A Phase 1 Randomized, Double Blinded, Placebo-Controlled Single Dose Escalation Study of OsrHSA in Adult Healthy Male and Female Volunteers
Phase: PHASE1
Conditions: Ascites Hepatic
Sponsor: Healthgen Biotechnology Corp.

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
A Phase 1 Randomized, Double Blinded, Placebo-Controlled Single Dose 
Escalation Study of OsrHSA in Adult Healthy Male and Female 
Volunteers 
This study will be conducted according to this protocol, including protocol amendments and 
in compliance with Good Clinical Practice, the ethical principles, and other applicable 
regulatory requirements. 
Protocol Number: 
US-HY1001 
Clinical Phase:  
Phase I 
IND Number:  
19136 
Sponsor:  
Wuhan Healthgen Biotechnology Corporation 
Version: 
V 1.2 
Version Date: 
11/20/2019 
CONFIDENTIAL 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from Wuhan Healthgen Biotechnology 
Corporation.   In the event of any actual or suspected breach of this obligation, Wuhan 
Healthgen Biotechnology Corporation must be promptly notified. These restrictions on 
disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
CONFIDENTIAL 
Page 2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES ........................................................................................................................ 8 
LIST OF FIGURES ...................................................................................................................... 8 
SPONSOR SIGNATURE ............................................................................................................. 9 
INVESTIGATOR AGREEMENT ............................................................................................ 10 
SPONSOR STUDY CONTACTS .............................................................................................. 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 12 
1 
Protocol Summaries ............................................................................................................... 15 
1.1 
Synopsis ................................................................................................................... 15 
1.2 
Study Design Schema .............................................................................................. 19 
1.3 
Schedule of Activities .............................................................................................. 20 
2 
Introduction ............................................................................................................................ 22 
2.1 
Background .............................................................................................................. 22 
2.2 
Risk/Benefit Analysis .............................................................................................. 23 
2.3 
Preclinical Studies .................................................................................................... 24 
 Non-clinical Pharmacology .............................................................................. 24 
 Non-clinical Pharmacokinetics ......................................................................... 24 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
CONFIDENTIAL 
Page 3 
 Safety Pharmacology and Toxicology .............................................................. 24 
3 
Objectives and endpoints ....................................................................................................... 26 
3.1 
Objectives ................................................................................................................ 26 
3.2 
Endpoints ................................................................................................................. 26 
4 
Study design ........................................................................................................................... 27 
4.1 
Overall Study Design ............................................................................................... 27 
4.2 
Study Process ........................................................................................................... 27 
 Definition of Dose Limiting Toxicity (DLT): .................................................. 28 
 Dose-escalation Criteria: ................................................................................... 28 
 Stopping Criteria: .............................................................................................. 29 
4.3 
Rationale for Starting Dose Selection ...................................................................... 29 
5 
Patient population .................................................................................................................. 30 
5.1 
Number of Subjects and Description of Population ................................................ 30 
5.2 
Inclusion Criteria ..................................................................................................... 30 
5.3 
Exclusion Criteria .................................................................................................... 31 
5.4 
Meals and Dietary Restrictions ................................................................................ 32 
5.5 
Alcohol ..................................................................................................................... 32 
5.6 
Activity .................................................................................................................... 33 

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Protocol Number: US-HY1001 
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5.7 
Randomization and Blinding .................................................................................... 33 
6 
Study Intervention .................................................................................................................. 34 
6.1 
Study Drug Description ........................................................................................... 34 
6.2 
Study Drug Packaging and Labeling ....................................................................... 34 
 Drug Storage and Handling .............................................................................. 34 
 Study Drug Compliance and Accountability .................................................... 34 
 Disposal and Destruction .................................................................................. 34 
 Treatment Allocation and Administration, Dosing Regimen ........................... 34 
6.3 
Duration of Treatment.............................................................................................. 35 
6.4 
Removal from Study Treatment and off-Study Criteria .......................................... 35 
 Criteria for Removal from Study Treatment ..................................................... 35 
 Off-Study Criteria ............................................................................................. 35 
 Subject Replacement ......................................................................................... 36 
7 
Study Assessment and Evaluations ........................................................................................ 38 
7.1 
Description of Assessment Procedures .................................................................... 38 
7.2 
Blood Samples for PK evaluations .......................................................................... 38 
7.3 
Immunogenicity Evaluations ................................................................................... 38 
8 
Data Collection and Management .......................................................................................... 39 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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8.1 
Study Record Retentions.......................................................................................... 39 
8.2 
Protocol Deviations .................................................................................................. 40 
8.3 
Publication and Data Sharing................................................................................... 40 
9 
Regulatory Human Subject Protection and Regulatory Oversight ........................................ 41 
9.1 
Informed Consent Processes and Documentation.................................................... 41 
9.2 
Confidentiality and Privacy ..................................................................................... 41 
9.3 
Conflict of Interest ................................................................................................... 42 
10 
Safety Reporting ............................................................................................................. 43 
10.1 
Definition of Adverse Event .................................................................................... 43 
10.2 
Causality of AEs ...................................................................................................... 44 
10.3 
Categorization of AEs .............................................................................................. 44 
10.4 
Reporting of SAEs and Suspected Unexpected Serious Adverse Reactions 
(SUSARs) ............................................................................................................................. 45 
10.5 
IRB Reporting .......................................................................................................... 45 
10.6 
Quality Assurance and Quality Control ................................................................... 46 
10.7 
Study Monitoring Plan ............................................................................................. 46 
10.8 
Study Closure ........................................................................................................... 47 
10.9 
Safety Review Committee (SRC) ............................................................................ 47 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
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11 
Statistical Considerations ................................................................................................ 49 
11.1 
General Statistical Considerations ........................................................................... 49 
11.2 
Determination of Sample Size ................................................................................. 49 
11.3 
Population Analysis ................................................................................................. 49 
 
PK and PD Population ............................................................................... 49 
 
Safety Population ....................................................................................... 49 
11.4 
Statistical Analysis ................................................................................................... 50 
 
PK Analysis ............................................................................................... 50 
 
Safety Analysis .......................................................................................... 50 
 
Immunogenicity Analysis .......................................................................... 51 
11.5 
Tabulation of Individual Participation Data ............................................................ 51 
12 
References ....................................................................................................................... 52 
 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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Page 7 
LIST OF TABLES 
Table 1 Schedule of Activities ..................................................................................................... 20 
 
LIST OF FIGURES 
Figure 1 Study Design Schema ..................................................................................................... 19 
 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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Page 8 
SPONSOR SIGNATURE 
 
Study Title:  
A Phase 1 randomized, double blinded, placebo-controlled single dose escalation study of 
OsrHSA in adult healthy male and female volunteers 
 
 
Protocol Number: US-HY1001 
 
Version: 1.2 
 
Person authorized to sign the protocol and protocol amendment(s) for the Sponsor,  
Qinhui Song  MD, PhD____________________________________ 
 
 
Signature by:  
 
____________________________________ 
Date: November 20, 2019 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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INVESTIGATOR AGREEMENT 
 
I have read Protocol “A Phase 1 randomized, double blinded, placebo-controlled single dose 
escalation study of OsrHSA in adult healthy male and female volunteers” and agree to conduct 
the study as described therein in compliance with ICH Guidelines for Good Clinical Practice and 
applicable regulatory requirements and to inform all who assist me in the conduct of this study of 
their responsibilities and obligations. 
The signature below constitutes my agreement to the contents of this protocol (version 1.2, 
date November 20, 2019). 
 
__________________________________________________________ 
Signature        Date 
 
__________________________________________________________ 
Name (please type or print) 
David Nguyen, MD 
__________________________________________________________ 
Institution 
WCCT Global, Inc. 
__________________________________________________________ 
Address 
5630 Cerritos Ave. 
Cypress, CA 90630 
USA 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
CONFIDENTIAL 
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SPONSOR STUDY CONTACTS 
 
Name  
Title/Role 
Contact Information 
QINHUI SONG 
CMO 
Tel:  086-27-59403931(O) 
086-13689001185(Cell) 
Email: sqhui@oryzogen.com 
WEITAO WU 
Medical Director 
Tel:  086-18710439305 
Email: wwtao@oryzogen.com 
   
 
 
 
 
 
 
 
 
 
 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
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Version: 1.2 
 
 
 
CONFIDENTIAL 
Page 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase  
ANC 
Absolute number of neutrophils 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
ConMeds 
Concomitant medications 
CRF (eCRF) 
Case Report Form (Electronic Case Report Form) 
CRO 
Contract Research Organization 
CSR 
Clinical study report  
CT 
Computed Tomography 
DLT 
Dose Limiting Toxicity  
DNA 
Deoxyribonucleic acid 
DP 
Drug Product 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EOS 
End-of-Study  
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 

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Protocol Number: US-HY1001 
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GMP 
Good Manufacturing Practice 
H1 
Histamine-1 
HbcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B Surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest noseverely toxic dose 
HR 
Heart rate 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form       
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reaction 
IUD 
intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenously 
IVIG 
IV immunoglobulin 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCSF 
Macrophage Colony-Stimulating Factor 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging  
MRSD 
Maximum Recommended Starting Dose  
Nabs 
Neutralizing antibodies 

