Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
Phase: PHASE4
Conditions: Thrombocytopenia
Sponsor: The Third People's Hospital of Chengdu

 
 
Efficacy and safety of hytrombopag ethanolamine tablets 
in the treatment of thrombocytopenia in patients 
scheduled for elective surgery 
 
 
 
 
 
 
Drug Name: Hytrombopag Ethanolamine Tablets 
Principal Investigator: Tan Jing 
Leading site: Chengdu City Third People's Hospital 
Version Number: 3.1 
Version Date: 30 December 2023 
 
 
 
 
 
 
 
 
 
 
 

protocol summary 
study title 
Efficacy and safety of hytrombopag ethanolamine tablets in the treatment of 
thrombocytopenia in patients scheduled for elective surgery 
protocol 
version No. 
3.1 
protocol 
version date 
December 30, 2023 
Type 
of 
clinical study 
Non-registration clinical trials 
Clinical Study 
Registry 
Investigator-Initiated Trial (IIT) 
Clinical 
Research Unit 
Chengdu City Third People's Hospital 
study drug 
Hytrombopag Ethanolamine Tablets 
subject 
population 
Patients with immune thrombocytopenia scheduled for elective surgery 
research 
purposes 
To observe the efficacy and safety of hytrombopag ethanolamine tablets in the 
treatment of thrombocytopenia in patients scheduled for elective surgery 
study design 
This is an investigator-initiated, single-arm, prospective clinical study to 
evaluate the efficacy and safety of hytrombopag in the treatment of 
thrombocytopenia occurring prior to scheduled surgery.9After signing the 
informed consent form, the patients will enter the screening period (up to 7 
days) and receive oral treatment with hytrombopag after screening. The 
specific dosage regimen is: 7.5 mg, once daily, orally before bed on an empty 
stomach, lasting for up to 14 days,PLT≥100×109/L. During oral 

administration of hytrombopag, when PLT≥200×109/L, the administration 
was suspended, and the hemogram was monitored weekly until PLT<100×
109/L. During the treatment period, blood routine was monitored once every 
7 days,PLT≤30×109/L or ≥300×109/L. Patients will have an end-of-
treatment visit within 7 days of treatment discontinuation, followed by a 30-
day safety follow-up period. 
study 
endpoints 
primary study endpoint： 
Proportion of patients achieving perioperative platelet count goals (≥80×10 
μ g/ L for major surgery and ≥50×10 μ g/ L for minor surgery) without 
rescue therapy 
Secondary endpoints: 
1. 
Median time to platelet count target; 
2. 
Subject platelet count ≥50×109/L maximum duration; 
3. 
Subject platelet count ≥80×109/L maximum duration; 
4. 
Proportion of patients with surgical delay due to thrombocytopenia; 
5. 
Proportion of patients undergoing surgery on schedule; 
6. 
Incidence and severity of bleeding in patients; 
7. 
Proportion of patients receiving emergency treatment; 
8. Safety: Adverse events (AEs): include type, incidence, severity, duration, 
and relationship to study drug. 
enrollment 
criteria 
(All must comply) 
1. Subjects ≥18 years of age, regardless of gender; definite diagnosis of 
immune thrombocytopenia. 
2. Platelet ≤75×10 prior to scheduled elective surgery9/L, Surgery is 
defined by the treating surgeon and hematologist as major or minor surgery 
based on the duration and complexity of the procedure and the patient's risk 
of bleeding. 
3. Voluntary participation in clinical research and signing of informed 
consent form. 
exclusion 
1. History of allergy to TPO-RA drugs; 

