A Randomized, Double-blind, Placebo-controlled, Phase 2/3 Operational Seamless Designed Clinical Study to Evaluate the Efficacy and Safety of HBM9161 Weekly Subcutaneous Injection in Patients With Primary Immune Thrombocytopenia
Phase: PHASE2
Conditions: Primary Immune Thrombocytopenic Purpura
Sponsor: Harbour BioMed (Guangzhou) Co. Ltd.

Harbour BioMed 
Protocol number: 9161.4 
HBM9161 
Version 3.0/27-Mar-2020 
 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of16 
 
 
 
Synopsis of Clinical Study Protocol 
 
Sponsor: Harbour BioMed (Suzhou) Co., Ltd. 
Address: 202, Building A3, Xinghu Street 218, Suzhou Industrial Park 
Version No./Version Date: Version 3.0/27-Mar-2020 
Study No.: 9161.4 
Protocol: 
A randomized, double-blind, placebo-controlled, operationally seamless phase 2/3 clinical 
study to evaluate the efficacy and safety of HBM9161 weekly subcutaneous injection in 
patients with primary immune thrombocytopenia 
Phase: Operationally seamless Phase 2/3  
Country and study center: China, multicenter 
Rationale: 
The onset of primary immune thrombocytopenia is thought to be caused by increased 
platelet destruction and decreased platelet production due to anti-platelet antibodies. 
HBM9161 is a fully human anti-FcRn monoclonal antibody that can effectively remove 
pathogenic IgG, thereby relieving platelet destruction, and result in rapidly increasing platelet 
counts in patients. This study has an operationally seamless Phase 2/3 design, with a high 
dose (680 mg), a low dose (340 mg) of HBM9161, and a placebo group in the Phase 2 part. 
After the completion of Phase 2 part, an appropriate treatment dose will be selected to be 
further studied in the Phase 3 part, aiming to provide a new treatment option for the patients 
with primary ITP as early as possible. 
Study Objectives: 
Phase 2: Dose Selection and Efficacy Evaluation 
Study Objectives: 
Study Endpoints: 
Primary Objectives 
- 
To evaluate the early efficacy of 
weekly subcutaneous HBM9161 
340 mg and 680 mg treatment in 
patients with primary immune 
thrombocytopenia (ITP) to make a 
go/no go decision for the phase 3 
part and select a dose to be further 
Primary Endpoints 
• Proportion of subjects who achieve a 
response (R) during the period from 
Week 1 to Week 7. 

Harbour BioMed 
Protocol number: 9161.4 
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studied in the phase 3 part, the the 
phase 3 part decision is go.  
Secondary Objectives 
- 
To assess the efficacy of weekly 
subcutaneous HBM9161 340 mg 
and 680 mg in patients with 
primary immune thrombocytopenia 
(ITP). 
Secondary Endpoints 
• Proportion of subjects whose platelet 
count is ≥ 30 × 109/L and at least 2 times 
of baseline at 4 or more visits out of the 
6 visits in the period of Week 19 through 
Week 24, and who had no bleeding 
events and no rescue treatment prior to 
those platelet counts 
• Proportion of subjects who achieve 
response (R) within 24 weeks 
• Proportion of subjects who achieve 
complete response (CR) within 7 weeks 
• Proportion of subjects who achieve 
complete response (CR) within 24 weeks 
• Proportion of subjects who achieve 
platelet count ≥ 50 × 109/L at least 2 
times within 7 weeks 
• Proportion of subjects who achieve 
platelet counts ≥ 50 × 109/L at least 2 
times within 24 weeks 
• Time to Response: time from imitation of 
treatment to first response (R) or 
complete response (CR) 
• 
Duration of response: time from 
response (R) or complete response (CR) 
to first unmet response (R) or complete 
response (CR) 
Note: 
- 
Reaction (R) is defined as: 
Platelet counts ≥ 30 × 10 9/L and at 
least 2 times of baseline, confirmed 
by 2 tests (at least 7 days apart) , 
and no prior bleeding events and no 
rescue treatment. 
- 
Complete response (CR) is defined 
as:  
platelet counts ≥ 100 × 10 9/L should 
be achieved and confirmed in at least 
2 tests (at least 7 days apart) without 
prior bleeding events and no rescue 
treatment. 

