject recruitment, and any other written 
information regarding this study to be provided to a subject must be approved by the IRB. 
The study will only start in the respective sites once the IRB’s written approval has been given.
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor.
It is the responsibility of the Sponsor, or their designee, to obtain the approval of the responsible 
IRB according to national regulations.  
12.3
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigator by the Sponsor 
or designee. All protocol amendments will undergo the same review and approval process as the 
original protocol. Substantial amendments must be approved as per local regulations prior to 
enrolling subjects.  A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for subject safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days.  
12.4
Informed Consent
The ICF and any changes 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 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 informed 
consent from each subject before any study-specific activity is performed and should document in 


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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 the 
Sponsor, their representatives, auditors, the IRB, and/or regulatory agencies. A copy of the signed 
ICF will be given to the subject. 
12.5 
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 
Investigator and site personnel the following documents: protocol, USPI, eCRFs and procedures 
for their completion, ICF 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/calls, information recorded on the eCRFs may be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the monitor 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, including visits and calls, will be reported and archived. In addition, on-
site monitoring visits will be documented at the investigational site by signature and date on the 
study-specific monitoring log. 
12.6 
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. 
The subject’s medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 


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12.7
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, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, forms for 
SAEs, source documents, and detailed records of treatment. 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. 
12.8
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.
12.9
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. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This coverage is 
designed for the event that a fatality, physical injury, or damage to health occurs during the clinical 
study’s execution.


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13
REFERENCES 
AkaRx. DOPTELET® (avatrombopag) [US Prescribing Information (USPI)]. 
U.S. Food and Drug Administration website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210238s001lbl.pdf.   
Accessed [02/2020].
Amgen. NPLATE® (romiplostim) [US Prescribing Information (USPI)].  
U.S. Food and Drug Administration website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125268s164lbl.pdf.   
Accessed [02/2020].  
Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR. Validation of a 
General Measure of Treatment Satisfaction, the Treatment Satisfaction Questionnaire for 
Medication (TSQM) using a National Panel Study of Chronic Disease. Health and Quality of Life 
Outcomes. 2004; 2(12): 1-13.  
Fogarty PF, Tarantino MD, Brainsky A, Signor-ovitch J, Grotzinger KM.  Selective Validation 
of the WHO Bleeding Scale in Patients with Chronic Immune Thrombocytopenia. Current 
Medical Research and Opinion. 2012; 28(1): 79-87. 
Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson B, Tian W, Allen L. Phase 3 
Randomized study of Avatrombopag, a Novel Thrombopoietin Receptor Agonist for the 
Treatment of Chronic Immune Thrombocytopenia. British Journal of Haematology. 2018; 183: 
479-490.  
Kuter DJ, Macahilig C, Grotzinger KM, Poston SA, Wang PF, Dawson KL, Ward M. Treatment 
Patterns and Outcomes in Patients with Chronic Immune Thrombocytopenia (ITP) Switched to 
Eltrombopag or Romiplostim. International Journal of Hematology. 2015; 101:255-263.  
Miller AB, Hoogstraten B, Staquet M, Winkler A.  Reporting Results of Cancer Treatment. 
Cancer. 1981; 47: 207-214. 
Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, 
et al.  American Society of Hematology 2019 Guidelines for Immune Thrombocytopenia.  Blood 
Advances. 2019; 3(23): 3829-3866.  
Novartis. PROMACTA® (eltrombopag) [US Prescribing Information (USPI)].  
U.S. Food and Drug Administration website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022291s021lbl.pdf.   
Accessed [06/2020].  
Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, et al. 
Updated International Consensus Report on the Investigation and Management of Primary 
Immune Thrombocytopenia. Blood Advances. 2019; 3(22): 3780-3817.  


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APPENDIX A:  Schedule of Events
Table 2 
AVA-ITP-401 Schedule of Events 
 
Screeninga 
Baselinea
Day 
15 
Day 
30 
Day 
60
Standard 
of Care 
Clinic 
Visitsb
Day 90/End 
of Study/ 
Early 
Termination
Visit
1
2
3
4
5
-
6
Day (Window) 
-28 to -1 
1 
15 (±2 
Days)
30 (±2 
Days) 
60 
(±2 
Days
)
- 
90 (±2 Days) 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria Review
X
X
Demographics 
X 
 
 
 
 
ITP Historyc
X
Xd
Record Subject Response to Questions Regarding Administration of Prior TPO-RA 
X 
 
 
 
 
Administer TSQM
X
X
X
WHO Bleeding Scalee
X
X
X
X
X
X
Assess Platelet Transfusions
X
X
X
X
X
Assess Rescue Procedures
X
X
X
X
X
Platelet Countf
Xg
X
X
X
X
X
TPO-RA = thrombopoietin receptor agonist; TSQM = Treatment Satisfaction Questionnaire for Medication; WHO = World Health Organization
a The Screening Visit may be combined with the Baseline Visit if the subject’s platelet count can be obtained prior to dosing with avatrombopag. 
b Additional study visits are not required, per the protocol, however, if a subject has a scheduled clinic visit according to their standard of care, the information included in this 
column, if available, should be recorded in the electronic case report form (eCRF).  In addition, avatrombopag should be dispensed and the Dosing Diary reviewed, as needed, 
during these visits.  
c Record ITP (immune thrombocytopenia) history that is available in the subject’s medical record, including date of ITP diagnosis, number of platelet transfusions in the previous 1 
year (including date of last transfusion), number of previous hospitalizations for ITP, number of previous significant bleeding events (e.g., blood loss 1/2 cup), dose and duration 
of previous treatments with eltrombopag and romiplostim (including qualifying eltrombopag/romiplostim treatment over the 90 days prior to study entry), other previous 
treatments for ITP (including duration), history of splenectomy (yes/no), history of thromboembolic events and reason for switching to avatrombopag.  
d Update the eCRF with any ITP history changes since Screening.
e The following question should be asked of the subject during the Baseline Visit: “Have you experienced any bruising or bleeding within the last 7 days?” while the following 
question should be asked of the subject during each subsequent protocol specified visit: “Have you experienced any bruising or bleeding since I saw you last?”.  The WHO 
Bleeding Scale should be performed after the TSQM at the Baseline Visit,  Visit Days 15, 30, 60, and at the Day 90 Visit and prior to any other visit procedures.  
f Only local lab results will be used. 
g Any platelet count measured within the previous 7 days will be accepted.  


