Study on Avatrombopag for the Promotion of Platelet Engraftment After Allogeneic Hematopoietic Stem Cell Transplantation
Phase: PHASE2
Conditions: Platelet Disorder
Sponsor: The First Affiliated Hospital of Soochow University

 
 
 
Study on avatrombopag for the promotion of platelet 
engraftment after allo-HSCT  
(Scheme No. SKX-2009) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Investigator: Depei Wu 
Sponsor: The First Affiliated Hospital of Soochow University 
Version 1.0 
Release Date: 20st February, 2021 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this article is confidential and owned by the 
sponsor. The purpose of this plan to provide relevant information is to conduct 

a clinical observation for the sponsor. The investigator can disclose the 
contents of the plan to trial participants, institutional review board, 
independent ethics committee or pharmacy administration committee for the 
same purpose on the basis of meeting the following conditions. The content of 
the protocol cannot be used in other clinical observations, nor can the content 
be disclosed to any other individual or group without the written permission of 
the sponsor. Although this condition does not apply to the disclosure required 
by government regulations, the investigator must promptly notify the sponsor. 
In addition, any information added to the protocol is also confidential and 
owned by the sponsor. The confidentiality principle is the same as the content 
of the plan. 
 
The protocol should keep confidential and be used only for matters authorized 
by the sponsor, and shall not be disclosed to any other person without prior 
written permission. If you are in possession of the protocol without prior 
authorization, please contact the study sponsor in a timely manner and return 
the protocol and a copy of it to the sponsor. 
 
 
 
 
 
 
 
 
 
PROTOCOL SYNOPSIS 
Title 
Study on avatrombopag for the promotion of platelet 
engraftment after allo-HSCT 

Version 
1.0 
Population 
Patients with thrombocytopenia after allogenic 
hematopoietic stem cell transplantation (Allo-HSCT) 
Objective 
To evaluate the efficacy and safety of avatrombopag in the 
treatment of thrombocytopenia after Allo-HSCT, and provide 
evidence-based instruction of avatrombopag in promoting 
hematopoietic function reconstruction and reducing PLT 
transfusion for patients with delayed PLT reconstruction 
after Allo-HSCT in clinical practice 
Design 
Single, prospective, randomized controlled trial 
Subject 
Number 
78 participants 
Eligibility 
Criteria 
Inclusion criteria 
Each participant must meet all of the following criteria: 
1. Male or female, aged between 18-60 years; 
2. PLT has not been reconstructed 14 days after Allo-
HSCT (PLT reconstruction was defined as the status of 
peripheral PLT count > 20*109/L for consecutive 7 days 
without the need for PLT transfusion); 
3. Expected survival time > 3 months; 
4. ECOG performance status 0-2; 
5. Agree to receive the treatment of avatrombopag after 
Allo-HSCT and must sign the informed consent form. 
Exclusion criteria 
Participant meets any of the following criteria will be 
excluded from this study: 
1. Pregnant or lactating; 
2. With severe and uncontrollable infection; 
3. With graft-versus-host disease (GVHD) with steroid 

resistance; 
4. With thrombotic microangiopathy; 
5. With active thromboembolism requiring anticoagulation 
6. With detected disease recurrence due to chimerism by 
flow cytometry; 
7. With chronic active hepatitis B and C virus infection; 
8. With secondary or multiple transplantation, or multiple 
organ transplantation; 
9. With severe heart disease, lung disease, diabetes and 
metabolic diseases; 
10. HIV positive; 
11. With a history of PLT dysfunction or bleeding disorders 
12. With the active hepatic venous occlusion disease, or a 
history of clinically significant hepatic venous occlusion 
disease (The disease was defined as the abnormal 
condition of painful hepatomegaly after transplantation 
with bilirubin ≥ 6.0 mg/dL); 
13. With progressive solid tumor; 
14. With severe bleeding requiring transfusion of more than 
2 units of red blood cells, or sudden drop of blood cell 
volume ≥10% within 7 days prior to screening; 
15. With any other clinical trial of investigational product or 
device within 30 days prior to the baseline visit, except 
for observational study; 
16. With treatment of thrombopoietin receptor agonist (TPO-
RA) one month before enrollment; 
17. Deemed unsuitable for enrollment by the investigator. 
Withdrawal criteria 
1. PLT remains less than 20*109/L after two weeks’ 
treatment of avatrombopag in a maximum dose of 60 