Harbour BioMed 
Protocol number: 9161.4 
HBM9161 
Version 3.0/27-Mar-2020 
 
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Safety Objective 
- 
To assess the safety of weekly 
subcutaneous HBM9161 340 mg 
and 680 mg in ITP patients 
Safety Endpoints 
• Severity and incidence of adverse 
events during 24 Weeks 
Exploratory Objectives 
- 
Other efficacy assessments  
- 
Biomarker assessments 
- 
Immunogenicity of HBM9161 
- 
Exploratory characteristics of the 
pharmacokinetics (PK) of 
HBM9161 in patients with primary 
immune thrombocytopenia based 
on population pharmacokinetic 
(PopPK) analysis 
- 
To assess the relationship 
between HBM9161 exposure and 
efficacy and adverse events 
Exploratory Endpoints 
• WHO bleeding score of subjects from 
baseline to Week 24 
• Change in platelet count over 24 weeks 
compared to baseline 
• Proportion of subjects with a decrease in 
ITP concomitant medication over 24 
weeks compared to baseline 
• Proportion of subjects treated with 
rescue therapy within 24 weeks 
compared to baseline 
• Change in serum IgG, IgM, IgA, albumin 
levels from baseline to Week 24 
• Anti-platelet autoantibodies: to assess 
changes compared to baseline of anti-
GPIIb/IIIa, anti-GPIb/IX, and anti-
GPIa/IIa antibodies. 
• Anti-drug antibodies: to assess changes 
in serum anti-HBM9161 antibodies 
compared to predose. 
• Pharmacokinetics evaluation: all data of 
HBM9161 plasma concentration 
obtained in this study will be used for the 
PopPK analysis, which is to establish a 
PK model to characterize the PK of 
subcutaneous injection of HBM9161. 
• Dose-response assessment: to explore 
the correlation between PK/efficacy and 
PK/safety. 
Phase 3: Efficacy and Safety Assessment 
Primary Objectives 
- 
To evaluate the efficacy of weekly 
subcutaneous HBM9161 (dose to 
be determined) in patients with 
primary immune thrombocytopenia 
(ITP) 
Primary Endpoints 
• Proportion of subjects with ≥ 4 visits with 
platelet counts ≥ 30 × 10 9/L and at least 
2 times higher than baseline and no 
bleeding events and no rescue treatment 
in 6 visits from Week 19 to Week 24. 

Harbour BioMed 
Protocol number: 9161.4 
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Note: The primary endpoint of Phase 3 
may be reasonably changed based on 
the data available in Phase 2 to more 
accurately reflect the long-term efficacy 
of the product. 
Secondary Objectives 
Secondary Endpoints 
- 
To assess the other efficacy 
assessments of weekly 
subcutaneous HBM9161 (dose to 
be determined) in patients with 
primary immune thrombocytopenia 
(ITP) 
• Proportion of subjects who achieve 
response (CR) within 7 weeks 
• Proportion of subjects who achieve 
response (R) within 24 weeks 
• Proportion of subjects who achieve 
complete response (CR) within 7 weeks 
• Proportion of subjects who achieve 
complete response (CR) within 24 weeks 
• Proportion of subjects who achieve 
platelet count ≥ 50 × 109/L at least 2 
times within 7 weeks 
• Proportion of subjects who achieve at 
least 2 platelet counts ≥ 50 × 10 9 /L 
within 24 weeks 
• Time to Response: time from initiation of 
treatment to first response (R) or 
complete response (CR) 
• Duration of response: time from 
response (R) or complete response (CR) 
to first unmet response (R) or complete 
response (CR) 
Safety Objective 
- 
To assess the safety of weekly 
subcutaneous HBM9161 (dose to 
be determined) in patients with 
primary immune thrombocytopenia 
(ITP) 
Safety Endpoints 
• Severity and incidence of adverse 
events during 24 weeks 
Exploratory Objectives 
- 
Other efficacy assessments  
- 
Biomarker assessments 
- 
Immunogenicity of HBM9161 
- 
Exploratory characterization of the 
PK of HBM9161 in patients with 
primary immune thrombocytopenia 
based on the PopPK assay, as 
needed 
Exploratory Endpoints 
• WHO bleeding score of subjects from 
baseline to Week 24 
• Change in platelet count over 24 weeks 
compared to baseline 