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NYHA 
New York Heart Association 
PDF 
Portable Document Format 
PDX 
Patient derived xenograft 
PE 
Physical examination 
PET 
Positron emission therapy 
PK 
Pharmacokinetics  
PT 
Prothrombin time 
QA 
Quality assurance 
QC 
Quality control 
QTcF 
QT-interval corrected according to Fridericia's formula 
RBC 
Red blood cells 
RDW 
Red Cell Distribution Width 
REB 
Research Ethics Board 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SMP 
Study Monitoring Plan 
SOC 
System organ class 
SOP 
Standard Operating Procedures 
SPR 
Surface plasma resonance 
SRC 
Safety Review Committee 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TCR 
Tissue cross-reactivity  
TEAE 
Treatment Emergent Adverse Event  
TK 
Toxicokinetics 
ULN 
Upper Limit of Normal 
UPCR 
Urine Protein to Creatinine Ratio 
WBC 
White Blood Cells 
 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
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Version: 1.2 
 
 
 
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1 PROTOCOL SUMMARIES 
1.1 
Synopsis 
Title: 
A Phase 1 randomized, double blinded, placebo-controlled single 
dose escalation study of OsrHSA in adult healthy male and female 
volunteers 
 
Sponsor: 
Wuhan Healthgen Biotechnology Corporation 
 
Study Drug: 
OsrHSA (Recombinant Human Albumin from Oryza sativa) for 
infusion 
Normal Saline (0.9% Sodium Chloride) will be used as the placebo 
Clinical Trial Phase: 
Phase 1 
Proposed Indication: 
Circulatory dysfunction due to hypovolemia, including patients 
with cirrhotic ascites and hypoalbuminemia 
 
Primary Objectives: 
 
 
 
• To assess the safety and tolerability profile of OsrHSA 
when administered as single dose IV infusion 
 
Secondary Objectives: 
 
 
• To characterize the pharmacokinetics (PK) of OsrHSA 
when administered as single dose IV infusion 
• immunogenicity profiles of OsrHSA when administered as 
single dose IV infusion 
Exploratory 
To assess changes in serum albumin level, colloid osmotic 
pressure, 
blood 
pressure 
and 
body 
weight 
when 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
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Version: 1.2 
 
 
 
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Objectives: 
 
administered as single dose IV infusion  
Study Population: 
Healthy male and female volunteers, non-smokers, 18-55 years of 
age 
 
Number of Subjects 
planned: 
Up to 40 subjects, additional subjects might be recruited depending 
on emerging data from current study and the ongoing trial in China 
 
Number of Study 
Centers Planned: 
One study site located in the United States 
 
Study Design: 
This is a Phase 1 randomized, double blinded, placebo-controlled, 
single dose escalation study to evaluate safety, tolerability, PK, and 
immunogenicity of OsrHSA in healthy volunteers (See study 
design schema).  
After a screening period of up to 28 days, the qualified subjects will 
be randomized to OsrHSA or placebo (6:2). Each enrolled subject 
will receive one single assigned dose of OsrHSA or placebo. The 
investigator and subjects will be blinded to treatment assignment. 
During the study, subjects will be evaluated for safety and 
tolerability, PK/PD, and activity of OsrHSA. 
On day 1, OsrHSA or placebo will be administered as single IV 
infusion at a rate lower than 2 ml/min to the subjects. Patients will 
be observed overnight. On Day 2, after completion of the study 
procedures and assessments, subjects will be discharged from the 
clinical research center. Seven-day dose-limiting toxicity (DLT) 
observational period will commence upon completion of dosing at 
the end of infusion (EOI). Subjects will have end-of-study (EOS) 
follow-up visits on Day 30 after infusion. 
The planned doses are 20, 40, 80, 140, and 200 mg/kg, dose 
level(s) higher than 200mg/kg might be an option(s) based on 
emerging data from this study and ongoing China clinical trial
（China IND#: CXSL1500135; Protocol Number: HY1001）.  
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
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Dose escalation decisions will be determined based on toxicities 
data as well as available all available PK data observed within 7 
days after dosing. 
 
Study participation 
Duration: 
The screening period is up to 28 days, one treatment day, and 
follow-up period of 30 days 
 
Pharmacokinetic (PK) 
evaluations: 
Blood samples for single dose PK will be collected from all 
subjects to determine the albumin concentration changes, they will 
be taken at time points listed in Table 1. The PK of OsrHSA will 
be analyzed using standard non-compartmental analysis (NCA) by 
validated software WinNonLin version 6.4 or higher (Certara, NJ, 
USA). PK parameters derived from NCA analysis will include, but 
not limit to, AUC0-∞ and AUC0-t, Cmax, t1/2, CL, and Vd. PK 
parameters will be listed for each subject and summarized with 
descriptive statistics by each dose level/cohort. PK parameters will 
also be presented with baseline corrected. 
Blood samples for immunogenicity will be collected at time points 
shown in Table 1. Neutralization activity will be evaluated if ADA 
is positive. 
 
Safety Evaluations: 
The safety population will consist of all subjects who are infused 
the study drug and have at least one post-dose safety assessment. 
Safety will be assessed by physical examinations, vital signs, 
electrocardiograms, AEs monitoring. AEs are graded per Guidance 
for Industry Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials.  
Efficacy Evaluations: 
The parameters including, but not limited to, serum albumin level, 
colloid osmotic pressure, blood pressure, 24-hour fluid input and 
urine output, and body weight will be measured at baseline and at 
time points listed in Table 1. The changes in serum albumin level, 
colloid osmotic pressure, blood pressure, body weight and other 
parameters will be assessed. 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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Immunogenicity: 
Blood samples for immunogenicity will be collected until 30 days 
after the infusion  
Statistical Analysis: 
All PK, immunogenicity, safety and efficacy data will be 
summarized using descriptive statistics (number of subjects, mean, 
median, standard deviation, minimum, and maximum) for 
continuous variables and using frequencies and percentages for 
discrete variables.   
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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Page 18 
1.2 
Study Design Schema 
Figure 1 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
CONFIDENTIAL 
Page 19 
1.3 
Schedule of Activities  
a. Screening procedures will be performed at screening visits from D-28 to D-2, including ultrasound, smoking, alcohol, drug 
use test, serum albumin. Pre-dose from D-1 to infusion, smoking, alcohol, drug use test, serum albumin will be performed 
again. (The two times serum albumin average will be used as subject’s baseline serum albumin) 
b. Urine collection will be performed 24hr after infusion 
c. The 0.5h time point after dose initiation will change to ± 5 minute window (instead of ± 2minute).   
d. The D3 and D5 time points will change to ± 6 hour window (instead of ± 4h) 
e. Abdominal ultrasound exam will be performed and reviewed during the 28 day screening period, prior to patient check-in 
on Day -1 
f. Alcohol and Cotinine will be tested at all follow-up visits (D3, D5, D8, D15, D22, D30) 
g. Syphilis will be tested at the screening timepoint, in order to adhere to the new exclusion criteria described above 
h. Anti-HCP antibody will be measured at the same time points as ADA 
i. In order to calculate accurate creatinine clearance, subjects’ body weight will be re-measured at Day 8 and Day 30 visits. 
j.  
 
Table 1 Schedule of Activities 
Protocol   Activity 
 
Clinical Research Unit (CRU) Confinement 
Outpatient Visits 
 
Scree
n 
-D28 
to  
– D2 
Pre-
dose 
-D1 
to 
dose 
Dose 
initiation 
 
0.5 h ± 
5m after 
Dose  
initiation 
1.0h ± 
10m 
after 
Dose 
initiation 
 
EOI+
10m 
0.5h 
Post 
EOI 
± 
10m 
4h 
± 
10m 
12h  
± 
10m 
D2 
24h  
± 30m 
D3 
± 6h 
D5 
± 6h 
D8 
± 1d 
D15 
± 2d 
D22 
± 2d 
D30 
± 2d 
Signed Informed Consent 
(ICF)1 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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Protocol   Activity 
 
Clinical Research Unit (CRU) Confinement 
Outpatient Visits 
 
Scree
n 
-D28 
to  
– D2 
Pre-
dose 
-D1 
to 
dose 
Dose 
initiation 
 
0.5 h ± 
5m after 
Dose  
initiation 
1.0h ± 
10m 
after 
Dose 
initiation 
 
EOI+
10m 
0.5h 
Post 
EOI 
± 
10m 
4h 
± 
10m 
12h  
± 
10m 
D2 
24h  
± 30m 
D3 
± 6h 
D5 
± 6h 
D8 
± 1d 
D15 
± 2d 
D22 
± 2d 
D30 
± 2d 
Demographics2 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight3 
× 
× 
 
 
 
 
 
 
 
× 
× 
 
x 
 
 
x 
Medical History4 
× 
× 
 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
Physical Examination5 
× 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Current 
Medications/OTC/suppleme
nts 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
Vital Signs6 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
12 Lead Electrocardiogram 
(ECG)7 
× 
× 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Abdominal Ultrasound)8 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events (AE)  
Ongoing 
Laboratory Tests 
Urine Drug Screen 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
× 
× 
 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
Urine Cotinine Test 
× 
× 
 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
Pregnancy Test for Female9 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
Ig E and Ig G Against Rice 
× 
 
 
 
 
 
 
 
× 
 
× 
× 
 
× 
 
× 
Hematology & Serum 
Chemistry10 
× 
× 
 
 
 
 
× 
 
 
× 
 
 
× 
 
 
× 
Coagulation Tests 
× 
 
 
 
 
 
 
 
 
 
 
 
× 
 
 
 
Screening for HIV, HBV, 
HCV, Syphilis 11 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Analysis (U/A)12 
× 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Study Drug Administration 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection Site Reaction 
 
× 
 
× 
 
× 
× 
 
× 
× 
 
 
 
 
 
 
Pharmacokinetics (PK)13 
 
× 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Colloid Osmotic Pressure14 
 