mg/d (Solution: receive other treatment after withdrawal 
from the study); 
2. The participant or his legal guardian requests a 
withdrawal ; 
3. c poor compliance(medicine taken less than 80% of the 
prescribed amount or more than 120% of the prescribed 
amount); 
4. With requirement of a medicine that is prohibited in the 
study; 
5. With adverse events that discontinues the study; 
6. With some unexplained serious complications; 
7. Be pregnant during treatment; 
8. Deemed unsuitable for further study by the investigator. 
Trial Termination 
1. Sponsor decides to stop the trial for safety reasons; 
2. Independent ethics committee decides to stop the trial; 
3. Principal investigator decides to stop the trial. 
Investigatio
nal Product 
 
Name: avatrombopag; 
 
Dosage form: tablet; 
 
Specification: 20 mg/tablet. 
Treatment 
Design 
 
The whole study is divided into two stages, including 4-
weeks’ core study and 4-weeks’ extended study; 
 
During the core study, participants are randomly 
assigned into the avatrombopag group and the rhTPO 
treatment group(standard group) with 1:1 ratio. The 
initial dose of avatrombopag is 20 mg/d. If the patient’s 
PLT count remains less than 20*109/L after one week, 
the maximum dose was increased to 40 mg/d. 
Avatrombopag will be taken orally with food. The rhTPO 

will be subcutaneously injected with dosage of 300 
U/kg/d; 
 
After the end of the core study, participants in the 
avatrombopag group who does not meet the withdrawal 
indication can be enrolled in the extended study and 
continue the avatrombopag treatment with a maximum 
dose of 60 mg/d. Participants who does not respond to 
treatment in the rhTPO group (PLT< 20*109/L ) can also 
be enrolled in the extended study to receive 
avatrombopag treatment, by titrating avatrombopag in 
the dose of 20-60 mg/d according to the participants’ 
condition; 
 
Patients who achieved PLT reconstruction during the 
core study and the extended study period are followed 
up to 4 weeks after investigational product withdrawal, 
and PLT count is measured for one time during the 
follow up; 
 
Adjustment Indication: When PLT ≥50*109/L excluding 
the factor of blood transfusion, the dosage of 
avatrombopag and rhTPO will be eventually decreased 
and stopped according to clinicians. 
 
Outcome 
Measure 
Primary outcome measures 
 
Percentage of participants whose PLT reaches ≥ 

20*109/L without the need for PLT transfusion for 
consecutive 7 days during core study 
Secondary outcome measures 
 
Percentage of participants whose PLT reaches ≥ 
20*109/L without the need for PLT transfusion for 
consecutive 7 days during extended study; 
 
Percentage of participants without PLT response in the 
standard group but with PLT reconstruction after 
receiving avatrombopag; 
 
Percentage of participants with PLT≥ 50*109/L without 
the need of PLT transfusion for consecutive 7 days 
during the core and extended study; 
 
The time to achieve PLT ≥ 20*109/L without the need of 
PLT transfusion for consecutive 7 days in both group; 
 
Proportion of participants achieving platelet 
reconstitution after 4 weeks of drug withdrawal; 
 
Volume of PLT transfusion; 
 
Hematopoietic reconstruction condition (absolute 
neutrophils, hemoglobin) 
 
PLT reconstruction is defined as the status of PLT ≥ 
20*109/L without the need of PLT transfusion for 
consecutive 7 days. 
pSafety 
Measure 
1. Liver and renal functions; 
2. Occurrence and severity of transplantation-related 
complications; 
3. Bleeding risk (WHO bleeding assessment scale); 
4. Adverse events. 
Study 
Screening stage (Day 10~14 after Allo-HSCT) 

process 
1. Informed consent; 
2. Subject’s demographic information and basic 
information; 
3. Medical history, current treatment, concomitant 
medication; 
4. Vital signs, physical examination; 
5. Transplantation mode and preprocessing scheme; 
6. Blood test: blood routine, blood biochemical (including 
liver and renal functions), virus infection; 
7. Pregnancy tests (women of childbearing age); 
8. Eligibility criteria review. 
Visit 1(Day 15 after Allo-HSCT, Initial treatment) 
1. Blood test: blood routine, blood biochemical (including 
liver and renal functions); 
2. Vital signs, physical examination; 
3. Concomitant medication, including PLT transfusion; 
4. Adverse events. 
Visit 2-9 (one visit per 1~2 weeks. Visit 2, day 21±2; visit 
3, day 28±2; visit 4, day 35±2; visit 5, day 42±2; visit 6, 
day 49±2; visit 7, day 56±2; visit 8, day 62±2; visit 9, day 
70±2 after Allo-HSCT) 
1. Blood test: blood routine, blood biochemical (including 
liver and renal functions); 
2. Vital signs, physical examination; 
3. Concomitant medication, including PLT transfusion; 
4. Adverse events; 
(Participants who achieved PLT reconstruction during 
the core and extended study period directly enter the 
follow up period; 
Participants who do not respond to the standard 