Harbour BioMed 
Protocol number: 9161.4 
HBM9161 
Version 3.0/27-Mar-2020 
 
Confidential and Proprietary  
- 
To assess the relationship 
between HBM9161 exposure and 
efficacy and adverse events as 
needed. 
• Proportion of subjects with a decrease in 
ITP concomitant medication over 24 
weeks compared to baseline 
• Proportion of subjects treated with 
rescue therapy within 24 weeks 
compared to baseline 
• Change in serum IgG, IgM, IgA, albumin 
levels from baseline to week 24  
• Platelet autoantibodies: to assess 
changes compared to baseline of anti-
GPIIb/IIIa, anti-GPIb/IX, and anti-
GPIa/IIa antibodies 
• Anti-drug antibodies: to assess changes 
in serum anti-HBM9161 antibodies 
compared to predose. 
• Pharmacokinetics evaluation: all data of 
HBM9161 plasma concentration 
obtained in this study will be used for the 
PopPK analysis, which is to establish a 
PK model to characterize the PK of 
subcutaneous injection of HBM9161. 
• Dose-response assessment: To explore 
the correlation between PK/efficacy and 
PK/safety. 
 
Study Design: 
A randomized, double-blind, placebo-controlled; Phase 2/3 operational seamless design 
Study Population: 
Phase 2 part: 36 patients (12 in Group 1, Group 2 and placebo group respectively) are 
planned to be randomized. If any subject drops out within 7 weeks after the first dose 
(including Visit 9), the same number of subjects will be enrolled to replace those who has 
dropped out (up to 6 subjects). The actual group will be assigned and balanced by 
randomization system.. 
Phase 3 part: 230 subjects (115 subjects each in the treatment and placebo groups) are 
planned to be randomized. The sample size may be increased according to the phase 2 
part results, but the final sample size will not exceed 400. 
Main Inclusion and Exclusion Criteria (for both phase 2 and phase 3 parts): 
Inclusion Criteria: 
1. Signed written informed consent. 
2. ≥ 18 years of age at the screening visit, male or female. 

Harbour BioMed 
Protocol number: 9161.4 
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Version 3.0/27-Mar-2020 
 
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3. Female patients will be eligible to participate if meeting the criteria below: 
a. Non-childbearing potential (i.e., physiologically incapable of pregnancy, including 
women who have been menopausal for 2 years) 
b. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy 
test at the first visit , and agreed to correctly use one of the following acceptable and 
effective methods of contraception (i.e., following the approved product label and 
physician's instructions) throughout the study from the start of study visit (Screening) until 
90 days after the last dose: 
• Complete abstinence (when consistent with the patient's preference and 
previous lifestyle); or 
• Levonorgestrel implant should be implanted at least 1 month ahead of study 
drug administration, but implant time cannot be more than 3 years; or 
• Progesterone should be injected at least 1 month ahead of that study drug 
administration; or 
• Oral birth control pills (combination contraceptives or progestins only) 
administered for at least 1 month prior to study drug administration; or 
• Dual birth control: condom or cervical cap (diaphragm or cervical cap) with 
spermicide (foam/gel/cream/suppository); or 
• Intra-uterine devices (published data showing an estimated maximum failure rate 
is less than 1% per year), implanted by qualified physicians; or 
• Estrogen vaginal ring; or 
• Transcutaneous contraceptive patch. 
4. Male patients must use effective contraception methods or their heterosexual partners 
must use effective birth control during their participation in this clinical trial. 
5. Diagnosis criteria: meet the American Society of Hematology 2011 diagnosis criteria 
for persistent or chronic ITP. The average number for platelet count at the screening 
visit and predose platelet count on the day of first dose (at least 1 day apart) is < 30 × 
10 9/L, and platelet count is not > 35 × 10 9/L for any of two tests. No severe bleeding 
occurs within 4 weeks prior to the screening visit. 
6. Patients who have received and failed (poor response, or unmaintained response, or 
relapse) at least 1 first line of ITP therapy (glucocorticoids and/or intravenous gamma 
globulin), or who are contraindicated, intolerable, or refuse standard therapy. 
7. This study allows concomitant drugs for the treatment of ITP, detailed requirements are 
as follows: 
• Glucocorticoids: prednisone or other equivalents ≤ 20 mg/day are allowed within 
at least 2 weeks prior to the first dose of the study drug, with dose unchanged or 
regularly reduced; 
• Danazol: The dose remained unchanged within 3 months prior to the first dose 
of study drug or has been discontinued for at least 2 weeks prior to the first dose 
of study drug; 
• Immunosuppressants (azathioprine, cyclosporine A, mycophenolate mofetil 
only): The dose remains unchanged within 3 months prior to the first dose of the 