criteria 
(Excluded if one of 
them is met) 
2. Severe bleeding symptoms, such as upper gastrointestinal bleeding, 
bleeding of important organs, intracranial hemorrhage, etc.; 
3. thrombotic diseases such as pulmonary embolism, arterial thrombosis 
and disseminated intravascular coagulation (DIC); 
4. Anti-human immunodeficiency virus antibody or anti-Treponema 
pallidum specific antibody positive; 
5. Congestive heart failure New York Heart Association (NYHA) class 3 or 
4; 
6. History of angina pectoris, myocardial infarction or cerebral infarction 
within 6 months prior to screening; 
7. Active infections that are difficult to control; 
8. Pregnant or lactating women; 
9. Other circumstances judged by the investigator to be unsuitable for 
inclusion in the study 
Study 
Early 
Termination 
Criteria 
1. Death; 
2. Unanticipated and unacceptable adverse drug reactions occur; 
3. Withdrawal from the study requested by the subject or his/her legal 
representative; 
4. Medical or ethical reasons affect the continuation of the study; 
5. The circumstances in which withdrawal from the study is deemed 
necessary by the investigator in the best interests of the subject; 
6. Subject lost to follow-up; 
7. Serious violations of the protocol (including serious violations of study 
enrollment conditions); 
8. Untolerable toxicity occurred during the study and could not be recovered 
after dose adjustment; 
9. Other circumstances necessitating withdrawal from the study in the 
opinion of the investigator. 
Sample 
Size 
Estimation 
and 
Data 
The study was designed as a single-arm exploratory design. Based on previous 
relevant data reports, the estimated proportion of patients meeting platelet 
targets was 65%. Using NCSS PASS 15 (LLC. Kaysville, Utah, USA, 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Background 
1.1 Significance and Necessity of the Study 
Perioperative bleeding is a thorny problem in surgical operation, and it is also an 
important reason for rapid recovery after operation.[1]Platelet is a blood cell directly 
involved in clot formation and inflammation regulation, its main function is to 
participate in the body's coagulation and hemostasis. Thrombocytopenia leads to a 
greatly increased risk of bleeding and transfusion. Thrombocytopenia is very common 
in perioperative period,Li [2]A retrospective study conducted by et al showed that 
patients with cirrhosis and severe thrombocytopenia (PLT≤50×10 μ g/L) had a 
Analysis and 
Statistical 
Methods 
ncss.com/software/pass) software, the two-sided 95% confidence interval 
(Clopper-Pearson method) for enrollment of approximately 50 subjects was 
(50.2%, 77.9%), and the confidence interval width was 27.7%. 

higher incidence of major bleeding events after invasive procedures (4.9% VS 1.6%, P 
= 0.008). Perioperative thrombocytopenia may increase bleeding risk, prolong hospital 
stay, lead to organ damage, increase medical costs, and in severe cases, lead to death.[3, 
4]The most important perioperative issue in patients with thrombocytopenia is the risk 
of bleeding. 
Several retrospective studies examined the incidence and prognostic impact of 
preoperative thrombocytopenia in different surgical settings, analyzing prospectively 
collected data from the American College of Surgeons National Surgical Quality 
Improvement Program (NSQIP) database. The largest and most comprehensive of these 
studies was an analysis of 3884400 adult patients who underwent noncardiac surgery 
between 2006 and 2016.[5]The incidence of asymptomatic thrombocytopenia was 8.1% 
in patients undergoing elective surgery. After propensity matching, perioperative 
transfusions in all patients with thrombocytopenia However, unlike a similar analysis 
that did not perform propensity matching, there was no increase in the incidence of 
other complications. Odds ratio and 95% CI for receiving red blood cell transfusions 
for mild thrombocytopenia (100-149 ×109/L) patients were 1.2, 1.1-1.2, for moderate 
thrombocytopenia (75-99 × 109/L) patients were 1.4, 1.3-1.5, for severe 
thrombocytopenia (50-74 × 109/L) patients were 1.5, 1.2 -1.7 and severe 
thrombocytopenia (<50 ×109Odds ratios and 95% CIs for mortality ranged from 1.2, 
1.1 - 1.3 for mild thrombocytopenia, 1.6, 1.3 - 1.8 for moderate thrombocytopenia, 1.6, 
1.2 - 2.1 for severe thrombocytopenia, and 1.9, 1.4 - 2.5 for severe thrombocytopenia. 
Thrombocytopenia can be caused by many factors during perioperative period, 
including patient's disease factors, operation type, cardiopulmonary bypass device, 
drugs, etc.9/L is associated with an increased risk of bleeding, and current clinical 
practice recommends using different cut-off values prior to invasive surgery. The 
minimum platelet count required for different surgical procedures varies. Therefore, it 
is recommended that platelet counts>50 × 10 be used prior to major general 
surgery.9/L, platelet count>100×10 in neurosurgery and posterior eye interventions9/L. 
At present, there is no official standardized process for clinical management of 
perioperative thrombocytopenia. In March 2023, Guangdong Province Pharmaceutical 

