Clinical trial NCT04076293
Conditions: Pharmacology
Sponsor: Hanmi Pharmaceutical Company Limited
Start date: 2019-10-08; Completion date: 2021-05-03
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A First-in-Human, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM15912 in Healthy Korean Subjects

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: HM15912 intervention 2: Placebo
Intervention descriptions: intervention 1: The study will be conducted in approximately 5 sequential dosing cohorts, enrolling 8 subjects per cohort. Subjects will be randomized to HM15912 or placebo in a ratio of 6:2 (6 active, 2 placebo). intervention 2: The study will be conducted in approximately 5 sequential dosing cohorts, enrolling 8 subjects per cohort. Subjects will be randomized to HM15912 or placebo in a ratio of 6:2 (6 active, 2 placebo).

Protocol documents:
Prot_000.pdf: 
Hanmi Pharmaceutical Co., Ltd. 
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Clinical Study Protocol 
 
 
A First-in-Human, Double-blind, Randomized, Placebo-
controlled, Single Ascending Dose Study to Assess Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
HM15912 in Healthy Korean Subjects 
Sponsor: 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu, Seoul, 05545, 
Korea 
Principal Investigator: 
Hyeong-Seok Lim, MD, PhD 
Sponsor Study Number: 
HM-GLP2-101 
IP Name: 
HM15912 or placebo 
Development Phase: 
Phase 1 
Version of Final Protocol 
Final 4.2, 6 Apr 2020 
 
 
This clinical study will be conducted in accordance with the International Council for Harmonisation Tripartite 
Guideline for Good Clinical Practice (GCP) (E6), the protocol and other applicable regulatory requirements. 
 
Confidentiality Statement 
 
 
This document contains confidential information of Hanmi Pharmaceutical Co., Ltd. Do not copy or distribute it 
without written permission from the Sponsor. 
 
 
 


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SPONSOR SIGNATURE PAGE 
Declaration of Sponsor or Responsible Medical Expert 
Protocol Title: A First-in-Human, Double-blind, Randomized, Placebo-controlled, Single 
Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of HM15912 in Healthy Korean Subjects 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product (IP), 
as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the guidelines on GCP applicable to this clinical study. 
Sponsor Signatory/Responsible Medical Expert 
 
 
 
 
Date 
Seungjae Baek, MD, PhD  
Executive Director of Clinical Science  
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu, Seoul, 05545, Korea 
 
 
 


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Principal Investigator 
Protocol Title: A First-in-Human, Double-blind, Randomized, Placebo-controlled, Single 
Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of HM15912 in Healthy Korean Subjects 
This clinical study protocol was subjected to critical review and has been released by the 
Sponsor. The information it contains is consistent with current knowledge of the risks and 
benefits of the investigational product (IP), as well as with the moral, ethical and scientific 
principles governing clinical research as set out in the guidelines on GCP applicable to this 
clinical study. 
Principal Investigator 
 
 
 
Hyeong-Seok Lim, MD, PhD 
Department of Clinical Pharmacology and Therapeutics Asan 
Medical Center  
88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea 
Date 
 
 
 


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LIST OF STUDY STAFF 
Sponsor 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu, Seoul, 05545, Korea 
Responsible Medical Expert 
Seungjae Baek, MD, PhD  
Executive Director of Clinical Science 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu, Seoul, 05545, Korea 
Institution 
Asan Medical Center 
88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea 
Principal Investigator 
Hyeong-Seok Lim, MD, PhD 
Department of Clinical Pharmacology and Therapeutics  
Asan Medical Center 
Serious Adverse Event 
Reporting 
Hanmi Pharmaceutical Co., Ltd. Drug Safety & PV Team 
Telephone number: +82-2-410-0342 
Fax number: +82-50-2260-0479 
Email: newdrugsafety@hanmi.co.kr 
 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
A First-in-Human, Double-blind, Randomized, Placebo-controlled, Single 
Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of HM15912 in Healthy Korean Subjects 
Study Number 
HM-GLP2-101 
Development Phase 
Phase 1 
Sponsor 
Hanmi Pharmaceutical Co., Ltd. 
Institution 
Asan Medical Center 
88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea 
Principal Investigator 
Hyeong-Seok Lim, MD, PhD 
Department of Clinical Pharmacology and Therapeutics  
Asan Medical Center 
Study Objectives 
Primary Objective: 
To assess the safety and tolerability of HM15912 after single subcutaneous 
(SC) doses 
Secondary Objective: 
To assess the PK profile of HM15912 after single SC doses 
Exploratory Objective: 
To explore the PD properties of HM15912 after single SC doses 
Study Design 
This is a double-blind, randomized, placebo-controlled, single ascending dose 
(SAD) study to assess the safety, tolerability, PK and PD of the SC 
administration of HM15912 in healthy Korean subjects. 
The study will be conducted in approximately 5 sequential dosing cohorts, 
enrolling 8 subjects per cohort. Subjects will be randomized to HM15912 or 
placebo in a ratio of 6:2 (6 active, 2 placebo). When necessary, one dosing 
cohort may be added or removed. 
In this first-in-human (FiH) study, each cohort will be divided in 2 blocks in 
order to implement the sentinel dosing approach. Within each cohort, the first 
block will consist of 2 sentinel subjects; 
1 subject will receive HM15912, and 1 subject will receive matched placebo. 
The second block will consist of 6 subjects randomized to receive HM15912 (n 
= 5) or matched placebo (n = 1). Individual subjects in the second block will be 
dosed at least 24 hours after the first block when safety and tolerability are 
found to be satisfactory by the Principal Investigator. 
Following an overnight fast of at least 10 hours, each subject will receive a single 
dose of either HM15912 or matched placebo-administered SC in the abdomen on 
the morning (8:00 AM - 10:00 AM) of Day 1. Subjects will continue fasting 
through approximately 4 hours postdose. Water intake is also limited for 
approximately 1 hour before dosing and approximately 2 hours after dosing. 
Water intake is also limited for approximately 1 hour before dosing and 
approximately 2 hours after dosing. 
The planned maximum dose of HM15912 is 1.5 mg/kg; however, higher doses 
may be administered if safety is confirmed in previous cohorts. If dose is 
escalated to 1.5 mg/kg or above, approval of the Ministry of Food and Drug 
Safety (MFDS) will be obtained. After at least 6 subjects (HM15912, n ≥ 4) in 
each cohort have completed assessments through at least Day 17, blinded safety 
data will be reviewed and a dose decision/dose escalation decision for the 


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subsequent cohort will be made by the Principal Investigator and the Sponsor. 
If there are PK/PD data obtained from the preceding or current cohorts, the 
PK/PD data will be reviewed as well when necessary. Escalation will only 
proceed if safety and tolerability data related to the dose of the prior cohort are 
verified. Determination of whether to proceed to the next cohort will be made 
by the Principal Investigator and the Sponsor, and changes in the dose and the 
number of cohorts will be approved by the MFDS and the IRB. 
PK data will only be reviewed if available. After review of the PK data from 
the preceding or current cohorts, changes in time points for PK collection, 
clinical laboratory assessments, and PD collection may be required and will be 
approved by the MFDS and the IRB. 
If dose escalation is stopped based on available blinded safety data, the current 
dose level will be considered as the minimum intolerable dose (MID). The dose 
just below the MID will be regarded as the maximum tolerated dose (MTD). If 
the dose escalation is stopped due to reaching exposure limit without dose-
limiting safety findings, the MTD cannot be determined. Dose de-escalation 
may occur in the last cohort or additional cohorts to further refine clinically 
relevant dose levels. 
The study will be comprised of: 
• A Screening visit up to 28 days before dosing 
• An inpatient assessment period of approximately 8 days, with admission to 
the institution on Day-1, dosing on Day 1, and discharge on Day 7 once the 
planned schedule is completed 
• Two Outpatient visits on Day 8 (± 4 hours), Day 10 (± 1 day), Day 17 (± 1 
day) and Day 30 (± 3 days) 
• A final Follow-up visit on Day 44 (± 3 days) 
The total duration of the clinical study per subject will be up to approximately 
72 days, including the Screening period. 
Investigational Product 
HM15912 and matching placebo will be supplied by the Sponsor as a sterile 
solution in prefilled syringes, manufactured by Hanmi Pharm. Co., Ltd. The 
concentration of HM15912 is 30 mg/mL as protein and the fill volume is 0.52 
mL including overfill. 
Doses will be administered via SC injection to subjects in approximately 5 dose 
cohorts. Additional cohorts may be enrolled and proceed at a dose higher or 
lower than the planned maximum dose of 1.5 mg/kg, if deemed appropriate by 
the Principal Investigator and the Sponsor, but cohorts are planned as follows: 
Cohorts 
Number of Subjects 
Treatment1 
Cohort 1 
N = 6 
HM15912 0.05 mg/kg 
N = 2 
Placebo 
Cohort 2 
N = 6 
HM15912 0.1 mg/kg 
N = 2 
Placebo 
Cohort 3 
N = 6 
HM15912 0.5 mg/kg 
N = 2 
Placebo 
Cohort 4 
N = 6 
HM15912 1 mg/kg 
N = 2 
Placebo 
Cohort 5 
N = 6 
HM15912 1.5 mg/kg 
N = 2 
Placebo 
1 After at least 6 subjects (HM15912, n ≥ 4) in each cohort have completed assessments 
through at least Day 17, blinded safety data (PK/PD data from the preceding or current 


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cohorts will also be reviewed when necessary) will be reviewed and a dose 
decision/dose escalation decision for the subsequent cohort will be made by the 
Principal Investigator and the Sponsor. If dose escalation is stopped, dose de-escalation 
may occur in additional cohorts, to further refine clinically relevant dose levels. The 
planned maximum dose of HM15912 is 1.5 mg/kg; however, higher doses may be 
administered if safety is confirmed in previous cohorts. If dose is escalated to 1.5 mg/kg 
or above, MFDS approval will be obtained. 
Number of Subjects 
Approximately 40 subjects, divided in approximately 5 cohorts with 8 subjects 
per cohort (6 HM15912, 2 placebo), are planned for enrollment. 
Study Population 
Healthy Korean male and female subjects ≥ 19 and ≤ 60 years of age with a 
body mass index (BMI) ≥ 18.5 kg/m2 and ≤ 27 kg/m2 are planned for 
enrollment. 
Inclusion Criteria 
1. Subject voluntarily agrees to participate in this study and signs an IRB-
approved informed consent prior to performing any of the Screening visit 
procedures. 
2. Korean males and females ≥ 19 and ≤ 60 years of age at the Screening 
visit 
3. Female subjects must be non-pregnant and non-lactating and either 
surgically sterile (e.g., bilateral tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy), or post-menopausal for ≥ 12 
months. Postmenopausal status will be confirmed through testing of 
follicle-stimulating hormone (FSH) levels ≥ 40 IU/L at the Screening visit 
for amenorrheic female subjects ≤ 60 years of age. 
Male subjects must be surgically sterile (at least 1-year post vasectomy), 
abstinent or if engaged in sexual relations with women of child-bearing 
potential, the subject and his partner must be using the following 
acceptable effective or medically recognized dual protection contraceptive 
methods from the administration of IP to up to 60 days after receiving the 
dose of the IP. 
• 
Effective contraceptive method: Sexual partner's surgical sterilization 
(e.g., bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy), intrauterine contraception/device of the sexual 
partner 
• 
Dual protection contraceptive method: Combinational use of physical 
barrier methods (male condom, female condom and diaphragm for the 
sexual partner, sponge, cervical cap), spermicide for females in the 
form of foam/gel/film/cream/suppository, oral or hormonal 
contraceptives for the sexual partner 
The adequacy of other methods of contraception will be assessed on a case-
by-case basis by the Principal Investigator. 
4. Body mass index (BMI) ≥ 18.5 kg/m2 and ≤ 27 kg/m2 at the Screening 
visit and with a weight ≥ 50 kg for males and ≥ 45 kg for females 
Healthy, determined by pre-study medical evaluation (medical history, physical 
examination, vital signs, 12-lead ECG and clinical laboratory assessments) 
Exclusion Criteria 
Subjects who meet 1 or more of the following criteria at the Screening visit will 
not be considered eligible to participate in the clinical study. Also, subjects who 
meet 1 or more of the following criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 
16, 17, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, and 31 when they are hospitalized 


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(Day-1) will not be considered eligible to participate in the clinical study. 
1. Subject with a history or presence of clinically significant active diseases of 
the gastrointestinal, cardiovascular (including a history of arrhythmia or 
any clinically significant conduction delays in the ECG), hepatic, 
pulmonary, neurological, renal, pancreatic, immunological, dermatological, 
endocrine, genitourinary or hematological system 
2. Subject with a history or presence of skin rashes or dermatitis 
3. Subject with a history or presence of any psychiatric disorder that, in the 
opinion of the Principal Investigator, might confound the results of the 
study or pose additional risk in administering the investigational product to 
the subject 
4. Subject who has participated in other clinical studies (including 
bioequivalence tests) within 6 months before the Screening visit and has 
received IPs 
5. Subject who has received GLP-1, GLP-2, human growth hormones, or 
analogues in the past 
6. Subject with a history of any serious adverse reaction, hypersensitivity, or 
intolerance to IP components 
7. Subject who has any clinically significant history of allergic conditions 
(including drug allergies, asthma, eczema, or anaphylactic reactions, but 
excluding untreated, asymptomatic, seasonal allergies) prior to IP 
administration 
8. Subject with a history of gallstones, intestinal obstruction, or 
surgery/surgical resection of stomach or intestine (simple appendectomy is 
allowed) 
9. Subject with a history or presence of gastrointestinal illnesses such as 
malabsorption, pancreatic disease, gastrointestinal polyps, irritable bowel 
syndrome, Crohn's disease, or ulcerative colitis 
10. Subject with a personal or family history of hypercoagulability or 
thromboembolic disease 
11. Subject who has FPG < 70 or > 110 mg/dL at the Screening visit. 
12. Subject with a history of any major surgery within 6 months prior to the 
Screening visit 
13. Subject with a history or current diagnosis of heart diseases, defined as 
symptomatic heart failure (New York Heart Association class III or IV), 
myocardial infarction, unstable angina requiring medication, transient 
ischemic attack, cerebral infarct, or cerebral hemorrhage or invasive 
cardiovascular procedure, such as coronary artery bypass graft surgery, or 
angioplasty/percutaneous coronary intervention within 6 months before the 
Screening visit (a diagnostic cardiac catheterization without any 
intervention does not exclude the subject) 
14. Subject with cardiac arrhythmia requiring medical or surgical treatment 
within 6 months prior to the Screening visit 
15. Subject who has/had febrile illness or symptomatic, viral, bacterial 
(including upper respiratory infection), or fungal (noncutaneous) infection 
within 1 week prior to the Screening visit 
16. Subject with daily use of more than 5 cigarettes or equivalent use of any 
tobacco product within 6 weeks prior to the Screening visit. Subject must 
be able to abstain from smoking during the confinement period. 
17. Subject with a history of any active infection, except mild viral diseases, 


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within 30 days prior to the Screening visit 
18. Subject with a history of hepatitis B surface antigen (HBsAg), hepatitis B 
core antibody (anti-HBc), hepatitis C antibody (HCV Ab), or human 
immunodeficiency virus (HIV) 
19. Subject with the existence of any surgical or medical condition that, in the 
judgment of the Principal Investigator, might interfere with the absorption, 
distribution, metabolism or excretion of the IP 
20. Subject with the presence of clinically significant physical, clinical 
laboratory or ECG findings (e.g., QTcB > 450 msec for males, QTcB > 470 
msec for females, left bundle branch block) at the Screening visit that, in 
the opinion of the Principal Investigator, may interfere with any aspect of 
study conduct or interpretation of results. 
21. Subject who has a mean pulse < 45 or > 90 beats per minute (bpm); mean 
systolic blood pressure (SBP) > 140 mmHg; mean diastolic blood pressure 
(DBP) > 90 mmHg (measurements taken for 2 consecutive times after the 
subject has been resting in supine or sitting position for 5 minutes) (mean 
values from 2 consecutive measurements will be used). 
22. Subject who has donated whole blood within 60 days before the Screening 
visit, who has done apheresis within 1 month before the Screening visit or 
who has received blood products 
23. Subject who has a history of alcohol or illicit drug abuse as judged by the 
Principal Investigator or who reports use of recreational drugs (e.g., 
marijuana) within 6 weeks prior to the Screening visit 
24. Subject who has a positive urine drug test (e.g., cocaine, amphetamines, 
barbiturates, opiates, benzodiazepines, cannabinoids, phencyclidine, etc.) at 
the Screening visit or on Day-1 
25. Female subject who is currently pregnant or breastfeeding or who has a 
positive serum pregnancy test at the Screening visit or on Day-1 
26. Subject who has used over-the-counter (OTC) medications (including 
acetaminophen and vitamins), prescription medications, or herbal remedies 
from 3 days prior to the Screening visit, unless it is approved by the 
Principal Investigator 
27. Subject who is unwilling to avoid consumption of coffee and caffeine-
containing beverages within 24 hours before each study visit and while the 
subject is confined to the institution 
28. Subject who is unwilling to avoid use of alcohol or alcohol-containing 
foods, medications or beverages within 48 hours before each study visit and 
while the subject is confined to the institution 
29. Subject who is unwilling to abstain from vigorous exercise from 48 hours 
prior to admission until the Follow-up visit 
30. Subject who is unable to understand the protocol requirements, instructions, 
study-related restrictions, and the nature, scope and possible consequences 
of the clinical study or who is unlikely to comply with the protocol 
requirements, instructions and study-related restrictions; e.g., uncooperative 
attitude, inability to return for Follow-up visits and improbability of 
completing the clinical study 
31. Subject who is deemed by the Principal Investigator to be inappropriate in 
conducting the clinical study 
Subjects who have screen failed may be allowed to re-screen once at the 
discretion of the Principal Investigator. 


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Evaluation Criteria 
Primary Endpoints 
 General safety variables: Adverse event (AE) assessments, clinical 
laboratory tests (hematology, clinical chemistry, coagulation and urinalysis), 
vital signs (blood pressure [BP], pulse, tympanic temperature and 
respiratory rate [RR]), 12-lead electrocardiogram (ECG), physical 
examinations 
 Specific safety variables: Injection site assessments, immunogenicity 
assessments (ADA, NAb, anti-PEG) (performed only if analysis is 
necessary) 
Secondary Endpoints 
 Cmax: Maximum serum HM15912 concentration determined from the 
concentration-time profile 
 Tmax: Time of maximum serum HM15912 concentration determined from 
the concentration-time profile 
 AUC0-t: Area under the concentration-time curve from predose (time 0) to 
the last quantifiable concentration 
 AUCinf: Area under the concentration-time curve from predose (time 0) 
extrapolated to infinite time (AUC0-t + Clast/λz) calculated using the linear-
log trapezoidal rule 
 AUC%extrap: Percentage of AUCinf that is due to extrapolation beyond tlast  
 λz: The terminal elimination rate constant determined by selection of at least 
3 data points on the terminal phase of the concentration-time curve 
 t½: Terminal elimination half-life calculated as: ln2/λz  
 CL/F: Total body clearance calculated as: Dose/AUCinf 
 Vz/F: Apparent volume of distribution calculated as: Dose/(AUCinf * λz) 
Exploratory Endpoints 
 Blood plasma citrulline 
 Albumin, prealbumin 
 Fasting lipid panel (total cholesterol, triglycerides, low-density lipoprotein 
[LDL], high-density lipoprotein [HDL], very low-density lipoprotein 
[VLDL], free fatty acid [FFA]) 
 Blood glucose-related panel (fasting plasma glucose, gastric inhibitory 
polypeptide [GIP], glucagon-like peptide-1 [GLP-1], C-peptide, glucagon, 
insulin) 
 Insulin-like growth factor-1 (IGF-1) and keratinocyte growth factor (KGF) 
Statistical Methods 
Sample Size Considerations 
Enrolling 8 subjects per cohort (HM15912:placebo=6:2) has been set based on 
the experience and the general properties of exploratory studies, and this 
matches the typical sample size used in similar studies conducted to assess 
safety and PK. Therefore, no formal sample size calculation will be performed. 
Safety and tolerability of the IP will be assessed based on AEs, clinical 
laboratory parameters, physical examinations, vital signs and ECG parameters 
throughout the duration of the study. Safety analysis will involve examination 
of the descriptive statistics and individual subject listings for any effects of 
study treatment on clinical tolerability and safety. 


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Data Presentation/Descriptive Statistics 
All demographic, safety, PK and PD data will be listed and summarized in 
tabular format by descriptive and comparative statistics as appropriate. PK data 
will also be displayed graphically as appropriate. The PK/PD relationship 
between IP exposure and exploratory endpoints may also be analyzed by 
graphical displays. 


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Table 1 
Schedule of Assessments 
Table 1-1. Schedule of Assessments (Cohort 1-3) 
Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Outpatienta 
Visit 4 
Outpatienta 
Visit 5 
Follow-upb 
Day 
-28 ~ -2 
-1 
Outpat
ient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Heightd, BMIe 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Body weightd 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and alcohol screening 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Outpatient 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Standardized meals 
 
 
X 
Xh 
X 
X 
X 
X 
X 
 
 
 
 
IP administrationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, pulse, tympanic temperature, RR)i 
X 
X 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
X 
X 
Clinical laboratory tests (hematology, chemistry, 
coagulation, urinalysis)j 
X 
X 
 
Xk 
 
Xk 
Xk 
 
 
X 
 
X 
X 


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Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Outpatienta 
Visit 4 
Outpatienta 
Visit 5 
Follow-upb 
Day 
-28 ~ -2 
-1 
Outpat
ient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
12-lead ECGl 
X 
X 
 
Xl 
X 
X 
X 
 
 
X 
X 
X 
X 
Immune response assessments (ADA, NAb, anti-PEG) 
 
 
Xm 
 
 
 
 
 
 
 
X 
 
X 
Injection site assessmentsn 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examinations 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Citrullinep 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GIP, GLP-1, C-peptide, glucagon, insulinq 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
IGF-1 and KGFr 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
ADA = anti-drug antibody; Anti-PEG = anti-polyethylene glycol; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; FFA = free fatty acid; FPG = fasting plasma glucose; 
FSH = follicle-stimulating hormone; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IP = investigational product; LDL = low-density 
lipoprotein; NAb = neutralizing antibody; PK = pharmacokinetics; RR = respiratory rate; SC = subcutaneous; VLDL = very low-density lipoprotein 
a. An additional Outpatient visit may be included in later cohorts, if required, after PK data are evaluated. If so, assessments scheduled on Day 17 will be performed at the additional Outpatient 
visit. 
b. If a subject is discontinued from the study or withdraws consent, the Principal Investigator must make every possible effort to perform the evaluations described for the Follow-up visit. 
Efforts will be made to perform the Follow-up visit within 30 days from the date the subject is discontinued from the study or withdraws consent. 
c. The criteria applicable for admission prior to randomization, i.e., exclusion criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, and 31, will be 
checked again. 
d. Height will be measured only at the Screening visit. Height and weight measurements will be performed with shoes removed. Weight will be recorded rounded to 1 decimal place. If weight 
is measured rounded to 2 decimal places, the number is rounded off from the second digit after the decimal point. 
e. BMI will be calculated by the following formula: BMI = Weight (kg) ÷ ((Height (m) x Height (m)). The calculated BMI will be rounded to 1 decimal place. The height measured at the 
Screening visit will be used for BMI calculation, and if a value is calculated as 2 decimal places, the number is rounded off to the first place. 
f. Medical history which will be checked on Day-1 is limited to the medical history related to exclusion criteria 1, 2, 3, 6, 8, 9, 10, 11, 13, 14, 15, and 17. 
g. Serum pregnancy tests at the Screening visit and on Day-1; urine pregnancy tests at the Day 30/Follow-up visit. 
 