 
× 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Anti-Drug Antibodies 
(ADA); Anti-HCP antibody 
15 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
× 
× 
× 

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Protocol Number: US-HY1001 
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Abbreviations: ADA = anti-drug antibody; EOI=End of Infusion; EOS=End of Study; EOT=End of Treatment; ECOG = Eastern Cooperative Oncology Group; 
ConMeds = Concomitant medications; CT = computed tomography; MRI = magnetic resonance imaging; HIV = human immunodeficiency virus; HBV = 
hepatitis B virus; HCV = hepatitis C virus; PD = pharmacodynamics; PK = pharmacokinetics 
1. 
Written consent must be obtained prior to performing any protocol specific procedure. 
2. 
Age, height, gender, ethnicity, and race at screening where possible. 
3. 
Body weight will be measured at screening, predose and postdose at Day 2, D 3, Day 8 and Day 30 visits ..  24-hour liquid input (drinking water) and output 
(urine) will be recorded post EOI 
4. 
Medical History:  includes any significant or relevant diseases, surgeries, or other medical events during the past 5 years and any new conditions arising while 
enrolled in the study.  
5. 
PE: Full physical examination including the cardiovascular, pulmonary, GI, and nerve system, and skin will be performed at screening and EOS visits, and partial 
physical examination can be done at other visits to assess any abnormalities or change from baseline, including focused skin and cardiopulmonary examination.  
6. 
Vital signs include temperature, pulse, respiratory rate, and blood pressure. Vital signs will be assessed at screening and on the visits at the clinical research unit. 
Vital sign will be performed within 30 minutes prior to the infusion, at the EOI (+ 5 minutes) and before every PK sampling. Additionally, blood pressure will be 
measured every 10 minutes during infusion, every 30 min post EOI up to 6 hours, every 1 hour after 6 hours up to 12 hours post EOI, and every 2 hours until 24 
hours post EOI or discharge, and at every outpatient visit. Blood pressure should be measured prior to Colloid osmotic pressure sampling when blood pressure 
measuring and colloid osmotic pressure sampling are specified to be done at the same time.  
7. 
ECGs (12 lead) will be collected at screening, predose, during infusion(1hr),and EOI, prior to PK sampling during Day 1, and as clinically indicated, and at EOS. 
8. 
Abdominal ultrasound exam will be performed and reviewed during the 28 day screening period, prior to patient check-in on Day -1 
9. 
Only in women of childbearing potential. Urine pregnancy test will be done at screening and EOS, serum pregnancy test will be done pre-dose and on D15, or as 
clinically indicated. 
10. Hematology includes Complete blood count (CBC) (hematocrit (HCT), hemoglobin, red blood cells (RBC), Red Cell Distribution Width (RDW), Mean 
Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), platelets, white blood cells (WBC) 
with absolute differential counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils).  Serum Chemistry ALT, AST, ALP, K+, Na+, Cl-, Ca2+, 
TBIL, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted).  
11. HIV screening (Antigen/antibody test), HCV antibodies, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), total hepatitis B core antibody 
(anti-HBc), IgM antibody to hepatitis B core antigen (IgM anti-HBc), Syphilis.  
12. Twenty-four hours urine for D1 after the administration will be collected for 24 hours urine protein. Dipstick is acceptable for other time points. Microscopic analyses if 
clinically indicated. If ≥ 2+ protein on urine dipstick, then collect spot urine sample to calculate urine protein to creatinine ratio (UPCR) or collect 24h urine.  
13. PK samples (Serum albumin) will be collected at pre-dose, 0.5h after dose initiating, EOI, and 0.5h, 4h, 12h, 24h (Day 2), 48h (Day 3), Day 5, Day 8, Day 15, Day 
22, and Day 30 post EOI. The exact/actual time to collect blood will be documented.  
14. Colloid osmotic pressure will be measured within 30 min predose, every 30 min after dose initiating until EOI, EOI, every 1 hour up to 6 hours post EOI, every 2 
hour after 6 hours up to 12 hours post EOI, and every 4 hours until 24 hours post EOI or discharge, 48h (D3), D5, D8, D15, D22, and D30 post EOI. Blood 
pressure should be measured prior to each colloid osmotic pressure sampling. 
15. Blood samples for ADA and Anti-HCP antibody analyses will be collected at pre-dose, D8, D15, D22, and D30 post EOI. 

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2 INTRODUCTION 
2.1 
Background  
Human serum albumin (HSA), the main protein of human blood plasma, is a soluble, globular, 
and unglycosylated monomeric protein. It is responsible for 70-80% of colloid pressure of 
normal plasma, thus plays a primary role in regulating blood volume by maintaining the colloid 
osmotic pressure and stabilizing extracellular fluid volume. HSA also functions as a carrier 
protein for steroids, fatty acids, hormones, and small molecules (1).  
Clinically, HSA is widely used for restoration and maintenance of circulating blood volume 
where volume deficiency has been demonstrated and use of a colloid is appropriate, such as adult 
respiratory distress syndrome, hypovolemia, large-volume paracentesis, ovarian hyperstimulation 
syndrome, plasma exchange, and ascites caused by cirrhosis of the liver (2, 3). Moreover, HSA is 
also used as an excipient for vaccines or therapeutic protein drugs and as a cell culture medium 
supplement in the production of vaccines and pharmaceuticals (4). Many other novel uses for 
HSA in biological applications have recently been explored, such as carrier of oxygen (5), 
nanodelivery of drugs (6), and fusion of peptides (7). Currently, clinical used production of HSA 
is primarily based on collected human plasma, which raises a public health concern with plasma-
derived HSA (pHSA) with its potential risk for transmission of blood-derived infectious 
pathogens, such as bacteria (syphilis, Chagas disease), viruses (including but not limited to HBV, 
HCV, HIV, HTLV, West Nile virus, CMV) and prions (Mad Cow Disease) (9, 10). The market 
demand for HSA is estimated around 1000（Human Serum Albumin Market In-deep Analysis 
and Experts Review Report 2019-2024） tons per year worldwide. It was reported that the 
shortage of human plasma led to a rapid increase in price of HSA, which in turn resulted in fake 
albumin appearing on the market (8). In fact, illegal plasma collection has caused HIV to spread 
rapidly, creating what are known as AIDS villages in Henan Province in China (11). 
The development of screening has been greatly decreased the risk for transmission of blood-
derived infectious pathogens, however, the risk has never been eliminated and is always there. 
To eliminate the potential risk of viral contamination, regulatory agencies in some have 
encouraged pharmaceutical companies to use non–animal-derived sources for pharmaceutical 
production (12). Thus, the development of a low-cost method for the production of recombinant 
HSA (rHSA) is essential as a safer and potentially unlimited alternative to pHSA. 
Over the past decades, various expression systems have been used to produce rHSA, including 
Escherichia coli (13), Saccharomyces cerevisiae (14), Kluyveromyces lactis (15), Pichia pastoris 
(16), transgenic animals (17), and transgenic plants (18–21). Attempts to produce rHSA in 
tobacco leaves and potato tubers achieved expression levels of 0.02% of total soluble protein 
(TSP) (18), and expression was increased to 0.2% of TSP by targeting the rHSA to the apoplast 
of potato tubers (19). Recently, an expression level of 11.1% of TSP was obtained by expressing 

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rHSA in tobacco leaf chloroplasts (20). More recently, an rHSA expression level of 11.5% of 
total proteins was achieved in a rice cell culture by a sugar starvation-induced promoter (21). 
Although rHSA has been successfully expressed in these systems, none of them has proven to be 
cost-effective at large scale. 
Plant seeds, especially cereal crop seeds, are promising vehicles for producing recombinant 
proteins, because they can achieve high accumulation of recombinant protein, display high levels 
of protein stability, stored for long periods of time, and are well controlled on a production scale 
(22, 23). Human lysozyme and lactoferrin produced for oral administration have been 
successfully expressed in rice seeds (24, 25). Here, Healthgen developed rice seeds as a 
bioreactor for large-scale production of Oryza sativa recombinant HSA (OsrHSA). OsrHSA can 
be highly and stably expressed in rice seeds and can be processed cost-effectively. OsrHSA was 
found to be equivalent to pHSA in terms of biochemical properties, physical structure, functions, 
and immunogenicity. 
2.2 
Risk/Benefit Analysis 
Potential risks to subjects receiving OsrHSA are considered to be similar to pHSA, which have 
been shown to be well-tolerated in general. As there is no difference in in vivo efficacy, 
immunopharmacological activity, safety pharmacology, toxicology, and pharmacokinetic 
profiles observed between OsrHSA and HpHSA, OsrHSA is expected to have similar clinical 
effects as HpHSA in indications that are currently approved for HpHSA. 
Furthermore, a randomized, double blinded, positive-controlled Phase 1 single dose and dose 
escalation study to evaluate safety, tolerability, PK and PD (PK/PD) of OsrHSA in adult healthy 
volunteers (IND Number: CXSL1500135; Protocol Number: HY1001) is ongoing in China. The 
planned dose levels in this study are 2.5, 5, 10, 15 and 20 g, IV, which are equal to 35.7, 71.4, 
142.9, 214.3, and 285.7 mg/kg respectivelly, assuming a body weight of 70 kg.  
The current available data of dose level of 2.5 g (35.7 mg/kg assuming body weight of 70 kg) 
have been showing an acceptable safety profile. Five subjects have received 2.5 grams, IV, 
OsrHSA in clinical trial in China. The data indicated that ADA and anti-HCP antibody were 
negative at 85 days (5 subjects) of post-dosing. No cytokines promotion was found at 28 days (5 
subjects) of post-dosing. No allergic and hypersensitivity symptom was observed during or at 
post-dosing. One subject with SAE of ALT, AST and GGT increasing was observed at 7 day of 
post-dosing. This subject had a gall-stone with size 1.5*1.4cm in cystic duct by ultrasound 
examination. He was diagnosed a biliary obstruction cholecystitis with gall-stone. The subject 
recovered after 7 days of the symptom and left the investigative center. The safety assessment of 
SAE was performed by DSMB. The conclusion is that the SAE was caused by biliary obstruction 
cholecystitis. It is most likely no relevant to OsrHSA. The current data from clinical trial in the 
China indicated that the risks to subjects receiving OsrHSA is acceptable. 
Additional safety and PK/PD data from the Phase 1 study ongoing in China will be provide once 
available. 