Association 
issued the Consensus 
of Medical 
Experts on Perioperative 
Thrombocytopenia Management.[6]The principle of treatment is to remove or control 
the predisposing factors and primary diseases of thrombocytopenia as soon as possible, 
and give symptomatic treatment if necessary according to the perioperative platelet 
count requirements. Patients with thrombocytopenia are recommended to control their 
platelets above the reference threshold of the operation or operation performed to 
reduce the risk of bleeding during the operation and ensure the smooth operation. 
The optimal drug regimen for increasing platelet count in perioperative pat
ients preparing for invasive procedures should take into account the patient's u
nderlying disease. The patient's underlying disease is an immune disease such a
s ITP, and corticosteroids or immunoglobulin may be given first.[7]Recombinant 
human thrombopoietin (rh-TPO), TPO receptor agonist (TPO-RA), etc. can be 
used to treat thrombocytopenia associated with liver disease.[8]At present, there 
are not many drug-related studies on perioperative platelet count increase, and 
TPO-RA has more evidence-based evidence, among which avatrombopag is also
 the only one approved by China National Drug Administration. The National 
Medical Products Administration (NMPA) approves platelet-raising drugs for pat
ients with thrombocytopenia associated with chronic liver disease who are sche
duled for diagnostic procedures or surgery. Immunoglobulins can be used when 
rapid platelet elevation is needed, such as emergency surgery, especially in pati
ents before pregnancy or delivery. 
1.2 research status at home and abroad 
In Lancet Hematology, Donald et al.[9]Two methods, intravenous immunoglobulin 
and eltrombopag, were compared to achieve perioperative platelet count goals By 
intention-to-treat analysis, 30 of 38 patients (79%) treated with eltrombopag and 22 of 
36 patients (61%) treated with intravenous immunoglobulin met perioperative platelet 
targets (absolute risk difference 17.8%, 95% CI lower bound 0.4%; noninferiority 
=0.005). 
Hani et al.[10]A single-center, retrospective study of perioperative thrombopoietin 
receptor agonist romistine in patients with thrombocytopenia was conducted. Patient 

characteristics, patient use, procedure, and safety outcomes were collected and 
analyzed (bleeding, thrombosis, transfusion). 47 patients underwent 51 surgical 
procedures Causes of thrombocytopenia include immune thrombocytopenia, chronic 
liver disease, hematologic malignancies, drug-related thrombocytopenia, and 
hereditary thrombocytopenia. Median (range) platelet count improved. From 47 ×10 
μ g/L(9-120×10 μ g/L) to 164×10 μ g/L(28-603×10 μ g/L) at the time of 
surgery (P<0.0001). Twice-weekly doses of 3µg/kg increased platelet counts to>100×
10 μ g/L within 14 days in 79% of patients. In 96% of cases, surgery was performed 
as scheduled without delay or cancellation. 
Thrombopoietin receptor agonist (TPO-RA) activates tyrosine kinase/signal 
transducer and activator of transcription (JAK/STAT) by acting on the transmembrane 
domain of human TPO receptor, induces megakaryocyte survival, proliferation and 
differentiation, stimulates platelet production, and is not resistant to drug resistance. 
As a novel oral thrombopoietin receptor agonist, hytrombopag has been 
structurally optimized to achieve synergistic and attenuated therapeutic effects, 
especially in terms of safety, and its effect on bilirubin metabolism is superior to 
eltrombopag. In a clinical trial to explore the efficacy and safety of hytrombopag in ITP 
patients, 424 patients were enrolled in a 4:4:1: 1Randomization to treatment with 2.5 
mg or 5mg of Hatrombopag and two dose-matched placebo groups. A 10-week double-
blind treatment phase followed by a 14-week open-label extension phase. The primary 
endpoint was platelet response (PLT≥50×10) at 8 weeks of treatment.9Results After 
8 weeks of treatment, 58.9% and 64.3% of patients in the 2.5 mg and 5mg groups 
achieved platelet response, respectively, which was much higher than that in the 
placebo group (5.9%). 
Based on the above results, we intend to conduct a study on the efficacy and safety 
of hytrombopag in the treatment of patients with preoperative thrombocytopenia. 