treatment can enter the extended study after visit 3 to 
receive avatrombopag treatment) 
Visit 10 (day 28±5 after achieved PLT reconstruction)  
1. Vital signs, physical examination; 
2. Blood test: blood routine, blood biochemical (including 
liver and renal functions). 
 
Long-term follow up is recommended.  
Adverse events are closely observed and 
concomitant medication is recorded in detail during 
the study. 
Concomitant 
Treatment 
1. PLT transfusion is allowed according to the bleeding 
situation: PLT transfusion is given to participant when 
PLT account < 20*109/L, or between 21-60 *109/L with 
active bleeding; 
2. G-CSF treatment (subcutaneous injection of G-CSF at 5 
μg/kg/d from the first day after transplantation until the 
neutrophils count (ANC) recovered to ≥ 1*109/L); 
3. Cyclosporine A, short courses of mycophenolate mofetil 
and methotrexate are allowed to use for the prevention 
of GVHD; 
4. For medications that have been used before the trial, try 
to maintain the same dose during the trial; 
5. Other TPO-RA (such as Eltrombopag and Romiplostim) 
should be prohibited during the study period; 
6. Participants are allowed to take concomitant 
medications that are not specified as prohibited during 
the study period; Medications used one month prior to 
screening will be recorded on the case report form. All 

prescription medicines, herbal medicines, nutritional 
supplements (including vitamins), and over-the-counter 
medicines should be recorded, as well as any changes 
in medication taken, including the dose. CYP2C9 or 
CYP3A4/5 medium or strong inducers may affect the 
exposure level of avatrombopag in vivo, and medication 
regimen should be comprehensively assessed by the 
investigator; 
7. Observation of adverse events and concomitant 
medication assessment are conducted for all 
participants at each visit from the signing of informed 
consent to the end of the study; 
8. All concomitant medications should be recorded and 
described in the corresponding section of the case 
report form (CRF). 
Statistical 
Analysis 
 
The sponsor will utilize appropriately qualified 
individuals to supervise the conduct of the trial to make 
sure the data collection, entry and management are in 
accordance with good clinical practice (GCP); 
 
Corresponding database will be established and source 
data will be input independently; 
 
Data administrator uses Epidata software to compile 
data entry program and carry out following process. 
Two data administrators will independently enter and 
proofread the data in double copies to ensure the 
accuracy. 
Sample size estimation 
 
78 participants 
Based on the known literature, 35% of patients in the 
control group and 60% of patient in the trial group were 

estimated to achieve the primary endpoint. Under the 
condition of the number ratio of control to trial group 1:1, 
α=0.05 (bilateral) and 1-β=0.9, the number of 
participants in the control group and the test group was 
79 and 79 respectively, calculated by the pros and cons 
test method of the clinical controlled study with PASS 
software. Further taking into account a 20% shedding 
rate per group, 95 cases per group were actually 
needed, for a total of 190 cases 
Statistical analysis data set 
 
Full analysis set (FAS): All subjects who were enrolled 
and had at least one dose of investigation product along 
with efficacy evaluation were included in FAS as per the 
intention-to-treat (ITT) principles. FAS contributes to the 
main population for efficacy evaluation in this study. 
 
Per-protocol set (PPS): PPS includes all subjects who 
have fulfilled the protocol-required treatment or have not 
seriously violated the protocol. The exact definition of 
serious violation will be finalized during data review, 
which includes but not limited to the following 
conditions: fails to meet the main inclusion criteria, 
experiences the treatment that significantly interferes 
with efficacy evaluation after enrollment, poor 
compliance, poor follow-up record that significantly 
beyond the time window. PPS contributes to the 
secondary population for efficacy evaluation in this 
study. However, if the analysis results of PPS are 
inconsistent with the FAS, detailed analysis of the 
inconsistent results is required. 