Harbour BioMed 
Protocol number: 9161.4 
HBM9161 
Version 3.0/27-Mar-2020 
 
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study drug, or has been discontinued for at least 2 weeks prior to the first dose 
of the study drug; 
• Eltrombopag: The dose remained unchanged within 4 weeks prior to the first 
dose of the study drug or has been discontinued for at least 2 weeks prior to the 
first dose of the study drug. 
8. Willing and be able to receive treatment and complete appropriate assessments as 
required by the protocol, at the discretion of the investigator. 
9. Clinical laboratory results at screening must be acceptable to the investigator. 
Exclusion criteria: 
1. The patient has severe ITP condition at screening, inappropriate for participation in the 
study as judged by the investigator (e.g., life-threatening platelets decrease, major 
bleeding events or symptoms or signs suggestive of potential major bleeding events, 
and requirement of rescue treatment, including intravenous gamma globulin, anti-D 
immunoglobulin, high-dose glucocorticoid, or plasmapheresis, etc.). 
2. Has a history of serious allergic disease or known sensitivity to any components of the 
study drug. 
3. Other autoimmune systemic diseases beyond ITP. 
4. Multi-lineage immune cytopenia, such as Evan's syndrome, autoimmune pancytopenia. 
5. Secondary ITP caused by leukemia; lymphoma; lymphoproliferative disorders; multiple 
myeloma; drugs (e.g., quinine, heparin); thyroid disease; cirrhosis; HIV infection; 
hepatitis C; and antiphospholipid antibody syndrome, etc. 
6. Has received a vaccine within 4 weeks prior to the first dose of the study drug or is 
scheduled to receive a vaccine during the study. 
7. Takes anticoagulants or any agents that have antiplatelet effect or can affect 
thrombopoiesis within 3 weeks prior to the first dose of the study drug. 
8. Has received transfusion of blood (including platelet transfusion) within 1 week prior to 
the first dose of the study drug. 
9. Has received the intravenous gamma globulin, anti-D immunoglobulin, or 
plasmapheresis within 2 weeks prior to the first dose of the study drug. 
10. Has received high-dose dexamethasone or high-dose methylprednisolone within 2 
weeks prior to the first dose of the study drug. 
11. Has received recombinant human thrombopoietin (rhTPO) within 4 weeks prior to the 
first does of the study drug. 
12. Has received romiplostim within 4 weeks prior to first dose of the study drug. 
13. Has received splenic tyrosine kinase inhibitors (Syc inhibitors such as fostamatinib) 
within 4 weeks prior to the first dose of the study drug. 
14. Has received rituximab or other non-rituximab anti-CD20 drugs within 6 months prior to 
the first does of the study drug. 
15. Has been treated with splenectomy within 4 weeks prior to first dose of the study drug. 