1.2 Investigational Product Description 
 
1.2.1 Drug name, molecular structure and pharmaceutical properties 
Generic Name: Hytrombopag Ethanolamine Tablets 
Chemical 
name: 
(Z)-5-(2-hydroxy-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-pyrazole-4 (5H)-ylidene) hydrazino) phenyl) furan-2-
carboxylic acid ethanolamine salt (1:2) 
Chemical formula: 
 
Molecular Formula: C25H22N4O5 ·2C2H7NO 
Molecular weight: 580.64 
Appearance: This product is a film-coated tablet, light brown to brown after removing 
the coating 
Formulation: Tablet 
Strength: 2.5 mg 
Route of Administration: Oral 
1.2.2 Nonclinical pharmacology studies 
In vitro studies showed that hytrombopag ethanolamine significantly promoted the 
proliferation of thrombopoietin (TPO) receptor positive cell line 32D-MPL with EC50 
of 0.4 nM, which was significantly stronger than that of eltrombopag (about 34 times), 
and also significantly promoted the proliferation and differentiation of human umbilical 
cord blood CD34 + cells in vitro with EC50 of 2.3 nM and 4.5 nM, which were 

significantly stronger than that of eltrombopag.(about 38 and 20 times); In the 
experiments of promoting cell cycle, resisting apoptosis and activating TPO receptor-
dependent STAT and MAPK signal transduction pathways, the activity of hytrombopag 
ethanolamine was stronger than that of eltrombopag. By using the hollow fiber 
evaluation model established in nude mice, it was found that hytrombopag 
ethanolamine was effective (the drug effect lasted for 3 days), and it specifically 
promoted the proliferation of 32D-MPL cells in vivo and the activation of downstream 
STAT/MAPK signal transduction pathway. In addition, M1, a metabolite of 
hytrombopag ethanolamine, promoted the proliferation of 32D-MPL cells and the 
activation of STAT/MAPK signal in a dose-dependent manner, but its activity was 
significantly weaker than that of hytrombopag ethanolamine. 
1.2.3 pharmacokinetic study 
The pharmacokinetics of hytrombopag administered orally to healthy subjects and 
patients with chronic ITP for 10 consecutive days at doses ranging from 2.5 mg to 7.5 
mg were evaluated. The results were similar to those of single-dose trials. The plasma 
concentration-time curve showed a double-peak phenomenon, i.e., the first peak 
occurred at 1-2 h after administration, indicating a rapid absorption process, and the 
second peak occurred at 7-10 h after administration.(Zheng et al., 2017). After oral 
administration of 2.5~7.5 mg of hitrombopag in patients with chronic ITP on an empty 
stomach, the plasma concentration increased with the increase of dose. Once daily, the 
plasma concentration reached its peak at 2-5 h after administration, and the plasma 
concentration reached steady state on about the 10th day after continuous 
administration. After absorption, hitrombopag was extensively metabolized, and the 
main excretion route was feces. The elimination half-life of hatrombopag in plasma was 
estimated to be 11.9- 40.1 h. 
1.2.4 pharmacodynamic studies 
After 10 consecutive days of oral administration of 2.5-7.5 mg dose range of 

hetrombopag to healthy subjects, platelet count (PLT) showed a continuous increase 
from the sixth day of continuous administration, and reached the peak at about 12~14 
days (2~4 days after discontinuation). The average maximum increase percentage of 
PLT compared with baseline in 2.5 mg, 5 mg and 7.5 mg groups was 34.1%, 69.9% and 
98.2%, respectively. PLT basically returned to baseline in the 2.5 mg group on D28 
after drug withdrawal, while platelet growth remained 18.8% and 32.2% in the 5 mg 
and 7.5 mg groups. Patients with chronic ITP received oral doses ranging from 2.5 mg 
to 7.5 mg for 14 consecutive days. The results showed that PLT≥50×10 in 12.5%, 58.3% 
and 66.7% of patients in the 2.5 mg, 5 mg and 7.5 mg groups, respectively, on D28 (14 
days after drug withdrawal).9/L. 
1.2.5 clinical efficacy studies 
1.2.5.1 A Phase III Clinical Study of Hytrombopag in Primary Immune 
Thrombocytopenia 
In a multicenter, randomized phase III clinical study of hetrombopag in primary 
immune thrombocytopenia, 424 patients (PLT<30×10 at 48 hours prior to enrollment) 
with at least 6 months of history of primary ITP who had failed or relapsed to at least 
one line of ITP therapy9After 10 weeks of treatment, the patients entered the 14-week 
open-label phase. The treatment group continued to receive the dose adjusted in the 
previous phase, while the placebo group received the positive control drug eltrombopag 
(initial dose 25 mg/d) and maintained PLT(50-150)×109/L. The results showed that after 
8 weeks of treatment, hetrombopag achieved therapeutic response (PLT≥50×109/L) was 
significantly higher than placebo (Hytrombopag 2.5 mg vs. Hytrombopag 5 mg vs. 
placebo: 58.9% vs. 64.3% vs. 5.9%, P <0.0001), and the onset of action was rapid, with 
a median of 21 days for the 2.5 mg group, respectively (95CI: 15-25),5mg group 14 
days (95%CI: 8-14). 24 weeks of treatment with hitrombopag produced a sustained 
platelet response, with 44.8% of subjects having platelet counts ≥50×109/L times 
greater than 75% of total detection times, platelet count ≥50×109The median (minimum, 
maximum) maximum duration of/L was 64(6,168) days and the median total duration 