 
Safety set (SS): SS is defined as the data that 
collected from subjects receiving at least one dose of 
investigation product. 
Statistical analysis method 
 
PLT and other mean variation trends were processed 
by repeated measurement data analysis of variance; 
Kaplan-Meier survival analysis was used to estimate the 
recovery of PLT count, cumulative predicted survival 
rate, cumulative recurrence rate of malignant 
hematologic disease, cumulative mortality associated 
with transplantation, and cumulative incidence of 
GVHD, and log-rank test was performed. Independent 
sample nonparametric test was used to analyze the 
accumulative demand of PLT suspension. The 
statistical process and graph were all run on SPSS 13.0 
software. All tests were bilateral, and P≤0.05 was 
considered to be significant. The PLT recovery time, 
granulocyte implantation time and PLT infusion number 
were compared by one-way analysis of variance. OS 
and DFS are estimated by Kaplan-Meier method. Risk 
factor analysis: variables: age, sex, HLA match, CD34+ 
cell number, incidence of GVHD within 100 days after 
transplantation, CMV infection rate. Multivariate Cox 
regression analysis was performed on the factors with 
significant differences (P<0.05) by one-way analysis of 
variance. 
Safety analysis 
 
Safety and tolerance evaluation consist of adverse 
events and changes in laboratory values. Adverse 

events were statistically described and listed in terms of 
occurrence, endurance, severity, relationship to the 
investigation product and outcome. Abnormalities in 
laboratory values were summarized in toxicity grade as 
per CTC AE 5.0. At the same time, the statistical 
description of the changes of the assessment values 
was carried out. 
Study 
Duration 
1.5 years 
 
 
Subject No. : 
Version: 1.0 
Final version: May 28, 2021 
Informed consent for biomedical research 
Study on avatrombopag for the promotion of platelet engraftment after allo-
HSCT. 
Dear Madam/Sir, 
We are considering inviting you to participate in a "study on 
avatrombopag for the promotion of platelet engraftment after allo-HSCT". It is 
important that you understand the details of the study before agreeing to 
participate. Please read this document carefully and ask questions. This study 
has been approved by the ethics committee of the medical institution. It is up 
to you to participate in this study. 
1. Research purpose 
To observe the efficacy and safety of Avatripolpa in the treatment of 
thrombocytopenia after allogeneic hematopoietic stem cell transplantation, 
and to provide evidence-based evidence for promoting hematopoietic 
reconstruction and reducing platelet transfusion after avatripolpa in patients 

with delayed platelet recovery in clinical practice. 
2. background 
Persistent thrombocytopenia is one of the common complications after 
allogeneic hematopoietic stem cell transplantation, including primary 
thrombocytopenia and secondary thrombocytopenia. Persistent 
thrombocytopenia after allogeneic hematopoietic stem cell transplantation 
often leads to fatal bleeding, resulting in transplant-related mortality, and 
seriously affecting the quality of life of patients. 
Now after allogeneic hematopoietic stem cell transplantation, no standard 
for the treatment of persistent thrombocytopenia, commonly used treatment 
with glucocorticoid, human recombinant platelet hormone, human 
recombinant interleukin - 11, intravenous immunoglobulin of choose and 
employ persons, but the above treatment response rate between patients with 
heterogeneity, and once the treatment is invalid, patients with poor prognosis. 
In order to prevent bleeding, most patients need platelet infusion, but platelet 
infusion may also lead to many adverse reactions, such as acute lung injury, 
heart failure, viral infection, etc., and invalid infusion may also occur in some 
patients. Therefore, platelet infusion cannot be used as a means of long-term 
prevention of bleeding. For patients with thrombocytopenia after allogeneic 
hematopoietic stem cell transplantation, it is urgent to find new therapeutic 
methods to improve the efficacy. 
Avatrombopag is a novel oral thrombopoietin receptor agonist that 
mimics the biological effects of thrombopoietin in vitro and in 
vivo.Avatrombopag stimulates megakaryocytes through binding and activation 
of thrombogenietin receptors, thereby promoting platelet production. 
Avatrombopag has been approved in the United States, the European 
Union and China for the treatment of thrombocytopenia associated with 
chronic liver disease in adults undergoing elective diagnostic operations or 
surgery, and in the United States in June 2019 and the European Union in 
January 2021 for the treatment of immune thrombocytopenia (ITP) with 

