A Prospective Observational Study of Switching Eltrombopag and Recombinant Human Thrombopoietin In Primary Immune Thrombocytopenia
Conditions: Corticosteroid-resistant or Relapsed ITP
Sponsor: Peking University People's Hospital

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A Study of Eltrombopag and Recombinant Human 
Thrombopoietin In Primary Immune Thrombocytopenia 
 
NCT number 
04214951 
Date 
August 13, 2020  
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
Title of trial 
A prospective and retrospective observational study of switching eltrombopag and 
rh-TPO in Chinese adult patients with primary immune thrombocytopenia 
Participants 
Peking University People’s hospital, Institute of Hematology 
Background  
Immune thrombocytopenia (ITP), an autoimmune disorder characterized by 
thrombocytopenia due to platelet destruction and impaired platelet production, is 
responsible for various degrees of bleeding signs 1, 2. The pathogenesis of ITP 
includes immune-mediated clearance of antibody-coated platelets by macrophages, 
together with antibody-mediated megakaryocyte apoptosis and the suppression of 
thrombopoiesis activities 3, 4. Primary ITP is defined as isolated thrombocytopenia 
with platelet counts <100*109/L after the exclusion of all other conditions that lead 
to thrombocytopenia 2, 4, 5. 
ITP is a highly heterogeneous disorder in adults with symptoms ranging from mild 
bruising to intracranial hemorrhage 4, 6. The goal of treatment is to achieve a platelet 
count adequate to prevent bleeding while minimizing treatment-related toxicity 2, 6. 
When platelet counts fall below 30*109/L, treatment is considered as the patient 
suffers from increasing risk of fatal bleeding 2. Corticosteroids (high-dose 
dexamethasone or prednisone) with or without intravenous immunoglobulin (IVIg) 
are the first-line treatment strategies to decrease autoantibody-mediated platelet 
destruction, increase platelet production, and reduce bleeding 5, 7. For most adult 
patients, however, relapse occurs upon cessation of steroid treatment; as a result, 
second-line therapies are considered to maintain a sustained increase in the platelet 
count while minimizing adverse events to allow for the possibility of attaining a 
remission (defined as a platelet count ≥30*109/L in the absence of any ITP-specific 
treatment) 8. 
Thrombopoietin receptor agonists (TPO-RAs) represent a highly effective and well-
tolerated second-line ITP treatment that provides excellent responses (>60%) in 
splenectomized and nonsplenectomized ITP patients (Grade A recommendation, 
evidence level Ib) 5, 8. In China, rh-TPO and eltrombopag are the two distinct TPO-
RAs widely used in clinical practice. Rh-TPO is a TPO peptide mimetic that is 
injected subcutaneously, whereas eltrombopag is a TPO nonpeptide mimetic 
administered orally 1, 3, 9. Rh-TPO, composed of two IgG1 constant regions (Fc 
fragments) linked to a peptide domain containing four binding sites for the 
thrombopoietin receptor (TPO-R), activates TPO-R by binding to the 
extramembrane domain like endogenous TPO 1, 10. Eltrombopag is a 442-Da drug 
that binds to the transmembrane domain of TPO-R and activates it 1, 10. There is a 
local rh-TPO launched in China 7 years ahead of eltrombopag, which used to 
dominate the market. Both drugs are recommended by the latest Chinese guideline 
as second-line or emergent therapy for treatment of adult primary immune 
thrombocytopenia 7. 