Sobi, Inc. Clinical Study Protocol AVA-ITP-401
Confidential & Proprietary  
Version 2.0, 28 January 2022  
44 
 
 
Screeninga 
Baselinea
Day 
15
Day 
30
Day 
60
Standard 
of Care 
Clinic 
Visitsb
Day 90/End 
of Study/
Early 
Termination
Visit 
1 
2 
3 
4 
5 
- 
6 
Dispense Avatrombopagh
X
X
X
X
X
Dispense Dosing Diary 
 
X 
 
 
 
Record Prescribed Avatrombopag Dose Regimen in eCRF
 
X 
X
X
X 
X 
X 
Review Subject Dosing Diary
Xi
X
X
X
X
Retrieve Unused Avatrombopag, if Applicable 
 
 
X
X
X 
X 
Retrieve Dosing Diary
X
Record Adverse Eventsj 
X 
X 
X
X
X 
X 
X 
Record Concomitant Medicationsk
X
X
X
X
X
X
X
h Dispense avatrombopag, based on the subject’s current dosage regimen, per the DOPTELET Unites States Prescribing Information (USPI)
i During the Baseline Visit/Visit 2, the study team should review with the subject instructions for completion of the Dosing Diary. 
j Adverse events, including AESIs, will be collected from the time of informed consent. 
k Including concomitant ITP medications. 


Sobi, Inc. Clinical Study Protocol AVA-ITP-401 
Confidential & Proprietary  
Version 2.0, 28 January 2022  
45 
 
APPENDIX B:  WHO Bleeding Scale
Grade 0 
No bleeding
Grade 1 
Petechial bleeding 
Grade 2
Mild blood loss (clinically significant)
Grade 3 
Gross blood loss
Grade 4
Debilitating blood loss
a: Fogarty, 2012; Miller, 1981 
 


Sobi, Inc. Clinical Study Protocol AVA-ITP-401 
Confidential & Proprietary  
Version 2.0, 28 January 2022  
46 
 
APPENDIX C: PROTOCOL AMENDMENTS
Protocol Amendment 1 (protocol v2.0) updates the sponsor name to Sobi, Inc. Dova 
Pharmaceuticals, Inc. (the initial study sponsor) and Sobi, Inc. are affiliates that have a common 
ownership, Swedish Orphan Biovitrum AB (publ) (Sobi).  Each is a wholly owned subsidiary of 
Sobi. Dova Pharmaceuticals, Inc. will soon cease to exist as a legal entity, and Sobi, Inc. will be 
the sponsor going forward.  
 
Summary of Changes: 
 
 The Sponsor name and address have been updated throughout the protocol.
 
 The National Clinical Trial (NCT) identifier from clinicaltrials.gov has been added to the 
cover page. 
   
 The estimated number of sites has been modified to 20. 
 
 A small number of typographical and editorial errors have been corrected in background 
text; these spelling and wording corrections have no impact on any protocol definitions or 
procedures.   
 
Revisions to individual sentences due to these administrative updates and non-substantive 
corrections are not presented. 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Study Title 
Prospective, Multi-center, Open-label Study Measuring Safety and 
Treatment Satisfaction in Adult Subjects with Chronic Immune 
Thrombocytopenia (ITP) after Switching to Avatrombopag from 
Eltrombopag or Romiplostim 
Protocol Number:  
AVA-ITP-401  
NCT Number 
04638829 
Investigational Product:  
Avatrombopag  
Sponsor:  
Sobi, Inc.  
Analysis Plan Date:  
31-JAN-2024  
Analysis Plan Version:  
Version 2.0 
 


Signature Page for AVA_ITP_401_SAP
Study AVA-ITP-401 v2.0
Signature Page for AVA_ITP_401_SAP
Study AVA-ITP-401 v2.0
eSignature for Approval
Sponsor
30-Jan-2024 22:09:34 GMT+0000
eSignature for Approval
Statistician
n-2024 22:10:14 GMT+0000
eSignature for Approval
Sponsor
31-Jan-2024 15:41:39 GMT+0000
eSignature for Approval
Statistician
n-2024 15:55:34 GMT+0000
Dova - AVA-ITP-401                                                                   Version: 2.0
Type of Approval: Approved in Vault, Approval Date: 31 Jan 2024


 
 
 
 
 
 
 
 
 
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SAP Template (for eTMF) 
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Department: Biostatistical Services 
 
Confidential
Statistical Analysis Plan 
 
SPONSOR:  
Sobi 
PROTOCOL TITLE: Prospective, Multi-center, Open-label Study Measuring Safety and 
Treatment Satisfaction in Adult Subjects with Chronic Immune 
Thrombocytopenia (ITP) after Switching to Avatrombopag from 
Eltrombopag or Romiplostim 
STUDY CODE: 
AVA-ITP-401 
 
 
For 
 
Author: 
 – Senior Biostatistician, 
 
Approver: 
 – Team Leader, Biostatistical Services,
 
 
For Sponsor: 
Approver: 
 – Director, Biostatistics 
Approver: 
 – VP, Global Drug Development 
 
 
 
 
 
Dova - AVA-ITP-401                                                                   Version: 2.0
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Department: Biostatistical Services 
 
Confidential
Change History 
 
Version 
Date 
Author 
Summary of Changes 
29APR2021 
 
N/A – First Version 
04JUN2021 
 
 
• 
General wording/language clarifications and 
alignment with protocol. 
• 
Figure clarity. 
• 
Updated TSQM scoring algorithm based on 
IQVIA TSQM manual. 
• 
Added language to clarify that a separate table 
for bleeding, listing for platelet count, and two 
listings for exposure/treatment compliance will 
be included. 
• 
Moved WHO Bleeding assessments to safety 
evaluation section. 
09JUL2021 
 
• 
Added link to study design figure 
• 
General language for addition of table to 
compare prior TPO-RA with stable dose of Ava. 
To be finalized after discussion 
• 
Added listing of procedures to 
prior/concomitant treatment section 
• 
Added clarification describing WHO bleeding 
leading question at Baseline vs other visits in 
section 9.3.2 
30JUL2021 
 