was 103(6,168) days. 
1.2.5.2 A Phase II Clinical Study of Hytrombopag in Severe Aplastic Anemia with 
Poor Response to IST 
In a multicenter, single-arm, open-label phase II study of severe aplastic anemia 
with poor response to IST, 55 SAA patients who had a poor response to IST and were 
not transplant candidates/unwilling received hetrombopag at a starting dose of 7.5 
mg.9The results showed that 23 patients (41.8%) achieved hematological response at 
week 18 and 24 patients (43.6%) achieved hematological response at week 24. For 
those patients who achieved hematologic response during the study, the median 
remission time was not reached due to the small number of relapses, and the relapse-
free survival rates at 9 and 12 months were 82.2%(95% CI: 62.2%, 92.2%). 
2 Purpose of the study 
To observe the efficacy and safety of hytrombopag ethanolamine tablets in the 
treatment of thrombocytopenia in patients undergoing elective surgery. 
3 Study endpoints 
3.1 primary study endpoint 
Proportion of patients achieving perioperative platelet count goals 
(≥80×10 μ g/ L for major surgery and ≥50×10 μ g/L for minor
 surgery) without rescue therapy 
 
3.2 secondary study endpoints 
1)Median time to platelet count target; 
2)Subject platelet count ≥50×109/L maximum duration; 

3)Subject platelet count ≥80×109/L maximum duration; 
4)Proportion of patients with surgical delay due to thrombocytopenia; 
5)Proportion of patients undergoing surgery on schedule; 
6)Incidence and severity of bleeding in patients; 
7)Proportion of patients receiving emergency treatment; 
8)Safety: Adverse events (AEs): include type, incidence, severity, duration, and 
relationship to study drug. 
4 Experimental design 
This is an investigator-initiated, single-arm, prospective clinical study to evaluate 
the efficacy and safety of hytrombopag in the treatment of thrombocytopenia 
occurring prior to scheduled surgery.9After signing the informed consent form, the 
patients will enter the screening period (up to 7 days) and receive oral treatment with 
hytrombopag after screening. The specific dosage regimen is: 7.5 mg, once daily, 
orally before bed on an empty stomach, lasting for up to 14 days,PLT≥100×109/L. 
During oral administration of hytrombopag, when PLT≥200×109/L, the 
administration was suspended and the hemogram was monitored every 7 days until 
PLT<100×10.9/L. During the treatment period, blood routine was monitored once 
every 3 days,PLT≤30×109/L or ≥300×109/L. Patients will have an end-of-treatment 
visit within 7 days of treatment discontinuation, followed by a 30-day safety follow-
up period. 
5 Management of Subjects 
5.1 Inclusion criteria (all must be met) 
1)Subjects ≥18 years old, regardless of gender;The diagnosis was immune 
thrombocytopenia. 
2)Platelet ≤75×10 prior to scheduled elective surgery9/L, Surgery Major or minor 
surgery is defined by the treating surgeon and hematologist based on the duration 

and complexity of the procedure and the risk of bleeding for the patient; 
3)Willing to participate in clinical study and sign informed consent form. 
5.2 Exclusion criteria (one of which is excluded) 
1) History of allergy to TPO-RA drugs; 
2) Severe bleeding symptoms, such as upper gastrointestinal bleeding, bleeding of 
important organs, intracranial hemorrhage, etc.; 
3) thrombotic diseases such as pulmonary embolism, arterial thrombosis and 
disseminated intravascular coagulation (DIC); 
4) Anti-human immunodeficiency virus antibody or anti-Treponema pallidum 
specific antibody positive; 
5) Congestive heart failure New York Heart Association (NYHA) class 3 or 4; 
6) History of angina pectoris, myocardial infarction or cerebral infarction within 6 
months prior to screening; 
7) Active infections that are difficult to control; 
8) Pregnant or lactating women; 
9) Other circumstances deemed unsuitable for inclusion in the study by the 
investigator. 
6 Dosing Regimen 
Subjects must take the drug on an empty stomach every morning (overnight fasting 
for at least 8 hours), breakfast must not be eaten for 2 hours after dosing, and subjects 
are required to take all trial drugs of the day once a day, swallow the trial drugs whole, 
and do not chew, divide or crush them. 
7. Concomitant Medications/Concomitant Therapy 
The investigator has the right to decide at any time whether to give the following 
supportive treatment to the subject: transfusion supportive treatment (such as red blood 
cells and platelets). During this trial, except for the basic treatment and drugs used for 