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Study Rationale 
According to the findings of mechanism-based studies, rhTPO competes with 
endogenous TPO for binding to TPO-R while eltrombopag has an additive effect 
with endogenous TPO 10, indicating that the treatment mechanism and side-effect 
profiles could be somewhat different between these drugs 9, 10. Therefore, when 
there’s a lack of response or when adverse events become a problem with one TPO-
RA, switching to another TPO-RA provides useful information for the management 
of adult ITP patients 8, 9.  
Khellaf et al. retrospectively reviewed data of 46 ITP patients who sequentially 
switched from eltrombopag to romiplostim (a TPO-RA similar to rhTPO in 
mechanism) or vise versa due to varying reasons including lack of efficacy (n=23), 
platelet-count fluctuations (n=11), side effects (n=4), and patient’s preference (n=8). 
Switching was shown effective in 50-80% of the patients, with eradication of platelet 
fluctuations in 54% and side effects resolved in 100% 1. Another retrospective 
analysis of 26 ITP patients showed that for patients who switched the TPO-RA as a 
result of inefficiency (n=10), switching from romiplostim to eltrombopag led to 
100% response rates, whereas switching from eltrombopag to romiplostim led to 
66% response rates. The response rate was 100% in patients who switched due to 
side effects (n=5) or patient preference (n=8) 10. In a study of 51 primary ITP adult 
patients switching from romiplostim to eltrombopag, response rate was 80% (41/51) 
with efficacy maintained for a median of 5.5 (range, 2–9) months in all patients who 
switched because of patient preference (n = 16), platelet-count fluctuation (n = 6) 
and side-effects (n = 4) 9. Cantoni et al. analyzed clinical characteristics associated 
with response to the switch of TPO-RAs and found that lines of previous therapy, as 
well as disease duration would lower the probability to respond. According to the 
study, response was achieved/regained in 57.8% of patients who switched for 
efficacy issues and 80% who switched for non-efficacy issues; once response to the 
2nd TPO-RA is achieved, it is possible to maintain long-term effect in these patients 
3. 
Based on the clinical evidence, it is shown that switching from one TPO-RA to 
another, as well as sequential therapy, provides favorable outcomes of response and 
tolerability (evidence levels IIb, III) 8. However, current studies almost exclusively 
focus on the effect of switching between romiplostim and eltrombopag; whether 
there is also absence of cross-resistance between rhTPO and eltrombopag remains 
to be investigated. In addition, clinical evidence on TPO-RA switching is proposed 
on the basis of retrospective studies. Therefore, we propose here an observational 
study with retrospective and prospective design to evaluate the response and safety 
profiles of switching between eltrombopag and rh-TPO in Chinese adult ITP 
patients; the preference of patients and doctors will also be assessed in this study. 
Objectives 
Primary Objective:  
To assess the response on one TPO-RA after switching from another.  
Secondary Objectives:  
To assess the patterns of response and switching. 

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To understand the preference of patients and doctors. 
To study the safety profiles associated with rhTPO and eltrombopag after switching. 
Exploratory Objectives: 
To analyze the associations between clinical characteristics and response after 
switching. 
To explore the effect of rescue medication on response after TPO-RA switching. 
Endpoints 
Primary endpoint: 
 
Rate of response at 6 weeks after switching from rhTPO to eltrombopag or vise 
versa 
Response is defined according to the Chinese guidelines for treatment of adult 
primary immune thrombocytopenia as 7: 
Complete response (CR): platelet count ≥ 100 × 109/L and absence of bleeding. 
Response (R): platelet count range 30-100 × 109/L, at least doubling of the baseline 
count, and absence of bleeding. 
No response (NR): platelet count <30 × 109/L, or less than doubling of the baseline 
count, or bleeding. 
The rate of response at 6 weeks includes the total proportion of patients who 
achieved CR and R at 6 weeks in the groups switch from rhTPO to eltrombopag and 
eltrombopag to rhTPO, respectively. 
Secondary endpoints: 
 
Rate of response at 6 weeks after switching, according to the reasons of 
switching  
The reasons of switching include 3: 
Lack of efficacy: 
-1st TPO-RA failure: no response to either one TPO-RA administered before switch 
-Loss of response: relapsed after transient response to 1st TPO-RA (relapse is defined 
as platelet count < 30 × 109/L, or less than doubling of the baseline count, or 
bleeding, after the achievement of CR or R. The blood platelet count should be 
confirmed on at least two separate occasions, which is at least 1 day apart when used 
to define relapse 7) 
Platelet count fluctuations: unstable platelet counts necessitating rescue therapy or 
transient TPO-RA dose modifications/withdrawal with associated risk of either 
rebound thrombocytopenia/bleeding or thrombocytosis 
Patient’s preference 
Development of adverse events necessitating 1st TPO-RA discontinuation 
 
Proportion of patients who achieved, regained, and maintained response at 6 
weeks after switching 
Response achieved refers to patients who failed the 1st TPO-RA achieve CR or R at 
6 weeks after switching. 
Response regained refers to patients who lost response to the 1st TPO-RA achieve 

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CR or R at 6 weeks after switching. 
Response maintained refers to patients who achieved CR or R with the 1st TPO-RA 
and still respond to the 2nd TPO-RA at 6 weeks after switching. 
 
Rate of response at 3 months after switching from rhTPO to eltrombopag or 
vise versa 
 
Rate of response at 3 months after switching, according to the reasons of 
switching  
 
Proportion of patients who achieved, regained, and maintained response at 3 
months after switching 
 
Time to response from 1st TPO-RA switching for patients who switch due to 
lack of efficacy 
 
Duration of response from 1st TPO-RA switching for patients who switch due 
to lack of efficacy 
Duration of response is defined as the time from when CR or R is 
achieved/regained to the time of relapse. 
 