 


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h. HM15912 or placebo will be administered via SC injection into the abdomen on the morning of Day 1 after a minimum 10-hour fast. Subjects will continue fasting through approximately 4 
hours postdose. Water consumption will also be limited for 1 hour before dosing and for approximately 2 hours after dosing. After the planned 4-hour post-dose blood sampling (clinical 
laboratory tests and analysis of citrulline) and testing (12-lead ECG) are performed, subjects will be served lunch by the institution. 
i. Vital signs will be measured twice per day on Day 1 through Day 6 (AM and PM). Vital signs will be measured at predose and 6 hours postdose on Day 1. Vital signs will be measured 
whenever possible in the morning and afternoon between Day 2 and Day 6. All other assessments will be performed once per day whenever possible. BP and pulse will be measured for 2 
consecutive times after a subject has been lying down or sitting to rest ≥ 5 minutes, and mean values will be recorded. 
j. Samples for clinical laboratory tests will be collected after at least 12 hours of fasting. If the PK sampling time points are changed, the sampling times for clinical laboratory tests may be 
adjusted accordingly. 
k. 4, 48 and 72 hours postdose 
l. The 12-lead ECGs will be performed after a subject has been resting supine for ≥ 5 minutes. ECGs will be measured in triplicate in the morning during admission. Only for Day 1, however, 
ECGs will be measured in triplicate predose and 4 hours postdose, and a ±30-minute sampling window is allowed for measurement at 4 hours postdose. Triplicate ECGs will be recorded at 
least 30 seconds apart from each other, not exceeding a time period of 3 minutes for the completion of all 3 ECGs. 12-lead ECGs during the Outpatient visit will be measured once per day 
whenever possible. 
m. Blood sampling for immunogenicity assessments will be performed only for hospitalized patients after admission on Day-1, Day 10, and Day 30. 
n. Injection site assessments will be performed predose, within 1 hour postdose and at 4 and 12 hours postdose on Day 1, and then between 9:00 AM and 12:00 PM daily from Day 2 through 
Day 7. 
o. Blood will be collected for PK assessments predose and at 1, 4, 8, 12 (Day 1), 24, 36 (Day 2), 48, 54, 60 (Day 3), 72, 78, 84 (Day 4), 96, 102, 108 (Day 5), 120 (Day 6), 144 (Day 7), 216 
(Day 10), 384 (Day 17) and 696 (Day 30) hours postdose. The time points for citrulline sampling are identical to those for PK blood sampling, but 126 hours (Day 6) will be added. PK 
sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. See Table 2-1 for the PK sampling schedule. 
p. If the PK sampling time points are changed, the citrulline sampling times may be adjusted accordingly. See Table 2-1 for the citrulline sampling schedule. 
q. Blood will be collected for GIP, GLP-1, C-peptide, glucagon and insulin immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 
30/Follow-up visit. If the PK sampling time points are changed, sampling times may be adjusted accordingly. 
r. Blood will be collected for IGF-1 and KGF immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 30/Follow-up visit. If the PK 
sampling time points are changed, sampling times may be adjusted accordingly. 
 
 
 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 15 of 75 
Apr 06, 2020 
Table 1-2. Schedule of Assessments (Cohort 4, 5) 
Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Out 
patienta 
Visit 4 
Out 
patienta 
Visit 5 
Out 
patienta 
Visit 6 
Out 
patienta 
Visit 7 
Follow- 
upb 
Day 
-28 ~ -2 
-1 
Outpa
tient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
8 
(±4 hours) 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
44 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heightd, BMIe 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Body weightd 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and alcohol screening s 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Outpatient 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standardized meals 
 
 
X 
Xh 
X 
X 
X 
X 
X 
 
 
 
 
 
 
IP administrationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
(BP, pulse, tympanic temperature, RR)i 
X 
X 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests  
(hematology, chemistry, coagulation, 
X 
X 
 
Xk 
 
 
Xk 
 
 
X 
 
 
X 
X 
X 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 16 of 75 
Apr 06, 2020 
Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Out 
patienta 
Visit 4 
Out 
patienta 
Visit 5 
Out 
patienta 
Visit 6 
Out 
patienta 
Visit 7 
Follow- 
upb 
Day 
-28 ~ -2 
-1 
Outpa
tient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
8 
(±4 hours) 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
44 
(±3 days) 
urinalysis)j 
12-lead ECGl 
X 
X 
 
Xl 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Immune response assessments 
 (ADA, NAb, anti-PEG) 
 
 
Xm 
 
 
 
 
 
 
 
 
 
X 
 
X 
Injection site assessmentsn 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Physical examinations 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Citrullinep 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GIP, GLP-1, C-peptide, glucagon, insulinq 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
IGF-1 and KGFr 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
ADA = anti-drug antibody; Anti-PEG = anti-polyethylene glycol; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; FFA = free fatty acid; FPG = fasting plasma glucose; 
FSH = follicle-stimulating hormone; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IP = investigational product; LDL = low-density 
lipoprotein; NAb = neutralizing antibody; PK = pharmacokinetics; RR = respiratory rate; SC = subcutaneous; VLDL = very low-density lipoprotein 
a. An additional Outpatient visit may be included in later cohorts, if required, after PK data are evaluated. If so, assessments scheduled on Day 17 will be performed at the additional Outpatient 
visit. 
b. If a subject is discontinued from the study or withdraws consent, the Principal Investigator must make every possible effort to perform the evaluations described for the Follow-up visit. 
Efforts will be made to perform the Follow-up visit within 30 days from the date the subject is discontinued from the study or withdraws consent. 
c. The criteria applicable for admission prior to randomization, i.e., exclusion criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, and 31, will be 
checked again. 
d. Height will be measured only at the Screening visit. Height and weight measurements will be performed with shoes removed. Weight will be recorded rounded to 1 decimal place. If weight 
is measured rounded to 2 decimal places, the number is rounded off from the second digit after the decimal point. 
e. BMI will be calculated by the following formula: BMI = Weight (kg) ÷ ((Height (m) x Height (m)). The calculated BMI will be rounded to 1 decimal place. The height measured at the 
Screening visit will be used for BMI calculation, and if a value is calculated as 2 decimal places, the number is rounded off to the first place. 
f. Medical history which will be checked on Day-1 is limited to the medical history related to exclusion criteria 1, 2, 3, 6, 8, 9, 10, 11, 13, 14, 15, and 17. 
g. Serum pregnancy tests at the Screening visit and on Day-1; urine pregnancy tests at the Day 44/Follow-up visit. 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 17 of 75 
Apr 06, 2020 
h. HM15912 or placebo will be administered via SC injection into the abdomen on the morning of Day 1 after a minimum 10-hour fast. Subjects will continue fasting through approximately 4 
hours postdose. Water consumption will also be limited for 1 hour before dosing and for approximately 2 hours after dosing. After the planned 4-hour post-dose blood sampling (clinical 
laboratory tests) and testing (12-lead ECG) are performed, subjects will be served lunch by the institution. 
i. Vital signs will be measured twice per day on Day 1 through Day 6 (AM and PM). Vital signs will be measured at predose and 6 hours postdose on Day 1. Vital signs will be measured 
whenever possible in the morning and afternoon between Day 2 and Day 6. All other assessments will be performed once per day whenever possible. BP and pulse will be measured for 2 
consecutive times after a subject has been lying down or sitting to rest ≥ 5 minutes, and mean values will be recorded. 
j. Samples for clinical laboratory tests will be collected after at least 12 hours of fasting. If the PK sampling time points are changed, the sampling times for clinical laboratory tests may be 
adjusted accordingly. 
k. 4 and 72 hours postdose 
l. The 12-lead ECGs will be performed after a subject has been resting supine for ≥ 5 minutes. ECGs will be measured in triplicate in the morning during admission. Only for Day 1, however, 
ECGs will be measured in triplicate predose and 4 hours postdose, and a ±30-minute sampling window is allowed for measurement at 4 hours postdose. Triplicate ECGs will be recorded at 
least 30 seconds apart from each other, not exceeding a time period of 3 minutes for the completion of all 3 ECGs. 12-lead ECGs during the Outpatient visit will be measured once per day 
whenever possible. 
m. Blood sampling for immunogenicity assessments will be performed only for hospitalized patients after admission on Day-1, Day 17, and Day 44. 
n. Injection site assessments will be performed predose, within 1 hour postdose and at 4 and 12 hours postdose on Day 1, and then between 9:00 AM and 12:00 PM daily from Day 2 through 
Day 7. 
o. Blood will be collected for PK assessments predose and at 6, 12 (Day 1), 24, 36 (Day 2), 48, 54, 60 (Day 3), 72, 78, 84 (Day 4), 96, 102, 108 (Day 5), 120 (Day 6), 144 (Day 7), 168 (Day 8), 
216 (Day 10), 384 (Day 17), 696 (Day 30) and 1032 (Day 44) hours postdose. The time points for citrulline sampling are identical to those for PK blood sampling, but 126 hours (Day 6) will 
be added. PK sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. See Table 2-2 for the PK sampling 
schedule. 
p. If the PK sampling time points are changed, the citrulline sampling times may be adjusted accordingly. See Table 2-2 for the citrulline sampling schedule. 
q. Blood will be collected for GIP, GLP-1, C-peptide, glucagon and insulin immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 30 
Outpatient visit. If the PK sampling time points are changed, sampling times may be adjusted accordingly. 
r. Blood will be collected for IGF-1 and KGF immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 30 Outpatient visit. If the PK 
sampling time points are changed, sampling times may be adjusted accordingly. 
s. Alcohol breath test procedure could be replaced with the examination by interview to avoid infection of COVID-19. 
 
 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 18 of 75 
Apr 06, 2020 
Table 2 
Citrulline Sampling Schedule for Exploring PK Samples and PD 
Table 2-1 Citrulline Sampling Schedule for Exploring PK Samples and PD (Cohort 1~3) 
Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
Day 1 
Immediately before administration (- 15 min)b 
Immediately before administration (- 15 min)b 
1 h (± 15 min)b 
1 h (± 15 min)b 
4 h (± 15 min)b 
4 h (± 15 min)b 
8 h (± 15 min) 
8 h (± 15 min) 
12 h (± 15 min) 
12 h (± 15 min) 
Day 2 
24 h (± 15 min)b 
24 h (± 15 min)b 
36 h (± 15 min) 
36 h (± 15 min) 
Day 3 
48 h (± 15 min)b  
48 h (± 15 min)b 
54 h (± 15 min) 
54 h (± 15 min) 
60 h (± 15 min) 
60 h (± 15 min) 
Day 4 
72 h (± 15 min)b 
72 h (± 15 min)b 
78 h (± 15 min) 
78 h (± 15 min) 
84 h (± 15 min) 
84 h (± 15 min) 
Day 5 
96 h (± 15 min)b 
96 h (± 15 min)b 
102 h (± 15 min) 
102 h (± 15 min) 
108 h (± 15 min) 
108 h (± 15 min) 
Day 6 
 
120 h (± 15 min)b 
120 h (± 15 min)b 
- 
126 h (± 15 min) 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 19 of 75 
Apr 06, 2020 
Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
 
 
Day 7 
144 h (± 15 min)b 
144 h (± 15 min)b 
Day 10 
216 h (± 24 h)b,c 
216 h (± 24 h)b,c 
Day 17 
384 h (± 24 h)b,c 
384 h (± 24 h)b,c 
Day 30 
696 h (± 72 h)b,d 
696 h (± 72 h)b,d 
a. Sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. 
b. Samples will be collected with an empty stomach. 
c. PK and citrulline samples may be collected ±1 day (24 hours) from the scheduled sampling time points at the Days 10 and 17 Outpatient visits. The samples may also be 
collected ±1 day (24 hours) from the scheduled sampling time points in case there is an additional Outpatient visit. 
d. PK and citrulline samples may be collected ±3 days (72 hours) from the scheduled sampling time points at the Day 30 Outpatient visit. 
 
 
 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 20 of 75 
Apr 06, 2020 
Table 2-2 Citrulline Sampling Schedule for Exploring PK Samples and PD (Cohort 4, 5) 
Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
Day 1 
Immediately before administration (- 15 min)b 
Immediately before administration (- 15 min)b 
6 h (± 15 min) 
6 h (± 15 min) 
12 h (± 15 min) 
12 h (± 15 min) 
Day 2 
24 h (± 15 min)b 
24 h (± 15 min)b 
36 h (± 15 min) 
36 h (± 15 min) 
Day 3 
48 h (± 15 min)b  
48 h (± 15 min)b 
54 h (± 15 min) 
54 h (± 15 min) 
60 h (± 15 min) 
60 h (± 15 min) 
Day 4 
72 h (± 15 min)b 
72 h (± 15 min)b 
78 h (± 15 min) 
78 h (± 15 min) 
84 h (± 15 min) 
84 h (± 15 min) 
Day 5 
96 h (± 15 min)b 
96 h (± 15 min)b 
102 h (± 15 min) 
102 h (± 15 min) 
108 h (± 15 min) 
108 h (± 15 min) 
Day 6 
120 h (± 15 min)b 
120 h (± 15 min)b 
- 
126 h (± 15 min) 
Day 7 
144 h (± 15 min)b 
144 h (± 15 min)b 
Day 8 
168 h (± 4 h)b 
168 h (± 4 h)b 
Day 10 
216 h (± 24 h)b,c 
216 h (± 24 h)b,c 


Hanmi Pharmaceutical Co., Ltd. 
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CONFIDENTIAL 
Final 4.2 
Page 21 of 75 
Apr 06, 2020 
Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
Day 17 
384 h (± 24 h)b,c 
384 h (± 24 h)b,c 
Day 30 
696 h (± 72 h)b,d 
696 h (± 72 h)b,d 
Day 44 
1032 h (± 72 h)b,d 
1032 h (± 72 h)b,d 
 
a. Sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. 
b. Samples will be collected with an empty stomach. 
c. PK and citrulline samples may be collected ±1 day (24 hours) from the scheduled sampling time points at the Days 10 and 17 Outpatient visits. The samples may also be 
collected ±1 day (24 hours) from the scheduled sampling time points in case there is an additional Outpatient visit. 
d. PK and citrulline samples may be collected ±3 days (72 hours) from the scheduled sampling time points at the Day 30 and Day 44 Outpatient visit. 
 
 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 22 of 75 
Apr 06, 2020 
Table 3 
PD Sampling Schedule 
Table 3-1 PD Sampling Schedule (Cohort 1~3) 
 
Study Day 
Screening 
-28 ~ -2 
-1 
1 
2 
3 
4 
5 
6 
7 
OP 10 
OP 17 
FU 30 
Assessment 
 
 
Predose 
(-30 min) 
4 h 
(±15 min) 
24 h 
(±15 min) 
48 h 
(±15 min) 
72 h 
(±15 min) 
96 h  
(±15 min) 
120 h  
(±15 min) 
144 h  
(±15 min) 
216 h 
(±24 h) 
384 h 
(±24 h) 
696 h 
(±72 h) 
Chemistry test - 
albumin, prealbumina,b 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
Chemistry test - fasting lipid 
panel (total cholesterol, 
triglycerides, LDL, HDL, 
VLDL, FFA)a,b 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
Chemistry test - fasting plasma 
glucosea,b 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
Blood GIP, GLP-1, C-peptide, 
glucagon, insulina 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
IGF-1 and KGFa 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
FFA = free fatty acid; FPG = fasting plasma glucose, FU = follow-up; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IGF-1 = 
insulin-like growth factor-1; KGF = keratinocyte growth factor; LDL = low-density lipoprotein; OP = outpatient; VLDL = very low-density lipoprotein 
a. 
All samples will be collected after a minimum 12-hour fast. If the PK sampling time points are changed, sampling times may be adjusted accordingly between the cohorts. 
b. 
Included in clinical laboratory tests. 
 
 
 
 


Hanmi Pharmaceutical Co., Ltd. 
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CONFIDENTIAL 
Final 4.2 
Page 23 of 75 
Apr 06, 2020 
Table 3-2 PD Sampling Schedule (Cohort 4, 5) 
FFA = free fatty acid; FPG = fasting plasma glucose, FU = follow-up; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IGF-1 = 
insulin-like growth factor-1; KGF = keratinocyte growth factor; LDL = low-density lipoprotein; OP = outpatient; VLDL = very low-density lipoprotein 
a. 
All samples will be collected after a minimum 12-hour fast. If the PK sampling time points are changed, sampling times may be adjusted accordingly between the cohorts. 
b. 
Included in clinical laboratory tests. 
 
Study Day 
Screening 
-28 ~ -2 
-1 
1 
2 
3 
4 
5 
6 
7 
OP 8 
OP 10 
OP 17 
OP 30 
FU 44 
Assessment 
 
 
Predose 
(-30 
min) 
4 h 
(±15 
min) 
24 h 
(±15 
min) 
48 h 
(±15 
min) 
72 h 
(±15 
min) 
96 h 
(±15 
min) 
120 h 
(±15 
min) 
144 h 
(±15 
min) 
168 h 
(±4 h) 
216 h 
(±24 h) 
384 h 
(±24 h) 
696 h 
(±72 h) 
1032 h 
(±72 h) 
Chemistry test - 
albumin, prealbumina,b 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Chemistry test - fasting lipid 
panel (total cholesterol, 
triglycerides, LDL, HDL, 
VLDL, FFA)a,b 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Chemistry test - fasting 
plasma glucosea,b 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Blood GIP, GLP-1, C-
peptide, glucagon, insulina 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
IGF-1 and KGFa 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 


Hanmi Pharmaceutical Co., Ltd. 
HM-GLP2-101 
 
CONFIDENTIAL 
Final 4.2 
Page 24 of 75 
Apr 06, 2020 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE .................................................................................... 2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE....................................................... 3 
LIST OF STUDY STAFF .............................................................................................. 4 
PROTOCOL SYNOPSIS ............................................................................................... 5 
TABLE OF CONTENTS ............................................................................................. 24 
List of Tables .............................................................................................................. 28 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................... 29 
1. 
INTRODUCTION ................................................................................................ 32 
1.1. 
Background ................................................................................................. 32 
1.2. 
Rationale for the Clinical Study ..................................................................... 32 
1.3. 
Risk-benefit Assessment ............................................................................... 33 
2. 
STUDY OBJECTIVES ......................................................................................... 34 
2.1. 
Primary Objective ........................................................................................ 34 
2.2. 
Secondary Objective ..................................................................................... 34 
2.3. 
Exploratory Objective ................................................................................... 34 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY ............................................... 35 
3.1. 
Overview .................................................................................................... 35 
3.2. 
Endpoints .................................................................................................... 37 
3.2.1. 
Primary Endpoints ................................................................................. 37 
3.2.2. 
Secondary Endpoints.............................................................................. 37 
3.2.3. 
Exploratory Endpoints ............................................................................ 37 
3.3. 
Rationale for the Study Design ...................................................................... 38 
3.4. 
Dose Escalation and Study Stopping Criteria................................................... 38 
4. 
STUDY POPULATION ........................................................................................ 40 
4.1. 
Number of Subjects ...................................................................................... 40 
4.2. 
Inclusion Criteria ......................................................................................... 40 
4.3. 
Exclusion Criteria ........................................................................................ 41 
4.4. 
Subject Withdrawal and Replacement ............................................................ 43 
4.5. 
Termination of the Clinical Study .................................................................. 43 
5. 
INVESTIGATIONAL PRODUCT ......................................................................... 45 
5.1. 
Identity of the Investigational Products ........................................................... 45 
5.1.1. 
Study Drug ........................................................................................... 45 
5.1.2. 
Control Drug ......................................................................................... 45 


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Final 4.2 
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5.2. 
Dose Rationale Including Time of Dosing....................................................... 45 
5.2.1. 
Rationale for Dose Escalation ................................................................. 46 
5.2.2. 
Definition of the Maximum Tolerated Dose .............................................. 46 
5.3. 
Supply, Packaging, Labelling and Storage ...................................................... 46 
5.4. 
Drug Preparation, Dispensing, Accountability and Destruction ......................... 46 
5.5. 
Subject Identification and Randomization ....................................................... 47 
5.5.1. 
Screening Numbers ................................................................................ 47 
5.5.2. 
Randomization Numbers ........................................................................ 47 
5.6. 
Administration of Investigational Products...................................................... 48 
5.7. 
Compliance ................................................................................................. 48 
5.8. 
Blinding and Breaking the Blind .................................................................... 49 
5.9. 
Prior and Concomitant Medications ............................................................... 49 
5.10. Overdose of Investigational Product ............................................................... 49 
6. 
VARIABLES, PARAMETERS AND METHODS OF ASSESSMENT ..................... 50 
6.1. 
Medical History, Demographic and Other Baseline Information ........................ 50 
6.2. 
Safety Variables ........................................................................................... 50 
6.2.1. 
Adverse Events ..................................................................................... 50 
6.2.1.1. 
Definitions ..................................................................................... 51 
6.2.1.1.1. Definition of Adverse Event .......................................................... 51 
6.2.1.1.2. Definition of Serious Adverse Event .............................................. 51 
6.2.1.2. 
Recording of Adverse Events ........................................................... 51 
6.2.1.3. 
Assessment of Adverse Events ......................................................... 52 
6.2.1.3.1. Severity ...................................................................................... 52 
6.2.1.3.2. Causality ..................................................................................... 52 
6.2.1.3.3. Seriousness ................................................................................. 53 
6.2.1.4. 
Reporting of Serious Adverse Events ................................................ 53 
6.2.1.5. 
Follow-up of Adverse Events ........................................................... 54 
6.2.1.6. 
Suspected Unexpected Serious Adverse Reactions .............................. 54 
6.2.1.7. 
Pregnancy ...................................................................................... 55 
6.2.2. 
Clinical Laboratory Assessments ............................................................. 55 
6.2.3. 
Vital Signs ............................................................................................ 58 
6.2.4. 
12-lead Electrocardiograms .................................................................... 58 
6.2.5. 
Injection Site Assessments ...................................................................... 58 
6.2.6. 
Immunogenicity Assessments ................................................................. 59 


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Final 4.2 
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6.2.7. 
Physical Examinations ........................................................................... 60 
6.3. 
Pharmacokinetics Variables ........................................................................... 60 
6.4. 
Pharmacodynamics Variables ........................................................................ 60 
6.4.1. 
Blood Sample Collection ........................................................................ 60 
7. 
STUDY CONDUCT ............................................................................................. 61 
7.1. 
Screening Visit ............................................................................................ 61 
7.2. 
Admission ................................................................................................... 61 
7.3. 
Inpatient Treatment Period ............................................................................ 61 
7.4. 
Outpatient Visits .......................................................................................... 61 
7.5. 
Follow-up .................................................................................................... 61 
7.6. 
Termination Visit ......................................................................................... 62 
7.7. 
Restrictions ................................................................................................. 62 
7.7.1. 
Dietary and Fluid Restrictions ................................................................. 62 
7.7.2. 
Alcohol and Caffeine ............................................................................. 62 
7.7.3. 
Smoking and Tobacco ............................................................................ 62 
7.7.4. 
Activity and Exercise ............................................................................. 63 
7.7.5. 
Other Restrictions .................................................................................. 63 
7.8. 
Handling of Hypersensitivity Reactions .......................................................... 64 
7.8.1. 
Anaphylaxis .......................................................................................... 64 
7.8.2. 
Subacute Hypersensitivity Reactions (Type III Hypersensitivity Reactions) ... 64 
8. 
STATISTICAL METHODS .................................................................................. 65 
8.1. 
Definition of Analysis Populations ................................................................. 65 
8.2. 
General Considerations ................................................................................. 65 
8.3. 
Subject Disposition ...................................................................................... 65 
8.4. 
Demographic Data and Predose Assessments .................................................. 65 
8.5. 
Prior and Concomitant Medication and Drug Administration ............................ 66 
8.6. 
Exposure ..................................................................................................... 66 
8.7. 
Safety Analyses ........................................................................................... 66 
8.7.1. 
Adverse Events ..................................................................................... 66 
8.7.2. 
Clinical Laboratory Tests ....................................................................... 66 
8.7.3. 
Vital Signs ............................................................................................ 66 
8.7.4. 
12-lead Electrocardiogram ...................................................................... 66 
8.7.5. 
Immune Response Assessments .............................................................. 67 
8.7.6. 
Physical Examinations ........................................................................... 67 


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8.7.7. 
Injection Site Assessments ...................................................................... 67 
8.8. 
Pharmacokinetics Analyses ........................................................................... 67 
8.9. 
Pharmacodynamics Analyses ......................................................................... 67 
8.10. Interim Analyses .......................................................................................... 67 
8.11. Determination of Sample Size ....................................................................... 68 
9. 
DATA MANAGEMENT ...................................................................................... 69 
9.1. 
Data Management ........................................................................................ 69 
9.2. 
Electronic Case Report Form ......................................................................... 69 
9.2.1. 
Process of Clinical Data Management ...................................................... 69 
9.2.2. 
Data Input in eCRF ................................................................................ 69 
9.2.3. 
Modification of eCRF Data ..................................................................... 70 
9.2.4. 
eCRF Data Approval of the Principal Investigator ..................................... 70 
9.3. 
Document Storage ........................................................................................ 70 
10. ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ...................................... 71 
10.1. Quality Control and Reliability Assurance ...................................................... 71 
10.2. Subject Safety Assurance .............................................................................. 71 
10.3. Finance and Insurance .................................................................................. 72 
10.4. Access to Source Data/Documents ................................................................. 72 
10.5. Archiving Study Documents .......................................................................... 73 
10.6. Good Clinical Practice .................................................................................. 73 
10.7. Informed Consent ......................................................................................... 73 
10.8. Protocol Approval and Amendment(s) ............................................................ 74 
10.9. Confidentiality Data Protection ...................................................................... 74 
10.10. Publication Policy ........................................................................................ 74 
11. REFERENCE LIST .............................................................................................. 75 
 