Harbour BioMed 
Protocol number: 9161.4 
HBM9161 
Version 3.0/27-Mar-2020 
 
Confidential and Proprietary  
16. Has received biotherapeutic or investigational drugs not mentioned above within 3 
months or 5 half-lives of drugs, whichever is longer, prior to the first dose of the study 
drug. 
17. Any thromboembolic or embolic events within 12 months prior to the first does of the 
study drug. 
18. Plans to take surgery during the study. 
19. Active infection at the screening visit, or a serious infection (requiring intravenous 
antimicrobial therapy or hospitalization) within 8 weeks prior to the first dose of the 
study drug, or any infection requiring oral antibiotics within 2 weeks prior to the first 
dose of the study drug, or has symptoms due to fever or viral, bacterial (including upper 
respiratory tract infection), fungal (non-skin sites), or other infection within 1 week 
before the first dose of the study drug, previous or current human immunodeficiency 
virus (HIV) or hepatitis C virus (HCV) infection and current hepatitis B virus (HBV) 
infection. Patients to be enrolled at the screening visit must have negative results for 
the tests below: HBV surface antigen, HCV antibody, HIV antibody. Patients with 
negative HBV surface antigen but positive core antibody should be tested HBV-DNA, 
and patients with clinical significantly HBV-DNA increase should be excluded. 
20. Has tuberculosis (TB) infection; with a high risk of TB infection; latent TB infection; or a 
history of TB infection should be excluded. Other patients are required to receive 
tuberculin test or interferon-gamma release test to rule out active TB infection. 
21. Serum total IgG < 700 mg/dL at the screening visit. 
22. Severe anemia (hemoglobin < 90 g/L), leukopenia (white blood cell count < 3 x 109/L), 
neutropenia (absolute neutrophil count < 1.5 x 109/L), or coagulation dysfunction 
(international normalized ratio[INR] > 1.5 or activated partial thromboplastin time [aPTT] 
> 1.5 times the upper limit of normal range). 
23. Hepatic insufficiency with one or more of the following criteria met: 
a. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 times 
the upper limit of normal range at the screening visit; 
b. Total bilirubin > 1.5 times the upper limit of normal range at the screening visit; 
c. Severe cirrhosis (Child-Pugh grade C). 
24. Creatinine clearance ≤ 50 ml/min (calculated by the Cockcroft Gault formula) at the 
screening visit. 
25. Uncontrolled hypertension, i.e., blood pressure is still higher than 160/100 mmHg after 
appropriate treatment. 
26. Severe cardiovascular (including arrhythmias increasing the risk of embolism at 
discretion of the investigator, such as atrial fibrillation), liver, kidney, respiratory, or 
hematological disorders, or other medical or mental illness considered to prevent the 
patients from participating in the study. 
27. History of malignant tumor, unless cured with appropriate treatment and no relapse for 
more than 3 years before the first dose of the study drug. Non-melanoma skin cancer in 
situ that has been completely resected by surgery (e.g., basal cell carcinoma or 
squamous cell carcinoma) or cervical cancer in situ can be enrolled. 

Harbour BioMed 
Protocol number: 9161.4 
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Version 3.0/27-Mar-2020 
 
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28. Pregnant or lactating patients; or those who are going to become pregnant during the 
study. 
29. Patients who are alcohol or drug dependence/abuse at present or during the past 1 
year, except for nicotine and coffee. 
30. The investigator/study center personnel directly related to the study, or an immediate 
relative of the investigator/study center personnel ("immediate family member" means a 
spouse, parent, child, or sibling [whether biological or legal adoptive relationship]). 
Study Drug: 
Phase 2 part: HBM9161 
-Dose: Group 1: 340 mg; Group 2: 680 mg 
- Method and route(s) of administration: The drug will be administered by 
subcutaneous injection once a week and 4 times per cycle. The number of treatment 
cycles will be as clinically indicated, with no more than 3 cycles per subject in the overall 
trial. 
Phase 3 part: HBM9161 
- Dose: to be determined (based on data from phase 2 part) 
- Method and route(s) of administration: The drug will be administered by 
subcutaneous injection once a week, 4 times per cycle. The number of treatment cycles 
will be as clinically indicated, with no more than 3 cycles per subject in the overall trial. 
Rescue treatment: 
- Rescue treatment will be allowed during this study, including an increase in the dose 
or frequency of existing ITP concomitant drugs, and the addition of intravenous gamma 
globulin, anti-D immunoglobulin, high-dose glucocorticoid pulse, recombinant human 
thrombopoietin (rhTPO) or thrombopoietin receptor agonists, vinblastine, platelet 
transfusion, and plasmapheresis. The use of rescue treatment is based on the investigator’s 
medical judgement and can be referred to the Expert Consensus on the Diagnosis and 
Treatment of Primary Immune Thrombocytopenia in Adults (2016 Edition), e.g., life-
threatening thrombocytopenia, major bleeding events (WHO Bleeding Score Grade 3 or 4) 
or the presence of symptoms or signs suggestive of potential bleeding, and should be 
confirmed by the sponsor. Patients who achieve a response (R) after receiving rescue 
treatment should be considered nonresponsive when calculated the response rate. 
Control Drug: 
Placebo 
- Dose: Not applicable 
- Method and route(s) of administration: The drug will be administered by 
subcutaneous injection once a week and 4 times per cycle, with no more than 3 cycles per 
subject in the overall trial. 
Treatment Duration (for both phase 2 and phase 3 parts): 
3 weeks, once a week, 4 doses. 