Proportion of patients with any bleeding (WHO bleeding scale grade 1‒4 11) 
and clinically significant bleeding (WHO bleeding scale grade 2‒4 11) 
 
Total score of bleeding calculated according to the Bleeding Rating System 7 
 
Patient and physician’s treatment preference 
At 6 weeks after switching, patients will be asked whether they prefer to continue 
treatment with rhTPO or eltrombopag, or whether they had no preference 12. In 
addition, patients who prefer one TPO-RA over the other will be quired on the 
reasons of preference (Patient preference questionnaire attached as Appendix 1). 
At 6 weeks after switching, physicians will also be asked whether they prefer to 
further treat the patient with rhTPO or eltrombopag, or whether they had no 
preference, taking into account the patient’s preference, response, and tolerability 12. 
At 3 months after switching, the measurement will be applied again. 
 
Safety of treatment 
The safety of treatment will be determined from adverse events summarized by 
incidence and severity, and from clinical laboratory evaluations, physical 
examinations and ophthalmological examinations carried out during scheduled 
study visits. 
Exploratory endpoints: 
 
Association between clinical characteristics and response after switching 
The following clinical characteristics will be compared between responders and non-
responders at 6 weeks and 3-month after switching, respectively: gender (male vs 
female), age at 1st TPO-RA, time from diagnosis to 1st TPO-RA, lines of previous 
therapy before 1st TPO-RA, maximum 1st TPO-RA dose received vs. not received, 
splenectomy status (yes vs no), switch sequence (rhTPO to eltrombopag or vise 
versa), switching behavior, switch due to efficacy vs non-efficacy issues, and 1st 
TPO-RA failure vs loss of response. 

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 
The effect of rescue medication on response after TPO-RA switching. 
Clinically, a stable response refers to response achieved without receiving rescue 
treatment 1. Additional analysis will be conducted to explore the influence of rescue 
medication on response after switching from rhTPO to eltrombopag or vise versa. 
Trial Design 
This is a prospective and retrospective observational study of switching eltrombopag 
and rh-TPO in Chinese adult patients with primary immune thrombocytopenia. A 
schematic illustration of the study design is shown as follows: 
 
The study includes two stages: the retrospective stage and the prospective stage. 
Primary ITP patients who failed initial glucocorticosteroid treatment and receive rh-
TPO and then switch to eltrombopag or vice versa will be screened for eligibility. 
Medical records will be retrospectively reviewed to collect baseline data before 1st 
TPO-RA administration, information on the 1st TPO-RA, as well as the reason for 
switch. Patients who meet the eligibility criteria upon medical history review and 
clinical evaluation will be enrolled at the time of switch. The switch procedure is as 
per physician preference and clinical practice. 
After enrollment, patients will be followed up prospectively on administering the 2nd 
TPO-RA. Both rh-TPO and eltrombopag are applied according to the approved label 
and clinical practice, in considering the actual condition of a patient. For patients 
who switch from rhTPO to eltrombopag, platelet counts will be obtained weekly 
under stable dose and monthly following establishment of a stable platelet count 
(≥50*109/L for at least 4 weeks), while platelet counts will be obtained at least once 
a week during dose adjustment. Liver function tests (ALT, AST, TB) will be 
performed monthly under stable dose but increased to bi-weekly during dose 
adjustment. For patients who switch from eltrombopag to rhTPO, platelet counts 
will be obtained every other day during initial treatment and weekly during 
maintenance therapy. 
Platelet counts will be obtained at least once a week for all patients who suspend/stop 
their 2nd TPO-RA, while liver function tests will be performed bi-weekly in patients 
who suspend/stop eltrombopag as their 2nd TPO-RA. Once treatment is resumed, 
monitoring of platelet counts and liver function will be performed as per during 
treatment administration. An end-of-study visit will be performed for all patients at 