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2.3 
In summary, the risk/benefit balance is considered acceptable to administer OsrHSA 
to healthy volunteers. Preclinical Studies 
 Non-clinical Pharmacology 
The nonclinical pharmacology program for OsrHSA has been designed to evaluate the in vivo 
efficacy, immunopharmacological activity and safety profiles in animals to predict the 
pharmacologic profile of OsrHSA in human. The in vivo efficacy of OsrHSA was evaluated in 
the treatment of ascites of high-fat diet induced hepatic cirrhosis in a Wistar rat model, as well as 
in hemorrhagic shock model using male Japanese rabbits. Similar efficacy of OsrHSA and 
HpHSA has been demonstrated in these two animal disease models. 
The effects of OsrHSA on the immune function of mammalian systems were investigated in 
three studies. No active systemic anaphylaxis (ASA) reaction was induced in rabbits, after 
primed with OsrHSA/CFA and challenged with OsrHSA/IFA, with, no elevated total IgG, IgM, 
IgA, IgE production detected. No passive cutaneous anaphylaxis (PCA) induced in the guinea 
pigs after transfer the sensitized serum from the rabbits. 1/1436 and 0/200 anti-HCP IgE 
antibody was detected in a preliminary non GLP study and an US-GLP study, suggesting a low 
risk of the HCP from Oryza sativa in inducing allergic responses in humans. T-cell mediated 
DTH study confirmed that OsrHSA and HpHSA were weakly immunogenic in soluble forms as 
a foreign antigen to mice.  If administered as soluble proteins, OsrHSA was unable to induce 
DTH response in mice, which suggested a low risk of inducing type IV hypersensitivity in 
human subjects. 
 Non-clinical Pharmacokinetics 
The pharmacokinetic (PK) and toxicokinetics (TK) profiles of OsrHSA were characterized in 
rats and monkeys following intravenous administration, which is the intended route of 
administration in human. In order to distinguish exogenous OsrHSA from endogenous rat serum 
albumin, OsrHSA was labeled with 125I by Chloramine-T method before administration. 
Distribution, metabolism and excretion was evaluated in the single-dose PK study in rats. 
OsrHSA is expected to behave like HSA, an endogenous protein, in drug transportation as well 
as in interactions with CYP enzymes or other drug transporters. Therefore, no pharmacokinetic 
drug interaction studies of OsrHSA were conducted. 
HpHSA was included as a benchmark control and compared with OsrHSA side-by-side in 
several pharmacokinetic and toxicokinetics studies. HpHSA and OsrHSA showed similar PK and 
TK profile among all the studies, except HpHSA showed stronger immunogenicity in rats 
following repeat dose administration. 

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 Safety Pharmacology and Toxicology 
Safety pharmacology was conducted in mice to evaluate the effect on CNS function, as well as in 
cynomolgus monkeys to evaluate the effect on cardiovascular and respiratory functions. HpHSA 
was included as a control in all these studies to detect off-target or impurity induced side effects. 
Because of pre-clinical and clinical experiences over many years of using with HpHSA, the full 
battery of toxicology studies conducted were not to evaluate the pharmacological and 
toxicological effects of the active ingredient albumin in OsrHSA, but mainly to evaluate 
unexpected toxic activities due to the impurities in the OsrHSA drug product. Evaluation of the 
potential risk to humans receiving OsrHSA was conducted in a series of US-GLP compliant 
toxicology studies according to 21 CFR 58. 
While albumin are variable among the species, the tertiary structures and biological functions are 
highly conserved (Nurdiansyah, R., Rifa’I, M. 2016). Since the MOA of albumin for treatment of 
circulatory dysfunction is attribute to the increase of plasma volume, which is similar among 
species, therefore, multiple species (both rodent and non-rodent) were included in the toxicology 
evaluation. 
Single-dose study in rats, 2-week repeat-dose with 4-week recovery phase studies in rats and 
monkeys were conducted to assess the toxicity and toxic organs as well as the reversibility, 
persistence, or delayed occurrence of any safety findings. Among these studies, the toxic levels 
and toxic organs identified were similar in animals treated OsrHSA and HpHSA. The treatment-
related clinical and pathological changes were directly resulted from the biologic functions of 
albumin, and the daily injection induced fluid overload and increased blood pressure. No 
OsrHSA specific toxicity was identified, indicating the entire formulation of OsrHSA, including 
all possible impurities, exerted similar biological function, as well as toxicity at high dose, as that 
of the formulation of HpHSA. Both OsrHSA and HpHSA were immunogenic in animals via i.v. 
dosing. Formation of ADA was prevalent in rats and monkeys, although no impact on TK or 
systemic exposures were observed. Regardless with HSA formulation administered, ADA 
formed can be cross-recognized by the other HSA reagent, indicating that these ADA were 
against the same epitopes common in both OsrHSA and HpHSA, further supported the tertiary 
structure similarity between OsrHSA and HpHSA. 
A full battery of study was conducted to evaluate the genotoxicity of OsrHSA as required in ICH 
S2 (R1) on Genotoxicity testing and Data Interpretation for Pharmaceuticals Intended for Human 
Use, June 2012. Ames test, chromosomal aberration test as well as in vivo micronucleus study 
confirmed that OsrHSA has no potential genotoxicity. 
Host cell protein (HCP) is the main impurity in the formulations of OsrHSA. The potential 
toxicity and immunogenicity induced by HCP was evaluated in a 2-week daily repeat i.v. dose 
non-GLP study in SD rats. No clinical findings were observed for 25 µg/kg HCP, that is 
equivalent to the possible HCP presented in 5 g/kg OsrHSA.

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3 OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
Primary Objectives: 
• To assess the safety and tolerability profile of OsrHSA when IV administered as single 
dose  
Secondary Objectives: 
• 
To characterize the PK of OsrHSA when IV administered as single dose 
• 
Immunogenicity profiles of OsrHSA when IV administered as single dose  
 
Exploratory Objectives:  
• To assess changes in serum albumin level, colloid osmotic pressure, blood pressure and 
body weight when IV administered as single dose  
3.2 
Endpoints 
Primary Endpoints 
1) Safety and tolerability profile including adverse events, changes in safety assessment 
parameters (e.g. vitals, ECGs, clinical laboratory results) 
Secondary Endpoints 
1) PK parameters: AUC0-∞ and AUC0-t , Cmax, t1/2, CL, Vss, etc. 
2) ADA: Samples confirmed to be positive for ADA will be further tested for NAb. 
Exploratory Endpoints 
• Changes in serum albumin level and colloid osmotic pressure  
• Changes in body weight and blood pressure 
 
 

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4 STUDY DESIGN 
4.1 
Overall Study Design 
This is a Phase 1 randomized, double blinded, placebo-controlled, single dose escalation study in 
healthy volunteers to evaluate safety, tolerability, PK, PD and immunogenicity of OsrHSA (See 
study design schema).  
4.2 
 Study Process 
The trial will include a screening period, treatment period, and follow-up period of 30 days 
after administration. The screening period will be up to 28 days prior to investigational product 
administration. The screening process will initiate upon completion of the informed consent 
process. Once consent is provided by each participant, a thorough screening process will take 
place, including detailed medical history, physical examination, vital signs, concomitant 
medications, safety labs (see Table 1), 12 lead electrocardiogram, urine pregnancy test, 
urinalysis, serology panel (refer Table 1), assessment of inclusion and exclusion criteria. Upon 
completion of the screening, qualified subjects will be randomized to OsrHSA or placebo (6:2). 
Each enrolled subject will receive one single assigned dose of OsrHSA or placebo. The 
investigator and subjects will be blinded to treatment assignment. During the study, subjects will 
be evaluated for safety and toxicity, PK/PD, and activity of OsrHSA. 
OsrHSA or placebo will be administered as single IV infusion at a rate lower than 2 ml/ min to 
the subjects. The actual start and stop times of the infusions, along with any interruptions in the 
infusion will be recorded. Subjects will have end-of-study (EOS) follow-up visits on Day 30 
after infusion. 
The planned doses are 20, 40, 80, 140, and 200 mg/kg (Table 2), dose level(s) higher than 200 
mg/kg might be an option(s) based on emerging data from this study and ongoing China clinical 
trial, if that is the case, an amendment will be submitted. 
The protocol for the repeat dose study will be submitted as an amendment to the IND after the 
single dose study has been completed and analyzed. The dose schedule of the repeat dose study 
will be based on results obtained from the single dose study. The safety of the dose that will be 
used in the repeat dose study will be established before the initiation of the repeat dose study. 
Dose escalation will occur sequentially after review of safety data for each dosing cohort by the 
safety review committee (SRC). Dose escalation to the next dose level will proceed 
uninterrupted as long as no pre-defined DLT or stopping criteria are met. 
 Definition of Dose Limiting Toxicity (DLT): 
AEs will be graded according to the FDA Guidance for Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. DLT is 

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defined according to the criteria below as any TEAEs occurring during the DLT observation 
period (7 days) and considered to be related to OsrHSA: 
Any Grade≥ 3 AE or laboratory abnormality as defined in the FDA Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials 
All Grade 3 toxicities for vital signs and laboratory parameters must be confirmed with a repeat 
measurement obtained within 1 hour or as soon as possible for vital signs and within 24 hours for 
laboratory parameters.  
 
