Clinical trial NCT05711381
Conditions: Renal Impairment
Sponsor: Hanmi Pharmaceutical Company Limited
Start date: 2022-12-02; Completion date: 2023-08-15
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability of HM15912 in Subjects with Renal Impairment and Matched Control Subjects with Normal Renal Function

Detailed description:
A single-dose, open-label, Phase 1 study (HM-GLP2-102) was conducted to evaluate the impact of renal impairment (RI) on the pharmacokinetics (PK) of HM15912. This study aimed to assess the safety and PK profile of HM15912 at a minimum effective dose of 0.5 mg/kg, which was determined based on findings from a previous clinical study (HM-GLP2-101).

The study was initially designed to be conducted in two parts.

Part 1: An open-label, single-dose, parallel-group study to investigate the effect of RI on the PK, safety, and tolerability of HM15912 in subjects with severe RI and subjects with normal renal function as a control group.

Part 2 (if applicable): An open-label, single-dose, parallel-group study to investigate the effect of RI on the PK, safety, and tolerability of HM15912 in subjects with moderate and mild RI.

Arms: arm 1: Subjects with eGFR \< 30mL/min/1.73m\^2, but not requiring hemodialysis arm 2: Subjects with eGFR ≥ 90 mL/min/1.73m\^2 arm 3: Subjects with 30 mL/min/1.73m\^2 ≤ eGFR \< 60 mL/min/1.73m\^2 arm 4: Subjects with 60 mL/min/1.73m\^2 ≤ eGFR \< 90 mL/min/1.73m\^2
Interventions: intervention 1: HM15912
Intervention descriptions: intervention 1: Singe subcutaneous administration of HM15912 0.5 mg/kg

Protocol documents:
Prot_000.pdf: 
Title Page 
 
 
Clinical Trial Protocol 
 
 
AN OPEN-LABEL, SINGLE-DOSE STUDY TO EVALUATE THE 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF HM15912 IN SUBJECTS 
WITH RENAL IMPAIRMENT AND IN MATCHED CONTROL SUBJECTS WITH 
NORMAL RENAL FUNCTION 
 
 
Investigational product 
: HM15912 
Protocol number 
: HM-GLP2-102 
Version (completion date) 
: 1.0 (05 August 2022) 
Previous version (completion date) 
: Not Applicable 
Clinical phase 
: Phase 1 
 
 
 
CONFIDENTIAL 
The information contained in this protocol is provided to the principal investigator 
and other study personnel, institutional review board, and regulatory authorities. This 
document may not be disclosed to third parties without prior written permission from 
Hanmi Pharmaceutical. Co., Ltd., unless this is necessary to obtain informed consent 
from the person who is a potential subject for this study.  


GENERAL INFORMATION 
Protocol No.: 
HM-GLP2-102 
Date of the Protocol: 
05-August-2022 
Synopsis Version: 
1.2 (29-July-2022) 
Sponsor: 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu, 
Seoul, 05545 
Korea 
Sponsor Signatory & Medical Expert: 
  
 
 
 


Protocol No.HM-GLP2-102 
Clinical Protocol (Ver. 1.0) 
HM15912 
2022.08.05 
 
 
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SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability of HM15912 in Subjects with Renal Impairment and Matched 
Control Subjects With Normal Renal Function 
PROTOCOL NUMBER: HM-GLP2-102 (Version 1.0) 
Hanmi Pharmaceutical Co., Ltd. 
I have read the attached protocol and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite Guideline 
on Good Clinical Practice (GCP) and applicable Health Authority regulations/guidelines. The 
human-rights and privacy of patients will be protected based on the Declaration of Helsinki. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Hanmi Pharmaceutical Co., Ltd. 
 
Clinical Science Director 
Hanmi Pharm. Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu,  
Seoul, 05545 
Korea 
 
Date (Day/Month/Year) 
 
August 5, 2022


Protocol No.HM-GLP2-102 
Clinical Protocol (Ver. 1.0) 
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INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability of HM15912 in Subjects with Renal Impairment and Matched 
Control Subjects With Normal Renal Function 
PROTOCOL NUMBER: HM-GLP2-102 Version 1.0 
Hanmi Pharmaceutical Co., Ltd. 
I have read the attached protocol and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite Guideline 
on Good Clinical Practice (GCP) and applicable Health Authority regulations/guidelines. The 
human rights and privacy of patients will be protected based on the Declaration of Helsinki. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Hanmi Pharmaceutical Co., Ltd. 
 
 
 
Signature of Investigator 
 
Date (Day/Month/Year) 
 
 
 
 
 
 
Investigator Name (print or type) 
 
 
 
 
 
 
 
 
Investigator’s Title 
 
 
 


Protocol No.HM-GLP2-102 
Clinical Protocol (Ver. 1.0) 
HM15912 
2022.08.05 
 
 
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Table of Contents 
 
Title Page ........................................................................................................................................1 
GENERAL INFORMATION .......................................................................................................2 
Table of Contents ...........................................................................................................................5 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schedule of Assessments ................................................................................................15 
1.3. 
Study Schema .................................................................................................................19 
2. 
Introduction ...................................................................................................................20 
2.1. 
Study Rationale ...............................................................................................................20 
2.2. 
Background .....................................................................................................................21 
2.3. 
Benefit/Risk Assessment ................................................................................................22 
2.3.1. 
Risk Assessment .............................................................................................................22 
2.3.2. 
Benefit Assessment .........................................................................................................27 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................27 
3. 
Objectives and Endpoints ............................................................................................28 
4. 
Study Design ..................................................................................................................29 
4.1. 
Overall Design ................................................................................................................29 
4.2. 
Scientific Rationale for Study Design ............................................................................31 
4.3. 
Justification for Dose ......................................................................................................31 
4.4. 
End of Study Definition ..................................................................................................32 
4.5. 
Study Termination ..........................................................................................................32 
5. 
Study Population ...........................................................................................................33 
5.1. 
Inclusion Criteria ............................................................................................................33 
5.1.1. 
All Subjects .....................................................................................................................33 
5.1.2. 
Additional Inclusion Criteria for Subjects with Normal Renal 
Function (Cohort 1).........................................................................................................33 
5.1.3. 
Additional Inclusion Criteria for Subjects with Impaired Renal 
Function (Cohort 2, Cohort 3 [if applicable] and Cohort 4 [if 
applicable]) .....................................................................................................................34 
5.2. 
Exclusion Criteria ...........................................................................................................34 
5.2.1. 
All Subjects .....................................................................................................................35 
5.2.2. 
Additional exclusion Criteria for Subjects with Normal Renal 
Function (Cohort 1).........................................................................................................36 
5.2.3. 
Additional Exclusion Criteria for Subjects with Impaired Renal 
Function (Cohort 2, Cohort 3 [if applicable] and Cohort 4 [if 
applicable]) .....................................................................................................................36 