Harbour BioMed 
Protocol number: 9161.4 
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If subjects who had a response (R) or complete response (CR) to study drug in the 
previous cycle during the 21-week follow-up period had relapse (platelets < 30 × 10 9/L 
confirmed in 2 tests at least 1 day apart). Additional treatment cycle of study drug may be 
arranged once investigators considered as subjects were not indicated for rescue 
treatment and this should be confirmed by the sponsor. The treatment of the additional 
cycles continues with the original double-blind treatment, and the drugs are given once 
weekly for 4 weeks. The interval between the first dose of the additional cycles and the last 
dose of the previous cycle must be at least 4 weeks. The total number of the treatment 
cycles for subjects should not exceed 3, i.e. the total number of doses should not exceed 
12. 
Study Duration (for both phase 2 and phase 3 parts): 
26 weeks in total (2-week screening + 3-week treatment + 21-week follow-up). 
During the 21-week follow-up period, for subjects who receive additional treatment cycles, 
the subsequent visits after the first dose of additional cycles should be performed same as 
the visits from Day 0 (Visit 2) as specified in the study schedule. Except for randomization, 
all the procedures should be done. However, assessments to be performed should accord 
toVisit 20 in the study schedule. If the Week 24 visit is less than 5 weeks from the last dose 
of study drug, or the last treatment cycle has not been completed at the Week 24 visit, the 
follow-up period will be extended up to 5 weeks after the last study dose. For those 
subjects with extended follow-up period, the last visit assessments will also be performed 
as according to Visit 20 in the study schedule (see Flow Chart of Additional Treatment 
Cycles). 
Statistical Analysis: 
The primary endpoint in the phase 2 part is the proportion of subjects who achieve a 
response (R) between the Week 1 and Week 7. Based on data observed in this study and 
external information available, the sponsor will make following decisions based on the 
totality of information at the interim analysis at the end of Week 7 in the phase 2 part: 
• whether to proceed to the phase 3 part; 
• select a dose to befurther studied in the phase 3 part. 
Whether to proceed to the phase 3 part will be based on the Go/No-Go decision 
framework. If at least one dose shows a high likelihood that the target efficacy can be 
achieved and the safety of this dose is acceptable, the phase 3 part will start. On the other 
hand, if the efficacy of both doses is shown to be unlikely to be clinically significant, the trial 
will be terminated and Phase 3 will not be initiated. If the analysis results do not meet any 
of the two situations above, the subjects will continue to be observed or sample size will be 
increased to collect more long-term efficacy data to decide whether to enter Phase 3. The 
dose selection for the Phase 3 will be based on the comparisons of the efficacy, safety and 
biomarkers between the two doses. 
The primary efficacy endpoint in the Phase 2 is set primarily to verify the mechanism of 
action of the drug. Since the primary efficacy endpoint in the Phase 2 is for short-term 
efficacy assessment and the primary efficacy endpoint in the Phase 3 is for long-term 
efficacy assessment, the decision for Phase 3 will consider not only the observed short-
term efficacy as measured by the Phase 2 primary efficacy endpoint, but also the long-
term efficacy observed in subjects who have partially completed the trial, the predictions of 