Table 2 Dose Escalation Schedule 
Dose Escalation Level 
Dose (mg/kg) 
Subjects 
(OsrHSA:placebo) 
cohort 1 
20, IV  
8(6:2) 
cohort 2 
40, IV  
8(6:2) 
cohort 3 
80, IV  
8(6:2) 
cohort 4 
140, IV 
8(6:2) 
cohort 5 
200, IV 
8(6:2) 
 
 Dose-escalation Criteria: 
Tolerability and safety of subjects in a cohort will be reviewed by the SRC which is comprised 
of an independent Medical Monitor, site Principal Investigator, and Sponsor Study Director. 
Dose escalation may be stopped at any time based upon the Sponsor or Investigator’s clinical 
assessment or judgment. Upon completion of the DLT observational period (first week after 
dosing), the SRC will examine safety data through Week 1 for each dose cohort in combination 
with all available, previously accumulated safety data, as well as available PK data, if any, from 
all subjects enrolled in the study to date. All cohorts will enroll 8 subjects (safety data from at 
least 6 or 7 subjects would be needed for SRC meeting, in case a subject discontinues the study), 
if no more than 2 out of 8 subjects experiences DLT as defined in the section 4.2.1, dose will be 
escalated to the next dose level.  
 Subject Stopping Criteria:  
Dosing will be permanently stopped for any individual subject experiencing any of the following: 
• 
Any SAE, regardless of causality to the study drug. 

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• 
Subject experience DLT. 
• 
Hypersensitivity or anaphylactic reaction following start of infusion. 
• 
Medical condition that is judged by the Investigator as to jeopardize the subject’s safety if he or she 
continues to receive the study drug. 
• 
QTc prolongation defined as QTcF increasing ≥ 60 msec and persisting for at least 10 minutes or 
QTcF > 500 msec and persisting for at least 30 minutes, or episode of torsade de pointes. 
 Dose Escalation Stopping Criteria:  
Dose escalation will not occur if any of the following criteria are met: 
• Subject stopping rules met for ≥ 2 subjects in the same cohort suggesting to the 
Investigator that other subjects in the cohort are at risk for similar adverse drug 
reactions. 
• Any SAE as defined in the section 10.1 in any participant receiving study drug 
unless obviously not related. 
•  ≥2 out of 8 subjects experience toxicity ≥ Grade 3 as defined in the Food and 
Drug Administration (FDA) Guidance for Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. 
The safety review will initially be performed on blinded data, and if any of the above criteria are 
met, the cohort will be subsequently unblinded to all SRC members and the safety and 
tolerability reassessed. Upon unblinding, the dose may be determined to be safe and tolerable, on 
the basis of events observed in the OsrHSA vs. placebo groups, allowing for dose escalation to 
proceed. 
 
4.3 
Rationale for Starting Dose and Maximum Dose Selection 
As there is no difference in in vivo efficacy, immunopharmacological activity, safety 
pharmacology, toxicology, and pharmacokinetic profiles observed between OsrHSA and 
HpHSA, OsrHSA is expected to have similar exposure and clinical effects as HpHSA in 
indications that are currently approved for HpHSA. The starting dose and the maximum dose for 
proposed US clinical trial of OsrHSA were selected based on the current clinical doses of 
HpHSA, which are in the range of 5 to 100 g (0.071 – 1.429 g/kg) [ Guidelines for Intravenous 
Albumin Administration at Stanford Health Care. Stanford Health Care.  Created: 03/2017 
Pharmacy Department] depending on the condition for which HpHSA is used to treat, for 
example, 50 to 100 g, IV, over 4 hours, repeat at 4 to 12 hours intervals as needed, can be used 
to treat ovarian hyperstimulation syndrome.  

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Regarding the potential toxicity of host cell proteins, daily i.v. infusions of 25 µg/kg HCP 
induced no clinical findings in rats. Thus, the proposed 1.5 g (0.021 g/kg, contains 0.10 µg/kg 
possible HCP) starting dose provides 40-fold safety margin from the 25 µg/kg HCP rat dose (4 
µg/kg HED, converted based on BSA). 
In an ongoing randomized, double blinded, positive-controlled Phase 1 single dose and dose 
escalation study of OsrHSA in adult healthy volunteers for safety, tolerability, PK and PD 
(PK/PD) study in China, five healthy volunteer were administerd single dose of 2.5 g OsrHSA 
(35.7 mg/kg assuming body weight of 70 kg), IV. The data indicated that ADA, anti-HCP 
antibody are negative at 85 days (5 subjects) of post-dosing. No cytokines promotion was found 
at 28 days (5 subjects) of post-dosing. No allergic and hypersensitivity symptom was observed 
during dosing or post dosing. One subject experienced abdominal pain and a transient 20 x 
elevation in ALT/AST. The subject was recovered and the AEs were considered highly likely 
due to pre-existing cholelithiasis and cholecystitis by DSMB. Another subject was found a 
transient 2.4x ALT/AST elevation without any symptoms and signs. Please see M2.7 for the 
detailed clinical data. 
The next dose levels of 5.0, 10, 15, and 20 g OsrHSA are being tested in healthy volunteer in 
China, data will be updated when data available. 
In summary, OsrHSA has shown acceptable safety profile at dose level of 35.7 mg/kg. The 
proposed starting dose of 20 mg/kg in the current protocol is justified by 1.8-fold lower than the 
tested dose in China and considered to be safe. 
5 PATIENT POPULATION  
5.1 
Number of Subjects and Description of Population 
This study will enroll up to 40 healthy male or female subjects, 8 subjects for each of 5 cohorts, 
18-55 years old, or more subjects might be recruited based on emerging data from this study and 
ongoing China clinical trial. Subject Selection and Numbering: 
5.2 
Inclusion Criteria 
Subjects must meet all the following criteria to be enrolled in the trial: 
1. Able to understand and willing to sign the ICF 
2. Healthy male and female subjects, non-smokers, 18-55 years of age, non-smokers, or 
subjects must have been non-smoking for at least 3 months prior to their screening visit 
3. Has adequate venous access 
4. With no significant medical history, and in good health as determined by detailed medical 
history (neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, 
psychiatric, gastrointestinal, renal, hepatic, and metabolic disease), full physical examination, 

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vital signs, 12-lead electrocardiogram (ECG), urinalysis and laboratory tests at screening. For 
eligibility purposes, abnormal laboratory or vital signs results may be repeated once if 
abnormal result is observed at the initial reading. Moreover, abnormalities found in the ECG 
may need to be confirmed by repeated measurements. 
5. Subjects must have adequate organ function according to the following laboratory values: 
o Bone marrow function (absolute neutrophil count ≥1500/mm3 and platelet count 
≥100,000/mm3) 
o Adequate liver function [alanine aminotransferase (ALT) ≤1.5 × 
upper limit normal (ULN) and alkaline phosphatase ≤1.5 × ULN, 
total bilirubin ≤1.5 mg/dL] 
o Adequate renal function creatinine clearance 60 mL/min based 
on Cockcroft- Gault equation, or serum creatinine level ≤1.5 
times the ULN. 
6. Be a female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant, including any female who is 2 years post-menopausal and have an FSH > 
40mIU/mL, or surgically sterile [defined as having a bilateral oophorectomy, hysterectomy 
or tubal ligation]) or agree to one of the following to prevent pregnancy and, if a woman of 
childbearing potential, have a negative urine pregnancy test at screening:  
- Practicing abstinence  
- If a sexually active woman of childbearing potential (sexually active with a non-sterile male 
partner) agrees to prevent pregnancy by using double methods of contraception as follow 
until at least 30 days after the administration of the investigational product:  
a. simultaneous use of intra-uterine contraceptive device, placed at least 4 weeks prior to 
study drug administration, and condom for the male partner; 
b. simultaneous use of hormonal contraceptives, starting at least 4 weeks prior to study drug 
administration and must agree to use the same hormonal contraceptive throughout the 
study, and condom for the male partner; 
c. simultaneous use of diaphragm with intravaginally applied spermicide and male condom 
for the male partner, starting at least 21 days prior to study drug administration. 
 
- Male subjects who are not vasectomized for at least 6 months and who are sexually active 
with a non-sterile female partner must agree to use double methods of contraception below 

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from the first dose of randomized study drug until 90 days after their dose and must not 
donate sperm during their study participation period: 
a)  simultaneous use of a male condom and, for the female partner, hormonal contraceptives 
(used since at least 4 weeks) or intra-uterine contraceptive device (placed since at least 4 
weeks); 
b) simultaneous use of a male condom and, for the female partner, a diaphragm with 
intravaginally applied spermicide. 
7. Body mass index (BMI) 18-30 kg/m2 and body weight ≥ 50.0 kg for males and ≥ 45.0 kg for 
females. 
8. Blood pressure ≤ 139/89 mm Hg.  
9. Subjects are able to follow the study protocol and complete the trial. 
10. At least 25% of the enrolled subjects will be of Asian descent, defined as Chinese, Japanese, 
Korean, Vietnamese, Hmong, and their offspring.  
 