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5.3. 
Lifestyle Considerations .................................................................................................37 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................37 
5.3.2. 
Caffeine, Alcohol, and Tobacco .....................................................................................37 
5.3.3. 
Activity ...........................................................................................................................37 
5.4. 
Screen Failures ................................................................................................................37 
6. 
Study Intervention ........................................................................................................39 
6.1. 
Study Drug Administered ...............................................................................................39 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................40 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................40 
6.4. 
Study Drug Compliance..................................................................................................40 
6.5. 
Concomitant Therapy .....................................................................................................40 
6.5.1. 
Subjects with Normal Renal Function (Cohort 1) ..........................................................41 
6.5.2. 
Subjects with Impaired Renal Function (Cohort 2, Cohort 3 [if 
applicable] and Cohort 4 [if applicable]) ........................................................................41 
6.6. 
Intervention After the End of the Study..........................................................................41 
7. 
Discontinuation of Study Intervention and Subject 
Discontinuation/Withdrawal........................................................................................42 
7.1. 
Discontinuation of Study Intervention ............................................................................42 
7.2. 
Subject Discontinuation/Withdrawal from the Study .....................................................42 
7.3. 
Study Subject Replacement ............................................................................................43 
7.4. 
Lost to Follow up ............................................................................................................43 
8. 
Study Assessments and Procedures.............................................................................44 
8.1. 
Efficacy Assessments .....................................................................................................44 
8.2. 
Safety Assessments .........................................................................................................44 
8.2.1. 
Physical Examinations ....................................................................................................44 
8.2.2. 
Vital Signs .......................................................................................................................45 
8.2.3. 
Electrocardiograms .........................................................................................................45 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................45 
8.2.5. 
Injection Site Assessment ...............................................................................................46 
8.3. 
Adverse Events and Serious Adverse Events .................................................................47 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................47 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................47 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................47 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................48 
8.3.5. 
Pregnancy ........................................................................................................................49 
8.3.6. 
Cardiovascular and Death Events ...................................................................................49 
8.3.7. 
Adverse Events of Special Interest .................................................................................49 
8.4. 
Treatment of Overdose ...................................................................................................51 
8.5. 
Pharmacokinetics ............................................................................................................51 
8.6. 
Biomarkers ......................................................................................................................51 
8.7. 
Genetics ..........................................................................................................................51 


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8.8. 
Immunogenicity Assessments.........................................................................................52 
8.9. 
Medical Resource Utilization and Health Economics ....................................................52 
9. 
Statistical Considerations .............................................................................................53 
9.1. 
Statistical Hypotheses .....................................................................................................53 
9.2. 
Sample Size Determination ............................................................................................53 
9.3. 
Populations for Analyses ................................................................................................53 
9.4. 
Statistical Analyses .........................................................................................................53 
9.4.1. 
General considerations ....................................................................................................54 
9.4.2. 
Pharmacokinetic Analyses ..............................................................................................54 
9.4.3. 
Safety Analyses ...............................................................................................................55 
9.5. 
Interim Analyses .............................................................................................................56 
9.6. 
Data Monitoring Committee (DMC) ..............................................................................56 
10. 
Supporting Documentation and Operational Considerations ..................................57 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................57 
10.1.1. 
Regulatory and Ethical Considerations ...........................................................................57 
10.1.2. 
Financial Disclosure........................................................................................................57 
10.1.3. 
Informed Consent Process ..............................................................................................57 
10.1.4. 
Data Protection................................................................................................................58 
10.1.5. 
Dissemination of Clinical Study Data.............................................................................58 
10.1.6. 
Data Quality Assurance ..................................................................................................58 
10.1.7. 
Source Documents ..........................................................................................................59 
10.1.8. 
Study and Site Start and Closure ....................................................................................59 
10.1.9. 
Publication Policy ...........................................................................................................60 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................61 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................63 
10.3.1. 
Definition of AE .............................................................................................................63 
10.3.2. 
Definition of SAE ...........................................................................................................64 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ................................................................65 
10.3.4. 
Reporting of SAEs ..........................................................................................................67 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................68 
10.5. 
Appendix 5: Adverse Event Guidance............................................................................71 
10.6. 
Appendix 6: Abbreviations .............................................................................................78 
11. 
References ......................................................................................................................81 
 


Protocol No.HM-GLP2-102 
Clinical Protocol (Ver. 1.0) 
HM15912 
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1. 
Protocol Summary 
1.1. 
Synopsis  
 
Protocol Title: An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability 
of HM15912 in Subjects with Renal Impairment and Matched Control Subjects With Normal Renal Function 
Name of Sponsor: Hanmi Pharmaceutical Co., Ltd. 
Name of Investigational Product: HM15912 
Study Centers: Approximately 4 sites in Unite States 
Publication(s): N/A  
Planned Study Period: 
First subject first dose is estimated in 4Q 2022. The 
study is expected to be performed for about 2 years 
from approval of the regulatory authority and the 
duration may be shorten or extended depending on the 
study situation  
Development Phase: 
Phase 1 
Rationale 
The primary purpose of this open-label, single-dose study is to characterize the effect of renal impairment 
on the pharmacokinetics (PK) of HM15912 following subcutaneous (SC) administration of a single 0.5 
mg/kg dose. 
Recent Food and Drug Administration (FDA) draft guidance; Guidance for Industry Pharmacokinetics in 
Patients with Impaired Renal Function-Study Design, Data Analysis, and Impact on Dosing (2020)1, suggests 
that renal impairment studies be conducted in patients with decreased renal function for biologic drugs of 
which the molecular weight is less than 69 kDa, even if the drug or its active metabolite is not primarily 
eliminated by the kidneys. Furthermore, the guideline recommends that a PK study be conducted in subjects 
with renal impairment when the drug is likely to be used in patients with impaired renal function. While 
agency-specific requirements such as methodology for estimated glomerular filtration rate (eGFR) 
assessment differ, European Medicines Agency (EMA) also suggests quite similar guidance.2 
HM15912 with a molecular weight of 57 kDa is intended for use in patients with short bowel syndrome 
(SBS). The prevalence for renal impairment in patients with SBS remain unclear, but recent study reported 
that 28.1% of SBS patients developed renal impairment.3 Therefore, the present study is being conducted to 
evaluate whether renal impairment has an impact on PK of HM15912. Findings from this study will be used 
to develop dosing recommendations so that dose may be adjusted appropriately in the presence of renal 
impairment. 
This study is a staged and parallel-group study of HM15912 in subjects with severe renal impairment (eGFR 
< 30 mL/min/1.73m2) and subjects without renal impairment (eGFR ≥ 90 mL/min/1.73m2) as a control group 
(Part 1) and in subjects with moderate (30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2) and mild (60 
mL/min/1.73m2 ≤ eGFR < 90 mL/min/1.73m2) renal impairment (Part 2), matched for age, body weight and, 
to the extent possible, for gender to control group. The study will follow a staged approach as renal excretion 
is minor for HM15912 based on the results from pre-clinical study. Therefore, it is proposed that effect of 
renal impairment on PK of HM15912 be evaluated first in the population with severe renal impairment. 
If the study results confirm that severe renal impairment does not alter PK to an extent that warrants dosage 
adjustment, no further study is warranted. If the results do not strongly support such a conclusion, Part 2 will 
be conducted in subjects with moderate and mild renal impairment. 