 
 
 


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List of Tables 
Table 1 Schedule of Assessments ............................................................................... 12 
Table 2 Citrulline and Apolipoprotein AIV Sampling Schedule for Exploring PK Samples 
and PD......................................................................................................... 18 
Table 3 PD Sampling Schedule .................................................................................. 22 
Table 4 Cohorts and Dose Administration ................................................................... 36 
Table 5 Randomization Numbers and Treatment Assignment ........................................ 48 
Table 6 Assessment of Relationship of Adverse Events to Investigational Product .......... 52 
Table 7 Clinical Laboratory Assessments .................................................................... 56 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
anti-HBc 
Hepatitis B core antibody 
anti-PEG 
anti-polyethylene glycol 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC%extrap 
Percentage of AUCinf that is due to extrapolation beyond tlast  
AUC0-t 
Area under the concentration-time curve from predose (time 0) to the time of 
the last quantifiable concentration 
AUCinf 
Area under the concentration-time curve from predose (time 0) extrapolated to 
infinite time (AUC0-t + Clast/λz) 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
CHO 
Chinese hamster ovary 
CL/F 
Total body clearance 
Cmax 
Maximum serum concentration 
hs-CRP 
High sensitivity C-reactive protein 
DBP 
Diastolic blood pressure 
DMP 
Data Management Plan 
DPP-4 
Dipeptidyl peptidase-4 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FiH 
First-in-human 
FPG 
Fasting plasma glucose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C antibody 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HMC001 
Human immunoglobulin G4 Fc fragment 


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Abbreviation 
Definition 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IGF-1 
Insulin-like growth factor-1 
IP 
Investigational product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISEMFs 
Intestinal subepithelial myofibroblasts 
KGF 
Keratinocyte growth factor 
LDL 
Low-density lipoprotein 
ALD-PEG-ALD 
Aldehyde-Polyethylene glycol-Aldehyde 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
Minimum intolerable dose 
MTD 
Maximum tolerated dose 
MRSD 
Maximum recommended starting dose 
NAb 
Neutralizing antibody 
NOAEL 
No observed adverse effect level 
OTC 
Over-the-counter 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PN 
Parenteral nutrition 
PT 
Preferred Term 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s correction 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RR 
Respiratory rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SID 
Subject identification 
SOC 
System Organ Class 


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Abbreviation 
Definition 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal elimination half-life 
Tmax 
Time of maximum serum concentration 
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein 
Vz/F 
Apparent volume of distribution 
λz 
Terminal elimination rate constant 
 
 
 


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1. INTRODUCTION 
1.1. Background 
Hanmi Pharmaceutical is developing HM15912, a synthetic substance produced by 
combining a GLP-2 analogue (GT15912) and a human immunoglobulin G4 Fc fragment 
(HMC001) with aldehyde-polyethylene glycol-aldehyde (ALD-PEG-ALD), a bifunctional 
bonding molecule1. This medicinal product is developed as a new treatment for the short 
bowel syndrome (SBS). 
The SBS is a rare disease caused by broad surgical resection of the small intestine or as a 
result of an inborn condition. It is characterized by a decrease in the intestinal absorption 
surface area and subsequent malabsorption of essential macronutrients and micronutrients2. 
There is no definitive treatment for the SBS at present, and patients with a short residual 
bowel are likely to rely on parenteral nutrition (PN). Long-term PN may cause life-
threatening complications such as sepsis, osteopenia, and chronic liver diseases3. 
GLP-2 is known to increase the intestinal absorption surface area by promoting the growth of 
crypt cells within the intestine, and it has been developed as a treatment to reduce SBS 
patients' dependency on PN. GLP-2 is a major hormone that affects many aspects of intestinal 
physiology such as growth, barrier function, digestion, absorption, movement, and blood 
flow4. The half-life of GLP-2 within the human body is very short (approximately 7 minutes), 
so the GLP-2 medication currently on the market, teduglutide (GATTEX®), has been 
developed to have resistance to the dipeptidyl peptidase-4 (DPP-4) enzyme. Of note, however, 
that the half-life of teduglutide is 1.3~2.2 hours, which is still short, and it is provided as 
freeze-dried powder, thereby requiring medical staff to go through complicated preparation 
process to administer it to patients5. Thus, teduglutide cannot be a sufficient treatment option 
for SBS patients requiring long-term PN. 
Unlike teduglutide, HM15912 is a GLP product that prolongs the half-life and enhances 
stability by decreasing renal excretion resulting from increased molecular weight and with 
recycling of vascular endothelial cells through FcRn binding. GT15912 of HM15912 as a GLP-
2 analogue has been designed to be more effective than teduglutide, and PK and pharmaceutical 
stability have been enhanced by increasing water solubility through the binding of GT15912 
and HMC001. The nonclinical PD study results show that HM15912 induced human GLP-2 
receptor-mediated cAMP accumulation dose-dependently in hGLP-2R/CHO-K1 cells and 
stimulated IGF-1 production in mice's primary intestinal subepithelial myofibroblasts 
(ISEMFs). The secreted IGF-1 binds with the tyrosine kinase IGF-1 receptor in crypt and this is 
related to crypt cell proliferation through the paracrine signaling. The PD of HM15912 has been 
verified from in vivo experiments as well. When HM15912 was subcutaneously dosed multiple 
times to mice and rats, the growth of their intestine, especially the wet weight of their small 
intestine, has increased dose-dependently and shown higher intestinotrophic efficacy compared 
to teduglutide. Furthermore, it has been proved that there is a relationship between the physical 
improvement of intestinal environment and the functional improvement of intestine since the 
intestinal growth led by HM15912 in SBS rat models has enhanced nutrient absorption as a 
result. Based on such PD and PK properties, HM15912 is expected to be a promising option for 
treating the SBS. 
Additional details can be found in the Investigator's Brochure (IB)1. 
1.2. Rationale for the Clinical Study 


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This first-in-human (FiH) study evaluates the safety, tolerability, PK and PD of HM15912, a 
synthetic conjugate of a GLP-2 analogue (GT15912) and a human immunoglobulin G4 Fc 
fragment (HMC001). 
This study is conducted to define a tolerable dose range for most subjects and to provide 
exploratory data on the potential for prolonged intestinal absorption increase in healthy 
population. The results of this clinical study will provide data on design and dose selection for 
subsequent studies. 
1.3. Risk-benefit Assessment 
While HM15912 has not been evaluated in humans, clinical experiences with other GLP-2 
analogues and known pharmacologic and preclinical data suggest the following expected side 
effects: 
• Gastrointestinal: Abdominal pain, abdominal discomfort, nausea, vomiting, abdominal 
inflation, dysorexia, colon polyp, small intestinal tumor, intestinal obstruction, 
gallbladder/biliary tract disease, pancreatic disease 
• Respiratory: Upper airway infection, cough 
• Immunological: Hypersensitivity reaction 
• General: Injection site reaction, pyrexia 
• Investigational: Slight increase of amylase and lipase, slight decrease of ALP, ALT, and 
AST 
• Nervous system: Sleep disorder 
• Skin lesion: Skin hemorrhage 
• Fluid overload 
There will be no direct health benefit for healthy subjects from receipt of the investigational 
product (IP). The protocol has been designed to minimize the risk to research participants. 
Subjects will be monitored to detect AEs during the study and followed appropriately to 
ensure resolution of AEs. Sentinel dosing will be employed within each cohort, and available 
blinded safety data (together with PK/PD data if possible) will be assessed after each dose 
level to determine if it is safe to escalate to the next planned dose. 
 
 


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2. STUDY OBJECTIVES 
2.1. Primary Objective 
• To assess the safety and tolerability of HM15912 after single SC doses 
2.2. Secondary Objective 
• To assess the PK profile of HM15912 after single SC doses 
2.3. Exploratory Objective 
• To explore the PD properties of HM15912 after single SC doses 
 
 


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3. OVERALL DESIGN AND PLAN OF THE STUDY 
3.1. Overview 
This is a double-blind, randomized, placebo-controlled, single ascending dose (SAD) study to 
assess the safety, tolerability, PK and PD of the SC administration of HM15912 in healthy 
Korean subjects. 
The study will be conducted in approximately 5 sequential dosing cohorts, enrolling 8 
subjects per cohort. Subjects will be randomized to HM15912 or placebo in a ratio of 6:2 (6 
active, 2 placebo). When necessary, one dosing cohort may be added or removed. 
Each cohort will be divided in 2 blocks in this FiH study in order to implement the sentinel 
dosing approach. Within each cohort, the first block will consist of 2 sentinel subjects; 1 
subject will receive HM15912, and 1 subject will receive matched placebo. The second block 
will consist of 6 subjects randomized to receive HM15912 (n = 5) or matched placebo (n = 1). 
Individual subjects in the second block will be dosed at least 24 hours after the first block 
when safety and tolerability are found to be satisfactory by the Principal Investigator. 
Following an overnight fast of at least 10 hours, each subject will receive a single dose of 
either HM15912 or matched placebo-administered SC in the abdomen on the morning (8:00 
AM - 10:00 AM) of Day 1. Subjects will continue fasting through approximately 4 hours 
postdose. Water intake is also limited for approximately 1 hour before dosing and 
approximately 2 hours after dosing. 
The planned maximum dose of HM15912 is 1.5 mg/kg; however, higher doses may be 
administered if safety is confirmed in previous cohorts. If dose is escalated to 1.5 mg/kg or 
above, MFDS approval will be obtained. After at least 6 subjects (HM15912, n ≥ 4) in each 
cohort have completed assessments through at least Day 17, blinded safety data will be 
reviewed and a dose decision/dose escalation decision for the subsequent cohort will be made 
by the Principal Investigator and the Sponsor. If there are PK/PD data obtained from the 
preceding or current cohorts, the PK/PD data will be reviewed as well when necessary. 
Escalation will only proceed if safety and tolerability data related to the dose of the prior 
cohort are verified. Determination of whether to proceed to the next cohort will be made by 
the Principal Investigator and the Sponsor, and changes in the dose and the number of cohorts 
will be approved by the MFDS and the IRB. 
PK data will only be reviewed if available. After review of the PK data from the preceding or 
current cohorts, changes in time points for PK collection, clinical laboratory assessments, and 
PD collection may be required and will be approved by the MFDS and the IRB. 
If dose escalation is stopped based on available blinded safety data, the current dose level will 
be considered as the minimum intolerable dose (MID). The dose just below the MID will be 
regarded as the maximum tolerated dose (MTD). If the dose escalation is stopped due to 
reaching exposure limit without dose-limiting safety findings, the MTD cannot be 
determined. Dose de-escalation may occur in the last cohort or additional cohorts to further 
refine clinically relevant dose levels. 
Stopping rules are described in Section 3.4. 
 
The study will be comprised of: 
• A Screening visit up to 28 days before dosing 


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• An inpatient assessment period of approximately 8 days, with admission to the institution 
on Day-1, dosing on Day 1, and discharge on Day 7 once the planned schedule is 
completed 
• Two Outpatient visits on Day 8 (± 4 hours), Day 10 (± 1 day), Day 17 (± 1 day) and Day 
30 (±3 days) 
• A final Follow-up visit on Day 44 (± 3 days) 
The total duration of the clinical study per subject will be up to approximately 72 days, 
including the Screening period. 
Procedures related to the clinical study are detailed in the Schedule of Assessments, the PK 
Sampling Schedule, the Citrulline Sampling Schedule, and the PD Sampling Schedule (Table 
1-1 and 1-2, Table 2-1 and 2-2, Table 3-1 and 3-2, respectively). 
Doses will be administered via SC injection to subjects in approximately 5 dose cohorts. 
Additional cohorts may be enrolled and proceed at a dose higher or lower than the planned 
maximum dose of 1.5 mg/kg, if deemed appropriate by the Principal Investigator and the 
Sponsor, but cohorts are planned as follows: 
Table 4 
Cohorts and Dose Administration 
 
Cohorts 
Number of Subjects 
Treatment1 
Cohort 1 
N = 6 
HM15912 0.05 mg/kg 
N = 2 
Placebo 
Cohort 2 
N = 6 
HM15912 0.1 mg/kg 
N = 2 
Placebo 
Cohort 3 
N = 6 
HM15912 0.5 mg/kg 
N = 2 
Placebo 
Cohort 4 
N = 6 
HM15912 1.0 mg/kg 
N = 2 
Placebo 
Cohort 5 
N = 6 
HM15912 1.5 mg/kg 
N = 2 
Placebo 
1 After at least 6 subjects (HM15912, n ≥ 4) in each cohort have completed assessments through at least Day 17, 
blinded safety data (PK/PD data from the preceding or current cohorts will also be reviewed when necessary) 
will be reviewed and a dose decision/dose escalation decision for the subsequent cohort will be made by the 
Principal Investigator and the Sponsor. If dose escalation is stopped, dose de-escalation may occur in additional 
cohorts to further refine clinically relevant dose levels. The planned maximum dose of HM15912 is 1.5 mg/kg; 
however, higher doses may be administered if safety is confirmed in previous cohorts. 
 
 


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3.2. Endpoints 
3.2.1. Primary Endpoints 
• General safety variables: Adverse event (AE) assessments, clinical laboratory tests 
(hematology, clinical chemistry, coagulation and urinalysis), vital signs (blood pressure 
[BP], pulse, tympanic temperature and respiratory rate [RR]), 12-lead electrocardiogram 
(ECG), physical examinations 
• Specific safety variables: Injection site assessments, immunogenicity assessments (ADA, 
NAb, anti-PEG) (performed only if analysis is necessary) 
3.2.2. Secondary Endpoints 
• Cmax: Maximum serum HM15912 concentration determined from the concentration-time 
profile 
• Tmax: Time of maximum serum HM15912 concentration determined from the 
concentration-time profile 
• AUC0-t: Area under the concentration-time curve from predose (time 0) to the last 
quantifiable concentration 
• AUCinf: Area under the concentration-time curve from predose (time 0) extrapolated to 
infinite time (AUC0-t + Clast/λz) calculated using the linear-log trapezoidal rule 
• AUC%extrap: Percentage of AUCinf that is due to extrapolation beyond tlast  
• λz: The terminal elimination rate constant determined by selection of at least 3 data points 
on the terminal phase of the concentration-time curve 
• t½: Terminal elimination half-life calculated as: ln2/λz  
• CL/F: Total body clearance calculated as: Dose/AUCinf 
• Vz/F: Apparent volume of distribution calculated as: Dose/(AUCinf * λz) 
3.2.3. Exploratory Endpoints 
• Blood plasma citrulline 
• Albumin, prealbumin 
• Fasting lipid panel (total cholesterol, triglycerides, low-density lipoprotein [LDL], high-
density lipoprotein [HDL], very low-density lipoprotein [VLDL], free fatty acid [FFA]) 
• Blood glucose-related panel (fasting plasma glucose, gastric inhibitory polypeptide [GIP], 
glucagon-like peptide-1 [GLP-1], C-peptide, glucagon, insulin) 
• Insulin-like growth factor-1 growth factor-1; IGF-1) and keratinocyte growth factor (KGF) 
 
 


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3.3. Rationale for the Study Design 
This study evaluates the safety, tolerability, PK and PD of single ascending doses of 
HM15912 administered via SC injection. This study was designed to minimize bias and to 
obtain reference data (i.e., data from placebo-treated subjects) which will aid in the 
interpretation of results through double blind and placebo control. 
For this FiH study, sentinel dosing will be utilized for each cohort. This will minimize the 
number of subjects affected by rapid side effects after HM15912 administration. The Principal 
Investigator and the Sponsor will review available blinded safety and tolerability data after 
each cohort to determine the next dose and then decide whether the dose escalation should be 
stopped or whether the dose should be increased/decreased in the subsequent cohort. If 
PK/PD data have been obtained, they can be used for reference. This is not mandatory, 
however. 
The planned safety assessments that will be performed during the study are measures for 
ensuring the safety of subjects during a clinical trial. The PK sampling schedule is considered 
appropriate given the information obtained from the nonclinical study results of HM15912. 
The rationale for dose selection is discussed in Section 5.2. 
Based on the in vivo effect of endogenous GLP-2, the exogenous administration of HM15912, a 
GLP-2 analogue, is expected to expand the mucous epithelium of the small intestine and colon 
resulting from the proliferation of crypt cells1. Plasma citrulline is a nonprotein amino acid that 
is mostly synthesized in the small intestine cells, and is well-known as a noninvasive plasma 
biomarker for intestinal cell mass2. Apolipoprotein AIV is also mostly synthesized in the small 
intestine cells, and previous studies have shown the correlation between apolipoprotein AIV and 
plasma citrulline levels3. Therefore, effect of HM15912 on expansion of the intestinal mucous 
membrane will be explored by measuring plasma citrulline after HM15912 administration. The 
serum proteins, albumin and prealbumin, and serum lipid panel will also be evaluated to 
observe changes in nutrient status of subjects resulting from expansion of the intestinal mucous 
membrane4. 
GLP-2 affects the pancreas and is involved in the secretion of glucagon and maintenance of 
glucose homeostasis1. These pancreatic hormones are balanced in a physiological condition, 
and this study will explore the effect of GLP-2 administration on the homeostasis. 
3.4. Dose Escalation and Study Stopping Criteria 
Dose escalation will be stopped if 1 of the following conditions applies: 
• Death of a subject in 1 cohort, at any time, that is considered to be related to the IP, judged 
by the Principal Investigator 
• One or more of the subjects in 1 cohort have experienced serious AE that is considered to 
be related to the IP, judged by the Principal Investigator.  
• Two or more of the subjects in 1 cohort have experienced severe AE that is considered to 
be related to the IP, judged by the Principal Investigator. 
• Two or more of the subjects in 1 cohort have experienced moderate AEs that persist for 
more than 7 days and are considered to be related to the IP, judged by the Principal 
Investigator. 
• Two or more of the subjects in 1 cohort develop similar clinically significant laboratory, 
significant ECG or vital sign abnormalities, or severe AEs in the same organ class, 


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indicating dose-limiting intolerance. Dose escalation may proceed if after review of the 
data by the Principal Investigator and discussion with the Sponsor, it is concluded that the 
events are not drug related. 
• It is determined that the limit of safety and/or tolerability has been reached. Decision will 
be made between the Sponsor and the Principal Investigator. 
If any delayed reactions occur in subjects administered HM15912 during this study, the 
Principal Investigator will immediately stop the administration and take appropriate medical 
measures. If delayed reactions are suspected to be drug hypersensitivity reactions, appropriate 
medical measures will be taken in accordance with 7.9. Handling of Hypersensitivity 
Reactions. If Principal Investigator and Sponsor discuss and agree that administering 
HM15912 to other subjects is an unacceptable risk, they may stop the study as below. 
The Principal Investigator and the Sponsor may stop the clinical study after an appropriate 
discussion if conditions or events including, but not limited to, the following occur during the 
study. A sufficient written statement on the reason for stopping the study will be submitted to 
the IRB. 
• If clear risks or unacceptable risks are found in the subjects enrolled in this clinical study 
• If the Sponsor decides to postpone or stop development of the IP 
 
 


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4. STUDY POPULATION 
The study population will consist of healthy male and female volunteers. Subjects must be 
able to provide written informed consent and meet all the inclusion criteria and none of the 
exclusion criteria. 
4.1. Number of Subjects 
A total of approximately 40 subjects will be enrolled in the clinical study (N = 8 per cohort 
with 6 randomized to HM15912 and 2 randomized to matching placebo within each group) 
according to the inclusion/exclusion criteria. Enrolling 8 subjects per cohort 
(HM15912:placebo=6:2) has been set based on the experience and the general properties of 
exploratory studies, and this matches the typical sample size used in similar studies conducted 
to assess safety and PK. Therefore, no formal sample size calculation will be performed (refer 
to Section 8.11). 
4.2. Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to participate in the 
clinical study: 
1. Subject voluntarily agrees to participate in this study and signs an IRB-approved 
informed consent prior to performing any of the Screening visit procedures. 
2. Korean males and females ≥ 19 and ≤ 60 years of age at the Screening visit 
3. Female subjects must be non-pregnant and non-lactating and either surgically sterile (e.g., 
bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), 
or post-menopausal for ≥ 12 months. Postmenopausal status will be confirmed through 
testing of follicle-stimulating hormone (FSH) levels ≥ 40 IU/L at the Screening visit for 
amenorrheic female subjects ≤ 60 years of age. 
Male subjects must be surgically sterile (at least 1-year post vasectomy), abstinent or if 
engaged in sexual relations with women of child-bearing potential, the subject and his 
partner must be using the following acceptable effective or medically recognized dual 
protection contraceptive methods from the administration of IP to up to 60 days after 
receiving the dose of the IP. 
• Effective contraceptive method: Sexual partner's surgical sterilization (e.g., bilateral 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), 
intrauterine contraception/device of the sexual partner 
• Dual protection contraceptive method: Combinational use of physical barrier methods 
(male condom, female condom and diaphragm for the sexual partner, sponge, cervical 
cap), spermicide for females in the form of foam/gel/film/cream/suppository, oral or 
hormonal contraceptives for the sexual partner 
The adequacy of other methods of contraception will be assessed on a case-by-case basis 
by the Principal Investigator. 
4. Body mass index (BMI) ≥ 18.5 kg/m2 and ≤ 27 kg/m2 at the Screening visit and with a 


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weight ≥ 50 kg for males and ≥ 45 kg for females 
5. Healthy, determined by pre-study medical evaluation (medical history, physical 
examination, vital signs, 12-lead ECG and clinical laboratory evaluations) 
4.3. Exclusion Criteria 
Subjects who meet 1 or more of the following criteria at the Screening visit will not be 
considered eligible to participate in the clinical study. Also, subjects who meet 1 or more of 
the following criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 27, 
28, 29, 30, and 31 when they are hospitalized (Day-1) will not be considered eligible to 
participate in the clinical study. 
1. Subject with a history or presence of clinically significant active diseases of the 
gastrointestinal, cardiovascular (including a history of arrhythmia or any clinically 
significant conduction delays in the ECG), hepatic, pulmonary, neurological, renal, 
pancreatic, immunological, dermatological, endocrine, genitourinary or hematological 
system 
2. Subject with a history or presence of skin rashes or dermatitis 
3. Subject with a history or presence of any psychiatric disorder that, in the opinion of the 
Principal Investigator, might confound the results of the study or pose additional risk in 
administering the investigational product to the subject 
4. Subject who has participated in other clinical studies (including bioequivalence tests) 
within 6 months before the Screening visit and has received IPs 
5. Subject who has received GLP-1, GLP-2, human growth hormones, or analogues in the 
past 
6. Subject with a history of any serious adverse reaction, hypersensitivity, or intolerance to 
IP components 
7. Subject who has any clinically significant history of allergic conditions (including drug 
allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, 
asymptomatic, seasonal allergies) prior to IP administration 
8. Subject with a history of gallstones, intestinal obstruction, or surgery/surgical resection of 
stomach or intestine (simple appendectomy is allowed) 
9. Subject with a history or presence of gastrointestinal illnesses such as malabsorption, 
pancreatic disease, gastrointestinal polyps, irritable bowel syndrome, Crohn's disease, or 
ulcerative colitis 
10. Subject with a personal or family history of hypercoagulability or thromboembolic 
disease 
11. Subject who has FPG < 70 or > 110 mg/dL at the Screening visit. 
12. Subject with a history of any major surgery within 6 months prior to the Screening visit 
13. Subject with a history or current diagnosis of heart diseases, defined as symptomatic heart 
failure (New York Heart Association class III or IV), myocardial infarction, unstable 
angina requiring medication, transient ischemic attack, cerebral infarct, or cerebral 
hemorrhage or invasive cardiovascular procedure, such as coronary artery bypass graft 
surgery, or angioplasty/percutaneous coronary intervention within 6 months before the 