5.3 
Exclusion Criteria 
Subjects who meet any of the following criteria cannot be enrolled: 
1. 
History of severe infection within 4 weeks to dosing. 
2. 
Signs and symptoms of any active infection regardless of severity within 2 weeks prior to 
dosing. 
3. 
Meals & Dietary Restrictions: No seafood or high-fat food will be served during confinement 
in the clinical center 
4. 
Subjects who have any history of allergy to food or drug will be excluded ( Including 
allergies, hypersensitivity, or intolerance to rice or rice products ) 
5. 
Use of any prescription drugs,  herbal supplements, or nonprescription drugs including oral 
anti-histamines (for seasonal allergies) within 1 month or 5 half-lives (whichever is longer) 
prior to study drug administration, or dietary supplements within 1 week prior to study drug 
administration, unless, in the opinion of the Investigator and Sponsor, the medication will not 
interfere with the study. Over-the-counter multivitamins will be permitted. If needed, 
paracetamol/acetaminophen may be used, but must be documented in the Concomitant 
medications/Significant non-drug therapies page of the source data.  Any questions of 
concomitant medications should be directed to the Sponsor.  
6. 
Participation in a clinical research study involving the administration of an investigational or 
marketed drug or device within 30 days prior to the first dosing, administration of a 
biological product in the context of a clinical research study within 90 days prior to the first 

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dosing, or concomitant participation in an investigational study involving no drug or device 
administration. 
7. 
Donation of blood 12 week prior to dosing. 
8. 
Pregnant, or nursing females. 
9. 
A history of substance abuse, psychiatric and psychological condition that, in the judgment 
of the investigator, may interfere with the planned treatment and follow-up, affect subject 
compliance or place the subject at high risk from treatment-related complications 
10. 
A history of severe allergic reaction to any HpHSA component. 
11. 
A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTcF 
interval >450 milliseconds [ms]) 
12. 
History of or active obstructive disease in biliary tract, liver, kidney and spleen defined by 
ultrasound 
13. 
Subjects who test positive for hepatitis B or C. (no matter carriers or active will be excluded 
from the study 
14. 
Subjects who test positive for Syphilis, Human immunodeficiency virus (HIV) positive will 
also be excluded from the study  
15. 
Immunization with a live or attenuated vaccine is prohibited within 4 weeks prior to study 
drug administration. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed)  
16. 
Positive Ig E and Ig G against rice at screening 
17. 
History of significant alcohol abuse within one year prior to screening or regular use of 
alcohol within six months prior to the screening visit (more than fourteen units of alcohol per 
week [1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]) or positive 
alcohol breath test at screening 
18. 
History of significant drug abuse within one year prior to screening or use of soft drugs (such 
as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, 
phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine 
derivatives) within 1 year prior to screening 
19. 
Positive urine drug screen, cotinine test, or alcohol breath test at screening 
20. 
Any reason which, in the opinion of the Qualified Investigator, would prevent the subject 
from participating in the study. 
5.4 
Meals and Dietary Restrictions 
Subjects will receive a standard diet whilst resident in the clinical center. For standardization 
purpose, the study drug infusion will start at least 30 minutes after subjects have been served a 

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light breakfast. No food will be allowed until at least 1 hour after the end of infusion. 
Standardized meals will be served at appropriate times thereafter. 
Water will be provided ad libitum at all times. 
In addition, subjects will be required to abstain from: 
• food containing poppy seeds within 24 hours prior to admission; 
• food or beverages containing xanthine derivatives or xanthine-related compounds (coffee, 
black/green tea, chocolate) or energy drinks from 48 hours prior dosing until EOS; 
• dietary supplements within 1 week prior to study drug administration until EOS, unless, 
in the opinion of the Investigator and Sponsor, the dietary supplement will not interfere 
with the study; 
5.5 
Tobacco, Alcohol and Illicit Drugs 
Refrain from intake of alcoholic beverages from 72 hours prior to study treatment 
administration until Day 8 postdose. After Day 8, subjects are discouraged from 
consuming alcohol until the completion of the study, but may consume no more 
than 1 unit of alcohol per day. 
Subjects will be required to abstain from using nicotine products, or soft or hard 
drugs from screening and throughout the study. 
5.6 
Medication 
Use of any prescription, herbal supplements, or nonprescription drugs will be prohibited within 1 
month or 5 half-lives (whichever is longer) prior to study drug administration and until EOS, 
unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the 
study. No concomitant drug therapy will be allowed during the study except one(s) required for 
the medical management of an adverse event. 
Any concomitant medication use other than the occasional use of acetaminophen will be 
evaluated on a case-by-case basis by the Principal Investigator or a physician. The use of 
hormonal contraceptives will be allowed and documented. All concomitant medication use will 
be documented. 
5.7 
Activity 
Subjects should refrain from strenuous exercise for 48 hours before admission to 
the clinical center and throughout the study. Subjects may participate in light 
recreational activities during the study (eg, watching television, reading). 
Subjects will be advised not to donate blood or plasma from at least 12 weeks 
before study drug administration and for at least 3 months after the last dose 
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For safety reasons, subjects will be required to remain semi-reclined and avoid 
lying down or sleeping for the first 4 hours after the end of study drug infusion. 
However, failure of subjects to comply with these requirements does not 
constitute a deviation from the protocol if it is medically necessary, procedurally 
required, or to go to the bathroom. When appropriate, subjects will be 
accompanied by a staff member during ambulation.   
5.8 
Randomization and blinding 
Subjects in the clinical site will be 6:2 randomized to receive either the study 
product or placebo prior to dosing, the randomization code will not be available 
to the Bioanalytical Division until the clinical and analytical phases have been 
completed for each cohort. 
Both the principal investigator and subjects will be blinded as to whether a 
subject is receiving study product, or placebo. A designated person in the 
Investigational Pharmacy will dispense the appropriate drug accordingly. The 
Safety Review Committee can request unblinded randomization scheme in order 
to evaluate the data. 
Each bottle administered to subjects will have a unique code, and quick 
unblinding will be performed by Investigational Drug Pharmacy, the principal 
investigator, or the sponsor, should a medical emergency arise for a participant.  
Upon completion of the study participation, all subjects will be unblinded 

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6 STUDY INTERVENTION 
6.1 
Study Drug Description 
OsrHSA drug product is presented as a slightly viscous, yellow to brownish clear liquid packed in Type I 
neutral borosilicate moulded glass vial capped with chlorobutyl rubber stopper with Polytetrafluoroethylene 
(PTFE)/Polyhexafluoroethylene film and plastic-aluminum seal. Each vial contains 10 g OsrHSA protein, 0.261 
g sodium octanoate, 0.409 g sodium chloride, pH6.4~7.4. The total volume is 50 ml.  
Normal Saline (0.9% Sodium Chloride) will be used as the placebo. 
6.2 
Study Drug Packaging and Labeling 
OsrHSA drug product is packed in Type I neutral borosilicate moulded glass vial capped with chlorobutyl 
rubber stopper with Polytetrafluoroethylene (PTFE)/Polyhexafluoroethylene film and plastic-aluminum seal. 
There will be a carton package. The labels for carton and vial are shown below. 
Recombinant human serum albumin from Oryza sativa (OsrHSA). 20% solution with 10g of drug.   
 Drug Storage and Handling 
OsrHSA drug product is stored at 2-8℃, protected from light. At time of use, the drug product vial is directly 
connected to the infusion line equipped with a 0.2µm in-line filter and administered via IV infusion.  
 Study Drug Compliance and Accountability 
The site should record and maintain shipping and receiving records of the study drug, and report to the Sponsor 
immediately any defect or issues with quality, quantity or interruption in cold-chain shipping.  
The site will maintain accurate dosage preparation records and should ensure that all pertinent/required 
information on the preparation and administration of the dose is captured in source documents, and appropriate 
dosing information is entered onto eCRFs. Such information should be made available to the Sponsor’s site 
monitoring representative(s) during monitoring visits.  
 Disposal and Destruction 
Upon termination of the study, or at the request of the sponsor, the pharmacist (or designee) must return the 
study drugs to Sponsor, unless it is destroyed at the clinical site as agreed upon by both the sponsor and the 
clinical site. 
 Treatment Allocation and Administration, Dosing Regimen 
This is a Phase 1 randomized, double blinded, placebo-controlled study. Subjects will be randomized. Both 
subjects and investigator will be blinded.  

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1. Parenteral drug products should be prepared by using appropriate aseptic technique, and inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container permit.  
2. Treatment Allocation and Administration: OsrHSA will be diluted with normal saline to a total volume of 200ml
The total infusion time will be 2hr ± 20min. 
 The OsrHSA infusion rate is lower than 2ml/min. The procedures used for administration are following: 
• 
First, set up intravenous channel and intravenous injection of 50 ml saline. The infusion rate for 
normal saline will be 5ml/min.  
• 
Second, OsrHSA or placebo will be administered via an infusion line equipped with a 0.2µm in-line 
filter. And monitor for infusion-related AEs during administration. The rate of intravenous should be 
lower than 2 ml/ min and cautions should be taken. Dose interruption based on intolerability will be 
captured in the monitoring of infusion start and stop times. 
• 
Third, flush with 50ml normal Saline after the dose. The infusion rate for normal saline will be 5ml/min.  
  