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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Part 1: To evaluate the effect of severe renal 
impairment on the pharmacokinetics of HM15912 
following single SC dose 
• 
Maximum serum concentration (Cmax) 
• 
Area under the concentration-time curve from  
extrapolated to infinity (AUC0-∞) 
Part 2 (if applicable): To evaluate the effect of 
moderate and mild renal impairment on the 
pharmacokinetics of HM15912 following single SC 
dose 
Secondary 
To evaluate the safety and tolerability of a single 
SC dose of HM15912 in subjects between mild, 
moderate and severe renal impairment and normal 
renal function subjects. 
• 
Incidence of adverse events (AEs), treatment-
emergent AEs (TEAEs) and serious AEs 
(SAEs) 
• 
Changes from baseline in vital signs and 
12-lead electrocardiogram (ECG) parameters 
Exploratory 
To assess the immunogenicity of HM15912 after 
single SC dose in subjects with renal impairment 
and normal renal function 
• 
Anti-drug antibody (ADA) 
• 
Neutralizing antibody (NAb) 
• 
Anti-polyethylene glycol (anti-PEG) antibody   
To assess the additional PK parameters of 
HM15912 in subjects with renal impairment and 
normal renal function 
• 
Time to maximum serum concentration (tmax) 
• 
Elimination half-life (t1/2) 
• 
Volume of distribution (Vd/F) 
• 
Clearance (CL/F) 
• 
First order rate constant associated with the 
terminal (log-linear) portion of the curve (λz) 
• 
Area under the concentration-time curve from 
time zero to the last observable concentration 
(AUClast) 
• 
Percentage of AUC0-∞ due to extrapolation 
from Tlast to infinity (AUC%Extrap) 
 


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Methodology:  
This is a Phase 1 non-randomized, open-label, single-dose, parallel-cohort study to investigate the effect of 
renal impairment on the pharmacokinetics of HM15912 after administrating a single 0.5 mg/kg SC dose. 
Subjects will be selected and categorized into normal renal function or renal impairment groups based on 
their eGFR calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(2021). 
 
Part 1: A total of approximately 16 subjects; approximately 8 subjects with severe renal impairment (Cohort 
2) and approximately 8 with normal renal function (Cohort 1) will be enrolled. Cohort 2 will be recruited 
first. The demographics will be pooled across study sites to determine an average value for age and weight. 
Subsequently, the Cohort 1 will be recruited later such that each subject’s age is within ±10 years and weight 
is within ±15 kg of the mean of Cohort 2.  
 
Part 2: Part 2 will be conducted if the point estimate of geometric mean ratio (GMR) of AUC0-∞ for the severe 
renal impairment group (Cohort 2) compared to the control group (Cohort 1) 
 Based on whether the 
decision criterion to proceed to Part 2 is met, up to 8 subjects with moderate renal impairment (Cohort 3) 
and 8 subjects with mild renal impairment (Cohort 4) will be enrolled. 
 
Subject screening for participation in this study will be conducted within 28 days prior to IP dosing on Day 
1. At screening, eGFR will be calculated based on CKD-EPI equation (2021). Two times of blood sample 
will be taken during the screening period that are at least 3 days but no more than 14 days apart. The mean 
of the eGFR obtained from two screening visits will be used for group assignment. All subjects must have 
stable renal function to enter the study which is defined as ≤ 25% difference between 2 measurements of 
eGFR obtained. Investigator and medical monitor should sign off the eligibility check form and the document 
should be submitted to the sponsor before dosing the subject.  
Each subject will receive a single dose of HM15912 administered SC in the abdomen on the Day 1. Blood 
samples will be collected from subjects to determine PK of HM15912 up to 29 days post-dose.  
Subjects will be confined to the Clinical Research Unit (CRU) for PK sampling and safety assessments (as 
specified in the Schedule of Activities) from Day -1 to Day 8. After completion of study procedures on 
Day 2, if subjects request to discharge, they may be discharged from the CRU on their desired date, at the 
discretion of Investigator. If subjects discharge earlier than Day 8 based on the subject’s request, Day 3, 4, 
5, 6, and 7 procedures can be done in outpatient visits. These outpatient visit could be replaced to nurse 
home visit at the discretion of investigator.   
After the inpatient period, outpatient visits will take place on Day 10, 15, 22 and 29 for the collection of 
PK samples and safety assessments. On Day 10, if subject request, outpatient visit could be replaced with 
nurse home visit upon the investigator’s discretion. Day 29 follow up visit will mark the end of study visit. 
Physical examinations, supine 12-lead electrocardiogram (ECG), vital sign measurements, and clinical 
laboratory tests will be conducted and adverse events (AEs) will be monitored throughout the study to 
assess safety.  
Number of Subjects:  
Up to approximately 32 subjects, divided in approximately 4 cohorts with 8 subjects per cohort, are planned 
for enrollment. 
Criteria for Inclusion/ Exclusion: 
Patients eligible for enrolment in the study must meet all of the following criteria: 
Inclusion Criteria 
All subjects 


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1. Subjects voluntarily agree to participate in this study and sign an IRB-approved informed 
consent prior to performing any of the Screening visit procedures. 
2. Males and females ≥ 18 and ≤ 80 years of age at the Screening visit  
3. Body mass index (BMI) of ≥ 17.5 to ≤ 40.0kg/m2; 
4. 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. 
5. 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 contraceptive methods from the Screening visit and for 
a period of 60 days after the dose of IP. Acceptable methods of contraception for males are the 
use of condoms together with spermicidal foam/gel/film/cream/suppository. Effective 
contraceptives for the female partner include: surgical sterilization (e.g., bilateral tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), hormonal 
contraception, intrauterine contraception/device or barrier methods (female condom, 
diaphragm, sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository. 
The adequacy of other methods of contraception will be assessed on a case-by-case basis by 
the Investigator. 
Additional inclusion criteria for subjects with normal renal function (Cohort 1) 
1. No clinically relevant abnormalities identified by a detailed medical history, full physical 
examination, including blood pressure (BP) and heart rate measurement, 12-lead ECG and 
clinical laboratory tests. 
2. Normal renal function (eGFR≥ 90 mL/min/1.73m2) at Screening based on the CKD-EPI 
equation. 
3. Demographically comparable to the group of subjects with impaired renal function. 
3.1. The body weight of each subject will be within ±15kg of the mean body weight of the 
severe renal impairment group (Cohort 2). 
3.2. The age of each subject will be within ±10 years of the mean age of the severe renal 
impairment group (Cohort 2). 
3.3. Attempts will be made to ensure that the male-to-female distribution in Cohort 1 is 
comparable to that in Cohort 2; cohorts cannot comprise entirely of any one gender 
3.4. Other demographic characteristics, such as race and ethnicity, matched as closely as 
possible to the renal impairment cohort  
Additional inclusion criteria for subjects with impaired renal function (Cohort 2, Cohort 3 [if applicable] 
and Cohort 4 [if applicable]) 
1. Good general health commensurate with the population with chronic kidney disease (renal 
impairment). “Health” is defined as no clinically relevant abnormalities identified by a detailed 
medical history, full physical examination, measurement of heart rate and 12-lead ECG as well 
as clinical laboratory tests (except serum creatinine and eGFR). Hypertension, diabetes 
mellitus, hyperparathyroidism, ischemic heart disease and other common co-morbidities in this 
population are possible exemptions, as long as, in the opinion of the investigator, the subject is 
medically stable, is on a stable drug regimen and can abide by the meals and dietary 
restrictions.  
2. Meet the following eGFR criteria during the screening period based on the CKD-EPI equation: 
Severe renal impairment: eGFR < 30 mL/min/1.73m2, but not requiring hemodialysis.  
Moderate renal impairment (Part 2 only): 30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2 


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Mild renal impairment (Part 2 only): 60 mL/min/1.73m2 ≤ eGFR < 90 mL/min/1.73m2 
The difference of eGFR values obtained from the two screening visits (S1 and S2) should not 
be more than 25%. 
3. Any form of renal impairment except acute nephritic syndrome (subjects with history of 
previous nephritic syndrome but in remission can be included). 
4. Stable drug regimen, which means no change in medication within 3 months prior to the dose 
of IP, for the management of individual subject’s medical history; on a case-by-case basis, 
with input from the sponsor and medical monitor; subjects receiving fluctuating concomitant 
medication/treatment may be considered if the underlying disease is under control. 
 