• 
Added text describing summary of prior TPO-RA 
table vs stable dose in section 6.4 
23JUN2023 
 
• 
Added section 8.1 “Study Endpoints” 
• 
In section 8.2, added secondary analysis of 
using paired t-test to the other three domains 
of TSQM (global satisfaction, effectiveness, and 
side effects) 
• 
Added clarity to the definition of AESI in section 
9.2 
• 
Added procedure to identify AESI 
• 
Added definition to “Post screening exclusion” 
under disposition 
• 
Updated footer of the SAP per 
-FRM-TPL-
0105 
• 
Add subgroup analysis by prior history of TPO-
RA (eltrombopag vs romiplostim) and Overall. 
• 
Updated format/layouts and numberings 
• 
Updated MedDRA version to 26.1 or later 
10NOV2023 
 
• 
Last category of treatment compliance was 
updated to >100-110% 
Dova - AVA-ITP-401                                                                   Version: 2.0
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• 
Bleeding evaluation for overall study period was 
added and defined. 
• 
Specified subgroup analysis by prior history of 
TPO-RA (eltrombopag vs romiplostim) and 
Overall, in some additional sections. 
• 
Definition of concomitant medication updated. 
• 
Added a sentence to reflect number of adverse 
events to be summarised by SOC and PT. 
• 
Removed “surgical” from “Medical and Surgical 
History” as surgical history is not collected. 
• 
TSQM and Analysis of platelets counts were 
grouped into a separate “Efficacy/Effectiveness 
Evaluation” section.  
 
Dova - AVA-ITP-401                                                                   Version: 2.0
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Department: Biostatistical Services 
 
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Table of Contents 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 6 
2. 
INTRODUCTION ........................................................................................... 7 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................ 7 
3.1 
Study Objectives...................................................................................... 7 
3.1.1 
Primary Objective .............................................................................. 7 
3.1.2 
Secondary Objectives ........................................................................ 7 
3.2 
Study Endpoints ...................................................................................... 7 
3.2.1 
Primary Endpoint .............................................................................. 7 
3.2.2 
Secondary Endpoints ......................................................................... 7 
3.3 
Study Design ........................................................................................... 8 
Figure 1: AVA-ITP-401 Study Schematic ............................................................... 9 
3.4 
Sample Size Justification ........................................................................... 9 
4. 
GENERAL ANALYSIS DEFINITIONS .............................................................. 9 
4.1 
Study Period and Visit Window Definitions ................................................... 9 
4.1.1 
Study Periods ................................................................................... 9 
4.1.2 
Visit Windows ................................................................................. 10 
4.2 
Definition of Populations ......................................................................... 10 
4.2.1 
All Screened Population .................................................................... 10 
4.2.2 
All Enrolled Population ..................................................................... 10 
4.3 
Data Handling Conventions ..................................................................... 10 
4.3.1 
General Conventions........................................................................ 10 
4.3.2 
Definition of Study Day .................................................................... 10 
4.3.3 
Definition of Baseline ....................................................................... 11 
4.3.4 
Handling Missing Data...................................................................... 11 
4.3.5 
Partial Dates ................................................................................... 11 
4.4 
Treatment Groups .................................................................................. 11 
4.5 
Data Listings ......................................................................................... 12 
5. 
STUDY PATIENTS ....................................................................................... 12 
5.1 
Disposition of Patients ............................................................................ 12 
5.2 
Inclusion and Exclusion Criteria Details ..................................................... 12 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 12 
6.1 
Demographics and Baseline Characteristics ............................................... 12 
6.2 
Medical History ...................................................................................... 13 
6.3 
Immune Thrombocytopenia (ITP) History .................................................. 13 
6.4 
Administration of Prior TPO-RA ................................................................ 13 
7. 
PRIOR AND CONCOMITANT TREATMENT .................................................... 14 
8. 
EFFICACY/EFFECTIVENESS EVALUATION .................................................. 14 
8.1 
Treatment Satisfaction Questionnaire for Medication (TSQM) ....................... 14 
8.2 
Analysis of Platelet Count ........................................................................ 16 
9. 
SAFETY EVALUATION ................................................................................. 16 
Dova - AVA-ITP-401                                                                   Version: 2.0
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9.1 
Exposure and Treatment Compliance ........................................................ 16 
9.2 
Adverse Events ...................................................................................... 17 
9.3 
Other Safety Measures ........................................................................... 18 
9.3.1 
Platelet Transfusions ........................................................................ 18 
9.3.2 
World Health Organization Bleeding Scale .......................................... 18 
9.3.3 
COVID-19 Impact ............................................................................ 19 
10. 
REFERENCES .......................................................................................... 19 
11. 
LIST OF TABLES, LISTINGS, AND FIGURES ............................................. 19 
12. 
APPENDIX A: SCHEDULE OF EVENTS ...................................................... 20 
Dova - AVA-ITP-401                                                                   Version: 2.0
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1. List of Abbreviations and Definition of Terms 
Abbreviation 
Term 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomical Therapeutic Classification 
eCRF 
Electronic Case Report Form 
ICH 
International Conference on Harmonization 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
MedDRA Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SMQ 
Standardized MedDRA Query 
SOC 
MedDRA System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TPO-RA 
Thrombopoietin receptor agonist 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
USPI 
United States Prescribing Information 
WHO 
World Health Organization 
 