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3 months after switching. 
The observation period is 3-month for each patient enrolled. Response to 2nd TPO-
RA will be assessed throughout the observation period with response at 6 weeks 
being the primary evaluation. Adverse events, including bleeding events, will be 
assessed and recorded together with concomitant ITP treatment. Preference of 
patients and doctors on the two TPO-RAs will also be assessed. 
Investigational Drug 
Administration 
Patients will initiate eltrombopag treatment with a dose of 50 mg once daily. Dose 
adjustment of study medication will be allowed to maintain platelet counts between 
50*109/L and 250*109/L.  
Patients will initiate rh-TPO with a dose of 300 U/kg/d for ≤14d. Patients who 
attained stable PLT counts (≥50*109/L) in two consecutive tests will enter 
maintenance therapy, starting with every other day administration of rhTPO, then 
adjust dose interval to maintain platelet counts at 30-100*10 9/L. 
Dose Adjustment 
Guidelines 
The following information serves as a reference; actual dose adjustment will be 
conducted according to clinical practice in considering the medical condition of a 
patient: 
Eltrombopag: refer to Table 2. 
RhTPO:  
At initial treatment, rhTPO will be suspended when platelet counts ≥100*109/L. 
During maintenance therapy, patients with platelet counts >150*109/L will suspend 
treatment until platelet counts drop to ≤150*109/L. Dosing interval will be prolonged 
when platelet count is ≥100*109/L to ≤150*109/L. Dose modification is not required 
when platelet count is ≥30*109/L to <100*109/L13.  
Patient Population 
Chinese adult patients with primary immune thrombocytopenia who failed first-line 
corticosteroid therapy and received rhTPO and then switch to eltrombopag or vise 
versa. 
Key Inclusion 
Criteria 
• 
Age 18 years or older 
• 
Chinese ethnicity  
• 
Primary ITP diagnosed according to the current definitions 7, 8, 14, 15 
• 
Failed initial glucocorticosteroid treatment, 
• 
Applying rhTPO or Eltrombopag as subsequent treatment 
• 
Switch from rh-TPO to eltrombopag or vice versa   
• 
Treatment on rhTPO for 14 days minimum or Eltrombopag for 4 weeks 
minimum, if the reason of switching is lack of efficacy or platelet count 
fluctuations   
• 
Available follow-up at least 6 weeks after switching 

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Key Exclusion 
Criteria 
• 
HIV positive status, or active infection of HBV or HCV 
• 
Suffering from a serious or progressive disease, which, in the investigator’s 
judgment, put the subject at undue risk for participation in this study (i.e. 
cancer or pre-cancer, immunocompromised, uncontrolled diabetes, 
epilepsy, severe cardio-cerebrovascular  disease(s) (i.e. stroke, idiopathic 
aortic stenosis, aneurysm, hypertrophic obstructive cardiomyopathy, 
ischaemic heart disease, tachyarrhythmias, severe heart failure [classified 
as NYHA III-IV], severe lung dysfunctions, etc)) 
• 
History of thrombosis plus two or more risk factors as defined in Caprini 
thrombosis risk assessment model 16 
• 
Lactating or pregnant women, or WOCBP who are unwilling to use highly 
effective contraceptive measures during the study period 
• 
Abnormal liver and renal functions: AST or ALT or total bilirubin ≥1.5 × 
ULN, and/or creatinine ≥176.8 μmol/L 
• 
Women of childbearing potential (WOCBP) that are pregnant or wish to 
become pregnant during the prospective phase of the study. 
• 
Other conditions which the investigator considers inappropriate for 
enrollment 
Safety 
Monitoring 
and Reporting 
Adverse events (AEs) will be collected throughout the study period and classified 
according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 5.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE
_v5_Quick_Referenc e_5x7.pdf ) 
Also, whether an AE fulfills the criteria of a SAE will be judged according to the 
definition of ICH-E2. All SAEs occur during the study period will be reported to 
the Sponsor’s Pharmacovigilance contact within 24 hours upon knowledge of the 
investigator. The following information is the minimum requirement of reporting: 
• 
Patient identifier 
• 
Product name 
• 
SAE description including assessment of causal relationship and severity 
• 
Investigator name and contact details 
 
Women who become pregnant during the study have to immediately inform their 
physician and discontinue, as neither rhTPO nor Eltrombopag currently have 
sufficient data to inform a drug-associated risk of adverse developmental 
outcomes. 
Sample  
Size Justification  
 
Total Planned Number of Patients: 100 patients (~50 patients in each switch 
sequence but not a strict 1:1 ratio) 
 
The purpose of this study is not to compare the efficacy differences between 
the two switch groups but to describe the rate of response, so the sample size 
cannot be calculated. 

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Sample size rationale:  
 
According to a published similar literature, it is estimated that about 100 
patients can reveal a certain proportion of efficacy 3; 
 
Using the cross-sectional sampling method, the estimated response rate of these 
two drugs is ~70% (95% CI, 50%-90%), the sample size would be 80. So, 100 
patients’ size was decided taking the 20% drop-out rate into consideration. 
 