treatment or prevention of adverse events that have been taken stably before the trial, 
any other drugs are prohibited in principle. Any drugs used during the trial other than 
the trial drugs should be recorded in detail in the eCRF, and the records should include: 
drug name, dose, date of administration and indication for use. 
8 Test observation methods 
During the treatment period, blood routine was monitored once every 7 
days,PLT≤50×109/L or ≥300×109/L. Patients will have an end-of-treatment visit within 
7 days of treatment discontinuation, followed by a 30-day safety follow-up period. 
9 Adverse events and evaluations 
9.1 adverse event definitions 
Adverse Event (AE) refers to any adverse medical event occurring in this trial 
from the time the subject signs the informed consent form until 28 days after the last 
dose, regardless of whether it is causally related to the trial drug. All adverse events 
should be followed up by the investigator until the event has been resolved, or recovered 
to baseline level, or the investigator judges that the event has turned to "stable" without 
further follow-up, or the subject is lost to follow-up, or the subject dies. 
Adverse events include the following: 
1)Worsening of pre-existing (before entering clinical trial) medical condition/disease 
(including symptoms, signs, laboratory abnormalities); 
2)Any new adverse event: any new adverse medical condition (including symptoms, 
signs, newly diagnosed diseases); 
3)Abnormal clinically significant laboratory values or results indicating a new disease 
or organ toxicity worse than baseline. 
4)Decreases in platelet values were not recorded as AEs unless they were accompanied 
by new bleeding symptoms or worsening of existing bleeding symptoms from baseline, 

or required urgent treatment. 
The investigator should record any adverse event occurred by the subject in detail, 
including: description of adverse event and all related symptoms, onset time, severity, 
cause of adverse event, correlation with investigational drug, duration, measures taken, 
final results and outcome. 
9.2 Obtaining adverse event information 
Investigators should report all adverse events directly observed or spontaneously 
reported by subjects in concise language. In addition, subjects should be asked regularly 
about adverse events after the start of the trial. 
9.3 adverse event record 
During the trial, the adverse event record form should be truthfully filled in, including 
the occurrence time, severity, duration, measures taken and outcome of adverse events. 
Adverse events should be recorded in the adverse event form of the designated case 
report form. 
9.4 Criteria for severity of adverse reactions 
When completing the Adverse Event Form in the eCRF, the investigator will 
describe the severity of the adverse event using mild, moderate, and severe. For uniform 
criteria, the severity of the event will be graded as follows: 
- Grade 1 (mild): usually transient, generally does not interfere with activities of 
daily living, does not require medication or may require minimal treatment; 
- Grade 2 (moderate): Subject feels unwell, activities of daily living are affected, 
treatment is usually required to alleviate, but there is no risk of major or permanent 
harm to the subject; 
- Grade 3 (severe): The activities of daily living of the subject are interrupted, or 
the clinical condition is seriously affected, and intensive treatment and intervention are 

required; 
Severe is used only to describe degree. For example, headache may appear severe 
in degree but cannot be classified as a serious adverse event (SAE) unless it meets the 
criteria for an SAE. 
9.5 Criteria for determining the relationship between adverse events 
and investigational drug 
Adverse events include all unexpected clinical manifestations. As long as these 
events occur after signing the informed consent form, regardless of whether they are 
related to the investigational drug, they should be reported as adverse events. Any 
discomfort complained by patients or abnormal changes in objective laboratory test 
indicators during treatment should be recorded truthfully, and the severity, duration, 
treatment measures and outcome of adverse events should be indicated. Clinicians 
should also comprehensively judge the relationship between adverse events and the 
investigational drug. The possible association between adverse events and the 
investigational drug was evaluated according to the five-level classification method of 
"definitely related, possibly related, possibly unrelated, definitely unrelated and 
undeterminable.""definitely related,""possibly related" and "undeterminable" were all 
listed as adverse drug reactions. The total of these three factors was taken as numerator 
when calculating the incidence rate of adverse events, and the number of all subjects 
used for safety evaluation was taken as denominator. The judgment criteria were as 
follows: 
grading 
judgment standard 
definitely 
related 
The type of adverse event has been identified as a known reaction type to the drug 
and cannot be explained by other reasons (e.g. concomitant medications and 
concomitant diseases). The timing of the event strongly suggests a causal 
relationship (e.g. withdrawal and re-administration of the drug). 
possibly 
related 
The occurrence of adverse events was in a reasonable time sequence with the 
administration of the investigational drug. The occurrence of adverse events may be 
caused by the investigational drug. It cannot be ruled out whether other factors may 
be caused, such as concomitant drugs or concomitant diseases. The drug was not 