 
Dova - AVA-ITP-401                                                                   Version: 2.0
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2. Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methodology and data 
handling for the clinical trial for Sobi, Inc. (formerly Dova Pharmaceuticals) with 
Protocol Number: AVA-ITP-401 (Prospective, Multi-center, Open-label Study 
Measuring Safety and Treatment Satisfaction in Adult Subjects with Chronic 
Immune Thrombocytopenia (ITP) after Switching to Avatrombopag from 
Eltrombopag or Romiplostim). 
The ICH guideline E3 “Structure and Content of Clinical Study Reports” was used as 
a guide to the writing of the plan. 
This SAP is based on the following study document(s): 
• 
Clinical Study Protocol V2.0, dated 28 Jan 2022 
• 
Electronic Case Report Form V3.0, dated 15 March 2021 
3. Study Design and Objectives 
3.1 Study Objectives 
3.1.1 Primary Objective 
The primary objective of this study is to characterize the safety and tolerability of 
avatrombopag given for 90 days after stopping treatment with eltrombopag or 
romiplostim. 
3.1.2 Secondary Objectives 
The secondary objectives of this study are the following: 
• 
Evaluate the change in subject reported outcomes (TSQM) from Baseline 
after switching to avatrombopag from eltrombopag or romiplostim.  
• 
Evaluate the platelet counts after switching to avatrombopag from 
eltrombopag or romiplostim.  
3.2 Study Endpoints 
3.2.1 Primary Endpoint 
Occurrence of adverse events (AEs) and serious adverse events (SAEs). 
3.2.2 Secondary Endpoints  
Change from Baseline in each of the 4 domains of the TSQM Version 1.4 (e.g., 
convenience, global satisfaction, effectiveness, and side effects) to Day 90 or End 
of Study. 
Proportion of subjects who have a platelet count between ≥50×109/L to 
≤200×109/L at Day 15, Day 30, Day 60, and Day 90. 
 
 
 
Dova - AVA-ITP-401                                                                   Version: 2.0
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3.3 Study Design 
This is a Phase 4, prospective, multi-center, open-label study to evaluate safety, 
platelet count, and subject reported medication satisfaction in adult subjects with 
chronic ITP after switching to avatrombopag from eltrombopag or romiplostim. 
At least 100 subjects are planned to be enrolled, 50 (±10) who have received 
eltrombopag and 50 (±10) who have received romiplostim for at least 90 days 
prior to study entry. An overview of the study design is provided in Figure 1.  
The initial dose and dose adjustments of avatrombopag will be determined by the 
Investigator in conjunction with the DOPTELET® USPI (United States Prescribing 
Information). There is no protocol-required washout period between treatment with 
TPO-RAs (Thrombopoietin receptor agonists), however avatrombopag should not 
be administered on the same day as another TPO-RA. The start and stop dates of 
all prior and concomitant medications should be recorded in the electronic case 
report form (eCRF).  
Safety will be evaluated throughout the study. Bleeding severity will be captured 
using the World Health Organization (WHO) Bleeding Scale at each visit. Platelet 
counts will be collected per protocol at Baseline, Day 15, Day 30, Day 60, and Day 
90, however, all other platelet counts collected per the subject’s standard of care 
while they are enrolled in the study should be recorded in the eCRF. The TSQM 
(Treatment Satisfaction Questionnaire for Medication) will be administered prior to 
the first dose of avatrombopag (at Baseline), at Day 30, and at Day 90 or at the 
time of early termination from the study. Compliance with the Investigator 
prescribed avatrombopag dosing regimen will be captured via a subject reported 
Dosing Diary which should be evaluated by the study team during each visit to the 
clinic, per the subject’s standard of care.  
Subjects may be screened within 28 days of the Baseline Visit/Visit 2; however, the 
Screening Visit/Visit 1 may be combined with the Baseline Visit/Visit 2. The 
duration of subject participation and collection of clinical data will be a minimum of 
90 days from the Screening Visit/Visit 1 to Day 90. The only protocol-required clinic 
visits during the study are the Baseline Visit/Visit 2, Day 15, Day 30, Day 60, and 
the Day 90 or Early Termination Visit.  
If a subject is early terminated, the early termination assessments should be 
completed prior to discharge from the study. 
 
 
 
Dova - AVA-ITP-401                                                                   Version: 2.0
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Figure 1: AVA-ITP-401 Study Schematic 
 