According to our previous study, it is expected to complete the observation of 
100 patients within one and a half year.  
Statistical Analysis  
 
Statistical analysis methods: 
Statistical analysis will be conducted by SAS Version 9.2 or above. Descriptive 
statistics for continuous variables include minimum, maximum, mean ± standard 
deviation and median with inter-quartile ranges (IQR). Categorical variables will be 
described as frequencies and percentages. Percentage will be calculated based on 
non-missing data unless otherwise specified. Comparison between categorical 
variables will be performed using chi-square test or Fisher’s exact test, while 
comparison between continuous variables will be performed using two-sample t test 
for parametric data and Wilcoxon rank sum test for non-parametric data. Logistic 
regression will be used to assess the association between clinical characteristics and 
outcome of response. Time-to-event data will be described by Kaplan-Meier 
survival curve with log-rank test for between-group comparison. 
Unless specified, statistical testing will be carried out bilaterally with significance 
level alpha=0.05, i.e. a p-value of less than or equal to 0.05 will be considered as 
statistically significant. Methods of descriptive analysis and hypothesis testing will 
be selected according to the data characteristics. Transformations will be undertaken 
as needed. 
Analysis sets: 
Full Analysis Set (FAS): includes all patients who receive at least one dose of the 
2nd TPO-RA and have response assessed at 6 weeks after switching 
Safety Set (SS): includes all patients who receive at least one dose of the 2nd TPO-
RA after switching. 
Efficacy analysis will be conducted on FAS and safety analysis on SS.  
 
 
Table 1 Time and Events 
Study procedures 
Screening  
During Treatment 
Safety follow-
up 
after 
treatment 
suspension/stop 
End-of-study 
Visit 
Visit schedule 
-14~1d 
Every 
week±3d 
Every 
2 
weeks 
Every 
4 
weeks 
Every 
8 
weeks 
Every 
week 
±3d 
12 weeks ±7d 

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±3d 
±4d 
±4d 
Written 
informed 
consent 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
Ophthalmologic 
examination 
X 
 
 
 
 
 
X 
CBC 
(incl. 
platelet 
count) 
X 
X a, b 
 
X b 
 
X e 
X 
Peripheral blood smear 
X 
 
 
 
 
 
 
Liver 
function 
tests 
(ALT, AST, TB) 
X 
 
X c 
X c 
 
X d 
X 
Other clinical chemistry 
(incl. Cr) 
X 
 
 
 
 
 
X 
Coagulation tests 
X 
 
 
 
X 
 
X 
Thyroid function test 
X 
 
 
 
 
 
 
HBV, 
HCV, 
HIV 
testing 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
Ultrasound (spleen) 
X 
 
 
 
X 
 
X 
Chest X-ray 
X 
 
 
 
 
 
 
Bleeding assessment 
X 
X 
 
 
 
X 
X 
Bone marrow aspirate 
As clinically required. 
Pregnancy test 
X 
 
 
 
 
 
X 
Concomitant therapy f 
X 
X 
 
 
 
X 
X 
AE/SAE assessment 
X 
X 
 
 
 
X 
X 
a. 
For patients who switch from eltrombopag to rhTPO, CBC should be performed every other day during initial 
treatment and weekly during maintenance therapy. 
b. 
For patients who switch from rhTPO to eltrombopag, CBC should be monitored weekly until stable platelet 
count is observed (≥50*109/L for at least 4 weeks), then CBC will be monitored every 4 weeks. Platelet counts 
will be obtained at least once a week during dose adjustment. 
c. 
For patients who switch from rhTPO to eltrombopag, liver function tests (ALT, AST, TB) will be performed 
every 4 weeks under stable dose but increased to every 2 weeks during dose adjustment. 
d. 
For patients who switch from rhTPO to eltrombopag, liver function tests (ALT, AST, TB) will be performed 
every 2 weeks after treatment suspension/stop. 
e. 
The frequency of platelet monitoring can be increased to twice weekly for patients who suspend/stop 
eltrombopag due to platelet counts >250*109/L. 
f. 
Record concomitant ITP treatment (including rescue medications), anticoagulants, and NSAIDs. 
 