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Screening visit (a diagnostic cardiac catheterization without any intervention does not 
exclude the subject) 
14. Subject with cardiac arrhythmia requiring medical or surgical treatment within 6 months 
prior to the Screening visit 
15. Subject who has/had febrile illness or symptomatic, viral, bacterial (including upper 
respiratory infection), or fungal (noncutaneous) infection within 1 week prior to the 
Screening visit 
16. Subject with daily use of more than 5 cigarettes or equivalent use of any tobacco product 
within 6 weeks prior to the Screening visit. Subject must be able to abstain from smoking 
during the confinement period. 
17. Subject with a history of any active infection, except mild viral diseases, within 30 days 
prior to the Screening visit 
18. Subject with a history of hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(anti-HBc), hepatitis C antibody (HCV Ab), or human immunodeficiency virus (HIV) 
19. Subject with the existence of any surgical or medical condition that, in the judgment of 
the Principal Investigator, might interfere with the absorption, distribution, metabolism or 
excretion of the IP 
20. Subject with the presence of clinically significant physical, clinical laboratory or ECG 
findings (e.g., QTcB > 450 msec for males, QTcB > 470 msec for females, left bundle 
branch block) at the Screening visit that, in the opinion of the Principal Investigator, may 
interfere with any aspect of study conduct or interpretation of results. 
21. Subject who has a mean pulse < 45 or > 90 beats per minute (bpm); mean systolic blood 
pressure (SBP) > 140 mmHg; mean diastolic blood pressure (DBP) > 90 mmHg 
(measurements taken for 2 consecutive times after the subject has been resting in supine 
or sitting position for 5 minutes) (mean values from 2 consecutive measurements will be 
used). 
22. Subject who has donated whole blood within 60 days before the Screening visit, who has 
done apheresis within 1 month before the Screening visit or who has received blood 
products 
23. Subject who has a history of alcohol or illicit drug abuse as judged by the Principal 
Investigator or who reports use of recreational drugs (e.g., marijuana) within 6 weeks 
prior to the Screening visit 
24. Subject who has a positive urine drug test (e.g., cocaine, amphetamines, barbiturates, 
opiates, benzodiazepines, cannabinoids, phencyclidine, etc.) at the Screening visit or on 
Day-1 
25. Female subject who is currently pregnant or breastfeeding or who has a positive serum 
pregnancy test at the Screening visit or on Day-1 
26. Subject who has used over-the-counter (OTC) medications (including acetaminophen and 
vitamins), prescription medications, or herbal remedies from 3 days prior to the Screening 
visit, unless it is approved by the Principal Investigator 
27. Subject who is unwilling to avoid consumption of coffee and caffeine-containing 
beverages within 24 hours before each study visit and while the subject is confined to the 
institution 
28. Subject who is unwilling to avoid use of alcohol or alcohol-containing foods, medications 


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or beverages within 48 hours before each study visit and while the subject is confined to 
the institution 
29. Subject who is unwilling to abstain from vigorous exercise from 48 hours prior to 
admission until the Follow-up visit 
30. Subject who is unable to understand the protocol requirements, instructions, study-related 
restrictions, and the nature, scope and possible consequences of the clinical study or who 
is unlikely to comply with the protocol requirements, instructions and study-related 
restrictions; e.g., uncooperative attitude, inability to return for Follow-up visits and 
improbability of completing the clinical study 
31. Subject who is deemed by the Principal Investigator to be inappropriate in conducting the 
clinical study.  
Subjects who have screen failed may be allowed to re-screen once at the discretion 
of the Principal Investigator. 
4.4. Subject Withdrawal and Replacement 
Subjects may withdraw consent to participation in the clinical study at any time without 
penalty and for any reason without prejudice to his or her future medical care. The subject 
does not need to give a reason for withdrawal of consent to participation in the clinical study. 
Subject participation may be terminated prior to completing the study and the reason recorded 
as follows: 
• Adverse event 
• Protocol violation 
• Loss to follow-up 
• Subject withdraws consent. 
• Study discontinuation by the Sponsor 
• Withdrawn by the Principal Investigator 
• Pregnancy 
• Other 
In all cases, the reason(s) for withdrawal must be recorded. Should the randomization code be 
broken for a subject, the date, time and reason must be recorded. 
If a subject is withdrawn, or chooses to withdraw, from the clinical study for any reason, the 
Principal Investigator must make every possible effort to perform the evaluations described 
for the Follow-up visit. 
Once a subject who was administered IP is withdrawn by the Principal Investigator, the 
subject may not re-enter the study. 
A subject who has been withdrawn from the study before IP administration may be replaced 
with a candidate subject. Subjects withdrawn from the study for reasons unrelated to safety 
may be replaced at the discretion of the Investigator and the Sponsor. The study results 
obtained until their withdrawal may be reviewed for final evaluation. The numbers given to 
replaced subjects are described in Section 5.5.2. 
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If the Principal Investigator or the Sponsor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the clinical study continues, the clinical study may be 
terminated after appropriate consultation between the involved parties. The clinical study may 
be terminated at the Sponsor’s discretion also in the absence of such a finding. 
In case the safety of subjects is jeopardized, the study must be interrupted/terminated. For the 
stopping criteria, please refer to Section 3.4. 
The Sponsor reserves the right to discontinue this clinical study at any time for failure to meet 
expected enrollment goals, for safety or for any administrative reasons. 
The Sponsor will report in writing to all principal investigators, the regulatory authorities and 
the IRB regarding the early termination of the clinical study, including reasons. 
 
 
 


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5. INVESTIGATIONAL PRODUCT 
5.1. Identity of the Investigational Products 
5.1.1. Study Drug 
The study drug will be provided by Hanmi Pharmaceutical Co., Ltd. in a prefilled syringe. 
The concentration of HM15912 is 30 mg/mL and the fill volume is 0.52 mL including 
overfill. 
5.1.2.  Control Drug 
The control drug is a placebo matching the study drug HM15912. It is a sterile solution in a 
prefilled syringe without the main components of the study drug and is identical to the study 
drug in terms of formulation and appearance. Its fill volume including overfill is 0.52 mL, and 
it is provided by Hanmi Pharmaceutical Co., Ltd. 
5.2. Dose Rationale Including Time of Dosing 
The proposed starting dose of HM15912 is 0.05 mg/kg based on the results of the 4-week 
toxicology assessment in rats and monkeys. The NOAEL was 10 mg/kg in rats and 18 mg/kg 
in monkeys. The human equivalent dose was 1.61 mg/kg for rats and 5.8 mg/kg for monkeys. 
As suggested in the 2005 FDA Guidance for Industry Estimating Maximum Safe Starting 
Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, the maximum 
recommended starting dose (MRSD) applying a safety factor of 10 to the human equivalent 
dose calculated in rats and monkeys is 0.16 mg/kg for rats and 0.58 mg/kg for monkeys. The 
selected initial dose of 0.05 mg/kg provides the safety margin that is approximately 3-fold in 
rats and approximately 12-fold in monkeys, compared to the MRSD. 
The planned maximum dose of HM15912 is 1.5 mg/kg; however, higher doses may be 
administered based on the safety results of previous cohorts. The MTD of HM15912 was not 
determined since no toxicity was found in the 2-week toxicology assessment (10 mg/kg in rats 
and 18 mg/kg in monkeys). The set maximum dose provides a 1.1-fold safety margin 
compared to the human equivalent dose calculated at the rat NOAEL and a 3.9-fold safety 
margin compared to the human equivalent dose calculated at the monkey NOAEL. The 
similar GLP-2 analogue, Gattex®, has shown appropriate tolerability up to 80 mg (SC, 
administered once per day for 8 days) with repeated doses in healthy subjects; another GLP-2 
analogue, ZP1848 (Zealand Pharma, under clinical development), has shown appropriate 
tolerability up to 96 mg with single doses in healthy subjects.6,7 
Following an overnight fast of at least 10 hours, each subject will receive a single dose of either 
HM15912 or matched placebo administered SC in the abdomen on the morning of Day 1 in 
order to permit time for postdose safety, PK and PD assessments throughout the day. Subjects 
must continue fasting for approximately 4 hours after administration. Water consumption will 
also be limited for 1 hour before dosing and for approximately 2 hours after dosing. After the 
planned blood sampling (clinical laboratory tests) and testing (12-lead ECG) are performed 4 
hours postdose, subjects will be served lunch by the institution. 


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5.2.1. Rationale for Dose Escalation 
After at least 6 subjects (HM15912, n ≥ 4) in each cohort have completed assessments 
through at least Day 17, blinded safety data will be reviewed and a dose decision/dose 
escalation decision for the subsequent cohort will be made by the Principal Investigator and 
the Sponsor. If PK/PD data have been obtained, they can be reviewed as well. This is not 
mandatory, however. The parties will decide about the next dose level taking into 
consideration the outcome from the blinded safety review, the stopping rules (Section 3.4), 
and the available PK/PD data.  
Depending on the nature, frequency and severity of the safety profile observed in the clinical 
study, the Principal Investigator and the Sponsor will decide one of the followings. If dose is 
escalated to 1.5 mg/kg or above or dose is reduced from the planned dose, approval of the 
MFDS and the IRB will be obtained. 
1. Proceed with dose escalation and determine the next higher dose; 
2. Stop dose escalation (i.e., no further dosing); 
3. Investigate a lower dose level (intermediate between the current and prior ones). 
5.2.2. Definition of the Maximum Tolerated Dose 
If dose escalation is stopped based on available safety data, the current dose level will be 
considered as the MID. The dose just below the MID will be regarded as the MTD. If the dose 
escalation is stopped due to reaching exposure limit without dose-limiting safety findings, the 
MTD cannot be determined. 
5.3. Supply, Packaging, Labelling and Storage 
The IPs will be packaged by Hanmi Pharm. Co., Ltd. according to local legal requirement and 
labelled according to applicable health authority requirements. 
All supplies of IPs must be stored in accordance with the manufacturer’s instructions, 
refrigerated between 2°C and 8°C and protected from light (i.e., kept in cartons until ready for 
use). HM15912 is stable up to 12 hours at room temperature. The Investigator and the 
institution's staff in charge will check every day if the temperature for IP storage is 
appropriately maintained and the thermometer is properly functioning. If temperature 
excursions are found, it should be reported immediately. IPs must be handled and retained 
properly and safely by the clinical research pharmacist at the institution and stored in a 
secure area accessible only to the Investigator and clinical research pharmacist. 
5.4. Drug Preparation, Dispensing, Accountability and Destruction 
The IPs will be provided in prefilled syringes. Dose administration will be based on the body 
weight of a subject rounded to 1 decimal place as measured on the day before dosing. The 
injection volume will also be determined by dose level. HM15912 concentration is 30 
mg/mL. The determined injection volume will be prepared in dosing syringes in accordance 
with the instructions contained in the pharmacy manual. 
Each administered IP will be recorded, and used syringes and needles will be discarded. 
The Investigator or clinical research pharmacist is responsible for maintaining accurate 


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records regarding transportation and dispensing of IPs. The IPs must be used only for this 
clinical study. The unblinded monitor will check IP accountability during the clinical study 
period and at completion of the study.  
All unused IPs must be destroyed by the Sponsor according to IP destruction-related 
guidelines, and documents regarding the destruction must be managed. Therefore, unused IPs, 
packages, and IP labels must be returned to the Sponsor upon completion of the study or 
during the study if needed. Used or opened IPs will be destroyed properly according to the 
institution's SOP. The Investigator or clinical research pharmacist will provide one copy of IP 
accountability records for the Sponsor. 
5.5. Subject Identification and Randomization 
5.5.1. Screening Numbers 
All screened subjects are assigned a unique subject identification (SID) number. The SID 
numbers are sequentially assigned in the order of obtaining written consent, and contain 4 
digits (e.g., the numbers are sequentially allocated from X001 and X represents an institute) 
that identify subjects from the time of Screening until the time of randomization. Enrolled 
subjects who drop out of the clinical study before randomization after consent has been 
obtained will retain their SID number. 
5.5.2. Randomization Numbers 
Randomization numbers are assigned to subjects after completing the Screening and re-
checking the inclusion/exclusion criteria on Day-1. Randomization numbers are assigned in 
the order that subjects who meet all the inclusion/exclusion criteria of this study get 
hospitalized on Day-1. Randomization will be performed through the EDC, and 
randomization numbers will be assigned by the system. The randomization code (study drug 
or control drug) of each randomization number will be maintained in a room with restricted 
access to the non-blinded clinical research pharmacist only, and will be accessed by other 
personnel only in case of unblinding, as described in Section 5.8. A randomization number 
will include 3-digit subject numbers as shown in Table 5. 
 
 
 


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Table 5 
Randomization Numbers and Treatment Assignment 
 
Cohort 
Randomization Numbers 
Treatment Assignment 
1 
101-108 
0.05 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
2 
201-208 
0.1 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
3 
301-308 
0.5 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
4 
401-408 
1.0 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
5 
501-508 
1.5 mg/kg1 HM15912 (N = 6) 
Placebo (N = 2) 
1 The planned maximum dose of HM15912 is 1.5 mg/kg; however, higher doses may be administered if safety is 
confirmed in previous cohorts. 
Once a randomization number has been allocated to one subject, it may not be assigned to 
another subject. If subjects withdraw prematurely from the study and are replaced under the 
direction of the Sponsor, then a replacement randomization number will be assigned when a 
replaced subject has successfully completed Screening. A replacement randomization code 
will be generated such that replacement subjects are assigned to the same treatment as the 
discontinued subjects. The replacement randomization code will differ only in randomization 
numbers. It is composed of 4 digits by adding “1” in front of the randomization number for a 
withdrawn subject. For example, if Subject 202 withdraws and is replaced, then the 
randomization number for the replacement subject will be 1202. 
5.6. Administration of Investigational Products 
HM15912 or placebo will be administered via SC injection into the abdomen on the morning 
of Day 1 after a minimum 10-hour overnight fast. Subjects will continue fasting through 
approximately 4 hours postdose. Water intake is also limited for approximately 1 hour before 
dosing and approximately 2 hours after dosing. After the planned blood sampling (clinical 
laboratory tests) and testing (12-lead ECG) are performed 4 hours postdose, subjects will be 
served lunch by the institution. 
5.7. Compliance 
Dosing will be performed by the Investigator, but if a nurse administers, that will be carried 
out under the Investigator's supervision. Comments will be recorded if there are any 
deviations from the planned dosing procedures. 
 
 


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5.8. Blinding and Breaking the Blind 
The clinical study will be performed in a double-blind manner with the exception of the 
persons involved in the preparation of the IPs. These persons will not be involved in any other 
study activities. 
The study blind should not be broken except in a medical emergency (where knowledge of the 
IP administered would affect the treatment of the emergency), or if dose limiting toxicities 
occur or if it is necessary for dose escalation decisions as described in Section 3.4. The 
decision to break the blind will be made by the Principal Investigator on a case-by-case basis. 
The Investigator or the Principal Investigator will contact Hanmi Pharmaceutical Co., Ltd. 
and deliver related documents when breaking the blind. The results of breaking the blind for 
each subject will not be revealed. The Investigator or the Principal Investigator will record 
blind-breaking dates and reasons in the CRF. 
If blinding is not maintained in the Investigator, the institution's staff or subjects, the subject 
must be withdrawn. If blinding is accidently broken during the study or blinding is broken 
before completion of the study due to SAEs, the Investigator must record this and rapidly 
report to Hanmi Pharmaceutical Co., Ltd. However, if blinding is broken for ethical reasons 
or blind breaking is seen to have little effect on the subject's safety, the subject may continue 
to participate in the clinical study in the judgment of the Investigator after discussing with 
Hanmi Pharmaceutical Co., Ltd. 
After database lock, the overall randomization code will be broken. 
5.9. Prior and Concomitant Medications 
Use of prescription, herbal, OTC (including acetaminophen and vitamins) medications is 
prohibited from 3 days prior to the Screening visit until the Follow-up visit, unless approved 
by the Principal Investigator. Use of dietary supplements is prohibited from Inpatient 
Treatment Period until the Follow-up visit. Use of concomitant medication is permitted if 
deemed by the Principal Investigator to be necessary for treatment of an AE. 
Other IPs cannot be used concurrently during the study, and there are no other concurrent 
drugs prohibited. 
5.10. Overdose of Investigational Product  
Standard symptomatic support measures should be used in the case of excessive 
pharmacological effects or overdose. No antidotes are available. 
 
 
 
 


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6. VARIABLES, PARAMETERS AND METHODS OF ASSESSMENT 
Variables and parameters are listed per time point in the Schedule of Assessments, the PK 
Sampling Schedule, the Citrulline Sampling Schedule, and the PD Sampling Schedule (Table 
1-1 and 1-2, Table 2-1 and 2-2, Table 3-1 and 3-2, respectively). 
PK blood sampling will be performed nearest to the specified time. 
6.1. Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• General medical history 
• Medication history 
• Birth history (female subjects only) 
The following demographic information will be recorded: 
• Date of birth 
• Sex 
• Height, without shoes (cm) 
• Body weight, without shoes (kg) (rounded to 1 decimal place for calculation of IP dose) 
• Body mass index (kg/m2) 
Other baseline characteristics will be recorded as follows: 
• History of drug abuse 
• History of alcohol abuse 
• Smoking history 
• History of caffeine use (or other stimulating beverages) 
• Special diet (vegetarian) 
• History of blood or plasma donation 
6.2. Safety Variables 
6.2.1. Adverse Events 
AE reporting will begin for each subject from the date he/she signs the ICF and will continue 
until the Follow-up visit. 
 
 


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6.2.1.1. 
Definitions 
6.2.1.1.1. 
Definition of Adverse Event 
Any untoward medical occurrence in subjects and which does not necessarily have a causal 
relationship with the IP. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease, whether or not it is related to 
the IP. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, 
e.g., those occurring during treatment-free periods (including post-treatment Follow-up 
periods), in association with study-related procedures and assessments, or under placebo. 
Concomitant illnesses that existed prior to entry into the clinical study will not be considered 
as AEs unless they worsen during the treatment period. If a subject is withdrawn prior to 
randomization, AEs occurring in him/her will not be collected. 
6.2.1.1.2. 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening; this means that a subject was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• Requires inpatient hospitalization or prolongation in existing hospitalization 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Is a congenital anomaly/birth defect, or 
• Is another important medical event (see below) 
Important medical events that do not result in death, are not life-threatening or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize a subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or in a physician’s office, blood 
dyscrasias or seizures that do not result in inpatient hospitalization, and the development of 
drug dependency or drug abuse. 
A distinction should be drawn between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria above. For example, a mild degree of 
gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes 
would be considered an SAE, but is not necessarily severe. Similarly, an AE that is severe in 
intensity is not necessarily an SAE. For example, alopecia may be assessed as severe in 
intensity but would not be considered an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.2.1.2. 
Recording of Adverse Events 
AEs should be collected and recorded for each subject from the date he/she signs the ICF until 
the end of their participation in the study, i.e., the subject has discontinued or completed the 
study. If a subject is withdrawn prior to randomization, AEs occurring in him/her will not be 


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collected. 
All AEs and SAEs will be recorded in source documents and, if applicable, in relevant eCRF 
pages and SAE forms. The Investigator is responsible for reporting AEs or SAEs using 
medical terms if possible. 
AEs may be volunteered spontaneously by a subject, or discovered by the study staff during 
physical examinations or by asking an open, non-leading question such as "How have you 
been feeling since you were last asked?" All AEs and any required remedial action will be 
recorded. The type of AE, date (and time, if known) of AE onset, date (and time, if known) of 
AE end, severity and action taken of the AE will be documented together with the 
Investigator’s assessment of the seriousness of the AE and causal relationship to IP and/or 
study procedure. 
All AEs should be recorded using standardized medical terms. AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
6.2.1.3. 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the categories discussed in the 
following sections. 
6.2.1.3.1. 
Severity 
The Investigator will assess all AEs for severity in accordance with the following standard 
ratings. 
• Mild: Ordinarily transient symptoms, does not influence performance of a subject’s daily 
activities. Treatment is not ordinarily indicated. 
• Moderate: Marked symptoms sufficient to make a subject uncomfortable. Moderate 
influence on performance of a subject’s daily activities. Treatment may be necessary. 
• Severe: Symptoms cause considerable discomfort. Substantial influence on performance of 
a subject’s daily activities. May be unable to continue in the study and treatment may be 
necessary. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted for that day. Any change in severity of signs and 
symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade, and the date (and time, if known) of the change. 
6.2.1.3.2. 
Causality 
The Investigator will assess the causality/relationship between the IP and the AE. One of the 
categories described in Table 6 should be selected based on medical judgment, considering 
the definitions below and all contributing factors. 
 
Table 6 
Assessment of Relationship of Adverse Events to Investigational Product 
 
Related 
The AE follows a reasonable temporal sequence from IP administration, and 
cannot be reasonably explained by a subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, or concomitant medications). 
The AE follows a reasonable temporal sequence from IP administration, and 


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represents a known reaction to the drug under study or other drugs in its class, or 
is predicted by the known pharmacological properties of the drug. 
The AE cannot be judged because of insufficient or contradictory information. 
The AE cannot be supplemented or verified. 
Not related 
The AE does not follow a reasonable temporal sequence from IP administration, 
or can be reasonably explained by a subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, and concomitant medications). 
6.2.1.3.3. 
Seriousness 
Severity is a measure of intensity whereas seriousness is defined by the criteria in Section 
6.2.1.1.2. 
6.2.1.4. 
Reporting of Serious Adverse Events 
All SAEs that occur during the period of observation (from the date the subject signs on the 
ICF until the follow-up visit), whether they are considered to be related to the IP or not, must 
be reported to the Sponsor within 24 hours after becoming aware of the occurrence by fax or 
email via the completed SAE report. 
Serious AEs occurring after the Follow-up visit (end of the clinical study) should be reported 
to the Sponsor by the Principal Investigator if the Principal Investigator considers there is a 
reasonable causal relationship with the IP. 
The minimal information required for an initial report is: 
• Sender of report (name, address of Principal Investigator) 
• Subject identification (Screening/randomization number, NOT subject name) 
• Protocol number 
• Description of SAE (Start date, seriousness) 
• Details of the IP (Dosage, frequency, start date, end date) 
• Causality assessment 
However, as far as possible all points on the SAE form should be covered in the initial report, 
and the completed SAE form must be faxed or emailed to the Sponsor. 
After receipt of the initial report, the Sponsor will review the information and, if necessary, 
contact the Principal Investigator to obtain further information for assessment of the event. 
The Principal Investigator will be responsible for informing the IRB of the SAE, and the 
Sponsor will be responsible for informing the regulatory authorities of the SAE as per local 
requirements. 
Serious Adverse Event Reporting: 
Hanmi Pharmaceutical Co., Ltd. Drug Safety & PV Team  
Telephone number: +82-2-410-0342 
Fax number: +82-50-2260-0479 
Email: newdrugsafety@hanmi.co.kr 


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6.2.1.5. 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored 
until the event has resolved, until any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Principal Investigator, until there is a satisfactory 
explanation for the changes observed or until the subject is lost to follow-up. 
If there are any changes of condition in subjects reported with SAEs (e.g., discharge after 
admission, situation worsened) or if any additional information is collected, the Investigator 
will complete an SAE report and send it to the Sponsor by fax or email within 24 hours after 
becoming aware of the occurrence. 
6.2.1.6. 
Suspected Unexpected Serious Adverse Reactions 
Any AE that is considered to be a suspected unexpected serious adverse reaction (SUSAR) 
has additional reporting requirements, as described below: 
• If the SAE is fatal or life-threatening, associated with the use of the IP, and unexpected, 
the Sponsor will report it to the regulatory authorities within 7 calendar days after the 
Sponsor learns of the event, and the Principal Investigator will report it to the IRB in 
accordance with the institution regulations. If the required information in the SAE report is 
not fully reported, however, the Sponsor will report additional follow-up information to 
the regulatory authorities within 15 calendar days after the Sponsor first learns of the 
event, and the Principal Investigator will make an additional report in accordance with the 
institution regulations. 
• If the SAE is not fatal or life-threatening but is otherwise serious, associated with the use 
of the IP, and unexpected, the Sponsor will report it to the regulatory authorities within 15 
calendar days after the Sponsor learns of the event, and the Principal Investigator will 
report to the IRB in accordance with the institution regulations. 
The Sponsor will notify the Principal Investigator of relevant information about SUSARs that 
could adversely affect the safety of subjects in a timely fashion. Follow-up information may 
be submitted if necessary. 
 