Exclusion Criteria 
All subjects 
Subjects who meet any of the following criteria must not be enrolled in the study: 
1. 
Renal transplant recipients or subjects requiring hemodialysis and peritoneal dialysis 
2. 
Subject with a history or presence of any psychiatric disorder that, in the opinion of the 
Investigator, might confound the results of the study or pose additional risk in administering the 
IP to the subject 
3. 
Has participated in an interventional clinical trial (investigational or marketed product) within 1 
month of screening or 5 half-lives of the drug under investigation (whichever comes first), or 
plans to participate in another clinical trial 
4. 
Subject with a history of any serious adverse events, hypersensitivity reactions, or intolerance to 
IP components 
5. 
Subject who has any clinically significant history of allergic conditions (including drug allergies, 
asthma, eczema, or anaphylactic reactions, but excluding treatment not required, asymptomatic, 
seasonal allergies) prior to IP administration 
6. 
Subject with a history of any major surgery within 6 months prior to the Screening visit 
7. 
Subject with symptomatic heart failure (New York Heart Association class III or IV) 
8. 
Subjects with clinically significant infections within the past 30 days those requiring 
hospitalization, or as judged by the Investigator 
9. 
Evidence of any viral (including COVID-19), bacterial (including upper respiratory infection), or 
fungal (noncutaneous) infection within 1 week prior to the Screening visit 
10. History of known colon polyps (if resected, the subject can be allowed to participate in the study) 
or family history of familial adenomatous polyposis 
11. 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) 
12. Subject with the existence of any surgical or medical condition that, in the judgment of the 
Investigator, might interfere with the absorption, distribution, metabolism or excretion of the IP 
13. Any clinically significant abnormality at screening identified on ECG that in the opinion of the 
investigator would affect the subject’s ability to participate in the trial or cardiac arrhythmia 
requiring any treatment among medical or surgical treatment, device implantation and catheter 
ablation within 6 months prior to screening 
14. Subject who has done a full blood donation within 60 days before the Screening visit, who has 
done apheresis within 1 month before the Screening visit or who has received blood products 
15. Subject who has a history of alcohol, illicit drug or recreational drug abuse as judged by the 
Investigator within 6 weeks prior to the Screening visit 
16. Subject who has a positive urine drug test (e.g., cocaine, amphetamines, barbiturates, opiates, 
benzodiazepines) at the Screening visit or on Day -1, except for prescribed medications as judged 
by the Investigator 
17. 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 CRU 


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18. Subject who is unwilling to abstain from vigorous exercise from 48 hours prior to admission until 
the Follow-up visit 
19. 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 
20. Subject who is deemed by the Investigator to be inappropriate in conducting the clinical study 
 
Additional exclusion criteria for subjects with normal renal function (Cohort 1) 
1. 
Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including 
drug allergies, but excluding treatment not required, asymptomatic, seasonal allergies at the time 
of dosing). 
2. 
Subject who has a mean BP ≥140mmHg (systolic) or ≥90mmHg (diastolic). After at least 5 
minutes of supine rest, measurements will be taken 2 consecutive times, at least 2 minutes apart. 
If mean of the 2 BP is ≥140mmHg (systolic) or ≥90mmHg (diastolic), measurement should be 
repeated 1 more time and the average of the 3 BP values should be used to determine the 
subject’s eligibility. 
3. 
Subject who has a baseline corrected QT interval using the Fridericia formula QTcF >450 msec 
in males or QTcF >470 msec in females 
 
Additional exclusion criteria for subjects with impaired renal function (Cohort 2, Cohort 3 [if 
applicable] and Cohort 4 [if applicable]) 
1. 
Subject with clinically significant active diseases that may affect the safety of the subject or that 
may affect the pharmacokinetics of HM15912 (including drug allergies, but excluding treatment 
not required, asymptomatic, seasonal allergies at time of dosing). Subjects with any significant 
hepatic, cardiac, or pulmonary disease or subjects who are clinically nephrotic. Hypertension, 
diabetes mellitus, hyperparathyroidism, ischemic heart disease, etc. is not cause for exclusion as 
long as the subject is medically stable and any drugs that are administered for these conditions 
are not expected to interfere with the PK of HM15912. 
2. Subject who has a mean BP ≥ 180 mm Hg (systolic) or ≥ 120 mm Hg (diastolic). After at least 
5 minutes of supine rest, measurements will be taken 2 consecutive times at least 2 minutes 
apart. If mean of the 2 BP is ≥ 180mm Hg (systolic) or ≥ 120mmHg (diastolic), the BP should 
be repeated 1 more time and the average of the 3 BP values should be used to determine the 
subject’s eligibility. 
3. Subject who has a baseline corrected QT interval using the Fridericia formula QTcF > 480 
msec 
Test Product, Dose and Mode of Administration: 
HM15912 will be supplied by the Sponsor as a sterile solution in prefilled syringes, manufactured by Hanmi 
Pharm. Co., Ltd. The concentration of HM15912 is 125 mg/mL as protein and the charged volume is 0.55 
mL including 0.05 mL overfill. HM15912 dose will be administered subcutaneously once. 
Duration of Treatment:  
The total duration of the clinical study per subject will be up to approximately 57 days. 
The study will be comprised of: 
• 
Two screening visit up to 28 days before dosing. 
• 
An inpatient assessment period of approximately 9 days, with admission to the CRU on Day -1, 
dosing on Day 1 and discharge in the Day 8 


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• 
Outpatient visit on Day 10, 15, 22 and 29. Day 29 follow up visit will mark the end of study visit 
Statistical Methods:  
The planned sample size of 8 subjects for each cohort is selected to characterize the effect of renal impairment 
on the PK of HM15912 based on FDA and EMA guideline rather than calculated with consideration of 
statistical requirements. With 8 subjects for each cohort (renal impairment cohort and normal renal function 
cohort), half width of two-sided 90% confidence interval of natural log scaled AUC0-∞ difference between 
two cohorts is
 
 
 
PK parameter analyses such as AUC0-∞, AUClast, and Cmax will be conducted for PK population which is 
defined as all subjects who has at least 1 evaluable HM15912 serum concentration after receiving any amount 
of HM15912 without important protocol deviations or events through to significantly affect the PK of study 
drug. PK parameters will be derived by non-compartmental analysis using WinNonlin® or any available 
software.  
After Part 1, PK parameter of HM15912 from severe renal impairment group (Cohort 2) will be estimated 
and compared to control group (Cohort 1). A one-way analysis of variance (ANOVA) will be used to 
compare log transformed PK parameter. The estimates of adjusted mean difference and corresponding 90% 
confidence intervals (CI), as well as each exponentiation of estimates will be presented. After statistical or 
clinical evaluation of results from Part 1, whether to proceed to Part 2 will be further discussed. 
If Part 2 is conducted, same analysis with Part 1 will be implemented to compare of each moderate (Cohort 
3) or mild (Cohort 4) renal impairment subjects and control group (Cohort 1). In case the demographics of 
the moderate or mild renal impairment group compared to the normal renal function group are not within the 
criteria specified in the protocol, it will be considered to add that demographic information as a covariate of 
ANOVA. If needed, further evaluation to characterize the relationship between renal function and PK 
parameter will be explored. 
 