excellent efficacy. 
3. Approximate number of subjects and expected duration of study 
participation 
Eight patients with thrombocytopenia following allogeneic hematopoietic 
stem cell transplantation are planned to be enrolled in the study.The total 
duration of the study is estimated to be 3 months, and your participation is 
expected to be 1 month. 
4. The research process 
After you sign the informed consent, you will be screened and treated 
with Avatrombopag if you are eligible for inclusion. The duration of the study 
was 4 weeks. The initial dose of avatrombopag was 20 mg/d, and if your 
platelet count was still below 20×109/L after 1 week, the maximum dose was 
40 mg/d until the platelet count reached 50×109 /L and the drug was gradually 
discontinued. 
You will be followed up once a week for blood sampling during the study 
period.The specific follow-up time can follow the clinician's arrangement. 
5. Possible risks and discomfort of participating in the study 
Reference adverse reactions of Avatrombopaglpa in a global multicenter 
Phase iii clinical trial in the treatment of immune thrombocytopenia: 
During the 6-month core phase, three patients in the Avatrombopag group 
developed thrombosis, two of whom had multiple risk factors for thrombotic 
disease, and one of whom was considered by the investigator to be unrelated 
to treatment.One patient had abnormal liver function test, including fatty liver, 
hepatitis C, obesity, and gallstones. He had abnormal liver function in the past 
and was drinking alcohol at the time of abnormal liver function. The 
researcher believed that this event had nothing to do with treatment drugs. 
Other common adverse reactions are headache, bruising, upper respiratory 
tract infection, arthralgia, epistaxis, fatigue, bleeding gums, stasis, 
thrombocytopenia, pharyngitis, hypertension, and nasopharyngitis.After 
adjustment for exposure, the incidence of various adverse events in the 

avatrombopag group was comparable to that in the placebo group. 
6. Possible benefits 
For patients undergoing hematopoietic stem cell transplantation, 
avatrombopag offers a novel therapeutic option with the potential to shorten 
platelet transplantation in these patients. 
7. Expenses and Compensation 
You may use avatrombopag free of charge during the study period.In 
addition, you will receive a free insurance policy to cover the treatment costs 
and corresponding financial compensation for subjects who experience 
serious adverse reactions related to the study. 
Clinical diagnosis and treatment related examination and treatment and other 
expenses shall be borne by you. 
8. Confidentiality and privacy authorization 
The investigator is responsible for handling your study data in 
accordance with applicable data protection regulations.However, the ethics 
committee and higher administrative departments can inspect the data.The 
results may all be published in medical journals/conferences, but your 
personal information will not be made public. 
By signing this informed consent form, you consent to the collection, use and 
sharing of your health information data by the research physician and the staff 
of the research center.Your authorization to use your health information 
remains valid until the study is completed and the results are available.But 
you can withdraw the informed consent at any time through the study of the 
doctor in charge. 
9. Voluntary participation/complete or partial withdrawal from the study 
Participation in this study is entirely of your own free will.You can choose 
not to participate in this study, or you can withdraw at any time, and your 
medical treatment and rights will not be affected, nor will you be discriminated 
against by medical staff. 
10. Questions and Information 

All study group members will answer all your questions before you sign 
this consent form.If you still have questions, suggestions or comments after 
signing this consent form, you can also communicate with the researcher.You 
can know the information and progress of this study at any time. 
Researcher and Contact Number: 
11. Informed consent 
I have been orally informed about this study by the doctor in charge of the 
study or relevant researchers, and I have also read the above written 
information. 
I was given ample opportunity to discuss and ask questions about the 
study.I agree to participate in this study with the understanding that my 
participation in this study is entirely voluntary. I understand that I can withdraw 
from the study at any time and that my withdrawal will not affect my future 
medical treatment. By signing this informed consent, I agree that my personal 
information data, including my medical information data, will be used in the 
manner described above. I know I'm gonna get a copy of this informed 
consent. 
Signed by the patient or his/her legal representative:      year  month  day 
 
Researchers state: 
I will strictly perform the obligations stipulated in Article 22 of the Law of 
the People's Republic of China on Professional Doctors; Abide by laws, 
regulations and technical operation specifications;Set up professional 
dedication, abide by professional ethics, due diligence for the patient service; 
Care for, cherish, respect patients, protect patients' privacy;Strive to study 
business, update knowledge, improve professional and technical 
level;Disseminate knowledge of health care and educate patients about 
health. 
Investigator signed:                              year   month    day