 


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6.2.1.7. 
Pregnancy 
The Sponsor has a responsibility to monitor the outcome of all pregnancies reported during 
the clinical study. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the IP may have 
interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below). Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE. 
If a female subject is confirmed to be pregnant, IP administration will be stopped and her 
participation in the clinical study will be terminated. Immediately after becoming aware of a 
subject's pregnancy, the Investigator should report to the Sponsor the fact that she is pregnant 
together with the subject number and receive her consent that her pregnancy information will 
be collected and shared with the Sponsor. If the subject agrees, the Investigator must report to 
the Sponsor via the completed Clinical Trial Pregnancy Report; initial report within 24 hours 
after obtaining the subject's consent. Any pregnancy of a male subject's partner must also be 
reported to the Sponsor in the same manner as the pregnancy in a female subject. The 
Principal Investigator must follow-up and document the course and the outcome of all 
pregnancies even if the subject has been withdrawn from the clinical study or if the clinical 
study has finished. All outcomes of pregnancy (e.g., the normal delivery or elective abortion) 
must be reported by the Principal Investigator to the Sponsor via the completed Clinical Trial 
Pregnancy Report; follow-up report within 24 hours after becoming aware of the outcome. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., 
maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal 
death, congenital anomaly, birth defect) and reported within 24 hours (based on the calendar 
day) in accordance with the procedure for reporting SAEs. 
6.2.2. Clinical Laboratory Assessments 
The clinical laboratory tests specified in Table 7 will be determined at time points specified in 
the Schedule of Assessments (Table 1-1 and 1-2). 
Clinical laboratory tests will be performed by the laboratories specified in the Laboratory 
Manual(s). Samples will be collected in appropriate tubes and handled according to standard 
procedures of the applicable laboratory. 
 
 


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Table 7 
Clinical Laboratory Assessments 
 
Hematology 
 
• White blood cell (WBC) count 
• Red blood cell (RBC) count 
• Hemoglobin (Hb) 
• Hematocrit (HCT) 
• Mean corpuscular volume (MCV) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin 
concentration (MCHC) 
• Neutrophils (percentage and absolute count) 
• Lymphocytes (percentage and absolute count) 
• Monocytes (percentage and absolute count) 
• Eosinophils (percentage and absolute count) 
• Basophils (percentage and absolute count) 
• Platelet count 
• RBC distribution width (RDW) 
 
Clinical Chemistry 
 
[Blood glucose-related panel] 
• Fasting plasma glucose (FPG) 
 
[Lipid-related panel] 
• Total cholesterol 
• Low-density lipoprotein (LDL) 
• High-density lipoprotein (HDL) 
• Very low-density lipoprotein (VLDL) 
 
• Triglyceride 
• Free fatty acid 
[Liver function test] 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Alkaline phosphatase (ALP) 
• Lactate dehydrogenase (LDH) 
• Gamma glutamyl transferase (GGT) 
 
• Total bilirubin 
• Direct bilirubin 
• Total protein 
• Albumin 
• Prealbumin 
• Albumin/globulin ratio (A/G ratio) 
[Pancreas function test] 
• Amylase 
 
• Lipase 
[Kidney function test] 
• Blood urea nitrogen (BUN) 
• Sodium 
• Calcium 
• Uric acid 
 
• Creatinine 
• Potassium 
• Chlorine 
• Phosphorus 
• Creatine kinase (CK) 
• hs-CRP 
• Follicle-stimulating hormone (FSH) (Screening visit only; postmenopausal female subjects only) 
 


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Coagulation 
 
• Activated partial thromboplastin time (PTT) 
• Prothrombin time (PT) (sec) 
• International normalized ratio (INR) 
 
Urinalysis 
 
• Bilirubin 
• Glucose 
• Ketone 
• White blood cell (WBC) 
• Nitrite 
• Microscopic (WBC, RBC and squamous cell) 
• Blood (Occult blood) 
• pH and specific gravity (SG) 
• Albumin 
• Urobilinogen 
 
Viral Serology 
 
• Hepatitis B core antibody (anti-HBc) 
• Hepatitis B surface antigen (HBsAg) 
• Hepatitis C antibody (HCV Ab) 
• Human immunodeficiency virus (HIV) 
antibody 
• Syphilis reagin 
 
Urine Drug Screening 
 
• Amphetamines (AMP) 
• Barbiturates (BAR) 
• Benzodiazepines (BZO) 
• Cannabinoids (THC) 
• Cocaine (COC) 
• Opiates (OPI) 
• Phencyclidine (PCP) 
 
Pregnancy Testing 
• Serum/urine human beta chorionic gonadotrophin (all females) 
 
The Principal Investigator or the Investigator at the institution will indicate whether or not any 
value outside the normal range is of clinical significance. If the result of any test (or repeat 
test, if done) from the samples taken during the Screening period is indicated as clinically 
significant, the subject's participation in the study will be decided based on the Principal 
Investigator's medical judgment. Additional testing during the study may be done if medically 
indicated. If a clinically significant abnormality is found in the samples taken from the date 
the ICF is signed until the Follow-up visit, it should be recorded as an AE and the subject will 
be followed until the test(s) has (have) normalized or stabilized, at the discretion of the 
Principal Investigator. 
 
 


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6.2.3. Vital Signs 
Vital signs will be assessed at the time points specified in the Schedule of Assessments (Table 
1-1 and 1-2). The following vital signs will be measured: 
• Blood pressure (systolic and diastolic [mmHg]) 
• Pulse (bpm) 
• Tympanic temperature (°C) 
• Respiratory rate (breaths per minute) 
BP and pulse will be measured for 2 consecutive times after a subject has been lying down or 
sitting to rest ≥ 5 minutes, and mean values will be recorded. 
6.2.4. 12-lead Electrocardiograms 
12-lead ECGs will be performed at the time points specified in the Schedule of Assessments 
(Table 1-1 and 1-2). ECGs will be measured 3 times repeatedly predose and 4 hours postdose 
each on Day 1 only. A deviation of ± 30 minutes from the collection time points is allowed in 
case of measurement 4 hours after dosing. 
The 12-lead ECGs will be performed after a subject has been resting supine for ≥ 5 minutes. 
Triplicate ECGs will be recorded at least 30 seconds apart from each other, not exceeding a 
time period of 3 minutes for the completion of all 3 ECGs. The following ECG parameters 
will be collected: Ventricular rate, PR interval, QRS interval, RR interval, QT interval and QT 
interval corrected for heart rate (QTc) (QTc using Bazett’s correction [QTcB] and QTcF). 
All ECGs must be evaluated by the Investigator for the presence of abnormalities. If any 
clinically significant abnormality is observed, it must be recorded as an AE. 
6.2.5. Injection Site Assessments 
Injection site assessments will be performed at the time points specified in the Schedule of 
Assessments (Table 1-1 and 1-2). 
After injection of the study drug, the injection site will be marked with a pen. Injection site 
assessments will be performed predose, within 1 hour postdose and at 4 and 12 hours 
postdose on Day 1, and then once per day between 9:00 AM and 12:00 PM from Day 2 
through Day 7. A deviation of ± 30 minutes from the assessment time points is allowed in 
case of measurements 4 and 12 hours after dosing. 
It will be checked whether the injection site mark is well-maintained during injection site 
assessments. If the pen mark fades, it will be marked again to show clearly the injection site. 
If patients who show injection site reactions are discharged, they will be separately guided to 
maintain their injection site marks. 
Erythema and edema among the local reactions of injection sites will be evaluated 
quantitatively using the Draize scale described below. If an injection site reaction like pain on 
palpation, itching, erythema, edema, induration is observed, it must be recorded as an AE. 
Note, however, that pain during injection is a natural response, so it is not considered an AE. 
Local reactions of the injection sites will be evaluated and recorded by one Investigator using 
the following scale: 


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Erythema will be evaluated as follows: 
• 0 – No erythema 
• 1 – Very slight erythema (barely perceptible) 
• 2 – Well-defined erythema 
• 3 – Moderate to severe erythema 
• 4 – Severe erythema (beet redness) to slight eschar formations (injuries in depth) 
Edema will be evaluated as follows: 
• 0 – No edema 
• 1 – Very slight edema (barely perceptible) 
• 2 – Slight edema (edges of area well defined by definite raising) 
• 3 – Moderate edema (raised approximately 1 mm) 
• 4 – Severe edema (raised more than 1 mm and extending beyond the area of exposure) 
For the irritation assessment, all irritation events will be documented as AEs. If AEs occur, 
the diameter of affected sites will be measured in centimeters (cm) and the condition of the 
injection sites will be recorded. In case of clinically significant injection site reactions, 
subjects may undergo a dermatological consultation and/or cutaneous biopsies for further 
histological examination of the injection site reaction. 
6.2.6. Immunogenicity Assessments 
Blood for assessment of ADA, anti-PEG and NAb will be collected at the time points 
specified in the Schedule of Assessments (Table 1-1 and 1-2). 
Immunogenicity assessments will be performed when deemed necessary by the Principal 
Investigator or the Sponsor in any of the following cases: 
• When ADA formation is suspected based on PD analysis results 
• When biomarker changes related to drug efficacy are not observed at expected 
pharmacologically effective doses 
• When AEs suspected as immune responses occur after administration 
• When necessary for other clinical/scientific reasons 
Details of collection, processing, shipping, and storage of the blood samples collected for 
immune response assessments will be outlined in a separate Laboratory Manual. 
 
 


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6.2.7. Physical Examinations 
Physical examinations will be performed at the time points specified in the Schedule of 
Assessments (Table 1-1 and 1-2). 
The physical examination includes assessment of general appearance and review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic and psychiatric 
systems). 
Other evaluations may be performed as deemed necessary by the Principal Investigator. 
6.3. Pharmacokinetics Variables 
Blood for analysis of HM15912 will be collected at the time points specified in the Schedule 
of Assessments and the PK Sampling Schedule (Table 1-1 and 1-2, Table 2-1 and 2-2, 
respectively). PK sampling times may be adjusted between the cohorts in case available PK 
data show that other time points would be more beneficial. 
Blood sample collection, processing and shipping details will be outlined in a separate 
Laboratory Manual. In brief, blood will be processed and serum will then be analyzed using a 
validated assay. 
6.4. 
Pharmacodynamics Variables 
6.4.1. Blood Sample Collection 
Blood for analysis of citrulline, albumin, prealbumin, fasting lipid panel (total cholesterol, 
triglycerides, LDL, HDL, VLDL, FFA), FPG, GIP, GLP-1, C-peptide, glucagon, insulin, IGF-
1, and KGF will be collected at the time points specified in the Schedule of Assessments, the 
Citrulline Sampling Schedule for Exploring PD, and the PD Sampling Schedule (Table 1-1 
and 1-2, Table 2-1 and 2-2, Table 3-1 and 3-2, respectively). If the PK sampling time points 
are changed, sampling times may be adjusted accordingly between the cohorts. 
Blood sample collection, processing and shipping details will be outlined in a separate 
Laboratory Manual. In brief, blood for samples will be processed, and plasma and serum will 
then be analyzed using a validated assay. 
 
 


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7. STUDY CONDUCT 
7.1. Screening Visit 
The pre-screening will be performed according to the institution’s SOP using IRB-approved 
recruitment documents. 
Subjects will be fully informed of their responsibilities (in terms of attending the study visits, 
dietary and lifestyle restrictions), of all the procedures expected to be performed in the study, 
the possible risks and benefits of being dosed with HM15912 and their rights while 
participating in the study. They will have the opportunity to ask questions and have time to 
consider participation. If a subject wishes to participate in the study, he/she will be asked to 
sign and date an ICF. Written informed consent will be obtained from all subjects before any 
Screening procedures are performed. 
Subjects will be asked to comply with study precautions and to attend the Screening visit 
fasted apart from water (duration of fast is at least 12 hours). 
Screening tests and Day-1 tests may be conducted again in the judgment of the Investigator. 
Subjects who have screen failed may be allowed to re-screen once at the discretion of the 
Principal Investigator, and they are given a new SID in such case. 
Screening assessments are listed in the Schedule of Assessments (Table 1-1 and 1-2). 
7.2. Admission 
The subjects who successfully complete the Screening visit, meet all the inclusion criteria, do 
not demonstrate any exclusion criteria and comply with the precautions in the protocol will be 
allowed for admission after they complete planned tests at the Outpatient visit on Day-1 and 
are approved to participate in the study following randomization. The inclusion/exclusion 
criteria (applicable for admission only i.e., exclusion criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 
14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, and 31) will be reviewed to confirm 
subject eligibility for admission (refer to Section 4.3). 
7.3. Inpatient Treatment Period 
Administration of the IP will be on Day 1, and safety monitoring and serial blood sampling 
for PK and PD assessments will be conducted throughout the inpatient assessment period 
(from Day-1 to Day 7). 
7.4. Outpatient Visits 
Outpatient visits will be on Day 8 (± 4 hours), Day 10 (± 1 day), Day 17 (± 1 day) and Day 30 
(± 3 days) with safety, PK and PD assessments. An additional Outpatient visit may be 
included in later cohorts, if required, after PK data are evaluated. In this case, the additional 
Outpatient visit will proceed after approval from the MFDS and the IRB. 
7.5. Follow-up 
The Follow-up visit will occur on Day 44 (± 3 days) of the clinical study. 


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7.6. Termination Visit 
Subjects who withdraw consent or are withdrawn from the clinical study should, if possible, 
have a termination visit. This visit should take place as soon as possible after the subject 
withdrew consent or was withdrawn from the clinical study. For patients who have been 
dosed with the IP, they will make a termination visit within 30 days after the administration, if 
possible. The assessments and procedures scheduled for the Follow-up visit should be 
performed at the termination visit. 
7.7. Restrictions 
7.7.1. Dietary and Fluid Restrictions 
Subjects will be required to fast from all food or drink (except water) for at least 12 hours 
before admission, Outpatient and Follow-up visits. 
During the in-house stay at the institution, only meals and fluid provided by the institution 
will be allowed. 
Food will not be allowed within 10 hours before dosing and for approximately 4 hours after 
dosing. Water consumption will also be limited for 1 hour before dosing and for 
approximately 2 hours after dosing.  
Breakfast, lunch and dinner will be served daily, except on Day 1 and admission and 
discharge days. On Day 1 (IP dosing day), subjects will not receive breakfast; lunch will be 
served after 4-hour postdose assessments/collections are performed. 
Breakfast will be served after fasting samples are collected on Day 2 through Day 7. 
No food or drink containing grapefruit, pomelo or Seville orange (including marmalade) will 
be allowed within 48 hours before admission and while subjects are confined to the 
institution. 
Quinine-containing products (e.g., tonic water) will not be allowed within 7 days before 
admission and while subjects are confined to the institution. 
7.7.2. Alcohol and Caffeine 
Consumption of any alcoholic foods, medications, and drinks must be avoided within 48 
hours before any study visit except the Screening visit and while subjects are confined to the 
institution. Subjects should not consume more than 3 units per day during the off-site days 
during the study (1 unit is equal to approximately ½ pint [250 mL] of beer, 1 small glass [125 
mL] of wine, 1 measure [25 mL] of spirits, or 250ml of Korean rice wine). 
No food or drink containing caffeine (e.g., chocolate, coffee, tea, cola, Red Bull) will be 
allowed within 24 hours before each study visit except the Screening visit and while subjects 
are confined to the institution. 
7.7.3. Smoking and Tobacco 
Heavy smokers (smoke more than 5 cigarettes per day or equivalent use of any tobacco 
products) are excluded from the clinical study. Subjects must abstain from smoking during the 
confinement period. 


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7.7.4. Activity and Exercise 
Subjects should refrain from carrying out heavy physical training (e.g., long-distance running, 
weight lifting or any physical activity to which the subject is not accustomed) 48 hours before 
admission until the Follow-up visit. Subjects should neither start any new physical training 
nor increase the intensity of their usual training during study participation. Subjects may 
participate in light recreational activities during studies (e.g., watch television, play computer 
games, read). 
7.7.5. Other Restrictions 
Subjects must neither donate whole blood within 60 days before the Screening visit nor 
participate in apheresis nor get injected with blood products within 1 month before the 
Screening visit, and they must be guided not to donate blood or plasma > 400 mL for at least 
3 months after completion of the clinical study. 
Male subjects must not donate sperm for at least 60 days after receiving the dose of the IP. 
Female subjects must not donate eggs or breastfeed for at least 60 days after receiving the 
dose of the IP. 
To prevent a female partner of a male subject exposed to the IP from getting pregnant or 
getting exposed to his semen, he must be surgically sterile (at least 1-year post vasectomy), 
abstinent or if engaged in sexual relations with women of child-bearing potential, the subject 
and his partner must be using effective or medically recognized dual protection contraceptive 
methods from the administration of IP to up to 60 days after receiving the dose of the IP. 
• Effective contraceptive method: Sexual partner's surgical sterilization (e.g., bilateral tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), intrauterine 
contraception/device of the sexual partner 
• Dual protection contraceptive method: Combinational use of physical barrier methods 
(male condom, female condom and diaphragm for the sexual partner, sponge, cervical 
cap), spermicide for females in the form of foam/gel/film/cream/suppository, oral or 
hormonal contraceptives for the sexual partner 
The adequacy of other methods of contraception will be assessed on a case-by-case basis by 
the Principal Investigator. 
All female subjects participating in this study must not have any possibility of being pregnant. 
Having no possibility of being pregnant is defined as being surgically sterile (e.g., bilateral 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or being 
menopausal. For females who went through uterus removal or became surgically sterile, the 
institution will try to obtain medical records and document their sterile state. Note, however, 
that having no such records is not a requirement for excluding the subjects from the study. 
Serum or urine pregnancy tests will be conducted for all female subjects. Being post-
menopausal is defined as being amenorrheic for more than 12 months before the Screening 
visit and having an FSH level exceeding 40 U/mL. 


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7.8. 
Handling of Hypersensitivity Reactions 
7.8.1. Anaphylaxis 
Anaphylaxis, a rapid and serious allergic reaction all over the body, is a life-threatening acute 
immunoreaction. 
If any symptoms suggesting anaphylaxis shock (functional impairment of periphery organs, 
allergic reactions in skin-mucous membrane tissues, etc. due to worsening respiratory 
symptoms, decreased respiration or low-blood pressure) are observed within minutes after IP 
administration, IP administration must be stopped immediately. The subject will then be laid 
and stabilized with his/her legs in the air to prevent further problems from dyspnoea or 
vomiting. IP administration will be immediately stopped. 
If it is confirmed that the symptoms resulted from anaphylaxis, an intramuscular injection of 
epinephrine will be performed. The Investigator may also conduct clinical laboratory tests, 
such as serum tryptase, to screen for anaphylaxis in his/her judgment. Respiratory treatments, 
such as oxygen supply, or low-blood pressure/shock treatments, such as IV drips, may be 
performed when necessary. Monitoring of blood pressure, pulse, respiration, and oxygen 
saturation may also be done. 
7.8.2. Subacute Hypersensitivity Reactions (Type III Hypersensitivity Reactions) 
Type III hypersensitivity reactions are defined as subacute hypersensitivity reactions caused 
by the immune-complex of an antigen and an antibody, which induce arthralgia, skin rash, 
and pruritus accompanying myalgia and fever.  
If symptoms (arthralgia, skin rash, and pruritus accompanied by myalgia and fever, etc.) 
suggesting delayed hypersensitivity reactions are confirmed within a few weeks after IP 
administration, the IP administration will be immediately stopped. The Principal Investigator 
may perform clinical laboratory tests necessary for differential diagnosis.  
If the symptoms are confirmed to have been caused by delayed hypersensitivity reactions due 
to the IP administration, medical treatment will be carried out depending on the subject’s 
condition with the judgment of the Principal Investigator. Any medical products may be used 
to ease the symptoms when necessary, and the Principal Investigator may allow 
administration of steroids, etc. 
 
 
 


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8. STATISTICAL METHODS 
Before database lock, a statistical analysis plan (SAP) will be issued and finalized, providing 
detailed methods for the analyses outlined below. Any deviations from the planned analyses 
will be described and justified in the clinical study report. 
8.1. Definition of Analysis Populations 
Prior to unblinding, analysis populations will be defined through blinded data review. 
In this clinical study, the PK population is subject to PK assessments whereas the PD 
population is subject to PD assessments. The safety population is subject to all other analyses 
unless described otherwise. Each analysis population is included in the analyses, based on the 
actually administered IP and dosage. 
Safety population: All randomized subjects who received at least 1 dose of the IP 
PK population: All randomized subjects with at least one quantifiable HM15912 
concentration 
PD population: All randomized subjects who received at least 1 dose of the IP 
8.2. General Considerations 
Continuous data will be summarized using descriptive statistics (number, mean, standard 
deviation [SD], minimum, median and maximum). Where appropriate, change from baseline 
will also be summarized. Categorical data will provide the number of subjects and percentage 
by category. All summarized data will be presented by dose level, and the subjects 
administered with placebo will be analyzed as a separate pooled group. Individual subject 
data used for the analysis will be listed by analysis item. 
8.3. Subject Disposition 
Subject disposition will be summarized into the numbers and percentages of subjects dosed 
after randomization, subjects included in each analysis population, subjects completing the 
study, subjects who were withdrawn (including reasons for withdrawal) and subjects who 
have seriously violated the protocol. 
8.4. Demographic Data and Predose Assessments 
Demographic data, such as age, sex, height, weight, and BMI, and descriptive statistics of 
baseline characteristics or the number and percentage of subjects by category will be 
provided. 
By using MedDRA, data related to medical history will be presented as a list standardized by 
the System Organ Class (SOC) and preferred terms (PT). 
 
 


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8.5. Prior and Concomitant Medication and Drug Administration 
Prior medications are those that started and stopped prior to the dose of the IP. Concomitant 
medications are those taken after IP dosing (including medications that started prior to IP 
dosing and continued after). 
Prior and concomitant medications will be standardized and listed according to the World 
Health Organization Drug Dictionary (WHODD), and a summarized table will also be 
presented for concomitant medications. 
8.6. Exposure 
A listing of IP administration will be created by subject and will include the date and time of 
administration and dosage, etc. 
8.7. Safety Analyses 
8.7.1. Adverse Events 
Summarization and analysis of AEs will be conducted for treatment emergent adverse events 
(TEAE). TEAEs are defined as AEs that did not exist before IP administration but occurred 
after IP administration, or AEs that worsened after IP administration even if they existed 
before IP administration. 
The reported AEs will be coded according to the SOC and PT of MedDRA, and the number 
of subjects and percentage for AEs after IP administration, AEs related to the IP, SAEs, 
severe AEs, AEs that caused study withdrawal, and AEs coded for injection site reactions will 
be provided. 
All AEs, SAEs, AEs that caused study withdrawal, and injection site reactions will be listed 
by subject. 
8.7.2. Clinical Laboratory Tests 
Clinical laboratory test results will provide descriptive statistics for each category and 
collection time point, and change of clinical significance from baseline will be presented as a 
shift table. 
8.7.3. Vital Signs 
Vital sign measurement results and descriptive statistics by category and collection time point 
for change from baseline will be provided. 
8.7.4. 12-lead Electrocardiogram 
12-lead ECG measurement results and descriptive statistics by category and collection time 
point for change from baseline will be provided. The mean values and individual values from 
the triplicate ECG measurement results will be all listed by category and collection time point. 


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8.7.5. Immune Response Assessments 
When an immunogenicity test was conducted, it will be summarized into the number of 
subjects and percentage according to the results (ADA, anti-PEG, NAb). 
8.7.6. Physical Examinations 
Abnormal physical examination findings will be listed. 
8.7.7. Injection Site Assessments 
All injection site reactions will be documented as AEs and included in AE analysis. 
8.8. Pharmacokinetics Analyses 
PK parameters will be summarized by using descriptive statistics, and concentration-time data 
will be summarized descriptively with tables and graphs by dose level (linear and log scale). 
The noncompartmental PK parameters listed in Section 3.2.2 will be calculated using R, SAS, 
or Phoenix® WinNonlin®. 
Dose proportionality will be evaluated using the linear regression approach for the log-
transformed PK parameters AUC0-t, AUCinf, Cmax values and the log-transformed dose value. 
Graphical presentation of dose proportionality will also be provided. Additional analyses will 
be performed as deemed necessary upon review of the data as exploratory analyses. 
8.9. Pharmacodynamics Analyses 
Descriptive statistics by collection time point for PD parameters will be provided, and the 
PK/PD relationship between IP exposure and PD endpoints will be analyzed by graphical 
displays or by PK/PD modelling, as applicable. 
8.10. Interim Analyses 
No formal interim analysis is planned. However, available blinded safety and tolerability 
(including PK/PD data if available) from each cohort (Day-1 to Day 17) will be evaluated in a 
dose escalation review meeting by the Principal Investigator and the Sponsor. The data review 
will take place before dose escalation can proceed. Screening for the next cohort may be 
conducted even before proceeding to the next cohort is determined, but the IP should be 
administered after proceeding to the next cohort is determined. 
 