AEs, 12-lead ECG, vital signs, physical examination, and laboratory data will be summarized. Summary of 
AEs will be focused on treatment-emergent adverse events, and clinically significant change of 12-lead ECG, 
vital signs, physical examination, and laboratory data will be reported as AEs as well. 


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1.2. 
Schedule of Assessments 
Table 1. Schedule of Assessments 
Visit 
Screening 
Visita 
Inpatient 
Period 
Outpatient 
Period 
Day 
S1 
S2 
-1 
1 
2 
3e 
4e 
5e 
6e 
7e 
8 
10e 
(±1day) 
15 
(±1day) 
22 
(±1day) 
29m 
(±1day) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR assessmenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data (age, sex, etc.) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heightb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI, Body weightb 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test  
(female subjects with childbearing potential only)c 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and alcohol breath test 
X 
 
X 
 
 
 
 
 
 
 
Xf 
X 
X 
X 
X 
Check-in 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check-outd 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
IP administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
(BP, HR, tympanic body temperature, RR)g 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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ADA = anti-drug antibody; anti-PEG = anti-polyethylene glycol; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; HR=heart rate; IP = 
investigational product; NAb = neutralizing antibody; PK = pharmacokinetics; RR = respiratory rate; SC = subcutaneous;  
 
a. Screening will consist of two CRU outpatient visits (Screening Visit 1 and 2) -between 3 to 14 days apart, with the 1st screening visit occurring within 28 days 
prior to IP administration (Day 1). At each screening visit, blood sample will be taken for the eGFR assessment. The 2nd screening visit is only to demonstrate 
stable renal function with eGFR ≤ 25% of the value obtained at Screening visit 1. Other screening procedures completed during the first visit do not need to be 
repeated except eGFR, adverse event assessment and physical examinations. 
b. 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. BMI will be calculated with the height measured at S1. 
c. Serum pregnancy tests at the Screening visit; serum or urine pregnancy tests at the Day -1 and Day 29. A woman is considered to have childbearing potential, 
following menarche and until becoming post-menopausal unless permanently sterile. 
d. After completion of study procedures on Day 2, if subjects request to discharge, subjects may be discharged from the CRU on their desired date, upon 
investigator’s discretion. If subjects discharge from CRU, all the remaining procedures scheduled for inpatient period will be conducted by outpatient visit or 
nurse home visit as appropriate. 
e. If subjects discharge earlier than Day 8 based on the subject’s request, Day 3, 4, 5, 6, and 7 procedures can be done in outpatient visits. These outpatient visit 
could be replaced to nurse home visit at the discretion of investigator. Nurse home visit may replace outpatient visit on Day 10 as well. Outpatient visit on Day 
8,15,22 and 29 are not replaceable with nurse home visit. 
f. On Day 8, urine drug test and alcohol screening will be performed only if subjects discharge earlier than Day 8. 
Visit 
Screening 
Visita 
Inpatient  
Period 
Outpatient 
Period 
Day 
S1 
S2 
-1 
1 
2 
3e 
4e 
5e 
6e 
7e 
8 
10e 
(±1day) 
15 
(±1day) 
22 
(±1day) 
29m 
(±1day) 
Clinical laboratory tests  
(hematology, coagulation, chemistryh, urinalysis) 
X 
Xi 
X 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
12-lead ECGj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune response assessments  
(ADA, NAb, anti-PEG antibody) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Injection site assessmentsk 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationsl 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK sampling 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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g. Supine BP and HR will be measured for 2 consecutive times, at least 2 minutes apart, after the subject has been recumbent and at rest ≥ 5 minutes, and mean 
values will be recorded. If abnormal, at the Screening visit, measurement will be repeated 1 more time and the average of the 3 BP values should be used to 
determine the subject’s eligibility. 
h. Samples for a chemistry test will be collected after at least 4 hours of fasting.  
i. The 2nd screening visit is only to demonstrate stable renal function with eGFR ≤25% of the value obtained at Screening visit 1. Other clinical laboratory tests 
except serum creatinine assessment, do not need to be repeated. 
j. The 12-lead ECGs will be performed after the subject has been resting supine for ≥ 5 minutes. A triplicate 12-lead ECGs will be performed at screening period 
and Day1. At all other times, however, single 12-lead ECGs will be performed. Limited to Day 1, ECGs will be performed at predose and at 4 hours postdose, 
and a ±30-minute assessment window is allowed for measurement 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. 
k. Injection site assessments will be performed at predose and at 4 and 12 hours postdose on Day 1. 
l. Full physical examination at Screening Visit 1 (S1); brief physical examination at all other time points. 
m. At the early discontinuation visit, every effort must be made to complete the assessments planned at Day 29. 
 
 


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Table 2. Pharmacokinetic Sampling Schedule  
Study Day 
PK Sampling Time Point 
Day 1 
Inpatient 
Period 
Predose 
Day 2a 
24 h (± 15 min) 
Day 3b 
 48 h (± 60 min)  
Day 4b 
72 h (± 60 min) 
Day 5b 
96 h (± 60 min) 
Day 6b 
120 h (± 60 min) 
Day 7b 
144 h (± 60 min) 
Day 8c 
168 h (± 60 min) 
Day 10b 
Outpatient 
Period 
216 h (± 24 h) 
Day 15c 
336 h (± 24 h) 
Day 22c 
504 h (± 24 h) 
Day 29c 
672 h (± 24 h) 
a. After completion of study procedures on Day 2, if subjects request to discharge, subjects may be discharged from the CRU on their desired date, at the 
discretion of investigator If subjects discharge from CRU, all the remaining procedures will be conducted by outpatient visit or nurse home visit as appropriate. 
b. If subjects discharge earlier than Day 8 based on the subject’s request, Day 3, 4, 5, 6, and 7 procedures can be done in outpatient visits. These outpatient visit 
could be replaced to nurse home visit at the discretion of investigator. Nurse home visit may replace outpatient visit on Day 10 as well. 
c. Outpatient visit on Day 8, 15, 22 and 29 are not replaceable with nurse home visit.  
 
 


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1.3. 
Study Schema 
 
Figure 1. Study Schema 
 
Note  
* After completion of study procedures on Day 2, if subjects request to discharge, subjects may be discharged from the CRU on their desired date, at the 
discretion of investigator. If subjects discharge from CRU, all the remaining procedures  will be conducted by outpatient or nurse home visit as appropriate. 
** If subjects discharge earlier than Day 8 and based on the subject’s request, Day 3, 4, 5, 6, and 7 procedures can be done in outpatient visit. These outpatient 
visit could be replaced to nurse home visit at the discretion of investigator. Nurse home visit may replace outpatient visit on Day 10 as well. Outpatient visit on 
Day 8,15,22 and 29 will not be replaced with nurse home visit.