 
All dose administrations will be performed in the clinical center under the supervision of appropriately trained 
staff. 
Further detailed instructions on handling and administration of study drug is described in the separate Pharmacy 
Manual.  
6.3 
Duration of Treatment 
This is a single dose study. 
• 50ml with 
normal Saline 
IV infusion 
1
• Dilute OsrHSA
with normal saline 
to total volume 200 
ml for IV infusion 
2
• Flush with 50 
ml normal 
saline after 
the dose
3

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6.4 
Removal from Study Treatment and off-Study Criteria  
Participation in this research study is completely voluntary. Subjects are free to withdraw from this study at any 
time by informing the investigator. If a subject, for whatever reason, no longer appropriate to continue receiving 
study therapy, they will be notified and withdrawn from the study. Furthermore, if the subject is non-compliant 
(e.g. non-compliant with visits, concomitant medications.) they will be withdrawn from the study and a 
replacement subject may be recruited. 
Additionally, prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.  
 Criteria for Removal from Study Treatment 
• Completion of protocol therapy 
• Participant requests to be withdrawn from the study 
• Investigator discretion 
• Lost to follow-up or noncompliance 
• AEs or safety concerns by Investigator or Sponsor  
• Positive alcohol test, cotinine test, or drug screen 
• Positive pregnancy test. 
 Off-Study Criteria 
Once a subject is taken off study, no further data can be collected.   
• 
Participant request to be withdrawn from study 
• 
Subject withdrawal from the follow-up period 
• 
Subject completed all protocol required follow-ups 
• 
Death 
• 
Screen failure 
 Subject Replacement 
Subjects who do not receive the full dose of study drug, or who withdraw from the study or with 
significant protocol violations may be replaced at the discretion of the investigator after 
informing the Sponsor.

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7 STUDY ASSESSMENT AND EVALUATIONS 
7.1 
Description of Assessment Procedures 
Below are additional descriptions of study assessments not detailed in Table 1.  
Recording of AEs: AEs should be documented and recorded per Guidance for Industry Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials. After signing ICF and before the administration, only SAEs related to study 
intervention will be recorded. All AEs will be recorded once dosing starts and subjects must be 
followed for AEs for 30 days after the administration, or until all drug related toxicities have 
resolved, whichever is later. After 30 days only SAEs considered related to study treatment will 
continue to be recorded. 
7.2 
Blood Samples for PK evaluations 
Blood samples will be collected at pre-dose, 0.5h after dose initiating, EOI, and 0.5h, 4h, 12h, 
24h (Day 2), 48h (Day 3), Day 5, Day 8, Day 15, Day 22, and Day 30 post EOI, from all subjects 
to determine the serum concentration of OsrHSA using a validated immunoassay for PK 
analyses. Approximately 3 mL blood will be collected at each of the following time points. 
Serum will be separated and stored for bioanalysis of OsrHSA concentration with a validated 
assay. The exact/actual time to collect blood will be documented. 
An additional blood sample should be collected from subjects experiencing unexpected and/or 
serious AEs if possible. 
The sampling schedules are seen in Table 1.  
 
7.3 
Immunogenicity Evaluations 
Blood samples for ADA analyses will be collected at pre-dose, D8, D15, D22, and D30 post EOI 
. 
 

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8 DATA COLLECTION AND MANAGEMENT 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
Hardcopies of the study visit worksheets will be used as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data.   
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into 21 CFR Part 1 1-compliant data 
capture system provided. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
Only individuals who have received training on the EDC are allowed to make eCRF entries, 
corrections, and alterations. Training must be documented and a log of all EDC users and their 
rights within the system be maintained. The data management team will raise queries in the EDC 
system to resolve discrepancies. The Investigator must verify that all data entries in the eCRFs 
are accurate and correct. 
Any outstanding entries must be completed immediately upon notice. No blank sections should 
be left on CRF and explanations has to be recorded for all missing data. All source documents 
should be retained. All essential documents should only contain subject coded identifiers and no 
personal identifying information should be transmitted. 
8.1 
Study Record Retentions 
After completion of the study and when all collected data are validated, the database will be 
locked, pursuant to the prior approval by the Sponsor (or its designee). Final data will be 
extracted from the EDC system and delivered in the form of SAS® datasets. A Portable 
Document Format (PDF) copy of the eCRF will be produced for each study subject and included 
in the final delivery.  
All data obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with sponsors/CROs security standards. Each Subject will 
have identifiers that will be kept at the study sites.  
If clinical site/sponsor becomes aware of loss or destruction of data due to a major breach 
occurrence that has jeopardized subject confidentiality and trial data, the IRB will be notified.  
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 

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applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
8.2 
Protocol Deviations 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact the Sponsor if any, monitoring the study to request 
approval of a protocol deviation, as no authorized deviations are permitted. If the investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by the Sponsor and 
approved by the IRB/IEC/REB it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR. 
It is the responsibility of the site investigator to use continuous vigilance to identify and report, 
when applicable, deviations within 5 working days of identification of the protocol deviation, or 
within 5 working days of the scheduled protocol-required activity.  All deviations must be 
addressed in study source documents and if applicable, in eCRFs and study reports, in 
coordination with the sponsor or their designated CRO.  Protocol deviations must be sent to the 
reviewing IRB per their policies. The site investigator is responsible for knowing and adhering to 
the requirements of the reviewing IRB. 
8.3 
Publication and Data Sharing 
Both the use of data and the publication policy are detailed within the clinical study agreement.  
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the Institution and the Sponsor or their designee.   

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9 REGULATORY HUMAN SUBJECT PROTECTION AND 
REGULATORY OVERSIGHT 
9.1 
Informed Consent Processes and Documentation 
In obtaining and documenting informed consent, the investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should 
adhere to ICH GCP. Prior to the beginning of the trial, the investigator should have the IRB’s 
written approval for the protocol and the written ICFs and any other written information to be 
provided to the participants. Participants will be asked to read and review IRB-approved ICFs 
and other written information.  ICF should include detailed description of study procedures, risk 
and benefits, directions, participant’s rights, compensation if applicable, and contact of Human 
Subject Protection Services.  Additionally, investigator will explain the research study to the 
participant in terms suited to the participant’s comprehension and answer any questions that may 
arise. Investigator should explain their rights as research participants, study procedures, risk and 
benefits, anticipated adverse effects.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. ICF should be signed prior to any 
interventions for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. Participant will be given a 
copy of the signed consent form and the original consent form will be kept as a permanent 
record. 
9.2 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
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Research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the data management group at the designated CRO. This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by CRO staff will be secured, 
and password protected. At the end of the study, all study databases will be de-identified and 
archived at the CRO or Sponsor until further data integration with future studies of OsrHSA. 
 
9.3 
Conflict of Interest 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.

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10 SAFETY REPORTING 
10.1 Definition of Adverse Event 
An adverse event (AE) is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial whether or not the event is considered related to the 
treatment or clinically significant.  
For this clinical trial, AEs will include any events reported by the subject, any new medical 
conditions, and symptoms, any new abnormal findings on physical examination or laboratory 
evaluation. Additionally, any worsening of a pre-existing condition or abnormality will also be 
considered as an AE. 
All AEs must be recorded on eCRF. All AEs must be followed return to baseline or stabilizes. 
Serious adverse events (SAE) 
A serious adverse event is defined as any adverse experience that meets any of the following 
criteria:  
• Results in death;  
• Is life-threatening  
• Requires hospitalization or prolongation of existing hospitalization. Additionally, 
complications occurring during hospitalization are also considered AEs.  
• Results in persistent or significant disability or incapacity (This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.);  
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent one of the outcomes in the definition of SAE listed above 
should also be considered SAEs. Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations.  
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care  
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• Hospitalization for administration of study drug or insertion of access for administration 
of study drug 

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• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
 
Adverse Reaction  
Any AE caused by a drug is considered an adverse reaction. 
10.2 Causality of AEs 
Causality assessment has become a common routine procedure in pharmacovigilance. Causality 
assessments can decrease disagreement between assessors, classify relationship likelihood and 
improvement of scientific evaluation. 
Limitations of causality assessment are following:  
It can NOT assess accurate quantitative measurement of relationship likelihood 
It can NOT distinguish valid from invalid cases 
It can NOT prove the connection between drug and event 
It can NOT quantify the contribution of a drug to the development of an adverse event 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the 2 categories 
below. In a clinical trial, the study product must always be suspect. 
Related:  The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
Not Related:  There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
10.3 Categorization of AEs 
AEs will be graded according to the FDA Guidance for Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” and 
reported in the detail indicated on the CRF.  The definitions are as follows: 
Grade 1 Mild: discomfort noticed, but no disruption to daily activity 
Grade 2 Moderate: discomfort sufficient to reduce or affect normal daily activity 
Grade 3 Severe:  Inability to work or perform normal daily activity   

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Grade 4 Potentially Life-threatening  
10.4 Reporting of SAEs and Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any SAE, including death resulting from any cause, which occurs to any subject participating in 
this study must be reported by investigator to the sponsor within 24 hours (and IRB as required) 
of first becoming aware of the SAE. The study sponsor will be responsible for notifying the FDA 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in 
no case later than 7 calendar days after the sponsor's initial receipt of the information.  In 
addition, the sponsor must notify FDA and all participating investigators in an IND safety report 
of potential serious risks, from clinical trials or any other source, as soon as possible, but in no 
case later than 15 calendar days after the sponsor determines that the information qualifies for 
reporting 
SAEs will be collected by the investigator from day 1 through 30 days after the administration of 
study medication. SAEs that occur within 30 days following cessation of the study treatment, 
must also be reported within the same timeframe. Any SAE that is judged by the investigator to 
be related to the study medication must be reported regardless of the amount of time since the 
last dose received. Follow-up information collected for any initial report of an SAE must also be 
reported to the sponsor (or its designee) within 24 hours of receipt by the investigator. All SAEs 
will be followed until resolution, stabilization of condition, or until follow-up is no longer 
possible. To fully understand the nature of any SAE, obtaining follow-up information is 
important. Whenever possible, relevant medical records such as discharge summaries, medical 
consultations, reports of radiographic studies, and clinical laboratory reports should be obtained.  
In the event of death, regardless of cause, all attempts should be made to obtain the death 
certificate and any autopsy report, if performed. These records should be reviewed in detail, and 
the investigator should comment on any event, lab abnormality, or any other finding, noting 
whether it should be considered a serious or non-serious AE, or whether it should be considered 
as part of the subject’s history. In addition, all events or other findings determined to be SAEs 
should be identified on the follow-up SAE form and the investigator should consider whether the 
event is related or not related to study drug.  
10.5 IRB Reporting 
The investigators will report to the IRB the following according to the requirements of reviewing 
IRB: 
• All SAEs, except deaths due to progressive disease  
• Non-compliance to GCP or protocol deviations as required by IRB 
IND Safety Reports and any unexpected incidences or problems during the trial may be also 
reportable to the IRB as per IRB requirement.  