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Table 2 Dose Adjustment Guidelines of Eltrombopag 
After initiating eltrombopag, the dose should be adjusted to achieve and maintain a platelet count≥50*109/L as necessary 
to reduce the risk of bleeding. A daily dose of 75 mg must not be exceeded. 
Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dose 
regimen of eltrombopag modified based on platelet counts as outlined in Table 2.  
During therapy with eltrombopag, platelet counts should be assessed weekly until a stable platelet count (≥ 50*109/L for 
at least 4 weeks) has been achieved. Platelet counts should be obtained monthly thereafter. 
 
Platelet count 
Dosage adjustment or response 
<50*109/L following at least 
2 weeks of therapy 
Increase daily dose as per 25mg. Monitor platelet count at 
least once a week, wait for 2 weeks, assess the treatment 
effect after dose increase, and consider whether further dose 
adjustment is needed. Maximum daily dose is 75mg per day. 
≥50*109/L to ≤150*109/L 
Use lowest dose of eltrombopag and/or concomitant ITP 
treatment to maintain platelet counts that avoid or reduce 
bleeding. 
>150*109/L to ≤250*109/L * 
Decrease daily dose as per 25mg. Monitor platelet count at 
least once a week, wait for 2 weeks, assess the treatment 
effect after dose decrease, and consider whether further dose 
adjustment is needed. 
>250*109/L ** 
Suspend eltrombopag; increase the frequency of platelet 
monitoring to twice weekly. 
Once the platelet count is ≤ 100*109/L, reinitiate therapy at 
a daily dose reduced by 25 mg **. 
The standard dose adjustment, regardless of increase or decrease the dose, is per 25mg qd. 
Following any dose adjustment, platelet count should be monitored at least once a week for 2-3 
weeks. After waiting for at least 2 weeks, observe the effect of dose adjustment on platelet count, 
and then consider whether to continue to adjust the dose. 
Any patient with cirrhosis (i.e. child Pugh score ≥ 5) will wait for 3 weeks before increasing the 
dose. 
Notes:  
* For patients with platelet counts >150*109/L during any time point of treatment, decrease the dose to subsequent lower 
dose (for example, decrease 75mg qd to 50mg qd, or decrease 75mg qd to75mg qd and 50mg qd in turn, etc.) or decrease 
the dosing frequency (for example, decrease 25mg qd to 25mg qod, or consecutive 2 days for medication of 25mg qd 
and 1 day without the medication, or consecutive 3 days for medication of 25mg qd and 1 day without the medication, 
etc.). 
**Once platelet count is ≤100*109/L, restart the treatment but decrease to subsequent lower dose (for example, decrease 
75mg qd to 50mg qd, or decrease 75mg qd to75mg qd and 50mg qd in turn, etc.) or decrease the dosing frequency (for 
example, decrease 25mg qd to 25mg qod, or consecutive 2 days for medication of 25mg qd and 1 day without the 
medication, or consecutive 3 days for medication of 25mg qd and 1 day without the medication, etc.). 
 

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PISCES study[J]. Journal of Clinical Oncology, 2014, 32(14):1412-1418. 
13. Cai Huacong, Wang Shujie, Fu Ling, et al. Efficacy and safety of recombinant human thrombopoietin in 
maintenance treatment of primary immune thrombocytopenia: a multicenter clinical study [J]. Chinese 
Journal of Hematology, 2017, 38(5):379-383. 
14. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based 
practice guideline for immune thrombocytopenia[J]. Blood, 2011, 117(16):4190-4207. 
15. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the 
investigation and management of idiopathic thrombocytopenic purpura in adults, children and in 
pregnancy[J]. British Journal of Haematology, 2003, 120(4):574–596. 
16. Caprini JA. Risk assessment as a guide to thrombosis prophylaxis[J]. Current Opinion in Pulmonary 
Medicine, 2010, 16(5): 448-452. 
 
 

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Informed Consent Form 
A Study of Eltrombopag and Recombinant Human Thrombopoietin In Primary 
Immune Thrombocytopenia 
Dear subjects: 
We are going to carry out a prospective clinical study on the conversion between eltrombopag and 
recombinant human thrombopoietin (rhTPO) in the treatment of drug-resistant / relapsed primary ITP. 
As you have immune thrombocytopenia and will be treated with eltrombopag or rhTPO, and your 
specific conditions meet the inclusion criteria of the study, we would like to invite you to participate in 
this study. 
This informed consent will introduce you to the purpose, steps, benefits, risks and inconvenience 
of this study, as well as your rights and interests. Please carefully read it and make a decision on whether 
to participate in the study. When the researcher explains and discusses the informed consent form to 
you, you can ask questions at any time and ask him / her to explain to you what you don't understand. 
You can discuss with your family, friends and your doctor before making a decision. 
If you are currently participating in other clinical studies, please inform your doctor or researcher. 
The project leader of this study is Professor Zhang Xiao-hui, Peking University People’s Hospital, 
Peking University Institute of Hematology, Beijing, China. 
 