 


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8.11. Determination of Sample Size 
Enrolling 8 subjects per cohort (HM15912:placebo=6:2) has been set based on the experience 
and the general properties of exploratory studies, and this matches the typical sample size 
used in similar studies conducted to assess safety and PK. Therefore, no formal sample size 
calculation has been performed. Safety and tolerability of the IP will be assessed based on 
AEs, clinical laboratory parameters, physical examinations, vital signs and ECG parameters 
throughout the duration of the study. Safety analysis will involve examination of descriptive 
statistics and individual subject listings for any effects of study treatment on clinical 
tolerability and safety. 


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9. DATA MANAGEMENT 
9.1. Data Management 
Details of data management will be described in the Data Management Plan (DMP). 
AEs and medical history will be coded using the current version of MedDRA. Concomitant 
medications will be coded using the medication dictionary of the WHO. 
Serial numbers will be used to identify subjects and their biological data. Subjects' 
information will be encrypted or deleted in all published data and publications according to 
regulations of regions/countries to protect their identity. 
The information on subjects who failed the Screening will also be added to the database. 
The laboratory data of the central laboratory will be electronically transmitted for database 
reconciliation. Electronic laboratory data will be considered source data. If sensitive data 
other than PK data are transmitted to an unsecured network, the data will be encrypted before 
transmission. 
9.2. Electronic Case Report Form 
9.2.1. Process of Clinical Data Management 
The development, maintenance and data management of eCRFs will be performed by the 
contract research organization (CRO) designated by Hanmi Pharmaceutical Co., Ltd. The data 
manager will describe the data management process in the DMP. After data input, the monitor 
will verify data by comparing the source data and the eCRF. Queries may be created to clarify 
the input data. The Principal Investigator will sign electronically the eCRF after all data are 
input, all queries are solved, and the reconciliation of external data is completed. If queries 
need to be revised after the Principal Investigator's approval, the Principal Investigator will 
sign again the data affected by the change. Database lock may be conducted when the 
Principal Investigator's approval is completed. 
9.2.2. Data Input in eCRF 
The data required for safety assessments and analyses for subjects will be input in source 
documents through the eCRF. Data input will be described according to the Completion 
Guideline developed by the CRO designated by Hanmi Pharmaceutical Co., Ltd. All 
personnel who input data in the eCRF will be trained before accessing the study database. 
 
 


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9.2.3. Modification of eCRF Data 
Queries may be automatically created in the eCRF system during data input, and the data 
management personnel, monitor, or data reviewer may create queries manually. Only the 
specific personnel will be authorized to modify the eCRF. The monitor will train the 
personnel. Data modification (revising existing data, adding new data, or deleting data) will 
be directly performed in the eCRF, and all data modifications will be saved in the electronic 
audit trail. 
9.2.4. eCRF Data Approval of the Principal Investigator 
The Investigator or the personnel with investigator authorization will check if all information 
in source data matches the eCRF data and if it is accurately reflected. The Investigator will 
confirm that the information is complete and accurate by signing the eCRF electronically. 
9.3. Document Storage 
All records created under the Principal Investigator's supervision will be maintained 
according to the supervision authorities' guidelines and the GCP guideline when the study is 
completed. Clinical study documents will be stored for at least 3 years after the study is 
completed or for the period indicated in the local regulation and the applicable regulatory 
authorities' guideline, whichever is longer (up to 25 years). 
 
 


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10. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1. Quality Control and Quality Assurance 
The Sponsor or its representatives will perform activities for quality assurance and control of 
this clinical trial. However, the responsibility for accuracy, integrity and reliability of study 
data provided to the Sponsor will be taken by the Principal Investigator who creates such data. 
The Sponsor can conduct audits as part of quality assurance activities to ensure that the 
clinical trial is performed in accordance with the protocol, SOP, GCP and all related 
regulations. The Sponsor will conduct an institution visit to verify the qualifications of the 
Principal Investigator, to inspect the facilities and to inform the Principal Investigator of 
responsibilities and procedures that will ensure appropriate and accurate documentation. 
Audits will be carried out independently apart from routine monitoring and quality control 
activities. 
Monitoring will be performed to ensure that the study is conducted and documented according 
to the protocol, GCP and all related regulations. The institution will be visited at an 
appropriate time during the study. The monitor must have direct access to source documents 
to check consistency of the data recorded in eCRFs. 
The Principal Investigator must prepare and maintain adequate and accurate records on all 
observations and other data pertinent to the clinical study for each subject. The Principal 
Investigator will allow monitoring of source documents, medical records and source data 
required for completion of eCRFs. Frequent communication between the institution and the 
Sponsor is essential to ensure that the safety of the study is monitored adequately. The 
Principal Investigator will cooperate closely with the monitor and provide appropriate 
evidence that the clinical study is performed according to related regulations and the GCP 
guideline, when necessary. The Principal Investigator will make all appropriate safety 
assessments on an ongoing basis. The Responsible Medical Expert of the Sponsor may review 
safety information as it becomes available throughout the study. 
All aspects of the study will be carefully monitored with respect to Good Clinical Practice 
(GCP) and SOPs for compliance with applicable government regulations. The monitor will be 
an authorized individual designated by the Sponsor. The monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of 
the study with the Principal Investigator. 
10.2. Subject Safety Assurance 
The Investigator must be sufficiently aware of the AEs and precautions described in this 
protocol in advance to ensure subject safety, and he/she must enable subjects to receive 
appropriate medical treatment for all AEs (including clinically significant laboratory findings) 
occurring during or after the study. If medical treatment is needed for concurrent diseases of 
subjects, the Investigator must let the subject know the fact as rapidly as possible. If SAEs or 
other events occur during the study, they must be reported immediately to the IRB and Hanmi 
Pharmaceutical Co., Ltd. 
The institution must be perfectly prepared to conduct the study appropriately with necessary 
equipment and professional personnel. 
The Sponsor will review all AEs and new information related to the IP and regularly share 
them with the Principal Investigator to ensure subject safety. In addition, the Sponsor will 


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prepare compensation measures in case of possible damage of subjects and get the 
Investigator to fully understand compensation subjects and procedures and to guide subjects 
about them. 
10.3. Finance and Insurance 
Financial issues of the clinical study will be described in a separate contract. The Sponsor will 
provide insurance for the clinical study as required by national regulations. 
10.4. Access to Source Data/Documents 
An electronic data capture system will be used to manage data collection during this trial. The 
electronic data capture system is a software tool designed to ensure quality assurance and 
facilitate data capture during clinical trials. This system complies with all related regulations 
including GCP of Korea's Pharmaceutical Affairs Act (Article 30, Clause 1, attached Table 4). 
The Principal Investigator will ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor. Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability and consistency. A complete audit trail 
will be maintained for all data changes. The Principal Investigator or designee will cooperate 
with the Sponsor’s representative(s) for periodic review of study documents to ensure the 
accuracy and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to each institution by means of 
electronic or manual queries. 
The Principal Investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECG, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
subject receiving the IP. Originals of source documents will be stored, but copies that are 
clearly recorded identically to originals along with signatures of persons who copied and dates 
will also be considered as source documents. 
The Principal Investigator will allow Sponsor representatives, contract designees, authorized 
regulatory authority inspectors and the IRB to have direct access to all documents pertaining 
to the study. 
 
 


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10.5. Archiving Study Documents 
Hanmi Pharmaceutical Co., Ltd. and the Principal Investigator are responsible for storing 
clinical study data even if the trial is completed or closed, and it is mandatory to store the 
documents related to the clinical study for at least 3 years after the last reporting (approval 
date of result reporting). Note, however, that the storage period may be prolonged if deemed 
necessary by Hanmi Pharmaceutical Co., Ltd., Hanmi Pharmaceutical Co., Ltd. will inform 
the Principal Investigator and the head of the institution of the need to store data and storage 
period in writing. If Hanmi Pharmaceutical Co., Ltd. decides that there is no need to store the 
data anymore, it will inform the Principal Investigator and the head of the institution of this 
fact in writing. 
10.6. Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor 
and the Principal Investigator abide by the principles of the ICH guidelines on GCP. The 
clinical study will also be carried out in keeping with national and local legal requirements. 
10.7. Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
from the subject according to the regulatory and legal requirements of the participating 
country. As part of this procedure, the Principal Investigator or Investigator must explain to 
groups of subjects or individual subjects the IRB-approved ICF orally and in writing with 
regard to the nature, duration and purpose of the study and the action of the drug in such a 
manner that the subject is aware of potential risks, inconveniences or AEs that may occur. The 
subject is allowed to review study information and ask questions through one-on-one 
interviews in a separate room. The subject should be informed that he/she is free to withdraw 
from the study at any time. He/she will receive all information that is required by relevant 
regulations and ICH guidelines.  
The ICF must be signed and dated including time; 1 copy will be handed to the subject, and 
the Principal Investigator will retain 1 original as part of clinical study records. The Principal 
Investigator will not undertake any investigation specifically required for the clinical study 
until written consent has been obtained. The terms of consent and date and time when it was 
obtained must also be documented. 
If a protocol amendment is required, then the ICF may need to be revised to reflect the 
changes to the protocol. If the ICF is revised, it must be reviewed and approved by the 
responsible IRB, and signed by all subjects subsequently enrolled in the clinical study as well 
as those currently enrolled in the clinical study. 
 
 


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10.8. Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents 
will be approved by the IRB in accordance with local legal requirements. The Sponsor must 
ensure that the clinical study will proceed ethically and legally before the first subject is 
enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
which must be released by the responsible staff and receive IRB approval prior to 
implementation (as appropriate). 
Administrative changes may be made without the need for a formal amendment, but will also 
be mentioned in the integrated clinical study report. All amendments will be distributed to all 
study protocol recipients, with appropriate instructions. 
10.9. Confidentiality Data Protection 
All clinical study findings and documents will be regarded as confidential. The study staffs 
participating in the study, the MFDS, the Sponsor, clinical study inspectors, monitors, and the 
IRB and the Human Research Protection Center of the institution will be allowed to access 
study-related documents under the condition that they ensure confidentiality of subjects. 
Study documents (protocols, IBs, and other materials) will be stored appropriately in areas 
with a locking device to ensure their confidentiality. The Principal Investigator and members 
of his/her research team (including the IRB) must not disclose such information without prior 
written approval from the Sponsor, except to the extent necessary to obtain informed consent 
from subjects who wish to participate in the trial or to comply with regulatory requirements. 
The anonymity of participating subjects must be maintained. Subjects will be specified in 
study documents by their subject number or initial, not by name. Documents that identify 
subjects (e.g., signed ICF) must be maintained in confidence by the Principal Investigator. 
10.10. Publication Policy 
By signing the clinical study protocol, the Principal Investigator agrees with the use of results 
of the clinical study for the purposes of national and international registration, publication and 
information for medical and pharmaceutical professionals. If necessary, the regulatory 
authorities will be notified of the Principal Investigator’s name, address, qualifications and 
extent of involvement. 
The Principal Investigator shall not publish any data (poster, abstract, paper, etc.) without 
having consulted with the Sponsor in advance. 
 
 


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11. 
REFERENCE LIST 
1. HM15912 Investigator’s Brochure, Version 1.0, dated 19 April 2019. 
2. Buchman AL. Short Bowel Syndrome: In: Sleisenger and Fordtran’s Gastrointestinal and 
Liver Disease. 10th ed. Philadelphia, PA: Saunders; 1832-1848 (2016) 
3. American Gastroenterological Association Clinical Practice Committee. Gastroenterology 
2003;124:1111-1134. AGA Technical Review on Short Bowel Syndrome and Intestinal 
Transplantation. 
4. Rowland KJ, Brubaker PL. Mol Cell Endocrinol 2008;288: 63-70, Life in the crypt: a role 
for glucagon-like peptide 2? 
5. European medicines agency: EMA/CHMP/525255/2012 – Assessment report of 
Revestive® (teduglutide) 
6. Marier J et al. Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like 
peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administration in 
healthy subjects 
7. Zealand annual report, 2017 
 

SAP_001.pdf: 
Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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Statistical Analysis Plan 
 
 
 
Study Title 
A First-in-Human, Double-blind, Randomized, Placebo-controlled, Single 
Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of HM15912 in Healthy Subjects 
Protocol No  
HM-GLP2-101 
Version 
Final V2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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Signature Page 
Prepared by 
 
BioMetrics Associate 
_Statistician 
 
 
 
 
 
Sujin Seo 
 
Date (dd-mmm-yyyy) 
Reviewed by 
 
Investigator 
 
 
 
 
 
 
Hyeong-Seok Lim 
 
Date (dd-mmm-yyyy) 
Clinical Operation Associate 
 
 
 
 
 
 
Jiyoung Sin 
 
Date (dd-mmm-yyyy) 
Clinical Operation Manager 
 
 
 
 
 
 
Sujin Jung 
 
Date (dd-mmm-yyyy) 
Clinical Science Associate 
 
 
 
 
 
 
Minsoo Kang 
 
Date (dd-mmm-yyyy) 
Clinical Science Manager 
 
 
 
 
 
 
Jae Duk Choi 
 
Date (dd-mmm-yyyy) 
BioMetrics Associate 
_Pharmacometrician 
 
 
 
 
 
 
Jihyun Jeon 
 
Date (dd-mmm-yyyy) 
Biostaitstician 
Parexel International 
 
 
 
 
 
Bryant Ko 
 
Date (dd-mmm-yyyy) 
Approved by 
 
Director of Biometrics 
 
 
 
 
 
 
OakPil Han 
 
Date (dd-mmm-yyyy) 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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Revision history 
 
Approval Date Amended 
Version 
Prepared by 
Name 
Comment 
24-Mar-2020 
V1.0 
Kwan Ho Lee 
Initial document 
29-Apr-2020 
V1.1 
Youngmin Kim 
Per 
the 
amended 
protocol 
V4.2, 
updated 
Schedule of Assessments in 10. APPENDIX and 
listing of Alcohol Breath Test. 
18-Aug-2020 
V2.0 
Sujin Seo 
1. Study period in section 2.1 is corrected 
according to the protocol V4.2. 
2. Analysis set definition is descripted in more 
detailed (section 4). 
3. Range of listing of protocol deviations is 
changed to include all protocol deviation (section 
5.7). 
4. Summary criteria of multiple observations is 
changed from 'by visit' to 'by time-point' (section 
6.1.2). 
5. Change from baseline of Lab results (section 
6.2.2) and PD results (section 6.4) are added for 
tabulation. 
6. BMI is added for the tables and listings (section 
6.2.3). 
7. For the evaluations for the triplicated measured 
ECG values, the worst values would be used 
(section 6.2.4). 
8. PK line plot by cohort is added (section 6.3.1). 
9. 
Add 
detail 
explanation 
for 
the 
dose 
proportionality test (section 6.3.3). 
10. Adding analysis related to COVID-19 (section 
6.1 and 6.1.3) 
11. Detailed description for immunogenicity 
analysis is added (section 6.2.7) 
 
 
 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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Table of Contents 
Signature Page ....................................................................................................................................... 2 
1. 
INTRODUCTION ............................................................................................................................. 8 
2. 
STUDY OVERVIEW ........................................................................................................................ 9 
2.1 
Study Design .................................................................................................................... 9 
2.2 
Randomization and Blinding Procedures ....................................................................... 10 
2.3 
Sample Size and Power ................................................................................................. 12 
3. 
STUDY OBJECTIVES ................................................................................................................... 13 
3.1 
Primary Objectives and Endpoints ................................................................................. 13 
3.2 
Secondary Objectives and Endpoints ............................................................................ 13 
3.3 
Exploratory Objectives and Endpoints ........................................................................... 13 
4. 
ANALYSIS SET ............................................................................................................................. 15 
4.1 
Safety Set ....................................................................................................................... 15 
4.2 
Pharmacokinetic Analysis Set ........................................................................................ 15 
4.3 
Pharmacodynamics Analysis Set ................................................................................... 15 
5. 
STUDY SUBJECT ......................................................................................................................... 16 
5.1 
Subject Disposition ......................................................................................................... 16 
5.2 
Demographic and Baseline Characteristics ................................................................... 16 
5.3 
Medical History ............................................................................................................... 16 
5.4 
Subject Eligibility and Withdrawal Criteria ...................................................................... 16 
5.5 
Exposure ........................................................................................................................ 16 
5.6 
Concomitant Medication ................................................................................................. 16 
5.7 
Protocol Deviations ........................................................................................................ 17 
6. 
Statistical Methods ......................................................................................................................... 18 
6.1 
General Considerations.................................................................................................. 18 
6.1.1 Statistical Notation and Presentation ............................................................................. 18 
6.1.2 Handling of Multiple Observations or Out of Window Observations .............................. 18 
6.1.3 Handling of Missing and Partial Dates ........................................................................... 19 
6.1.4 Handling of Outliers and Unquantifiable Measurements ............................................... 19 
6.1.5 Study Baseline ............................................................................................................... 20 
6.2 
Safety Analyses .............................................................................................................. 20 
6.2.1 Adverse Events .............................................................................................................. 20 
6.2.2 Clinical Laboratory Assessments ................................................................................... 20 
6.2.3 Vital Signs ...................................................................................................................... 20 
6.2.4 12-lead Electrocardiograms ........................................................................................... 20 


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6.2.5 Physical Examination ..................................................................................................... 21 
6.2.6 Injection Site Reactions ................................................................................................. 21 
6.2.7 Immunogenicity .............................................................................................................. 21 
6.3 
Pharmacokinetic Analyses ............................................................................................. 22 
6.3.1 PK Concentration ........................................................................................................... 22 
6.3.2 PK Parameter ................................................................................................................ 22 
6.3.3 Dose Proportionality....................................................................................................... 23 
6.4 
Pharmacodynamic Analyses .......................................................................................... 23 
6.4.1 Fasting Lipid Panel ........................................................................................................ 23 
6.4.2 Blood Glucose-related Panel ......................................................................................... 23 
6.4.3 Albumin and Prealbumin ................................................................................................ 23 
6.4.4 Blood Plasma Citrulline .................................................................................................. 24 
6.4.5 Growth Factor ................................................................................................................ 24 
7. 
Interim Analysis .............................................................................................................................. 25 
7.1 
Dose Administration ....................................................................................................... 25 
7.2 
Subject status ................................................................................................................. 25 
7.3 
Adverse Events(AEs) and Serious AEs ......................................................................... 25 
7.4 
Clinical Laboratory Results............................................................................................. 25 
7.5 
12-lead ECG ................................................................................................................... 26 
7.6 
Vital Signs ....................................................................................................................... 26 
7.7 
Abnormal Physical Examination Results ........................................................................ 26 
7.8 
Injection Site Reaction .................................................................................................... 26 
7.9 
Concomitant Medication ................................................................................................. 26 
7.10 
Medical History ............................................................................................................... 26 
7.11 
Pharmacodynamic (PD) Assessments (if available) ...................................................... 26 
7.12 
Pharmacokinetic (PK) Assessments (if available) .......................................................... 26 
8. 
Statistical Software ........................................................................................................................ 27 
9. 
REFERENCES .............................................................................................................................. 28 
10. 
APPENDIX ............................................................................................................................. 29 
 


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ABBREVIATIONS 
Abbreviation 
Definition of Term 
_obs 
observed 
_pred 
predicted 
ADA 
Anti-drug antibody 
ADAbs 
Anti-drug antibodies 
Adj_RSq 
Adjusted r squared 
AE 
Adverse event 
anti-PEG 
Anti-polyethylene glycol antibodies 
ATC 
Anatomic Therapeutic Chemistry 
AUC 
Area under the concentration time curve 
AUC0-inf 
Area under the concentration time curve from zero to infinity 
AUC0-t 
Area under the concentration time curve from zero to time of last time 
observed, AUC0-t = AUC0-last 
AUC%extrapolation 
Percentage of AUCinf that is due to extrapolation beyond tlast 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence interval 
CL 
Apparent clearance 
CL/F 
Apparent clearance divided by bioavailability 
Cmax 
Maximum concentration 
CS 
Clinical significant 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
F 
Bioavailability 
FFA 
Free fatty acid 
FPG 
Fasting plasma glucose 
GIP 
Gastric inhibitory peptide 
GLP-1 
Glucagon like peptide-1 
HDL 
High-density lipids 
HR 
Heart rate 
ICH 
International Council for Harmonisation 
IGF-1 
Insulin-like growth factor-1 
IP 
Investigational product 
IRB 
Institutional Review Board 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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Abbreviation 
Definition of Term 
KGF 
Keratinocyte growth factor 
LDL 
Low-density lipids 
LLOQ 
Lower limit of quantitation 
LS 
Least squares 
max 
maximum 
MedDRA 
Medical dictionary for regulatory activities 
MFDS 
Ministry of Food and Drug Safety 
MID 
Minimum intolerable dose 
min 
minimum 
MTD 
Maximum tolerated dose 
n 
sample size 
nAbs 
Neutralizing antibodies 
NCA 
Non-compartmental analysis 
NCS 
Non-clinical significant 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetics 
PT 
Preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RR 
Respiratory rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
VLDL 
Very low-density lipids 
Vz 
Apparent volume of distribution at terminal phase 
Vz/F 
Apparent volume of distribution at terminal phase divided by bioavailability 
WHO  
World Health Organization  
λz 
Apparent elimination constant 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) has been developed based on following study documents: 
Protocol: A First-in-Human, Double-blind, Randomized, Placebo-controlled, Single Ascending Dose 
Study to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HM15912 in 
Healthy Subjects (Korean Version 4.2, English version 4.2) 
Electronic Case Report Form (eCRF), version 4.0 
This SAP describes the statistical analysis to be conducted for the above mentioned protocol, and 
has been developed and finalized prior to the database lock and unblinding of the clinical data base. 
 
This SAP is being written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principles for Clinical Trials”, the most recent ICH E3 Guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports”, and the most recent MFDS Guideline entitled 
“Guidance for Statistics of Clinical Trials. 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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2. STUDY OVERVIEW 
2.1 Study Design 
This is a first-in-human, double-blind, randomized, placebo controlled, single ascending dose (SAD) 
study to investigate the safety, tolerability, PK and PD of the SC administration of HM15912 in 
healthy subjects. 
The study will be conducted in approximately 5 sequential dosing cohorts, enrolling 8 subjects per 
cohort. Subjects will be randomized to HM15912 or placebo in a ratio of 6:2 (6 active, 2 placebo). 
To follow a sentinel dosing approach in this first-in-human (FiH) study, each cohort will be divided in 
2 blocks in order to implement the sentinel dosing approach. Within each cohort, the first block will 
consist of 2 sentinel subjects; 1 subject will receive HM15912, and 1 subject will receive matched 
placebo. The second block will consist of 6 subjects randomized to receive HM15912 (n = 5) or 
matched placebo (n = 1). Individual subjects in the second block will be dosed at least 24 hours 
after the first block. 
Following an overnight fast of at least 10 hours, each subject will receive a single dose of either 
HM15912 or matched placebo-administered SC in the abdomen on the morning (8:00 AM – 10:00 
AM) of Day 1. Subjects will continue fasting through approximately 4 hours post dose. Water intake 
is also limited for approximately 1 hour before dosing and approximately 2 hours after dosing.  
The planned maximum dose of HM15912 is 1.5 mg/kg; however, higher doses may be administered 
if safety is confirmed in previous cohorts. If dose is escalated to 1.5 mg/kg or above, approval of the 
Ministry of Food and Drug Safety (MFDS) will be obtained. After at least 6 subjects (HM15912, n ≥ 4) 
in each cohort have completed assessments through at least Day 17, blinded safety data will be 
reviewed and a dose decision/dose escalation decision for the subsequent cohort will be made by 
the Principal Investigator and the Sponsor. If there are PK/PD data obtained from the preceding or 
current cohorts, the PK/PD data will be reviewed as well when necessary. Escalation will only 
proceed if safety and tolerability data related to the dose of the prior cohort are verified. 
Determination of whether to proceed to the next cohort will be made by the Principal Investigator 
and the Sponsor, and changes in the dose and the number of cohorts will be approved by the MFDS 
and the IRB. 
PK data will only be reviewed if available. After review of the PK data from preceding or current 
cohorts, changes in time points for PK collection, clinical laboratory assessments, and PD collection 
may be required and will be approved by the MFDS and the IRB. 
If dose escalation is stopped based on available blinded safety data, the current dose level will be 
considered as the minimum intolerable dose (MID). The dose just below the MID will be regarded as 
the maximum tolerated dose (MTD). If the dose escalation is stopped due to reaching exposure limit 
without dose-limiting safety findings, the MTD cannot be determined. Dose de-escalation may occur 
in the last cohort or additional cohorts to further refine clinically relevant dose levels.  