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2. 
Introduction 
HM15912 is a novel long acting chemical conjugate of a glucagon-like peptide 2 (GLP-2) analog 
(GT15912) and a human immunoglobulin (Ig)G4 fragment crystallizable (Fc), linked together 
via a bifunctional maleimide polyethylene glycol aldehyde linker molecule. HM15912 is being 
evaluated for treatment of subjects with short bowel syndrome (SBS). 
2.1. 
Study Rationale  
The primary purpose of this single-dose, open-label study is to characterize the effect of renal 
impairment on the pharmacokinetics of HM15912 in order to guide dosing recommendations in 
patients with renal impairment.  
SBS is defined as the clinical syndrome associated with loss of residual small intestinal length 
due to disease or resection. A residual length of the small intestine < 200 cm meets the criteria 
for SBS.4 The condition which is reduced absorption of nutrients from the gastrointestinal tract 
resulting in the need for parenteral nutrition for survival can be defined as intestinal failure. The 
patients with short bowel syndrome associated intestinal failure (SBS-IF) who requires 
prolonged use of PN/IV may lead to various complications, including sepsis, osteopenia, and 
chronic liver disease.5 In addition, some SBS-IF patients have renal impairment because of long 
term dependence of PN/IV.6,7 Moreover, ischemic bowel disease is one of the important cause of 
SBS-IF and renal ischemia can be easily accompanied with this condition. Though, the 
prevalence and risk factors for renal impairment in patients with SBS still remain unclear, but 
recent study showed that 28.1% of SBS patients developed renal impairment.3 Overall, findings 
from previous studies in SBS patients indicate that a subpopulation of target patients of 
HM15912 have some degree of impaired renal function. 
FDA guideline1 suggests that a PK study should be conducted in subjects with renal impairment 
when the drug is likely to be used in patients with impaired renal function. The guideline also 
recommends that renal impairment studies needs to be conducted in patients with decreased renal 
function for biologic drugs of which the molecular weight is less than 69 kDa, even if the drug or 
its active metabolite is not primarily eliminated by the kidney. Although agency-specific 
requirements such as methodology for eGFR assessment differ, EMA also suggests quite similar 
guidance.2 
To characterize the effect of renal impairment on the pharmacokinetics (PK) of HM15912, a 
pharmacokinetic study was conducted in sham rats and experimental renal failure model rats. 
When rats were treated with HM15912 and then assessed, there were no significant differences 
in PK profile between sham rats and nephrectomized rats. These data indicate that the renal 
pathway might not be the main elimination route of HM15912, and impaired renal function did 
not affect the pharmacokinetic properties of HM15912. Though kidney was not a major 
elimination pathway of HM15912 in the nephrectomized rat model, the molecular weight of 
HM15912 is 57kDa, lower than cut off value for the PK study in renal impairment subjects 
which is suggested by the FDA and around one third of the target population have a potential to 
have impaired renal function. Taken together, the present study is being conducted to evaluate 


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whether renal impairment has an impact on HM15912 PK. Findings from this study will be used 
to develop dosing recommendations so that dose may be adjusted appropriately in the presence 
of renal impairment. 
2.2. 
Background 
GLP-2 is a major hormone that affects many aspects of intestinal physiology such as growth, 
barrier function, digestion, absorption, movement, and blood flow.8 GLP-2 is created by specific 
post translational proteolytic cleavage of proglucagon in a process that also liberates the related 
glucagon-like peptide-1 (GLP-1) from the intestinal endocrine L-cells. Intestinal GLP-2 is co 
secreted along with GLP-1 upon nutrient ingestion and is known to play a critical role in 
intestinal growth by promoting crypt cell proliferation. Because of its intestinal proliferation 
property, GLP-2 analog has long been used to treat people with SBS.8,9,10  
The half-life of native GLP-2 within the human body is very short (approximately 7 minutes), so 
the GLP-2 based 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 complicated preparation processes to administer it to patients.11 
Thus teduglutide cannot resolve inconvenience of daily dosing and error that may occur during 
the preparation process so there are still big unmet needs existed for SBS-IF patients requiring 
long-term PN/IV. 
To overcome the limitations of teduglutide and achieve a better subject quality of life, Hanmi 
Pharmaceutical Co. Ltd. has developed HM15912, a novel long-acting GLP-2 analog chemically 
conjugated, via a bifunctional polyethylene glycol linker, to a recombinant human IgG4 Fc 
fragment (HMC001) to prolong its duration of action. In HM15912, the amino acid sequence of 
the GLP-2 analog moiety is different from teduglutide, rendering a novel structure uniquely 
designed based on human GLP-2. The purpose of this novel design of GT15912 is to achieve a 
more potent activity than teduglutide. Furthermore, conjugation of GT15912 to the Fc domain of 
human IgG4 via a flexible non-peptidyl linker at the C-terminal position extends the half-life of 
GLP-2 analog by promoting neonatal Fc receptor (FcRn) mediated vascular endothelial 
recycling, preventing receptor-mediated clearance, and reducing renal clearance due to the 
increase in molecular weight. 
According to pharmacodynamic (PD) studies, HM15912 dose-dependently induced human GLP 
2 receptor-mediated intracellular cAMP accumulation in hGLP-2R/CHO-K1 cells and stimulated 
IGF-1 production in mouse primary intestinal subepithelial myofibroblasts. The secreted IGF-1 
acted in a paracrine fashion on the tyrosine kinase IGF-1 receptor expressed in the proliferative 
compartment of the crypt. The efficacy of HM15912 has also been demonstrated in in vivo 
studies. Multiple subcutaneous (SC) administrations of HM15912 dose-dependently increased 
intestinal growth, especially the wet weight of the small intestine, showing superior 
intestinotrophic efficacy to teduglutide in normal mice and rats. Furthermore, the intestinal 
growth induced by HM15912 improved nutrition absorption in an SBS rat model, confirming as 
well that the intestinotrophic effects of physical improvement was strongly co-related with 
functional improvement. 


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HM15912 has been evaluated in one clinical study to date. A first–in-human study (HM-GLP2-
101) was a Phase 1 double-blind, randomized, placebo-controlled, single ascending dose (SAD) 
study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the SC 
administration of HM15912 in healthy subjects conducted in Korea. The study was conducted in 
5 sequential dosing cohorts enrolling 8 subjects per cohort. Subjects were randomized to 
HM15912 or placebo in a ratio of 3:1 (active: 6, placebo: 2) and administered 0.05 mg/kg 
(Cohort 1), 0.1 mg/kg (Cohort 2), 0.5 mg/kg (Cohort 3), 1.0 mg/kg (Cohort 4) and 1.5 mg/kg 
(Cohort 5) of HM15912 or matching placebo. Healthy volunteers exposed to single ascending 
doses of HM15912 confirmed a favorable safety profile. Overall, 25 of 40 subjects reported at 
least one treatment emergent adverse event (TEAE) but all of the TEAEs were mild and 
moderate in severity. There have been no serious adverse events (SAEs) and no subjects have 
discontinued study due to adverse events (AEs). Plasma citrulline level, which is a biomarker for 
intestinal enterocyte mass, was measured to assess the PD property. The fasting plasma citrulline 
levels (nmol/mL) gradually increased by HM15912 administration from dose 0.5 mg/kg, and the 
values between 0.5 mg/kg and 1.5 mg/kg tended to be overlapped and saturated. Serum 
concentration of HM15912 reached its peak levels (mean tmax) in 71.8 to 142.9 hours. Mean 
terminal elimination t1/2 of HM15912 was estimated to approximately 108 to 167.4 hours that 
could support a potential for once every 4-week dosing frequency. Based on these results, the 
Sponsor aims to develop HM15912 as a long-acting treatment option for subjects with SBS and 
Phase 2 trial for SBS patients is currently ongoing (NCT04775706, EudraCT: 2021-000176-11). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of HM15912 may be found in the Investigator’s Brochure.  
2.3.1. 
Risk Assessment 
The planned dose of HM15912 for this study is 0.5 mg/kg and it was selected to minimize 
potential risks for both subjects with normal renal function and subjects with renal impairment.  
Experiences with native GLP-2 and teduglutide suggest that expected common AEs for this class 
of compounds include abdominal pain and distension, injection site reactions, nausea, headache, 
upper respiratory tract infection, and (in some studies) vomiting and fluid overload. 
HM15912 has shown no adverse effect on the central nervous system, respiratory function, or 
cardiovascular system in GLP studies. The in vitro acute effects of HM15912 on hERG K+ 
channel current, recorded from stably transfected HEK-293 cells, were evaluated and no effect 
was seen with the maximum concentration of HM15912 tested. In addition, no statistically 
significant increased heart rate was observed in cardiovascular telemetry study in monkeys at 
doses 100 times higher than the expected effective dose. No meaningful or toxicologically 
significant findings were observed in the cardiovascular system. Additionally, there was no 
significant change in body temperature. 
The safety of HM15912 has also been investigated in 26-week GLP toxicology studies (once 
weekly SC administration) in rats and monkeys. The no observed adverse effect levels 