withdrawn or unclear. 
unlikely 
related 
There was no evidence of a causal relationship between the occurrence of the event 
and the trial drug. The occurrence of the adverse event was more likely related to 
other factors, such as concomitant medications or concomitant diseases. However, 
an association between the two could not be ruled out. 
not 
related 
Adverse events are not related to the use of the investigational drug. 
Unable to 
assess 
There is insufficient information to determine the causal relationship between the 
event and trial medication. The investigator may change her/his causality 
assessment based on subsequent follow-up information and modify the AE/SAE 
report accordingly. 
 
9.6 the definition of serious adverse event 
Serious adverse events refer to medical events that require hospitalization or 
prolongation of hospitalization, disability affecting work ability, life-threatening or 
death, congenital malformation, etc. during the clinical trial, including the following 
unexpected medical events: 
 
Death; 
 
Life-threatening (defined as the subject being at immediate risk of death at the time 
of the event); 
 
Requires hospitalization or prolongation of hospitalization; 
 
Persistent or significant disability/loss of function; 
 
Congenital anomalies or birth defects; 
 
Other important medical events (defined as events that harm the patient or require 
intervention to prevent any of the above). 
Hospitalization does not include the following: 
 
rehabilitation institutions 
 
sanatorium 
 
Regular emergency room admissions 
 
same-day surgery (eg outpatient/same-day/ambulatory surgery) 
Hospitalization or prolongation of hospitalization not associated with worsening of an 
AE is not an SAE per se. Example: 

 
Admissions due to pre-existing diseases, no new adverse events, and no 
exacerbation of pre-existing diseases (e.g., to check for laboratory abnormalities 
that persist from pre-trial to present); 
 
Manage the cause of hospitalization (e.g. annual routine check-up); 
 
protocol-specified hospitalizations during the clinical trial (e.g., performed as per 
protocol requirements); 
 
Elective hospitalizations unrelated to worsening of adverse events (e.g. elective 
surgery); 
 
Scheduled treatments or surgical procedures should be documented throughout the 
trial protocol and/or in the subject's individual baseline profile; 
 
Admitted to hospital solely for blood product use. 
9.7 reporting of serious adverse events 
Any serious adverse event occurring during the clinical study and after drug 
discontinuation must be immediately reported to the monitor of the sponsor, the 
principal investigator of the clinical study site and the ethics committee of the clinical 
study site. Meanwhile, the investigator must fill in the serious adverse event report form 
(SAE), describe in detail the time of occurrence, severity, relationship with the 
investigational drug and measures taken, and sign the report. 
Follow-up reports should be submitted immediately if the intensity of an ongoing SAE 
or its relationship to the study drug changes. If the investigator believes that the 
information previously reported for an SAE is false, a correction, withdrawal, or 
downgrade can be made in the follow-up report and reported according to SAE 
reporting procedures. 
9.8 contraceptive 
All subjects who are considered by the investigator to be sexually active and 
capable of conceiving or impregnating a partner must agree to use an effective method 
of contraception throughout the duration of the study (from 2 weeks prior to the first 

dose of trial product to at least 30 days after the last dose). 
9.9 pregnancy report 
If a female subject becomes pregnant during the clinical trial, the subject 
withdraws from the trial, and if a male subject's partner becomes pregnant, the subject 
may continue the clinical trial. Pregnancy itself is not considered an SAE, but any 
negative pregnancy outcome (e.g. stillbirth, spontaneous abortion, fetal malformation) 
is considered an SAE and needs to be reported according to the time limit of SAE. If 
the subject also experiences an SAE during pregnancy, the SAE Report Form should 
be completed and reported according to the SAE Reporting Procedure. 
10 Statistical analysis 
10.1 statistical analysis plan 
Statistical analysis will be performed using SAS statistical analysis software. Detailed 
statistical analysis details will be provided in the formal statistical analysis plan (SAP). 
10.2 statistical hypothesis 
10.3 statistical methods 
10.3.1 Statistical Analysis Data Sets 
1)Safety analysis set (SAS): including subjects who have used the investigational drug 
at least once; 
2)FAS (full analysis set): including all subjects who were randomized into the study 
group, who used the investigational drug at least once, and who had efficacy indicators 
after randomization at least once; 
3)PPS (per-protocol set): subset of FAS, excluding subjects with serious protocol 
violations; 