 
3.4 Sample Size Justification 
The primary interest in assessing the TSQM in this study is the convenience domain 
score. An observational, retrospective study conducted in 2011 and supported by 
GlaxoSmithKline showed that the mean convenience score for eltrombopag-treated 
and romiplostim-treated subjects were 76.11 and 62.12, respectively. Study 
E5501-G000-302, a 6-month, randomized, placebo-controlled study in chronic ITP 
patients, showed that the mean TSQM convenience score assessed at Week 12 and 
at the End of Study for avatrombopag-treated patients was approximately 85 with 
a standard deviation (SD) which ranged from 12.2 – 14.8. Likewise, E5501-G000-
305, a 6-month, randomized, active-control study in chronic ITP patients, showed 
that the mean TSQM convenience score assessed at the End of Study was 78.9 (SD 
= 15.4) for avatrombopag-treated patients and 68.2 (SD = 21.0) for eltrombopag-
treated patients.  
Assuming a mean TSQM convenience score at Baseline and at the End of Study of 
74 and 82, respectively, with a SD of 19, 50 subjects will provide 83% power to 
detect a change from Baseline of 8 at a 2-sided significance level of 0.05 based on 
a paired t-test. The total sample size will be 100 subjects; approximately 50 
subjects who received prior treatment with eltrombopag and approximately 50 
subjects who received prior treatment with romiplostim. 
4. General Analysis Definitions 
4.1 Study Period and Visit Window Definitions 
4.1.1 Study Periods 
Screening Period: Starting the day of the Screening Visit/Visit 1 in which 
informed consent is signed up to the day before the Baseline Visit/Visit 2 during 
which avatrombopag is first administered. The Screening Visit must be completed 
Dova - AVA-ITP-401                                                                   Version: 2.0
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within 28 days prior to the Baseline Visit, however, the Screening and Baseline 
visits may be combined. 
Treatment Period: Starting from the Baseline Visit/Visit 2 (or combined Visit 
1/Visit 2, if applicable) through the End of Study Visit on Day 90 (±2 days) or the 
Early Termination Visit, whichever occurs first. 
4.1.2 Visit Windows 
The recommended and allowed intervals between study visits are presented in the 
protocol Section 7, Study Procedures (Appendix A). No recalculation of time 
windows or formal visit windowing will be conducted. By-visit tabular summaries 
will assume that observations are from the scheduled visit recorded in the eCRF 
irrespective of the date specified.  
4.2 Definition of Populations 
4.2.1 All Screened Population 
The All Screened Population is defined as all patients who have completed a 
Screening Visit. The summary of disposition and the listing of inclusion/exclusion 
criteria not met will be based on the All Screened Population.  
4.2.2 All Enrolled Population 
The All Enrolled Population is defined as all subjects who receive at least 1 dose of 
study drug. Analyses and summaries of demographic and Baseline characteristics, 
safety assessments, and subject reported outcomes will be based on the All 
Enrolled Population.  
4.3 Data Handling Conventions 
4.3.1 General Conventions 
Data will be analyzed using SAS (Version 9.4 or later). Descriptive analyses will be 
performed on demographic and baseline characteristics, safety assessments, 
platelet counts, and subject reported outcomes. 
Descriptive statistics will be tabulated as follows: 
• 
Categorical data will be summarized in contingency tables presenting 
frequencies and percentages, and  
• 
Continuous data will be summarized using number of non-missing values 
(n), mean, standard deviation, median, minimum, and maximum values.  
4.3.2 Definition of Study Day 
The first day of study treatment with avatrombopag will be during the Baseline 
Visit/Visit 2 and will be referenced as Study Day 1. There is no Study Day 0. The 
day before the first day of study treatment will be Study Day -1. If an event occurs 
on or after the first day of study treatment, Study Day will be calculated as (Date 
of Event - Date of first study treatment + 1).  If the event occurs prior to the first 
day of study treatment, Study Day will be calculated as (Date of Event - Date of 
first study treatment). 
Dova - AVA-ITP-401                                                                   Version: 2.0
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4.3.3 Definition of Baseline 
Baseline is defined as the last non-missing assessment done on or before the start 
of study treatment on Study Day 1. Assessments done on the date of study 
treatment administration are assumed to take place before the administration, 
unless specified otherwise. 
4.3.4 Handling Missing Data 
All available data will be included in data listings and tabulations.  
No imputation of missing data is planned for study endpoints. 
4.3.5 Partial Dates 
For the purpose of inclusion of appropriate data records in the analysis, some 
partially missing dates will have date imputation performed. However, these 
imputations will be limited to table summaries; listings will retain the date as 
entered in the database. The following imputations will be performed: 
Medications:  
• 
If a start date is missing the day 
o 
Set to the 1st of the month  
• 
If a start date is missing the day and month 
o 
Set to January 1st if study treatment began the year prior to the year of 
medication start  
o 
Set to January 1st if the medication is known to start in a year prior to study 
treatment  
o 
If the medication and the study treatment start the same year, the 
medication start date will be set to the study treatment start date.  
• 
No medication end dates will be imputed 
• 
No completely missing dates will be imputed. If, after imputation, it cannot 
be determined whether a medication was taken prior or concomitantly, it will 
be considered a concomitant medication.  
Adverse Events: 
• 
If a start date is missing the day 
o 
Set to the 1st of the month, or the same day as treatment start if it is the 
same month and year as treatment start 
• 
If a start date is missing the day and month 
o 
Set to treatment start date if it is the same year as treatment start; 
otherwise set to January 1st if it is the year after treatment start. 
• 
No adverse event end dates will be imputed 
• 
No completely missing start dates will be imputed. If, after imputation, it 
cannot be determined if an adverse event is treatment-emergent, it will be 
considered treatment-emergent for analysis purposes. 
4.4 Treatment Groups 
All subjects enrolled in the study will receive open-label avatrombopag. Data 
displays will have three columns for All Enrolled Population, presented by prior 
Dova - AVA-ITP-401                                                                   Version: 2.0
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TPO-RA (romiplostim and eltrombopag) and overall, unless otherwise specified in 
the mock TLFs. 
4.5 Data Listings 
Data listings will generally include Subject ID, Age, Sex, Race, and as applicable, 
prior TPO-RA by default. 
5. Study Patients 
5.1 Disposition of Patients  
A summary table by prior TPO-RA (romiplostim and eltrombopag) and overall 
group will include the total number of subjects screened and the numbers and 
percentages of screened subjects who enrolled in the study, subjects who failed 
screening, and the reason for screen failure. In addition, if any subjects are 
excluded after screening it will be reported as “Post screening exclusion” defined as 
subjects who screened but not enrolled to study and take medication yet.  
The summary table will also contain the numbers and percentages of patients who 
completed the study, discontinued the study early, and the primary reason for 
early discontinuation.   
A disposition listing will include the verbatim “Other” specified text from the eCRF if 
the reason for screen failure or the reason for early discontinuation from the study 
is entered as “Other.” If the reason for discontinuation is adverse event, then the 
listing will display the associated adverse event (AE) preferred term. 
5.2 Inclusion and Exclusion Criteria Details 
Details of inclusion/exclusion criteria for subjects in the All Screened Population will 
be provided in a listing. This listing will indicate the protocol version, informed 
consent date, whether the subject rescreened, and if the subject enrolled. Details 
of inclusion and exclusion criteria not satisfied for subjects who did not enroll will 
be provided. The listing will also indicate if the subject’s Screening and Baseline 
visits were combined. 
6. Demographic and other Baseline Characteristics 
Demographics and Baseline Characteristics will be summarized for subjects by prior 
TPO-RA (romiplostim and eltrombopag) and overall for all enrolled subjects. 
6.1 Demographics and Baseline Characteristics 
Descriptive statistics with respect to subject characteristics at baseline will be 
displayed by prior TPO-RA (romiplostim and eltrombopag) and overall for all 
enrolled subjects. The variables to be summarized are: 
Demographics 
• 
Age at enrollment (years) 
• 
Sex 
• 
Race 
• 
Ethnicity 
Dova - AVA-ITP-401                                                                   Version: 2.0
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Baseline subject characteristics  
• 
TSQM domain scores of effectiveness, side effects, convenience, and global 
satisfaction 
• 
Summary of WHO Bleeding Scale assessment (within the previous 7 days) 
• 
Platelet count as assessed by local lab (109/L) 
 