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(NOAELs) were determined at 30 mg/kg for rat and 18 mg/kg for monkey in 26-week 
toxicology studies. The human equivalent dose converted from the animal dose based on body 
surface area is 4.8 mg/kg and 5.8 mg/kg, respectively.  
In 26-week toxicity study in rats, elevation of liver enzymes, particularly, alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), bile acid and fluctuation of plasma lipids parameters 
were observed but these findings were fully resolved during the recovery period. Minimal bile 
duct hypertrophic or hyperplastic response on gastrointestinal(GI) tract were observed in female 
rats, predominantly. 
Additionally, in 26-week toxicity study in monkeys, elevated ALT and high individual bile acid 
and cholesterol and/or triglyceride concentrations were seen transiently in the treated groups, 
with no clear dose response relationship. The association of the occasionally low hematocrit and 
hemoglobin concentrations and the fluctuations in a few leukocytes (mainly lymphocytes, 
monocytes, and occasionally monocytes and basophils) to treatment with HM15912 was 
inconclusive in this study. The administration of HM15912 resulted in diffuse hypertrophy of the 
mucosa in the small intestine of treated animals and correlated with increased length, weight, and 
thickening of the small intestine in monkeys. These treatment-related histopathological changes 
were considered to be an expected pharmacological effect related to HM15912. 
To investigate the effect of renal clearance on the pharmacokinetic properties of HM15912, a 
pharmacokinetic study was conducted in sham and nephrectomized rats. In this study, impaired 
renal function didn’t impact pharmacokinetic properties of HM15912. This finding indicates that 
the renal elimination is not a main pathway in the disposition of HM15912. In other words, if 
HM15912 is administered in the same dose level to subjects with normal renal function and renal 
impaired subjects, there may be no significant differences in exposure. 
In the SAD study, HM-GLP2-101, HM15912 doses of 0.05, 0.1, 0.5, 1.0 and 1.5 mg/kg were 
administered and, all of the TEAEs reported were mild and moderate in severity. Overall, 25 of 
40 subjects reported at least one TEAE in this study. 22 of 40 subjects experienced at least one TEAE 
that were judged by the investigator as suspected of being related to study drug. Most common 
TEAEs were injection site bruising (7/40; 17.5%), nasopharyngitis (3/40; 7.5%) and headache (3/40; 
7.5%). There have been no serious SAEs and no subjects discontinued treatment due to TEAEs. 
Dose-limiting safety finding were not noted in clinical laboratory evaluations, vital signs, blood 
pressure measurements, 12-lead ECG measurements, physical examination, or local tolerability 
assessments. Subcutaneous administration of HM15912 was well tolerated in healthy volunteers at 
dose levels up to and including 1.5 mg/kg. A brief summary of TEAEs was presented in Table 3. 
In the SAD study, two (2) out of 30 (6.7%) HM15912 treated subjects had an anti-drug antibody 
(ADA) response. One (1) subject in the 0.1 mg/kg dose cohort had a treatment-induced ADA 
response on Day 30, that was specific to the Fc domain of HM15912 and cross-reactive to 
endogenous GLP-2. One (1) subject in the 1.0 mg/kg dose cohort had a positive ADA response 
on baseline (pre-existing antibody before treatment), Day 17 and Day 44, but titer was not 
increased at all, not specific to the Fc domain nor the active pharmaceutical portion of 
HM15912, and also not cross-reactive to endogenous GLP-2. None of these ADAs had 
neutralizing activities. Anti-polyethylene glycol (Anti-PEG) antibody assay as a specificity test 


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performed for the samples showed the post-dose titer increase by at least four (4) fold (2 titer 
dilution) compare to the pre-treatment. In this study, there was no subject who showed titer 
increase more than 4 times compared to baseline, so specificity assay did not need to be 
performed based on assessment rationale. 
 
Table 3: Treatment-Emergent Adverse Events Reported to Date in Study HM-GLP2-101 
System Organ Class 
Preferred Term, 
Subject (%) 
HM15912  
0.05mg/kg  
(N=6) 
HM15912  
0.1mg/kg  
(N=6) 
HM15912  
0.5mg/kg  
(N=6) 
HM15912  
1.0mg/kg  
(N=6) 
HM15912  
1.5mg/kg  
(N=6) 
HM15912  
(N=30) 
Placebo  
(N=10) 
All  
(N=40) 
 
 
 
 
 
 
 
 
 
General disorders and 
administration site 
conditions 
0 
0 
1 (16.7%) 
2 (33.3%) 
3 (50.0%) 
6 (20.0%) 
2 
(20.0%) 
8 
(20.0%) 
Injection site 
bruising 
0 
0 
0 
2 (33.3%) 
3 (50.0%) 
5 (16.7%) 
2 
(20.0%) 
7 
(17.5%) 
Pyrexia 
0 
0 
1 (16.7%) 
0 
0 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Investigations 
0 
0 
2 (33.3%) 
1 (16.7%) 
4 (66.7%) 
7 (23.3%) 
1 
(10.0%) 
8 
(20.0%) 
Blood creatine 
phosphokinase 
increased 
0 
0 
1 (16.7%) 
1 (16.7%) 
0 
2 (6.7%) 
0 
2 
(5.0%) 
Blood triglycerides 
increased 
0 
0 
0 
0 
2 (33.3%) 
2 (6.7%) 
0 
2 
(5.0%) 
Neutrophil count 
decreased 
0 
0 
1 (16.7%) 
0 
0 
1 (3.3%) 
1 
(10.0%) 
2 
(5.0%) 
Alanine 
aminotransferase 
increased 
0 
0 
0 
0 
1 (16.7%) 
1 (3.3%) 
0 
1 
(2.5%) 
Aspartate 
aminotransferase 
increased 
0 
0 
0 
1 (16.7%) 
0 
1 (3.3%) 
0 
1 
(2.5%) 
Blood bilirubin 
increased 
0 
0 
0 
0 
1 (16.7%) 
1 (3.3%) 
0 
1 
(2.5%) 
White blood cells 
urine positive 
0 
0 
0 
0 
1 (16.7%) 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Nervous system 
disorders 
2 (33.3%) 
1 (16.7%) 
0 
0 
0 
3 (10.0%) 
2 
(20.0%) 
5 
(12.5%) 
Headache 
2 (33.3%) 
0 
0 
0 
0 
2 (6.7%) 
1 
(10.0%) 
3 
(7.5%) 
Presyncope 
1 (16.7%) 
1 (16.7%) 
0 
0 
0 
2 (6.7%) 
0 
2 
(5.0%) 
Somnolence 
0 
0 
0 
0 
0 
0 
1 
(10.0%) 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
disorders 
0 
0 
0 
3 (50.0%) 
0 
3 (10.0%) 
0 
3 
(7.5%) 
Abdominal pain 
upper 
0 
0 
0 
1 (16.7%) 
0 
1 (3.3%) 
0 
1 
(2.5%) 
Paraesthesia oral 
0 
0 
0 
1 (16.7%) 
0 
1 (3.3%) 
0 
1 
(2.5%) 
Retching 
0 
0 
0 
1 (16.7%) 
0 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 