Harbour BioMed 
Protocol number: 9161.4 
HBM9161 
Version 3.0/27-Mar-2020 
 
Confidential and Proprietary  
the long-term efficacy and the duration of efficacy based on the biomarkers, the efficacy 
and safety of the competitive products, and the safety data observed from this trial. 
The primary endpoint of the Phase 3 is the proportion of subjects with a platelet count ≥ 30 
× 10 9/L at ≥ 4 of 6 visits from Week 19 to 24 and the platelet count is at least twice 
baseline level, without bleeding events or rescue treatment. The statistical tests for 
differences in response rates between groups will be performed based on a normal 
approximation of the binomial distribution without continuity correction. 
The hierarchical testing will be used to analyze the secondary endpoints in the Phase 3 
trial. If the statistical test of the primary efficacy endpoint is statistically significant, other 
efficacy measures between the treatment groups will continue to be tested. The secondary 
endpoints will be ranked tentatively as the response rate within 7 weeks, the response rate 
within 24 weeks, the complete response (CR) rate within 24 weeks, and the complete 
response (CR) rate within 7 weeks. 
An independent data monitoring committee (DMC) will be established prior to the 
enrollment of the first subject to periodically review the safety data for ensuring the safety 
of the subjects. The data monitoring committee will be responsible for the planned interim 
analysis, interpretation of the results, and the recommendations for action according to the 
protocol. To ensure the credibility of the trial, the sponsor will not be involved in the 
operation of this independent data monitoring committee. The persons involved in the trial, 
including all the sponsor employees, and the third-party personnel and investigators 
related to the trial, cannot be the members of the data monitoring committee. 
Population Pharmacokinetics and Dose-Response Analysis: 
All HBM9161 plasma concentration data obtained in this study will be used for the PopPK 
analysis (using a nonlinear mixed effects modeling [NONMEM]) to establish a PK model to 
characterize the PK of subcutaneous injection of HBM9161. The individual subject 
exposure parameters will be estimated based on the parameters estimated by the final PK 
model established for the further dose-response (exposure-response) analyses, including 
the exploratory analysis of correlation of PK/efficacy and PK/safety. The results of these 
analyses will be reported separately. 

Harbour BioMed 
Protocol number: 9161.4 
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Version 3.0/27-Mar-2020 
Page 12 of 16 
 
STUDY SCHEDULE 
Study Phase 
Screenin
g Phase 
Treatment Phase 
Follow-up Phasel 
Early 
Withdraw
al Visitb 
Visit Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ET 
Weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease and Treatment 
History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Treatment 
Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (temperature, 
blood pressure, pulse) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead Electrocardiogram 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biochemistry 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B Virus DNAe 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mycobacterium 
Tuberculosis Testf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Analysis 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Globulin, Albumin 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol number: 9161.4 
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Version 3.0/27-Mar-2020 
Page 13 of 16 
 
 
 
 
 
(continued) 
Study Phase 
Screen
ing 
Phase 
Treatment Phase 
Follow-up Phasel 
Early 
Withdraw
al Visitb 
Visit Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ET 
Weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection Site Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Dispensing/Return of 
Subject Diaryh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Subject Diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHO Bleeding Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HBM9161 Antibody 
Testi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins (IgG, IgM, 
IgA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Autoantibodiesj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample 
Collectionk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: 
a. Date of first dose of HBM9161 injection. 

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Protocol number: 9161.4 
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Version 3.0/27-Mar-2020 
Page 14 of 16 
 