A listing of demographic and baseline characteristics will also be provided. 
6.2 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Authorities 
(MedDRA) version 26.1 or later. The coding version may be updated prior to 
database lock if a newer version is available. 
Medical history will be tabulated by Preferred Term (PT) by prior TPO-RA 
(romiplostim and eltrombopag) and overall for all enrolled subjects. Subjects with 
more than one medical history event in a PT will only be counted once per PT.  
Only those PTs with >5% of enrolled subjects will be displayed in the summary 
table. However, all medical history details will be provided in a data listing.  
6.3 Immune Thrombocytopenia (ITP) History 
Descriptive statistics with respect to ITP history will be displayed by prior TPO-RA 
(romiplostim and eltrombopag) and overall for all enrolled subjects. The variables 
to be summarized are:  
• 
Time since ITP diagnosis (years), defined as (Date of enrollment – Date of 
Diagnosis+1)/365.25 
• 
Number of platelet transfusions in the previous 1 year 
• 
Number of previous hospitalizations for ITP 
• 
Number of previous significant bleeding events  
• 
History of splenectomy (yes/no) 
• 
History of thromboembolic events (yes/no) 
A listing of ITP history will also be provided. It will include the variables above 
along with the date of last platelet transfusion and the reason for switching to 
avatrombopag from eltrombopag or romiplostim. 
6.4 
Administration of Prior TPO-RA 
Descriptive statistics of variables related to the administration of prior TPO-RA will 
be displayed for all enrolled subjects. The table will be divided in 2 sections (one for 
romiplostim and one for eltrombopag) and include a summary of:  
• 
Duration of prior treatment with romiplostim and eltrombopag (weeks) as a 
continuous variable 
• 
Most recent dose level of eltrombopag and romiplostim (mg or mcg/kg) as a 
categorical variable 
Dova - AVA-ITP-401                                                                   Version: 2.0
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• 
Subject-reported responses to the 3 brief questions in the romiplostim and 
eltrombopag eCRF pages 
An additional table will be created comparing the most recent dose level of prior TPO-
RA (romiplostim and eltrombopag) recorded at the Baseline Visit to the stable dose 
of avatrombopag at the end of study. The stable dose of avatrombopag at the end 
of the study will be defined as the final avatrombopag dose recorded in the eCRF at 
the End of Study Visit on Day 90. The prior TPO-RA dose will be categorized into 3 
dose groups (low, medium, and high), and the table will summarize the stable dose 
of avatrombopag by prior TPO-RA within each group. 
Listings (one for romiplostim and one for eltrombopag) will present each individual 
subject's duration of prior treatment, most recent dose level (units), date of last 
dose, and answers to the 3 questions in the romiplostim and eltrombopag eCRF 
pages. 
7. Prior and Concomitant Treatment 
Prior and Concomitant medications will be classified according to the World Health 
Organization (WHO) Drug Dictionary Global (Enhanced w/WHO Herbal Dictionary). 
The coding version may be updated prior to database lock if a newer version is 
available. Medications will be coded per the Anatomical Therapeutic Classification 
(ATC). All medications will be documented from the time of informed consent up to 
the End of Study/Early Termination Visit.  
Prior medications are those which start and stop before the first day of study 
treatment. Concomitant medications are those which are being taken on or after 
the first day of study treatment.  
Tabular summaries will display the number and percentage of subjects with at least 
one medication in ATC Level 2 and preferred name categories by prior TPO-RA 
(romiplostim and eltrombopag) and overall groups. Subjects who have taken a 
medication more than once will only be summarized once per ATC Level 2 or 
preferred name.  
The tabular summaries to be provided are as follows: 
• 
Prior Medications  
• 
Concomitant Medications 
• 
Concomitant Medications taken as rescue for a bleeding event 
An overall listing of medications will be provided. The listing will designate whether 
a medication is considered prior or concomitant. A separate listing will also be 
produced for concomitant medications taken as rescue for a bleeding event. 
An overall listing of procedures will also be provided with procedure name, start 
and end dates, a flag for prior/concomitant procedure, and details about reason for 
the procedure (indication). 
8. Efficacy/Effectiveness Evaluation 
8.1 Treatment Satisfaction Questionnaire for Medication (TSQM)  
Dova - AVA-ITP-401                                                                   Version: 2.0
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The domain scores of effectiveness, side effects, convenience, and global 
satisfaction will be computed according to the Treatment Satisfaction Questionnaire 
for Medication (TSQM) User Manual (IQVIA, Version 1.6: 04 March 2020). Each 
domain score ranges from 0 to 100, and a higher score indicates a better outcome. 
The TSQM will be administered at Baseline (before the first dose of avatrombopag), 
Day 30, and Day 90.  
The scoring algorithms are as follows:  
If more than one item score is missing, the scale score should not be computed 
and set to missing. If a subject answers “No” to Item 4, the side effects scale score 
will not be computed.  
Effectiveness 
Effectiveness scale score = [(Item 1 + Item 2 + Item 3 – 3)/18] x 100 
If one item is missing: 
Effectiveness scale score = [(Item 1? + Item 2? + Item 3? -2)/12] x 100 
 
Side Effects  
If Question 4 is answered ‘No’ then score = 100 
Else: 
Side effects scale score = [(Item 5 + Item 6 + Item 7 + Item 8 – 4)/16] x 100 
If one item is missing: 
Side effects scale score = [(Item 5? + Item 6? + Item 7? + Item 8? – 3)/12] x 100 
 
Convenience 
Convenience scale score = [(Item 9 + Item 10 + Item 11 – 3)/18] x 100 
If one item is missing: 
Convenience scale score = [(Item 9? + Item 10? + Item 11? – 2)/12] x 100 
 
Global Satisfaction 
Global satisfaction scale score = [(Item 12 + Item 13 + Item 14 – 3)/14] x 100  
If Item 12 or 13 is missing  
([(Sum(the two completed items)) – 2] divided by 10) * 100  
If Item 14 is missing  
([(Sum(Item 12 and Item 13)) – 2] divided by 8) * 100  
 