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The study will be comprised of: 
• A Screening visit up to 28 days before dosing 
• An inpatient assessment period of approximately 8 days, with admission to the institution 
on Day -1, dosing on Day 1 and discharge on Day 7 once the planned schedule is completed 
• For Cohort 1~3 
- Two Outpatient visits on Day 10 (± 1 day) and Day 17 (± 1 day) 
- A final Follow-up visit on Day 30 (± 3 days) 
• For Cohort 4~5 
- Four Outpatient visits on Day 8 (± 4 hours), Day 10 (± 1 day), Day 17 (± 1 day) and Day 
30 (± 3 days) 
- A final Follow-up visit on Day 44 (± 3 days) 
The total duration of the clinical study per subject will be up to approximately 58 days for Cohort1-3 
and 72 days for Cohort4-5, including the Screening period. 
Table 1: Sample Allocation and Dose Escalation 
Cohorts 
Number of Subjects 
Treatment Period 
Cohorts 1 
N=6 
HM15912 0.05 mg/kg 
N=2 
Placebo 
Cohorts 2 
N=6 
HM15912 0.1 mg/kg 
N=2 
Placebo 
Cohorts 3 
N=6 
HM15912 0.5 mg/kg 
N=2 
Placebo 
Cohorts 4 
N=6 
HM15912 1.0 mg/kg 
N=2 
Placebo 
Cohorts 5 
N=6 
HM15912 1.5 mg/kg 
N=2 
Placebo 
 
2.2 Randomization and Blinding Procedures 
To maintain the double-blind of the study, except for the unblinded persons involved in the 
preparation of the IPs (these persons are not involved in any other study activities), everyone 
involved in the trial will be blinded until after completion of the study and the final data review. 
Subjects will be randomized to HM15912 or placebo in a ratio of 3:1 (6 subjects to HM15912, 2 
subjects to placebo) prior to dosing. 
Prior to dosing on Day 1, subjects will be assigned a randomization number in accordance with the 
randomization code. The randomization code of each randomization number will be maintained in a 
room with restricted access to the non-blinded clinical research pharmacist only, and will be 


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accessed by other personnel only in case of unblinding. The randomization number will include 3-
digit subject numbers as shown in Table 2. 
Table 2: Randomization Numbers and Treatment Assignment 
Cohort 
Randomization Numbers 
Treatment Assignment 
1 
101-108 
0.05 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
2 
201-208 
0.1 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
3 
301-308 
0.5 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
4 
401-408 
1.0 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
5 
501-508 
1.5 mg/kg HM15912 (N = 6) 
Placebo (N = 2) 
 
Once a randomization number has been allocated to one subject, it may not be assigned to another 
subject. If subjects withdraw prematurely from the study and are replaced under the direction of the 
Sponsor, then a replacement randomization number will be assigned when a replaced subject has 
successfully completed screening. A replacement randomization code will be generated such that 
replacement subjects are assigned to the same treatment as the discontinued subjects. The 
replacement randomization code will differ only in randomization numbers. It is composed of 4 digits 
by adding “1” in front of the randomization number for a withdrawn subject. For example, if Subject 
202 withdraws and is replaced, then the randomization number for the replacement subject will be 
1202. 
The study blind should not be broken except in a medical emergency (where knowledge of the IP 
administered would affect the treatment of the emergency), or if dose limiting toxicities occur or if it 
is necessary for dose escalation decisions. The decision to break the blind will be made by the 
Principal Investigator on a case-by-case basis. The Investigator or the Principal Investigator will 
contact Hanmi Pharmaceutical Co., Ltd. and deliver related documents when breaking the blind. 
The results of breaking the blind for each subject will not be revealed. The Investigator or the 
Principal Investigator will record blind-breaking dates and reasons in the CRF. 
If blinding is not maintained in the Investigator, the institution’s staff or subjects, the subject must be 
withdrawn. If blinding is accidently broken during the study or blinding is broken before completion 
of the study due to SAEs, the Investigator must record this and rapidly report to Hanmi 
Pharmaceutical Co., Ltd. However, if blinding is broken for ethical reasons or blind breaking is seen 
to have little effect on the subject’s safety, the subject may continue to participate in the clinical 
study in the judgement of the Investigator after discussing with Hanmi Pharmaceutical Co., Ltd. 
After database lock, the overall randomization code will be broken. 
 


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2.3 Sample Size and Power 
Due to exploratory nature of this study, sample size 8 subjects (6:2) is empirically determined and 
consistent with typical sample sizes used for similar studies to assess PK and safety data. No formal 
sample size calculation will be performed.


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3. STUDY OBJECTIVES 
 
3.1 Primary Objectives and Endpoints 
To assess the safety and tolerability of HM15912 after single SC doses, regarding: 
• General safety variables: Adverse event (AE) assessments; clinical laboratory tests 
(hematology, clinical chemistry, coagulation and urinalysis); vital signs (blood pressure [BP], 
pulse, tympanic temperature and respiratory rate [RR]); 12-lead electrocardiogram (ECG); 
physical examinations 
• Specific safety variables: Injection site assessments; immunogenicity assessments (ADA, 
Nab and anti-PEG) (performed only if analysis is necessary)  
 
3.2 Secondary Objectives and Endpoints 
To assess the PK profile of HM15912 after single SC doses, regarding: 
• Cmax: Maximum serum HM15912 concentration determined from the concentration-time 
profile 
• Tmax: Time of maximum serum HM15912 concentration determined from the concentration-
time profile 
• AUC0-t: Area under the concentration-time curve from predose (time 0) to the last 
quantifiable concentration 
• AUCinf: Area under the concentration-time curve from predose (time 0) extrapolated to 
infinite time (AUC0-t + Clast/λz) calculated using the linear-log trapezoidal rule 
• AUC%extrap: Percentage of AUCinf that is due to extrapolation beyond tlast 
• λz: The terminal elimination rate constant determined by selection of at least 3 data points 
on the terminal phase of the concentration-time curve 
• t½: Terminal elimination half-life calculated as: ln2/λz 
• CL/F: Total body clearance calculated as: Dose/AUCinf  
• Vz/F: Apparent volume of distribution calculated as: Dose/(AUCinf * λz) 
 
3.3 Exploratory Objectives and Endpoints 
To assess the PD properties of HM15912 after single SC doses, regarding: 
• Blood plasma citrulline  
• Albumin, prealbumin 
• Fasting lipid panel (total cholesterol, triglycerides, low-density lipoprotein [LDL], 
high-density lipoprotein [HDL], very low-density lipoprotein [VLDL], free fatty acid [FFA])  
• Blood glucose-related panel (fasting plasma glucose, gastric inhibitory polypeptide [GIP], 
glucagon-like peptide-1 [GLP-1], C-peptide, glucagon, insulin) 


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• Insulin-like growth factor-1 (IGF-1) and keratinocyte growth factor (KGF) 


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4. ANALYSIS SET 
 
An analysis sets classification meeting will be arranged to discuss the outputs and to decide which 
patients and/or patient data will be excluded from certain analyses. Decisions made regarding the 
exclusion of patients and/or patient data from analyses will be made after the database lock and 
before the unblinding and will be documented and approved. 
Prior to unblinding, analysis populations will be defined through blinded data review. In this clinical 
study, the PK population is subject to PK assessments whereas the PD population is subject to PD 
assessments. The safety population is subject to all other analyses unless described otherwise. Each 
analysis population is included in the analyses, based on the actually administered IP and dosage. 
 
4.1 Safety Set 
All randomized subjects who received at least 1 dose of the IP, HM15912 or placebo (actual treatment). 
 
4.2 Pharmacokinetic Analysis Set 
All subjects who are treated HM15912 (actual treatment) with at least one quantifiable HM15912 
concentration. 
 
4.3 Pharmacodynamics Analysis Set 
All randomized subjects who received at least 1 dose of the IP, HM15912 or placebo. (actual 
treatment) 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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5. STUDY SUBJECT 
 
Study subject data will be summarized by dose level, with pooled placebo using the Safety Set. 
  
5.1 Subject Disposition 
Subjects disposition will be summarized into the numbers and percentages of subjects dosed after 
randomization, subjects included in each analysis population, subjects completing the study, subjects 
who were withdrawn (including reasons for withdrawal) and subjects who have seriously violated the 
protocol.  
 
5.2 Demographic and Baseline Characteristics 
Demographic data, such as age, sex, height, weight, and BMI, and descriptive statistics of baseline 
characteristics or the number and percentage of subjects by category will be provided. 
 
5.3 Medical History 
Medical history is any significant medical condition or disease that is present at study start (signing of 
informed consent). The medical history recorded through clinically significant laboratory, 
electrocardiogram (ECG), or physical examination (PE) abnormalities noted at screening examination 
will be listed. 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA, version 22.0 
or over) and summarized by System Organ Class (SOC) and Preferred Term (PT) for the Safety Set. 
Medical history data will be listed by subject, description of the disease/procedure, MedDRA SOC, PT, 
start date and stop date (or ongoing if applicable). 
 
5.4 Subject Eligibility and Withdrawal Criteria 
Subject eligibility and subjects who meet withdrawal criteria will be presented in listings. 
 
5.5 Exposure 
A listing of IP administration will be created by subject and will include the date and time of 
administration and dosage, etc. 
 
5.6 Concomitant Medication 
Concomitant medication is medication given in addition to the study medication (including over-the-
counter medications, herbal medications, and vitamin supplements) administered between screening 
and follow-up. Medication will be categorized into the three following types: 
• Prior concomitant medication is defined as any medications that start before the date of 


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dosing of study medication and continue beyond that date.  
• New concomitant medication is defined as any medications that start after the date of dosing 
of study medication, including those started in the follow-up period.  
• Prior medication is defined as any non-study medication that stops before the date of dosing 
of study medication. 
The WHO DRUG Dictionary Global (March 2019 or over) will be used to categorize the verbatim 
descriptions of medications into the Anatomic Therapeutic Chemistry (ATC) classification system. 
Each verbatim name will be classified by anatomical main group (ATC level 1), therapeutic subgroup 
(ATC level 2), pharmacological subgroup (ATC level 3), chemical subgroup (ATC level 4), and trade 
name. 
Drug administration dates and times will be listed for each subject and the number and percentage of 
subjects receiving concomitant medications (including both prior and new concomitant medications) 
will be summarized and by ATC classification (ATC level 2 and level 4) for the Safety Set. Pre-
treatment medication administered during the study will only be listed. 
 
5.7 Protocol Deviations 
All the protocol deviations will be listed by subject. Category of important/non-important will be 
included in the listing. Protocol deviations will be handled in accordance with ICH guidelines and local 
regulation for management. Important protocol deviations will be identified prior to database lock and 
will be summarized for the Safety Set.  


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6. Statistical Methods 
 
6.1 General Considerations 
PK, PD, and Safety analyses will be performed with the PK Analysis Set, PD Analysis Set, and Safety 
Set, respectively. Placebo subjects will be pooled in summaries and listings.  
Exploratory analysis may be conducted assess any patterns due to COVID-19.  
All data collected during the study will be listed using the Safety Set. 
 
6.1.1 Statistical Notation and Presentation 
The continuous variables will be summarized by number of subjects (n), mean, standard deviation 
(SD), median, minimum (min), and maximum (max). Where appropriate, change from baseline will 
also be summarized. For categorical variables, the number and percentage of subjects in each 
category will be provided. For log-normal distributed data, geometric mean, standard error (SE) of the 
geometric mean, and coefficient of variation (CV) will also be provided. The geometric mean is 
calculated as the exponential of the arithmetic mean calculated from data on a log scale. The CV is 
calculated as CV% = 100%∗𝑠𝑞𝑟𝑡(exp(𝜎2) −1), where σ is the SD of the data on the natural log scale. 
Minimum and maximum values will be rounded to the precision of the original value. Means, least 
squares (LS) means, and medians will be rounded to 1 decimal place greater than the precision of the 
original value. SDs, SEs, and confidence intervals (CIs) will be rounded to 2 decimal places greater 
than the precision of the original value. Percentages for summarizing categorical data will be rounded 
to one decimal place. P-values will be presented with 4 decimal places and values less than 0.0001 
will be presented as <.0001. 
All inferential statistical testing will be two-sided and conducted at the 0.05 significance level, unless 
specified otherwise. No multiplicity adjustment is planned for this study. 
 
6.1.2 Handling of Multiple Observations or Out of Window Observations 
If there are multiple measurements within the same scheduled visit and time-point, the last 
observation will be used. 
For PK data, the actual clock time will be used for PK parameters calculations such as area under the 
curve (AUC). 
All values, scheduled or unscheduled, will be presented in data listings.  
On scheduled visits with missing assessments, unscheduled assessments within the visit window, if 
available, may be used for analysis. A footnote will be added to tables where unscheduled visits are 
used to impute missing scheduled visits. 
 


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6.1.3 Handling of Missing and Partial Dates  
In cases of incomplete dates for adverse events (AEs) or concomitant medications, the missing 
component(s) will be assumed as the most conservative value(s) possible. The imputation rule are 
designed to conservatively capture AEs as treatment-emergent AEs (TEAEs) and medications as 
concomitant. For example, the following algorithm for missing start date of AEs will be followed: 
• If “day” is the only missing field, impute the “day” as the later one between the first day of the 
month and the dosing date if their “month” are the same. 
• If “day” and “month” are the only missing fields, impute the “day” and “month” as the later one 
between January 1st of the year or the dosing date if the “year” is the same as the dose date. 
• If “day”, “month”, and “year” are all missing, to be conservative, the event will be assumed to 
occur on the same day as the dosing was administered.   
Adverse events and medications with missing or partial end dates will be imputed to conservatively 
capture treatment-emergent or concomitant status. 
Date imputation will only be used for computational purposes; e.g., treatment-emergent status or 
identifying concomitant medications. Actual data values, as they appear in the clinical database, will 
be shown in the data listings. 
Missing visits due to COVID-19 will be listed with the reason for missing.  
 
6.1.4 Handling of Outliers and Unquantifiable Measurements 
Prior to unblinding, PK data will be reviewed by the PK scientist and statistician to assess whether 
individual concentration values are inconsistent with other values from the same subject or if there are 
errors with the samples. Determination of data points subject to re-analysis or removal from 
determination of PK parameters (i.e., implausible data) will be documented prior to unblinding  
PK and PD parameter results will also be reviewed by appropriate representatives and a 
determination of plausibility will be made. Individual subject results deemed implausible may be 
removed prior to summarization of PK and PD parameter results by treatment group. Removal of 
individual subject PK/PD parameter results will be documented. 
The following rules will be applied when blood samples are assayed as below the limit of quantitation 
(BLQ) or if individual concentration results are deemed implausible prior to database lock: 
• For graphical presentations of the individual subject data: BLQ at pre-dose will be treated as 
0, values deemed implausible will be set to missing. Others retained in the data as assayed. 
• If any values are deemed implausible, final decisions and rationale will be documented in the 
pre-database lock meeting minutes.  
For the calculation of summary statistics of concentrations or derivation of PK and PD parameters: 
BLQ of PK concentration at pre-dose will be treated as 0, values deemed implausible will be set to 
missing. Others retained in the data as assayed. 


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6.1.5 Study Baseline 
Baseline will be defined as the last non-missing observation obtained prior to the administration of the 
study drug. 
 
6.2 Safety Analyses 
Safety data will be summarized by treatment, with pooled placebo. All safety data will be listed. 
  
6.2.1 Adverse Events 
Adverse events (AEs) will be coded using MedDRA, version 22.0 or over. All AEs will be listed. 
AEs with onset on or after the date of informed consent but before the date of dosing of study 
medication will be considered pre-treatment AEs. Pre-treatment AE will be listed only. 
AEs with onset date/time on or after receiving the dosing of study medication, or pre-existing AEs that 
increase severity on or after receiving the dosing of study medication will be considered as TEAE. 
The number and percentage of subjects who experience one or more AEs will be tabulated by SOC 
and PT and by SOC, PT and maximum severity for each cohort and overall. The sorting is by 
descending frequency of SOC and PT. TEAEs that are related to study medication per investigator’s 
decision, TEAEs leading to study discontinuation, and TEAEs that are serious (treatment-emergent 
SAEs), will be summarized similarly. 
 
6.2.2 Clinical Laboratory Assessments 
Individual data listings of laboratory results will be presented for each subject. The observed values 
and change from baseline of all hematology, clinical chemistry, coagulation and urinalysis results 
(observed values) will be summarized according to section 6.1.1. Laboratory assessments that are 
outside of normal ranges and with potential clinical importance will be summarized and flagged in the 
listings with the PI’s or investigator’s assessment such as NCS or CS. Shift tables of hematology, 
clinical chemistry, coagulation and urinalysis results will be generated to summarize the normal, NCS 
and CS status changes from baseline. 
 
6.2.3 Vital Signs 
Observed and change from baseline - vital sign values (body weight, BMI, blood pressure [BP], pulse, 
respiratory rate, and tympanic temperature) at each day and time-point will be listed and summarized. 
 
6.2.4 12-lead Electrocardiograms 
Average and individual triplicate ECG intervals will be listed with mean change from baseline by 
subject, day, and time point. Observed and change from baseline values of ECG parameters will be 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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summarized. The worst case of triplicated status of 12-lead ECG parameters, Normal, Abnormal NCS, 
and Abnormal CS, and their shifts from baseline will be summarized. 
 
6.2.5 Physical Examination 
The clinical findings (Abnormal NCS and Abnormal CS) on PE and severity will be listed. 
 
6.2.6 Injection Site Reactions 
Multiple syringes may be injected subcutaneously in the right upper abdomen (if not applicable, left 
upper abdomen) as the dose increases. All injection site irritation events will be documented as AEs 
and included in the AEs analysis in the Section 6.2.1. The number and percentage of subjects with 
specific site reactions such as erythema and edema will be summarized by treatment group, day, time 
point, and Draize scale. In addition, diameter of affected areas will be summarized descriptively by 
treatment group, day and time point. 
 
6.2.7 Immunogenicity 
Immunogenicity assessments will be performed when deemed necessary by the Principal Investigator 
or the Sponsor in any of the following cases: 
• When ADA formation is suspected based on PK/PD analysis results 
• When biomarker changes related to drug efficacy are not observed at expected pharmacologically 
effective doses 
• When AEs suspected as immune responses occur after administration 
• When necessary for other clinical/scientific reasons 
Anti-drug antibodies (ADAbs, anti-HM15912 antibodies) will be summarized categorically, 
hierarchically displaying the Positive and Negative results from screening assay and confirmatory 
assay by treatment group and visit. Confirmed positive ADAbs will be further summarized by titer fold 
categories. Domain specificity will be listed along with the screening, confirmatory assay and titer 
results. 
Neutralizing antibodies (Nabs) will be summarized categorically, hierarchically displaying the Positive 
and Negative results from screening and confirmatory assay by treatment group and visit. Cross 
reactivity for confirmed positive Nabs will be summarized by treatment group and visit.  
Anti-polyethylene glycol antibodies (anti-PEG) will be summarized categorically, displaying the Positive 
and Negative results from screening assay and specificity by treatment group and visit. The titer 
results are listed only.  
 


Protocol No. : HM-GLP2-101                                                             Statistical Analysis Plan 
 
 
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6.3 Pharmacokinetic Analyses 
6.3.1 PK Concentration 
Concentration of HM15912 will be summarized descriptively by treatment group and time point. A line 
plot for mean concentration +/- standard deviation over time will be generated for the PK set with dose 
level overlaid. Line plots on linear and log scales of HM15912 individual subject concentration overlaid 
with the mean concentration for each cohort will be plotted separately. 
 
6.3.2 PK Parameter 
The following PK parameters will be summarized by treatment group for the PK Analysis Set. 
• Maximum concentration (Cmax) is defined as the maximum HM15912 concentration measured 
after single SC dose 
• Time to reach Cmax (Tmax) is defined as the time from initial injection to time of Cmax 
• Area under the concentration-time curve for HM15912 up to the last point with concentrations 
above the lower limit of quantification (LLOQ), AUC0-last, will be calculated by linear-up log-down 
method. 
• Area under the concentration-time curve with extrapolation to infinity for HM15912, AUC0-inf, 
will be calculated by AUC0-last + Clast/ λz, where Clast is the last observed concentration (_obs), or 
the last predicted concentration (_pred). 
• AUC%extrap: Percentage of AUCinf that is due to extrapolation beyond tlast 
• λz, first-order terminal elimination rate constant, calculated by linear regression of time vs. log 
concentration curve in the terminal phase. For λz to be acceptable, it shall be determined over a 
time interval equal to at least 1.5 x t½ λz, with at least 3 different time points in the terminal 
phase for the regression analysis, and the coefficient of determination Adj_RSq shall be ≥0.8.  
If at least one of these three conditions is not fulfilled, the parameters depending on λz (e.g., 
AUC0-inf, the terminal half-life t1/2, λz, CL and Vz) shall be flagged as not reliable if calculated and 
listed. They will generally be excluded from descriptive statistics and statistical testing 
procedures, unless otherwise judged by the pharmacometrician in charge of PK analysis. 
• Apparent terminal half-life t1/2, will be determined from equation ln2/ λz. 
• CL (_obs, _pred), apparent total body clearance will be calculated by Dose/AUC0-inf.  Note, 
the Dose in calculating CL for HM15912 will be the total administered dose, which is the 
subcutaneous dose. 
• Vz (_obs, _pred), apparent volume of distribution at terminal phase and will be calculated by 
CL/ λz. 
• Apparent clearance divided by bioavailability (CL/F) 
• Apparent volume of distribution at terminal phase divided by bioavailability (Vz/F) 
Box plots of Cmax, AUC0-last and AUC0-inf for each cohort may be generated. The planned last sampling 


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time of each cohort will be informed as an annotation at AUC0-last of summary stat and box plot as 
planned last sampling times for Cohort 1-3 and Cohort 4-5 are different as Day 30 and Day 44, 
respectively.  
 
6.3.3 Dose Proportionality 
The power model will be used to analyze the dose proportionality in AUC0-last, AUC0-inf and Cmax of 
HM15912. The estimate of β and the corresponding 90% CI will be derived. 
The power model is defined as follows: 
log(𝑃𝐾𝑖) = α + (β) * log(dosei) + Ɛi 
where 𝑃𝐾𝑖 is the PK parameter (AUC or Cmax) observation for the subject i.  
α is the population intercept. 
β is the population slope. 
dosei is the dosage(mg) for the subject i. 
Ɛi is the random error; Ɛi ~ N(0, 𝜎𝜀
2) and independent. 
The assumption for the Power Model is that the underlying relationship between log(PK parameter) 
and log(dose) is linear. The dose proportionality corresponds to the ratio of dose normalized geometric 
means (Rdnm), which is defined as ratio of the predicted geometric mean of the highest dose relative 
to the predicted geometric mean of the lowest dose, The dose proportionality would be declared when 
the 90% CI for the R𝑑𝑛𝑚 falls entirely within the limit of 0.8 to 1.25.3 Scatter plot of log(PK parameter) 
and log(dose) will be plotted with an estimated line. 
 
6.4 Pharmacodynamic Analyses 
6.4.1 Fasting Lipid Panel 
The observed values and the change from baseline of fasting lipid panels, such as total cholesterol, 
triglycerides, LDL, HDL, VLDL, and FFA, will be summarized by treatment group, day and time point 
according to section 6.1.1. 
 
6.4.2 Blood Glucose-related Panel 
The observed values and the change from baseline of blood glucose panels, such as fasting plasma 
glucose, GIP, GLP-1, C-peptide, glucagon, and insulin will be summarized by treatment group, day 
and time point according to section 6.1.1. 
 
6.4.3 Albumin and Pre-albumin 
The observed values and the change from baseline of albumin and pre-albumin will be summarized by 
treatment group, day and time point according to section 6.1.1. 
 