10.3.2 Primary Efficacy Analysis 
Logistic regression was used for the primary efficacy measure, with treatment as the 
variable analyzed and baseline platelet count as the covariate. The primary analysis was 
based on FAS, and the secondary analysis was based on PPS. Baseline platelet count 
was defined as the most recent measurement before dosing. 
10.3.3 Secondary Efficacy Analyses 
10.3.4 Safety analysis 
Adverse events occurring during the trial will be coded using MedDRA dictionary 
based on safety analysis set. Frequency and incidence of adverse events will be 
described according to system organ class (SOC) and preferred term (PT). Correlation 
and seriousness of adverse events will be further tabulated. Other safety indicators will 
be summarized by descriptive statistics. Adverse events, adverse reactions, adverse 
events leading to withdrawal from the trial, adverse events leading to death, Incidence 
rate of serious adverse events; incidence rate calculated by subsystem and 
symptoms/signs (count of cases: number of subjects who have experienced at least one 
adverse event); severity of adverse events and adverse reactions: the same adverse event 
occurs multiple times in the same subject, and the most serious adverse event is 
included in the analysis; different adverse events occur in the same subject, and the 
most serious adverse event is included in the analysis. 
Laboratory test parameters: Descriptive summaries of laboratory test values 
focused on outliers. 
Vital signs: Mean, maximum, minimum, median, standard deviation are used to 
describe the measured values and changes at each visit. 
Physical examination, 12-lead ECG, etc. were analyzed descriptively. 
10.3.5 Missing Data Handling 
For the primary efficacy measure, if a patient has no measurement at a time point 

and thereafter, the platelet count at that time point and thereafter is counted as not 
reaching ≥50×109/L. 
10.4 sample size 
The study was designed as a single-arm exploratory design. Based on previous 
relevant data reports, the estimated proportion of patients meeting platelet targets was 
65%. Using NCSS PASS 15 (LLC. Kaysville, Utah, USA, ncss.com/software/pass) 
software, the two-sided 95% confidence interval (Clopper-Pearson method) for 
enrollment of approximately 50 subjects was (50.2%, 77.9%), and the confidence 
interval width was 27.7%. 
11 Research Management 
11.1 ethical requirements 
·Ethics Committee 
Prior to the start of the clinical trial, the clinical trial protocol shall be reviewed 
and approved by the Ethics Committee and approved by the Ethics Committee before 
implementation. During the clinical trial, major amendments to the clinical trial 
protocol, such as new impact on the safety of subjects, or amendments to the informed 
consent form, shall be approved by the Ethics Committee before implementation. 
·Protection of rights and interests of subjects in clinical trials 
The clinical investigator must explain to the subject that participation in the 
clinical trial is voluntary and that he/she has the right to withdraw from the trial at any 
time during any stage of the trial without discrimination, that his/her medical treatment 
and rights will not be affected in any way, and that he/she can continue to receive other 
effective treatment. The subject must be informed that participation in the trial and 
personal data in the trial are confidential. The subject must also be informed of the 
nature of the clinical trial, the purpose of the trial, the expected possible benefits and 

the possible risks and inconveniences that may occur. Subjects were informed of 
alternative treatment options and their rights and obligations in accordance with the 
Declaration of Helsinki, so that they had sufficient time to consider participation in the 
trial and sign the informed consent form. 
11.2 information requirements 
 
Protocol: read carefully, sign the study director after consent is confirmed, and 
implement the protocol strictly. Protocol revision can only be carried out after the 
investigators discuss and reach agreement. Any protocol revision, if it causes new 
impact on the safety of subjects, or requires revision of informed consent form, 
needs to be approved by the Ethics Committee. 
 
Clinical trial data: All kinds of original data of clinical trial shall be recorded timely, 
truthfully, accurately and completely, and copies of laboratory test sheets shall be 
kept for 5 years after the end of the trial. 
 
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