Descriptive statistics will be summarized for each domain score and each visit. The 
change from Baseline and percent change in each mean domain score will be 
Dova - AVA-ITP-401                                                                   Version: 2.0
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summarized descriptively by prior TPO-RA (eltrombopag vs romiplostim) and 
overall.  
The primary interest in the TSQM assessment is the convenience domain score. 
The hypothesis is that switching from a prior TPO-RA treatment (e.g., eltrombopag 
or romiplostim) to avatrombopag results in an improvement in the convenience 
domain score. Change from Baseline to Day 90 (or End of Study) in the 
convenience domain score will be tested using paired t-tests, by prior TPO-RA 
treatment (eltrombopag vs romiplostim) and overall. As a part of the secondary 
endpoint analyses, this paired t-test analysis will also be performed to examine the 
global satisfaction, effectiveness, and side effects domain score by prior TPO-RA 
treatment (eltrombopag vs romiplostim) and overall. 
A listing of TSQM scores will be provided. 
8.2 
Analysis of Platelet Count 
Platelet count (local lab) assessed at Baseline, Day 15, Day 30, Day 60, and Day 90 
will be summarized descriptively for all enrolled subjects. A graphical presentation 
of platelet count over time will be provided by prior TPO-RA (romiplostim and 
eltrombopag) and overall. 
The proportion of subjects who have a platelet count ≥50×109/L and ≤200×109/L 
will be tabulated using count and percentage for Baseline, Day 15, Day 30, Day 60, 
and Day 90. 
A listing will provide details of local lab platelet counts by visit. 
 
9. 
 Safety Evaluation 
Safety and tolerability will be assessed by examining exposure, treatment 
compliance, and adverse events by prior TPO-RA (romiplostim and eltrombopag) 
and overall of all enrolled subjects. 
9.1 Exposure and Treatment Compliance 
Exposure and treatment compliance will be summarized for all enrolled subjects by 
prior TPO-RA and overall.  
Duration of exposure (in days) will be calculated as (Last dose date – First dose 
Date +1).  
Number of tablets taken will be calculated as (total number of tablets dispensed – 
total number of tablets returned). 
Number of tablets expected to take will be calculated as sum of (regimen end date 
– regimen start date +1)*prescribed treatment regimen of each regimen period. 
Treatment compliance will be calculated as (number of tablets taken/number of 
tablets expected to take)*100. The treatment compliance will be summarized 
descriptively and also presented categorically (e.g. number and percentage of 
subjects with <80%, 80-100%, and >100-110%).  
Data listings will provide details of subject exposure including treatment regimen, 
regimen start and end dates, regimen adjustments, number of tablets dispensed 
Dova - AVA-ITP-401                                                                   Version: 2.0
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and returned according to the Drug Accountability eCRF page, and compliance as 
assessed by the Drug Regimen Adjustments eCRF page. 
Duration of exposure, number of tablets taken, number of tables expected to take, 
and treatment compliance of each subject will be listed as well. 
9.2 Adverse Events 
Adverse events (AEs) will be coded using MedDRA version 26.1 or later. The coding 
may be updated according to newly released versions of the dictionary.  
Severity of AEs is categorized according to the following categories as entered in 
the eCRF: Mild, Moderate, Severe.  
For investigator determined relationship to study drug, AEs are classified as 
“Related” or “Not Related”. 
AEs leading to discontinuation of avatrombopag are AEs where action taken is 
designated as “Drug Withdrawn” in the eCRF.  
Two categories for Adverse Events of Special Interest (AESI) will be summarized 
and are defined based on terms in Standardized MedDRA Queries (SMQs) from 
MedDRA v26.1 or later: 
1. Thromboembolic events - Any thrombotic or embolic event, whether arterial 
or venous – SMQ = Embolic and thrombotic events 
2. Bleeding Events - Any clinically significant blood loss [e.g., bleeding events 
with CTCAE grade 3+ (based on AE severity [AESEV]>=3] – SMQ = 
Haemorrhage terms (excl laboratory terms) 
TEAEs are defined as AEs occurring on or after the first dose of study treatment. 
TEAE will be tabulated by System Organ Class (SOC) and Preferred Term (PT) by 
prior TPO-RA (romiplostim and eltrombopag) and overall. TEAESI will be tabulated 
by AESI category and PT. Subjects with more than one TEAE in a SOC or PT will 
only be counted once per SOC or PT. 
An overview summary table will include the number and percentage of all enrolled 
subjects with at least one: 
• 
TEAE 
• 
Serious TEAE 
• 
TEAE of special interest (thromboembolic events and bleeding events) 
• 
TEAE related to avatrombopag 
• 
Severe TEAEs 
• 
TEAE leading to study drug discontinuation 
Summary tables of TEAEs will be provided for: 
• 
TEAE (by SOC and PT) 
• 
Serious TEAE (by SOC and PT) 
• 
TEAE of special interest (by AESI category and PT) 
• 
TEAE related to avatrombopag (by SOC and PT) 
Dova - AVA-ITP-401                                                                   Version: 2.0
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• 
Severe TEAEs (by SOC and PT) 
• 
TEAE leading to study drug discontinuation (by SOC and PT) 
 Summary tables will also include number of events for each AE by SOC and by PT. 
Listings of all adverse events reported after the consent form is signed (both TEAE 
and non-TEAE) will be provided and will include information such as the patient 
identifier, SOC, PT, reported term, date of onset/stop, duration of the event, TEAE, 
seriousness, severity, action taken, outcome, causality and relationship. A flag will 
be included in the listings to designate whether an adverse event is treatment-
emergent. 
Listings of adverse events will be provided for the following categories: 
• 
All Adverse Events 
• 
Serious AEs 
• 
AEs of special interest (thromboembolic events and bleeding events) 
• 
AEs related to avatrombopag 
• 
Severe AEs 
• 
AE leading to study drug discontinuation 
9.3  Other Safety Measures 
9.3.1  Platelet Transfusions 
A summary table will be created by prior TPO-RA (romiplostim and eltrombopag) 
and overall to display the frequency and percentage of enrolled subjects who have 
platelet transfusions (yes/no). The total number of platelet transfusions, and the 
reasons for transfusion (Thrombocytopenia, Bleeding Event, Adverse Event other 
than Bleeding Event, Other) will be summarized by category (subjects may appear 
in more than one category). The total number of packs/units received per 
transfusion will be summarized as a continuous variable.  
Details of platelet transfusions occurring during the study will be presented in a 
listing. 
9.3.2 World Health Organization Bleeding Scale 
Bleeding will be assessed using the WHO Bleeding Scale according to verbal 
response. This assessment will be completed after the TSQM at the Baseline, Day 
30, and Day 90 Visits. The Baseline WHO Bleeding Scale Assessment evaluates the 
severity of any bruising or bleeding the subject experienced within the 7 days prior 
to the Baseline Visit on Day 1. WHO Bleeding Scale assessed on Day 15, Day 30, 
Day 60, and Day 90 evaluates the severity of any bruising or bleeding the subject 
experienced since the previous visit. 
The baseline assessment will be summarized in a table of baseline characteristics 
according to Section 6.1. A separate table will summarize WHO Bleeding Scale 
assessed on Day 15, Day 30, Day 60, and Day 90 which evaluates the highest 
severity of any bruising or bleeding the subject experienced since the previous visit 
(exclusive) including unscheduled visits up to the planned study visit. Bleeding for 
overall study period will also be presented which will include all schedule and 
unscheduled visits bleeding assessments and subjects are counted at the highest 
Dova - AVA-ITP-401                                                                   Version: 2.0
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grade for the overall study period. A listing will be provided with details of the WHO 
Bleeding Scale assessment at all visits. The summary will be presented by prior 
TPO-RA (romiplostim and eltrombopag) and overall. 
9.3.3  COVID-19 Impact 
The eCRF includes a page for collecting the extent to which study visits may have 
been affected by the COVID-19 global pandemic. This page collects a Yes/No 
answer of whether there was any impact. If the answer was yes, additional data as 
to the type of impact (Visit not done, Visit delay, Study drug not taken as planned, 
Study discontinuation, Lab sample collection, Study procedures, Other), visit 
impacted, and description of impact were collected.  
The details of the COVID-19 Impact will be presented in a listing.  
10. References 
International Conference on Harmonization (ICH) guideline “Statistical principles 
for Clinical trials”: E9, 1998. 
IQVIA User Manual for the Treatment Satisfaction Questionnaire for Medication 
(TSQM): Version 1.6, 04 March 2020. 
11.  List of Tables, Listings, and Figures 
A separate document will detail the list of the planned tables, listings, and figures 
for the final statistical analysis. The document will also include the mock tables, 
listings, and figures. 
Dova - AVA-ITP-401                                                                   Version: 2.0
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12. APPENDIX A: Schedule of Events  
 