b. If the subject withdraws from the study early, the withdrawal visit should be completed within 2 days of the decision to withdraw from the study; 
if the subject withdraws in the middle of the treatment period, please observe the injection site reaction at the withdrawal visit until the reaction 
disappears. 
c. The complete physical examination should be performed at the Screening Visit, Visit 6 (Week 4), Visit 9 (Week 7), Visit 20 (Week 24), and the 
Early Withdrawal Visit (Includes cardiovascular, respiratory, gastrointestinal, skin, neurological, and musculoskeletal systems, as well as head, 
eyes, ears, mouth, nose, throat, neck, lymph nodes and edema). Height and weight will be measured and recorded at the screening visit. Key 
physical examinations (including skin, mucosa and organ hemorrhage and edema) may be performed at other visits. 
d. Viral serology test should be performed at screening, including HIV, HBsAg, HBcAb and HCV antibody. The HBV-DNA testing should also be 
performed in the subjects with HBsAg-negative but HBcAb-positive, and the subjects with clinically significant elevations in HBV-DNA are 
excluded. 
e. The HBV-DNA testing is only performed in the subjects with HBsAg negative but HBcAb positive. The subjects with clinically significant 
elevations in HBV-DNA should be considered for the addition of the anti-HBV drugs according to the relevant guidelines. 
f. The subjects with the known tuberculosis infection, a high risk of tuberculosis infection, latent tuberculosis infection or a history of tuberculosis 
infection should be excluded. Other subjects should have a tuberculin test or interferon gamma release assay to rule out the active TB infection. 
g. All the female subjects of childbearing potential should complete the blood human chorionic gonadotropin (HCG) pregnancy test at screening. 
The serum or urine pregnancy tests may be done at the subsequent visits. 
h. The subject diary helps the subjects record the medications and the adverse event across the visits. 
i. The ADA analysis will be performed under the control of the sponsor. The serum samples will be tested for anti-HBM 9161 antibodies using the 
currently approved bioanalytical methods. The raw data will be stored at the bioanalytical site. If the anti-HBM 9161 antibodies can be detected, 
the ADA titers will be further tested and further characterized using the validated cell-based NAb assays, if necessary, based on the ADA positive 
rate and titers. 
j. Platelet autoantibodies, including anti-GPIIb/IIIa, anti-GPIb/IX and anti-GPIa/IIa antibodies, will be detected by the monoclonal antibody-specific 
immobilization of platelet antigen (MAIPA) or enzyme-linked immunosorbent assay (ELISA) methods. From the start of the first dose of the 
additional cycles, the subsequent sampling will be performed according to the blood collection schedule from Day 0 (Visit 2) on the study 
schedule. 
k. The PK blood sample collection will be flexible and should be taken only within the time window. The blood samples will be collected within 2 h 
before dosing on Days 0, 7, 14 and 21, as close as possible to the time of dosing. The PK sampling can still be performed if the subject has taken 
the study drug before the blood collection, and the actual time of administration, dose and blood collection time need to be accurately recorded. 
The samples should be collected at site for follow-up visits on Day 28, 35 and 49, and the blood collection time needs to be accurately recorded. 
When an event of special interest (e.g., serious adverse event, etc.) occurs on and before Day 49, the investigator may choose to collect an 
unscheduled PK sample for the exploratory dose-response analysis, when available. If the subject withdraws from the study on or before Day 49, 
a PK sample may also be collected for the exploratory dose-response analysis. The PK blood samples may be collected as described above for 
subjects who receive the additional treatment cycles. 

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l. During the 21-week follow-up period, for the subjects who receive additional treatment cycles, the subsequent visits after the first dose of 
additional cycles should be performed same as the visits from Day 0 (Visit 2) as specified in the study schedule. Except for randomization, all the 
procedures will be consistent. However, the visit assessments will be performed same as with Visit 20 in the study schedule. If the Week 24 visit is 
less than 5 weeks from the last dose of study drug, or the last treatment cycle has not been completed at the Week 24 visit, the follow-up period 
will be extended to 5 weeks after the last study dose. For the subjects with extended follow-up period, the last visit assessments will also be 
performed same as Visit 20 in the study schedule (see Flow Chart of Additional Treatment Cycles). 
m. If the assessment has been performed within ≤ 7 days before, it may not be performed at that visit day. 
 
 

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Protocol number: 9161.4 
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Version 3.0/27-Mar-2020 
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FLOW CHART OF ADDITIONAL TREATMENT CYCLES 
Study Phase 
Screening 
Phase 
Treatment Phase 
Follow-up phase 
Adjustment Visits Caused by Additional Cycles 
Visit Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number for the Same Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
m.Initiation of the additional cycles per protocol requirements