1. Why do we do this research? 
ITP is an autoimmune disease, which is one of the most common hemorrhagic diseases that 
seriously endanger human health. Glucocorticoid and intravenous immunoglobulin are 
recommended as the first-line treatment for ITP patients. However, more than 30% of ITP patients 
have poor response to glucocorticoid treatment, and 50-85% of patients with effective 
corticosteroid therapy still relapse in the first year of treatment. In addition, long-term use of 
glucocorticoid treatment of patients with serious side effects, can lead to diabetes, hypertension, 
serious systemic infection and necrosis of the femoral head and other serious complications. 
Therefore, in-depth study of new treatment plan is an important clinical and scientific problem to 
be solved in this field. 

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Thrombopoietin (TPO) is the most important cytokine regulating megakaryocyte 
development and platelet production, which can promote the differentiation of megakaryocytes 
and the production of platelets. Studies have shown that the plasma TPO level is not increased or 
slightly increased in ITP patients, and megakaryocytes in bone marrow of ITP patients are 
increased or accompanied with maturation disorder. The relative deficiency of endogenous TPO 
production is one of the causes of thrombocytopenia, which provides a basis for the treatment of 
ITP with TPO and its receptor agonists. Many thrombopoietins (rhTPO, eltrombopag, 
romiplostim) have been recommended for second-line treatment of adult ITP. 
RhTPO, similar to endogenous TPO, has the effect of increasing platelets. The efficacy of 
rhTPO in the treatment of chronic, refractory and severe ITP has been confirmed. RhTPO has 
fewer adverse reactions, including occasional fever, chills, general discomfort, fatigue, muscle 
soreness, headache, dizziness and high blood pressure, which generally does not need to be 
addressed and can recover by itself. 
Eltrombopag is a TPO receptor agonist, which has been approved by FDA for the treatment 
of thrombocytopenia in patients with chronic ITP and poor response to corticosteroids, 
immunoglobulin or splenectomy. The common side effects of eltrombopag include nausea, 
vomiting, menorrhagia, muscle pain, paresthesia, cataract, dyspepsia, liver and kidney 
dysfunction, ecchymosis, thrombocytopenia and conjunctival hemorrhage. 
There are many differences between the effect of eltrombopag and that of rhTPO and 
romiplostim. First of all, although the two molecules are bound to the same receptor, they are 
bound to different sites. Eltrombopag does not compete with TPO to bind to the distal cytokine 
homologous region of TPO receptor. Whether in vitro or in vivo, the effect of eltrombopag is 
additive to that of TPO. Secondly, the activation of JAK and STAT pathway by eltrombopag is 
different from that of TPO. Different from rhTPO, the Akt pathway was not activated by 
eltrombopag after binding to TPO receptor. 
It has been confirmed in many retrospective studies that there is no cross resistance between 
eltrombopag and romiplostim. However, whether there is cross resistance between eltrombopag 
and rhTPO in clinical application, and whether their side effects overlap, especially for 

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glucocorticoid resistant / recurrent ITP, has not been reported. 
To sum up, our research group believes that the mechanism of action of eltrombopag and 
rhTPO is different, forming this study: To observe the safety and efficacy of eltrombopag in ITP 
patients, who are ineffective or intolerable to the treatment of rhTPO; to observe the safety and 
efficacy of rhTPO in ITP patients, who are ineffective or intolerable to the treatment of eltrombopag. 
2. Who will be invited to participate in the study? 
Adult ITP patients who have been confirmed to be resistant or relapsed after full dose corticosteroid 
therapy and currently use only one of the two drugs of eltrombopag or rhTPO and need to be replaced 
with another one. 
3. How many people will participate in this study? 
100 subjects. 
4. How will the study be conducted? 
Patients with glucocorticoid resistant / relapsed ITP who are currently using eltrombopag and need 
to be replaced with rhTPO for various reasons, or who are currently using rhTPO and need to change to 
eltrombopag for various reasons were included in the study. Physical examination and relevant 
laboratory tests were completed and informed consent was signed. The treatment was completed 
according to the clinical treatment plan, and the follow-up period was 1 year. Platelet count, adverse 
reactions and other indicators were followed up every week in the first three months of treatment, then 
once every two weeks until six months, and then once a month until one year. 
5. How long will this study last? 
Each patient will be followed up for 1 year. 
6. What are the risks of participating in this study? 
This study only collects clinical data and information, which is an observational study and does 
not bring the risk of examination and treatment to the subjects. 
7. What are the benefits of participating in this study? 