Screeninga 
Baselinea 
Day 15 
Day 30 
Day 60 
Standard of 
Care Clinic 
Visitsb 
Day 90/End 
of Study/ 
Early 
Termination 
Visit  
1 
2 
3 
4 
5 
- 
6 
Day (Window)  
-28 to -1 
1 
15 (±2 Days) 
30 (±2 Days) 
60 (±2 Days) 
- 
90 (±2 Days) 
Informed Consent  
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review  
X 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
ITP Historyc  
X 
Xd 
 
 
 
 
 
Record Subject Response to Questions Regarding 
Administration of Prior TPO-RA  
X 
 
 
 
 
 
 
Administer TSQM  
 
X 
 
X 
 
 
X 
WHO Bleeding Scalee  
 
X 
X 
X 
X 
X 
X 
Assess Platelet Transfusions  
 
 
X 
X 
X 
X 
X 
Assess Rescue Procedures  
 
 
X 
X 
X 
X 
X 
Platelet Countf  
 
Xg 
X 
X 
X 
X 
X 
Dispense Avatrombopagh 
 
X 
X 
X 
X 
X 
 
Dispense Dosing Diary 
 
X 
 
 
 
 
 
Record Prescribed Avatrombopag Dose Regimen in eCRF 
 
X 
X 
X 
X 
X 
X 
Review Subject Dosing Diary 
 
Xi 
X 
X 
X 
 
X 
Retrieve Unused Avatrombopag, if Applicable 
 
 
X 
X 
X 
 
X 
Retrieve Dosing Diary 
 
 
 
 
 
 
X 
Record Adverse Eventsj 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant Medicationsk 
X 
X 
X 
X 
X 
X 
X 
 
TPO-RA = thrombopoietin receptor agonist; TSQM = Treatment Satisfaction Questionnaire for Medication; WHO = World Health Organization  
aThe Screening Visit may be combined with the Baseline Visit if the subject’s platelet count can be obtained prior to dosing with avatrombopag.  
bAdditional study visits are not required, per the protocol, however, if a subject has a scheduled clinic visit according to their standard of care, the information included in this 
column, if available, should be recorded in the electronic case report form (eCRF). In addition, avatrombopag should be dispensed and the Dosing Diary reviewed, as needed, 
during these visits.  
Dova - AVA-ITP-401                                                                   Version: 2.0
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cRecord ITP (immune thrombocytopenia) history that is available in the subject’s medical record, including date of ITP diagnosis, number of platelet transfusions in the previous 1 
year (including date of last transfusion), number of previous hospitalizations for ITP, number of previous significant bleeding events (e.g., blood loss ≥1/2 cup), dose and duration 
of previous treatments with eltrombopag and romiplostim (including qualifying eltrombopag/romiplostim treatment over the 90 days prior to study entry), other previous 
treatments for ITP (including duration), history of splenectomy (yes/no), history of thromboembolic events and reason for switching to avatrombopag.  
dUpdate the eCRF with any ITP history changes since Screening.  
eThe following question should be asked of the subject during the Baseline Visit: “Have you experienced any bruising or bleeding within the last 7 days?” while the following 
question should be asked of the subject during each subsequent protocol specified visit: “Have you experienced any bruising or bleeding since I saw you last?”. The WHO 
Bleeding Scale should be performed after the TSQM at the Baseline Visit, Visit Days 15, 30, 60, and at the Day 90 Visit and prior to any other visit procedures.  
fOnly local lab results will be used.  
gAny platelet count measured within the previous 7 days will be accepted.  
 
hDispense avatrombopag, based on the subject’s current dosage regimen, per the DOPTELET Unites States Prescribing Information (USPI)  
iDuring the Baseline Visit/Visit 2, the study team should review with the subject instructions for completion of the Dosing Diary.  
jAdverse events, including AESIs, will be collected from the time of informed consent.  
kIncluding concomitant ITP medications.    
Dova - AVA-ITP-401                                                                   Version: 2.0
Type of Approval: Approved in Vault, Approval Date: 31 Jan 2024