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6.4.4 Blood Plasma Citrulline 
The observed values and the change from baseline of blood plasma citrulline will be summarized by 
treatment group, day and time point according to section 6.1.1. 
 
6.4.5 Growth Factor 
The observed values and the change from baseline of insulin-like growth factor-1 and keratinocyte 
growth factor will be summarized by treatment group, day and time point according to section 6.1.1. 


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7. Interim Analysis 
In the dose escalation meeting, blinded safety data collected at least 17 days post dose from at least 6 
subjects (HM15912, n̠ ≥4) in each cohort shall be reviewed prior to initiating the dosing of the next 
cohort. All pertinent blinded safety data, available PK and PD data, will be reviewed to make one of 
the following determinations: 
 
To continue with the study without modification. 
 
To continue with the study and add additional safety evaluations. 
 
To continue the study with adjustments made to the dose. 
 
Hold further enrollment pending evaluation / resolution of adverse events. 
The dose escalation meeting will be held after at least the 6th subject completes the investigation of 
safety lab results at Day 17 in each Cohort. It is possible and acceptable that some queries may 
remain open and SDV will not be 100% for the applicable data. The level of SDV % will vary 
depending on factors such as monitoring schedule and availability of completed data entry and will not 
affect the dose escalation decision. 
 
7.1 Dose Administration 
 
List of dose administration 
 
7.2 Subject status 
 
Listing of Demographic data (including randomization numbers and cohort) 
 
List of completed subjects and early discontinued subjects with reasons 
 
7.3 Adverse Events(AEs) and Serious AEs 
 
Listing of all AEs experienced, including reported terms, start/end date and time, severity, 
seriousness, relationship to study drug and outcome 
 
Highlight severity of “Moderate” or “Severe” 
 
Highlight relationship to study drug “Related” 
 
Identification of any AEs marked “Serious” 
 
Listing of dose administration 
 
7.4 Clinical Laboratory Results 
 
Listing of all clinical laboratory tests, including hematology, clinical chemistry, coagulation and 
urinalysis according to SAP section 6.1.1 
 
Graphs of all laboratory results, including High/Low indicators 
 
Listings of abnormal laboratory values (with CS or NCS) 
 


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7.5 12-lead ECG 
 
List of all ECG results 
 
Graphs of all ECG results 
 
Listing of abnormal ECG findings (with CS or NCS) 
 
7.6 Vital Signs 
 
List of all body weight, systolic/diastolic blood pressure, pulse rate, tympanic body 
temperature and respiratory rate assessments 
 
Graphs of vital sign assessments 
 
7.7 Abnormal Physical Examination Results 
 
Listing of all PEs performed, not assessed as Normal, ordered by clinical relevance and body 
system 
 
7.8 Injection Site Reaction 
 
Listing of all positive site reactions with diameter 
 
7.9  Concomitant Medication 
 
Listing of prior concomitant medications that start before the date of dosing of study 
medication and continue beyond that date 
 
Listing of new concomitant medications that start after the first study dose date, including 
those started in the follow-up period 
 
7.10 Medical History 
 
Listing of medical history by subject, description of the disease/procedure, MedDRA SOC, PT, 
start date and stop date (or ongoing if applicable) 
 
7.11 Pharmacodynamic (PD) Assessments (if available) 
 
Graphs of all laboratory results, including High/Low indicators 
 
Listings of abnormal laboratory values (with CS or NCS) 
 
7.12 Pharmacokinetic (PK) Assessments (if available) 
 
Graph of PK concentration 
 
Listing of PK concentration data 
 
Table of PK parameter with summary value 
 


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8. Statistical Software 
All statistical analyses will be performed using SAS® version 9.4. All PK and PD parameters will be 
derived with standard NCA methods using  SAS® version 9.4 or higher. 


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9.  REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles for 
Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and Content of 
Clinical Study Reports (E3), 30 November 1995. 
3. Hummel J, Mckendrick S, Brindley C, French R. Exploratory assessment of dose proportionality: 
review of current approaches and proposal for a practical criterion. Pharm Stat. 2009;8(1):38–49. 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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10.  APPENDIX 
Table 3 
Schedule of Assessments 
Table 3-1. Schedule of Assessments (Cohort 1-3) 
Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Outpatienta 
Visit 4 
Outpatienta 
Visit 5 
Follow-upb 
Day 
-28 ~ -2 
-1 
Outpat
ient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Heightd, BMIe 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Body weightd 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and alcohol screening 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Outpatient 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Standardized meals 
 
 
X 
Xh 
X 
X 
X 
X 
X 
 
 
 
 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Outpatienta 
Visit 4 
Outpatienta 
Visit 5 
Follow-upb 
Day 
-28 ~ -2 
-1 
Outpat
ient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
IP administrationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, pulse, tympanic temperature, RR)i 
X 
X 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
X 
X 
Clinical laboratory tests (hematology, chemistry, 
coagulation, urinalysis)j 
X 
X 
 
Xk 
 
Xk 
Xk 
 
 
X 
 
X 
X 
12-lead ECGl 
X 
X 
 
Xl 
X 
X 
X 
 
 
X 
X 
X 
X 
Immune response assessments (ADA, NAb, anti-PEG) 
 
 
Xm 
 
 
 
 
 
 
 
X 
 
X 
Injection site assessmentsn 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examinations 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Citrullinep 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GIP, GLP-1, C-peptide, glucagon, insulinq 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
IGF-1 and KGFr 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
ADA = anti-drug antibody; Anti-PEG = anti-polyethylene glycol; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; FFA = free fatty acid; FPG = fasting plasma glucose; 
FSH = follicle-stimulating hormone; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IP = investigational product; LDL = low-density 
lipoprotein; NAb = neutralizing antibody; PK = pharmacokinetics; RR = respiratory rate; SC = subcutaneous; VLDL = very low-density lipoprotein 
a. An additional Outpatient visit may be included in later cohorts, if required, after PK data are evaluated. If so, assessments scheduled on Day 17 will be performed at the additional Outpatient 
visit. 
b. If a subject is discontinued from the study or withdraws consent, the Principal Investigator must make every possible effort to perform the evaluations described for the Follow-up visit. 
Efforts will be made to perform the Follow-up visit within 30 days from the date the subject is discontinued from the study or withdraws consent. 
c. The criteria applicable for admission prior to randomization, i.e., exclusion criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, and 31, will be 
checked again. 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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d. Height will be measured only at the Screening visit. Height and weight measurements will be performed with shoes removed. Weight will be recorded rounded to 1 decimal place. If weight 
is measured rounded to 2 decimal places, the number is rounded off from the second digit after the decimal point. 
e. BMI will be calculated by the following formula: BMI = Weight (kg) ÷ ((Height (m) x Height (m)). The calculated BMI will be rounded to 1 decimal place. The height measured at the 
Screening visit will be used for BMI calculation, and if a value is calculated as 2 decimal places, the number is rounded off to the first place. 
f. Medical history which will be checked on Day-1 is limited to the medical history related to exclusion criteria 1, 2, 3, 6, 8, 9, 10, 11, 13, 14, 15, and 17. 
g. Serum pregnancy tests at the Screening visit and on Day-1; urine pregnancy tests at the Day 30/Follow-up visit. 
h. HM15912 or placebo will be administered via SC injection into the abdomen on the morning of Day 1 after a minimum 10-hour fast. Subjects will continue fasting through approximately 4 
hours postdose. Water consumption will also be limited for 1 hour before dosing and for approximately 2 hours after dosing. After the planned 4-hour post-dose blood sampling (clinical 
laboratory tests and analysis of citrulline) and testing (12-lead ECG) are performed, subjects will be served lunch by the institution. 
i. Vital signs will be measured twice per day on Day 1 through Day 6 (AM and PM). Vital signs will be measured at predose and 6 hours postdose on Day 1. Vital signs will be measured 
whenever possible in the morning and afternoon between Day 2 and Day 6. All other assessments will be performed once per day whenever possible. BP and pulse will be measured for 2 
consecutive times after a subject has been lying down or sitting to rest ≥ 5 minutes, and mean values will be recorded. 
j. Samples for clinical laboratory tests will be collected after at least 12 hours of fasting. If the PK sampling time points are changed, the sampling times for clinical laboratory tests may be 
adjusted accordingly.  
k. 4, 48 and 72 hours postdose 
l. The 12-lead ECGs will be performed after a subject has been resting supine for ≥ 5 minutes. ECGs will be measured in triplicate in the morning during admission. Only for Day 1, however, 
ECGs will be measured in triplicate predose and 4 hours postdose, and a ±30-minute sampling window is allowed for measurement at 4 hours postdose. Triplicate ECGs will be recorded at 
least 30 seconds apart from each other, not exceeding a time period of 3 minutes for the completion of all 3 ECGs. 12-lead ECGs during the Outpatient visit will be measured once per day 
whenever possible. 
m. Blood sampling for immunogenicity assessments will be performed only for hospitalized patients after admission on Day-1, Day 10, and Day 30. 
n. Injection site assessments will be performed predose, within 1 hour postdose and at 4 and 12 hours postdose on Day 1, and then between 9:00 AM and 12:00 PM daily from Day 2 through 
Day 7. 
o. Blood will be collected for PK assessments predose and at 1, 4, 8, 12 (Day 1), 24, 36 (Day 2), 48, 54, 60 (Day 3), 72, 78, 84 (Day 4), 96, 102, 108 (Day 5), 120 (Day 6), 144 (Day 7), 216 
(Day 10), 384 (Day 17) and 696 (Day 30) hours postdose. The time points for citrulline sampling are identical to those for PK blood sampling, but 126 hours (Day 6) will be added. PK 
sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. See Table 2-1 for the PK sampling schedule. 
p. If the PK sampling time points are changed, the citrulline sampling times may be adjusted accordingly. See Table 4-1 for the citrulline sampling schedule. 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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q. Blood will be collected for GIP, GLP-1, C-peptide, glucagon and insulin immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 
30/Follow-up visit. If the PK sampling time points are changed, sampling times may be adjusted accordingly. 
r. Blood will be collected for IGF-1 and KGF immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 30/Follow-up visit. If the PK 
sampling time points are changed, sampling times may be adjusted accordingly. 
 
 
 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Table 4-2. Schedule of Assessments (Cohort 4, 5) 
Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Out 
patienta 
Visit 4 
Out 
patienta 
Visit 5 
Out 
patienta 
Visit 6 
Out 
patienta 
Visit 7 
Follow- 
upb 
Day 
-28 ~ -2 
-1 
Outpa
tient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
8 
(±4 hours) 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
44 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heightd, BMIe 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Body weightd 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and alcohol screening s 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Outpatient 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standardized meals 
 
 
X 
Xh 
X 
X 
X 
X 
X 
 
 
 
 
 
 
IP administrationh 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Visit 
Visit 1 
Screening 
Visit 2 
Inpatient Treatment Period 
Visit 3 
Out 
patienta 
Visit 4 
Out 
patienta 
Visit 5 
Out 
patienta 
Visit 6 
Out 
patienta 
Visit 7 
Follow- 
upb 
Day 
-28 ~ -2 
-1 
Outpa
tient 
-1 
Inpa
tient 
1 
2 
3 
4 
5 
6 
7 
8 
(±4 hours) 
10 
(±1 day) 
17 
(±1 day) 
30 
(±3 days) 
44 
(±3 days) 
Vital signs  
(BP, pulse, tympanic temperature, RR)i 
X 
X 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests  
(hematology, chemistry, coagulation, 
urinalysis)j 
X 
X 
 
Xk 
 
 
Xk 
 
 
X 
 
 
X 
X 
X 
12-lead ECGl 
X 
X 
 
Xl 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Immune response assessments 
 (ADA, NAb, anti-PEG) 
 
 
Xm 
 
 
 
 
 
 
 
 
 
X 
 
X 
Injection site assessmentsn 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Physical examinations 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Citrullinep 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GIP, GLP-1, C-peptide, glucagon, insulinq 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
IGF-1 and KGFr 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
ADA = anti-drug antibody; Anti-PEG = anti-polyethylene glycol; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; FFA = free fatty acid; FPG = fasting plasma glucose; 
FSH = follicle-stimulating hormone; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IP = investigational product; LDL = low-density 
lipoprotein; NAb = neutralizing antibody; PK = pharmacokinetics; RR = respiratory rate; SC = subcutaneous; VLDL = very low-density lipoprotein 
a. An additional Outpatient visit may be included in later cohorts, if required, after PK data are evaluated. If so, assessments scheduled on Day 17 will be performed at the additional Outpatient 
visit. 
b. If a subject is discontinued from the study or withdraws consent, the Principal Investigator must make every possible effort to perform the evaluations described for the Follow-up visit. 
Efforts will be made to perform the Follow-up visit within 30 days from the date the subject is discontinued from the study or withdraws consent. 
c. The criteria applicable for admission prior to randomization, i.e., exclusion criteria 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, and 31, will be 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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checked again. 
d. Height will be measured only at the Screening visit. Height and weight measurements will be performed with shoes removed. Weight will be recorded rounded to 1 decimal place. If weight 
is measured rounded to 2 decimal places, the number is rounded off from the second digit after the decimal point. 
e. BMI will be calculated by the following formula: BMI = Weight (kg) ÷ ((Height (m) x Height (m)). The calculated BMI will be rounded to 1 decimal place. The height measured at the 
Screening visit will be used for BMI calculation, and if a value is calculated as 2 decimal places, the number is rounded off to the first place. 
f. Medical history which will be checked on Day-1 is limited to the medical history related to exclusion criteria 1, 2, 3, 6, 8, 9, 10, 11, 13, 14, 15, and 17. 
g. Serum pregnancy tests at the Screening visit and on Day-1; urine pregnancy tests at the Day 44/Follow-up visit. 
h. HM15912 or placebo will be administered via SC injection into the abdomen on the morning of Day 1 after a minimum 10-hour fast. Subjects will continue fasting through approximately 4 
hours postdose. Water consumption will also be limited for 1 hour before dosing and for approximately 2 hours after dosing. After the planned 4-hour post-dose blood sampling (clinical 
laboratory tests) and testing (12-lead ECG) are performed, subjects will be served lunch by the institution. 
i. Vital signs will be measured twice per day on Day 1 through Day 6 (AM and PM). Vital signs will be measured at predose and 6 hours postdose on Day 1. Vital signs will be measured 
whenever possible in the morning and afternoon between Day 2 and Day 6. All other assessments will be performed once per day whenever possible. BP and pulse will be measured for 2 
consecutive times after a subject has been lying down or sitting to rest ≥ 5 minutes, and mean values will be recorded. 
j. Samples for clinical laboratory tests will be collected after at least 12 hours of fasting. If the PK sampling time points are changed, the sampling times for clinical laboratory tests may be 
adjusted accordingly. 
k. 4 and 72 hours postdose 
l. The 12-lead ECGs will be performed after a subject has been resting supine for ≥ 5 minutes. ECGs will be measured in triplicate in the morning during admission. Only for Day 1, however, 
ECGs will be measured in triplicate predose and 4 hours postdose, and a ±30-minute sampling window is allowed for measurement at 4 hours postdose. Triplicate ECGs will be recorded at 
least 30 seconds apart from each other, not exceeding a time period of 3 minutes for the completion of all 3 ECGs. 12-lead ECGs during the Outpatient visit will be measured once per day 
whenever possible. 
m. Blood sampling for immunogenicity assessments will be performed only for hospitalized patients after admission on Day-1, Day 17, and Day 44. 
n. Injection site assessments will be performed predose, within 1 hour postdose and at 4 and 12 hours postdose on Day 1, and then between 9:00 AM and 12:00 PM daily from Day 2 through 
Day 7. 
o. Blood will be collected for PK assessments predose and at 6, 12 (Day 1), 24, 36 (Day 2), 48, 54, 60 (Day 3), 72, 78, 84 (Day 4), 96, 102, 108 (Day 5), 120 (Day 6), 144 (Day 7), 168 (Day 8), 
216 (Day 10), 384 (Day 17), 696 (Day 30) and 1032 (Day 44) hours postdose. The time points for citrulline sampling are identical to those for PK blood sampling, but 126 hours (Day 6) will 
be added. PK sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. See Table 2-2 for the PK sampling 
schedule. 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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p. If the PK sampling time points are changed, the citrulline sampling times may be adjusted accordingly. See Table 4-2 for the citrulline sampling schedule. 
q. Blood will be collected for GIP, GLP-1, C-peptide, glucagon and insulin immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 30 
Outpatient visit. If the PK sampling time points are changed, sampling times may be adjusted accordingly. 
r. Blood will be collected for IGF-1 and KGF immediately before administration and once daily on Days 4 and 7, at the Day 17 Outpatient visit and at the Day 30 Outpatient visit. If the PK 
sampling time points are changed, sampling times may be adjusted accordingly. 
s. Alcohol breath test procedure could be replaced with the examination by interview to avoid infection of COVID-19. 
 
 
 
 
 
 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Table 4 
Citrulline Sampling Schedule for Exploring PK Samples and PD 
Table 4-1 Citrulline Sampling Schedule for Exploring PK Samples and PD (Cohort 1~3) 
Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
Day 1 
Immediately before administration (- 15 min)b 
Immediately before administration (- 15 min)b 
1 h (± 15 min)b 
1 h (± 15 min)b 
4 h (± 15 min)b 
4 h (± 15 min)b 
8 h (± 15 min) 
8 h (± 15 min) 
12 h (± 15 min) 
12 h (± 15 min) 
Day 2 
24 h (± 15 min)b 
24 h (± 15 min)b 
36 h (± 15 min) 
36 h (± 15 min) 
Day 3 
48 h (± 15 min)b  
48 h (± 15 min)b 
54 h (± 15 min) 
54 h (± 15 min) 
60 h (± 15 min) 
60 h (± 15 min) 
Day 4 
72 h (± 15 min)b 
72 h (± 15 min)b 
78 h (± 15 min) 
78 h (± 15 min) 
84 h (± 15 min) 
84 h (± 15 min) 
Day 5 
96 h (± 15 min)b 
96 h (± 15 min)b 
102 h (± 15 min) 
102 h (± 15 min) 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
108 h (± 15 min) 
108 h (± 15 min) 
Day 6 
 
 
 
120 h (± 15 min)b 
120 h (± 15 min)b 
- 
126 h (± 15 min) 
Day 7 
144 h (± 15 min)b 
144 h (± 15 min)b 
Day 10 
216 h (± 24 h)b,c 
216 h (± 24 h)b,c 
Day 17 
384 h (± 24 h)b,c 
384 h (± 24 h)b,c 
Day 30 
696 h (± 72 h)b,d 
696 h (± 72 h)b,d 
a. Sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. 
b. Samples will be collected with an empty stomach. 
c. PK and citrulline samples may be collected ±1 day (24 hours) from the scheduled sampling time points at the Days 10 and 17 Outpatient visits. The samples may also be 
collected ±1 day (24 hours) from the scheduled sampling time points in case there is an additional Outpatient visit. 
d. PK and citrulline samples may be collected ±3 days (72 hours) from the scheduled sampling time points at the Day 30 Outpatient visit. 
 
 
 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Table 4-2 Citrulline Sampling Schedule for Exploring PK Samples and PD (Cohort 4, 5) 
Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
Day 1 
Immediately before administration (- 15 min)b 
Immediately before administration (- 15 min)b 
6 h (± 15 min) 
6 h (± 15 min) 
12 h (± 15 min) 
12 h (± 15 min) 
Day 2 
24 h (± 15 min)b 
24 h (± 15 min)b 
36 h (± 15 min) 
36 h (± 15 min) 
Day 3 
48 h (± 15 min)b  
48 h (± 15 min)b 
54 h (± 15 min) 
54 h (± 15 min) 
60 h (± 15 min) 
60 h (± 15 min) 
Day 4 
72 h (± 15 min)b 
72 h (± 15 min)b 
78 h (± 15 min) 
78 h (± 15 min) 
84 h (± 15 min) 
84 h (± 15 min) 
Day 5 
96 h (± 15 min)b 
96 h (± 15 min)b 
102 h (± 15 min) 
102 h (± 15 min) 
108 h (± 15 min) 
108 h (± 15 min) 
Day 6 
120 h (± 15 min)b 
120 h (± 15 min)b 
- 
126 h (± 15 min) 
Day 7 
144 h (± 15 min)b 
144 h (± 15 min)b 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Study Day 
PK Sampling 
Time Pointa 
Citrulline  
Sampling Time Pointa 
Day 8 
168 h (± 4 h)b 
168 h (± 4 h)b 
Day 10 
216 h (± 24 h)b,c 
216 h (± 24 h)b,c 
Day 17 
384 h (± 24 h)b,c 
384 h (± 24 h)b,c 
Day 30 
696 h (± 72 h)b,d 
696 h (± 72 h)b,d 
Day 44 
1032 h (± 72 h)b,d 
1032 h (± 72 h)b,d 
 
a. Sampling times may be adjusted between the cohorts in case available PK data show that other time points would be more beneficial. 
b. Samples will be collected with an empty stomach. 
c. PK and citrulline samples may be collected ±1 day (24 hours) from the scheduled sampling time points at the Days 10 and 17 Outpatient visits. The samples may also be 
collected ±1 day (24 hours) from the scheduled sampling time points in case there is an additional Outpatient visit. 
d. PK and citrulline samples may be collected ±3 days (72 hours) from the scheduled sampling time points at the Day 30 and Day 44 Outpatient visit. 
 
 
 
 
 
 
 
 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Table 5 
PD Sampling Schedule 
Table 5-1 PD Sampling Schedule (Cohort 1~3) 
 
Study Day 
Screening 
-28 ~ -2 
-1 
1 
2 
3 
4 
5 
6 
7 
OP 10 
OP 17 
FU 30 
Assessment 
 
 
Predose 
(-30 min) 
4 h 
(±15 min) 
24 h 
(±15 min) 
48 h 
(±15 min) 
72 h 
(±15 min) 
96 h  
(±15 min) 
120 h  
(±15 min) 
144 h  
(±15 min) 
216 h 
(±24 h) 
384 h 
(±24 h) 
696 h 
(±72 h) 
Chemistry test - 
albumin, prealbumina,b 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
Chemistry test - fasting lipid 
panel (total cholesterol, 
triglycerides, LDL, HDL, 
VLDL, FFA)a,b 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
Chemistry test - fasting plasma 
glucosea,b 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
Blood GIP, GLP-1, C-peptide, 
glucagon, insulina 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
IGF-1 and KGFa 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
FFA = free fatty acid; FPG = fasting plasma glucose, FU = follow-up; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IGF-1 = insulin-
like growth factor-1; KGF = keratinocyte growth factor; LDL = low-density lipoprotein; OP = outpatient; VLDL = very low-density lipoprotein 
a. 
All samples will be collected after a minimum 12-hour fast. If the PK sampling time points are changed, sampling times may be adjusted accordingly between the cohorts. 
b. 
Included in clinical laboratory tests. 
 
 
 
 


Protocol No. : HM-GLP2-101                                                                                                                              Statistical Analysis Plan 
 
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Table 5-2 PD Sampling Schedule (Cohort 4, 5) 
FFA = free fatty acid; FPG = fasting plasma glucose, FU = follow-up; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; HDL = high-density lipoprotein; IGF-1 = insulin-
like growth factor-1; KGF = keratinocyte growth factor; LDL = low-density lipoprotein; OP = outpatient; VLDL = very low-density lipoprotein 
a. 
All samples will be collected after a minimum 12-hour fast. If the PK sampling time points are changed, sampling times may be adjusted accordingly between the cohorts. 
b. 
Included in clinical laboratory tests. 
 
Study Day 
Screening 
-28 ~ -2 
-1 
1 
2 
3 
4 
5 
6 
7 
OP 8 
OP 10 
OP 17 
OP 30 
FU 44 
Assessment 
 
 
Predose 
(-30 
min) 
4 h 
(±15 
min) 
24 h 
(±15 
min) 
48 h 
(±15 
min) 
72 h 
(±15 
min) 
96 h 
(±15 
min) 
120 h 
(±15 
min) 
144 h 
(±15 
min) 
168 h 
(±4 h) 
216 h 
(±24 h) 
384 h 
(±24 h) 
696 h 
(±72 h) 
1032 h 
(±72 h) 
Chemistry test - 
albumin, prealbumina,b 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Chemistry test - fasting lipid 
panel (total cholesterol, 
triglycerides, LDL, HDL, 
VLDL, FFA)a,b 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Chemistry test - fasting 
plasma glucosea,b 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Blood GIP, GLP-1, C-
peptide, glucagon, insulina 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
IGF-1 and KGFa 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X