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Your participation in this study will not bring immediate benefits, but your participation will help 
to clarify the development of your disease; we hope that the information from your participation in this 
study will benefit you and other patients with the same condition in the future. 
8. Is it necessary to participate in and complete the study? 
Whether you participate in this study is entirely voluntary. If you don't want to, you can refuse to 
participate. This will not have any negative impact on your current or future medical treatment. The 
doctor will treat you according to the routine. Even if you agree to participate, you can change your 
mind at any time and tell the researcher to quit the study. Your withdrawal will not affect your access to 
normal medical services. In principle, after you quit, the researcher will keep the relevant information 
of you obtained until the final destruction, and will not continue to use or disclose the information during 
this period. During the study, we will inform you of any information that may affect your decision to 
continue to participate in the study. 
9. What are the costs and compensation for participating in the study? 
This study will only collect your relevant information during the follow-up. Your treatment plan, 
including medication and examination fees, should be paid by yourself. 
10. Are subjects remunerated for participating in the study? 
You were not paid for the study.      
11. How to deal with research-related injuries? 
If you are injured due to participating in this study, we hope you can inform the researcher as soon 
as possible, and we will provide necessary medical measures according to the clinical routine. Our 
institution (Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, 
China) will take necessary medical measures for the adverse reactions occurred during the study period. 
12. Will my information be kept confidential? 
If you decide to participate in this study, your personal data about your participation in the study 
are confidential. Information that identifies you will not be disclosed to members outside the research 

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group unless have your permission. All study members and study sponsors are required to keep your 
identity confidential. Your files will be kept in a locked file cabinet for researchers' reference only. If 
necessary, members of the government administration or medical ethics committee may access your 
personal data in the research unit according to regulations. When the results of this study are published, 
no identity information will be disclosed.     
13. Who should I contact if I have any questions or difficulties? 
The general director of the project is Zhang Xiao-hui, chief physician of Peking University People's 
Hospital (Tel: 010-88324577). If you have any questions related to this study, please contact Dr. Cai 
Xuan at 010-88324577. 
If you have questions related to your own rights and interests, you can contact the medical ethics 
committee of Peking University People's Hospital at 010-88324516.                                             

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Informed consent (signature page) 
Statement by the researcher  
I have informed the subject of the research background, purpose, steps, risks and benefits of 
the prospective clinical study project of converting eltrombopag and rhTPO for drug-resistant / 
relapsed ITP. I have given him / her enough time to read the informed consent form, discuss with 
others, and answer his / her research questions; I have informed the subject that he / she can contact 
Dr. Zhang Xiao-hui at any time when he / she encounters any research related problems and contact 
the medical ethics committee of Peking University people's Hospital at any time in case of problems 
related to his / her own rights / interests, and provided accurate contact information; I have informed 
the subject that he / she can withdraw from the study without any reason; I have informed the subject 
that he / she will obtain a copy of this informed consent form with my / his / her signature on it. 
                                                                
Signature of researcher with informed consent (in italics) 
 
 
   Date 
                                                                
Signature of researcher with informed consent (handwritten) 
 
   Date 
Statement by the subject 
I have been informed of the background, objectives, procedures, risks and benefits of the 
prospective clinical study of eltrombopag and rhTPO conversion therapy for resistant / relapsed ITP. 
I have enough time and opportunity to ask questions, and I am satisfied with the answers. I also 
have been told who I should contact when I have questions, want to reflect difficulties, concerns, 
have suggestions for research, or want further information or help with research. I have read this 
informed consent form and agree to participate in this study. I know that I can withdraw from this 
study at any time during the study without any reason. I also have been told that I would get a copy 
of this informed consent form with my signature and that of the researcher. 
                                                                
Signature of the subject (in italics)                                Date 
                                                                
Signature of the subject (handwritten)                             Date 
 (Add or replace the following methods when the subjects are lack of the ability of informed 
consent) 
                                                                  
Signature of legal representative (in italics)                         Date 
                                                                  
Signature of legal representative (handwritten)                      Date 
                                                                               

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Relationship with the subjects                                   Date 
                                                                  
Signature of the subject (if possible)                              Date