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10.6 Quality Assurance and Quality Control 
Quality control (QC) procedures will be implemented to assure that any missing data will be 
communicated with sites for clarification and resolution.  
Standard Operating Procedures (SOPs) should be available to monitors. Monitors will verify that 
all the clinical trial procedures are conducted, documented and reported in compliance with the 
protocol, ICH, GCP, GLP, GMP and other applicable regulatory requirements.  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
10.7 Study Monitoring Plan  
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
ICH GCP, and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by the Sponsor.  
Details of clinical site monitoring will be documented in a separate Study Monitoring Plan 
(SMP). The SMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. In general monitoring visits would include pre-study visits (to 
qualify the site and investigators), study initiation visit, interim visits at appropriate frequency 
based on recruitment speed and need to clean data for dose-escalation decisions, and study 
closeout visits after database lock.  
Independent audits may be conducted by the sponsor to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the SMP. 
Monitors are qualified by training and experience to monitor the progress of clinical trials. 
Personnel monitoring this study will not be affiliated in any way with the trial conduct.  
A monitor(s)/sponsor representative(s) will meet with the investigator and his/her staff prior to 
the entrance of the first subject to review study procedures and methods of recording study data. 
After enrollment of the first subject, a monitor(s)/sponsor representative(s) will be assigned to 
periodically monitor each investigator site for study progress and to verify that standards of 
Good Clinical Practice (GCP) and/or ICH guidelines were followed.  
The investigator is expected to prepare for the monitor visit, ensuring that all source documents, 
completed CRFs, signed consent forms and other study related documents are readily available 
for review.  

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FDA regulations require the Investigators to facilitate monitoring process. Monitors will evaluate 
adherence to the protocol, regulations, SOPs, human subject protection, study data, specifically 
data that could affect the interpretation of primary study endpoints. This is done through 
independent verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
10.8 Study Closure 
The investigator may terminate the study at any time in the interest of subject welfare. The 
sponsor may terminate the study prematurely at any time. Reasons for the closure of an 
investigational site or termination of a study may include:  
• The Investigator fails to comply with the protocol or ICH/GCP guidelines  
• Safety concerns  
• Inadequate recruitment of subjects by the investigator  
• Completion of the study 
If the clinical study is prematurely terminated or suspended, the sponsor or CRO representative 
will inform the investigator and the regulatory authorities of the termination/ suspension and the 
reasons for the termination/suspension as appropriate. The investigator should promptly notify 
the IEC/IRB of the termination or suspension and provide reasons. The sponsor reserves the right 
to close the investigational site or terminate the study in its entirety at any time, for reasonable 
cause.  
Premature termination of the study by either PI or sponsor will be governed under the terms of 
the contract between both parties. 
10.9 Safety Review Committee (SRC)  
To ensure the safety of study subjects and integrity of the study data, a Safety Review 
Committee (SRC) consisting of the study Investigators, Study Director, designated Medical 
Monitor and/or other key study personnel will convene to review cumulative data for the study.  
SRC will conduct dose decision teleconference meeting before each dose escalation. 
Before each dose escalation, the Investigators, Study Director and Medical Monitor(s), together, 
will review the safety data from the current cohort after enough subjects (7-8) have completed 
the first week. It will be determined whether escalation to the next dose level can proceed or 
whether dose level should be de-escalated.  

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.  
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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11 STATISTICAL CONSIDERATIONS 
11.1 General Statistical Considerations 
Descriptive statistics will be utilized for all safety, efficacy, and PK parameters. Data will be 
summarized using descriptive statistics (number of subjects, mean, and median, standard 
deviation, minimum and maximum) for continuous variables and using frequencies and 
percentages for discrete variables.  
In addition to descriptive summary, statistical testing will be performed to provide inferential 
summaries of group/subgroup comparison of endpoints. Univariate analyses will be conducted to 
determine the effects of key patient and disease characteristics on study endpoints, e.g., Two-
sample t-test or Wilcoxon rank sum test will be used for continuous variables as appropriate and 
Chi-square test or Fisher’s exact test for categorical variables. Kaplan-Meier method or log-rank 
test will be provided for time-to-event endpoints. For comparison of more than 2 groups, 
ANOVA test or Kruskal-Wallis test will be carried out. Multivariate analyses may be conducted 
to examining relationship between multiple variables and endpoints.  
11.2 Determination of Sample Size 
An estimated total of 40 subjects will enroll in this study. The sample size for this study was 
determined based on clinical, rather than statistical considerations. A projected sample size of 8 
subjects per dosing cohort is considered to be of reasonable size to achieve the objectives of this 
single dose escalation trial. Other factors may contribute to the final sample size, which is 
dependent upon the observed safety and tolerability profile, and determines the number of 
subjects per dose cohort, number of replacements, as well as the number of dose escalations 
required to achieve the maximal proposed dose of the study drug. 
11.3 Population Analysis 
 PK and PD Population  
The PK population will include all subjects who have at least one post-dose blood sample 
providing evaluable PK data. 
 Safety Population  
The safety population will include all subjects who receive the investigational drug. The safety 
analyses population will be the primary population for evaluating treatment administration, 
compliance and safety in the study.  

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
CONFIDENTIAL
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11.4 Statistical Analysis 
 PK Analysis 
PK parameters will include Tmax, Cmax, AUClast, AUC∞, t1/2, CL, and Vz. The concentration-time 
data will be summarized by descriptive statistics (n, mean, and standard deviation, coefficient of 
variation, median, minimum, maximum, and geometric mean) according to dosing cohort and 
time of the study. PK parameters will be estimated using a non-compartmental method with 
WinNonlin (Pharsight Corp, Cary, North Carolina). Individual serum concentration of versus 
actual day will be tabulated and plotted by dose level (linear and log scales). Plots of the mean or 
median concentrations of OsrHSA will be presented by nominal day (linear and log scale) by 
dose level. If 3 cohorts complete in the study, linearity in PK parameters will be tested by fitting 
the model: log (Cmax or AUC) =a+b*log(dose) +Dose. Dose-proportionality will be tested using 
Power Model.  
A population PK-based modeling approach may also be applied for PK characterization and PK 
covariate analyses. The steady state PK profile may be projected based on the population PK 
model. Population PK and PD data may be analyzed using modeling approaches and may also be 
pooled with data from other studies to investigate any association between investigational drug 
exposure and biomarkers or significant safety endpoints. Alternative dosing approach, e.g., body 
size-based or fixed dosing, may be evaluated using a population PK/PD approach. The results of 
these analyses, if performed, will be reported separately.  
 Safety Analysis 
Safety data will be summarized by treatment group using descriptive statistics. No formal 
inferential analyses are planned for safety comparisons. Continuous safety data will be 
summarized as sample size, mean, SD, minimum, and maximum, by scheduled time point and 
treatment for observed values and change from baseline values (as appropriate). Tabulations of 
frequencies and proportions, as appropriate will be used for the evaluation of categorical 
(qualitative) safety data.  
Adverse events will be classified by SOC and term using the Medical Dictionary of Regulatory 
Activities (MedDRA) coding dictionary. Incidence of treatment-emergent adverse events 
(TEAEs) will be summarized by SOC and preferred term for each treatment group. Incidence of 
TEAEs will also be summarized by severity and association with the study treatments. 
Concomitant medications will be presented in summary tables and listings. 
All safety data summaries will be based on the Safety Analysis Set. No statistical tests will be 
performed for the safety endpoints. 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
CONFIDENTIAL
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Missing data will be treated as they are. No imputations of missing data are planned. 
 
 Immunogenicity Analysis 
All samples will first be analyzed for ADAs in a screening assay. Study samples with results 
below the screening cut-off will be reported as negative for ADAs. In the event of a positive 
result in the screening assay, samples will be analyzed in the confirmatory assay.  
The incidence of ADA will be summarized for all subjects who received at least one 
administration of study drug. Impact of ADAs on PK, PD, and safety of the study drug will be 
evaluated, if applicable.  
11.5 Tabulation of Individual Participation Data 
Data tabulations will summarize the following numbers of subjects: 
• 
Enrolled 
• 
Study drug treatment dose received 
• 
Evaluable for safety  
• 
Protocol violations 
• 
Protocol completions 
• 
Withdraw from study due to: 
o 
Adverse event 
o 
Physician’s recommendation 
o 
Withdrew consent 
o 
Lost to Follow-up 
o 
Other reasons as collected on the eCRF 
 
 
 

Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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Sponsor: Wuhan Healthgen Biotechnology Corporation 
Protocol Number: US-HY1001 
Date: November 20, 
2019 
Version: 1.2 
 
 
 
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