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System Organ Class 
Preferred Term, 
Subject (%) 
HM15912  
0.05mg/kg  
(N=6) 
HM15912  
0.1mg/kg  
(N=6) 
HM15912  
0.5mg/kg  
(N=6) 
HM15912  
1.0mg/kg  
(N=6) 
HM15912  
1.5mg/kg  
(N=6) 
HM15912  
(N=30) 
Placebo  
(N=10) 
All  
(N=40) 
Infections and 
infestations 
0 
2 (33.3%) 
0 
0 
0 
2 (6.7%) 
1 
(10.0%) 
3 
(7.5%) 
Nasopharyngitis 
0 
2 (33.3%) 
0 
0 
0 
2 (6.7%) 
1 
(10.0%) 
3 
(7.5%) 
Gastroenteritis 
0 
1 (16.7%) 
0 
0 
0 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Musculoskeletal and 
connective tissue 
disorders 
1 (16.7%) 
0 
0 
0 
1 (16.7%) 
2 (6.7%) 
1 
(10.0%) 
3 
(7.5%) 
Back pain 
1 (16.7%) 
0 
0 
0 
0 
1 (3.3%) 
0 
1 
(2.5%) 
Myalgia 
0 
0 
0 
0 
0 
0 
1 
(10.0%) 
1 
(2.5%) 
Pain in extremity 
0 
0 
0 
0 
1 (16.7%) 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Skin and subcutaneous 
tissue disorders 
0 
0 
0 
0 
1 (16.7%) 
1 (3.3%) 
1 
(10.0%) 
2 
(5.0%) 
Fixed eruption 
0 
0 
0 
0 
0 
0 
1 
(10.0%) 
1 
(2.5%) 
Pruritus 
0 
0 
0 
0 
1 (16.7%) 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Metabolism and 
nutrition disorders 
0 
0 
0 
1 (16.7%) 
0 
1 (3.3%) 
0 
1 
(2.5%) 
Decreased appetite 
0 
0 
0 
1 (16.7%) 
0 
1 (3.3%) 
0 
1 
(2.5%) 
 
 
 
 
 
 
 
 
 
Surgical and medical 
procedures 
0 
0 
0 
0 
0 
0 
1 
(10.0%) 
1 
(2.5%) 
Blepharoplasty 
0 
0 
0 
0 
0 
0 
1 
(10.0%) 
1 
(2.5%) 
Taken together, administration of HM15912 dose of 0.5mg/kg will not likely to pose any risks to 
both normal and renal impaired subjects. 
 
Potential risks associated with this study and mitigation strategies are presented in Table 4. 
 
Table 4: Risks and Mitigation Strategies 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Drug (HM15912) 
Overall risk of fatigue, nausea, 
dizziness, polyuria, decreased 
appetite, itching, and redness 
Known pharmacology for drugs of 
this type 
Physical examination will be 
conducted by the investigator with 
every outpatient visit. If adverse 
event was observed, appropriate 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
medical intervention will be 
applied. 
Gastrointestinal side effects: 
Nausea or vomiting, abdominal 
pain or distension and biliary 
effects 
Known pharmacology for drugs of 
this type 
Undergo laboratory assessment 
(total bilirubin, alkaline 
phosphatase, liver tests [AST, ALT, 
GGT], and hematology) at the time 
points as specified in the SoA 
(Section 1.2). Additional time 
points may be added during the 
study period to ensure appropriate 
safety monitoring. 
Risk for acceleration of neoplastic 
growth 
Known pharmacology for drugs of 
this type 
Considering the nature of the polyp 
development, single dosing of 
HM15912 contains the minimal 
risk of adenoma hyperplasia.  
Upper respiratory tract infections 
and headache 
Known pharmacology for drugs of 
this type 
Monitor the subject closely for 
these events and treat per local 
standard of care 
Study Procedures 
Injection site reaction 
 
The most frequently reported 
symptoms were itching and 
redness. The reactions were dose 
dependent, mild to moderate in 
severity and transient in nature. 
Monitor the subject closely for 
these events and treat per local 
standard of care 
Electrocardiograms 
Minor skin irritation from the 
electrodes 
Monitor the subject closely for 
these events and treat per local 
standard of care 
Peripheral access for blood draws 
Tenderness, pain, bruising, bleeding 
and/or infection where the needle 
goes into the skin and blood vein as 
well as light-headedness and nausea 
Monitor the subject closely for 
these events and treat per local 
standard of care 


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2.3.2. Benefit Assessment 
There will be no direct health benefit for subjects from receipt of the investigational product (IP). 
Participation in this study will contribute to the process of developing new therapies in areas of 
growing unmet need. 
2.3.3. Overall Benefit: Risk Conclusion 
The protocol has been designed to minimize the risk to research subjects by careful selection of 
dose and subjects for the study. Subjects will be monitored to detect AEs during the study and 
followed appropriately to ensure resolution of AEs.


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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Part 1: To evaluate the effect of severe renal impairment 
on the pharmacokinetics of HM15912 following single 
SC dose 
• 
Maximum serum concentration (Cmax) 
• 
Area under the concentration-time extrapolated to 
infinity (AUC0-∞) 
Part 2 (if applicable): To evaluate the effect of moderate 
and mild renal impairment on the pharmacokinetics of 
HM15912 following single SC dose 
Secondary 
To evaluate the safety and tolerability of a single SC dose 
of HM15912 in subjects between mild, moderate and 
severe renal impairment and normal renal function 
subjects. 
• 
Incidence of adverse events (AEs), treatment 
emergent AEs (TEAEs) and serious AEs (SAEs) 
• 
Changes from baseline in vital signs and 12-lead 
electrocardiogram (ECG) parameters 
Exploratory 
To assess the immunogenicity of HM15912 after single 
SC dose in subjects with renal impairment and in  subjects 
with normal renal function 
• 
Anti-drug antibody (ADA) 
• 
Neutralizing antibody (NAb) 
• 
Anti-polyethylene glycol (anti-PEG) antibody 
To assess the additional PK parameters of HM15912 in 
subjects with renal impairment and in subjects with 
normal renal function 
• 
Time to maximum serum concentration (tmax) 
• 
Elimination half-life (t1/2) 
• 
Volume of distribution (Vd/F) 
• 
Clearance (CL/F) 
• 
First order rate constant associated with the terminal 
(log-linear) portion of the curve (λz)  
• 
Area under the concentration-time curve from time 
zero to the last observable concentration (AUClast) 
• 
Percentage of AUC0-∞ due to extrapolation from Tlast 
to infinity (AUC%Extrap) 
 


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4. 
Study Design 
4.1. 
Overall Design 
This study is a phase 1, open-label, single-dose, parallel-group study to investigate the effect of 
renal impairment on the pharmacokinetics of HM15912 in subjects with severe renal impairment 
and subjects without renal impairment as a control group (Part 1), and in subjects with moderate 
and mild renal impairment (Part 2). 
At Screening, subjects will be enrolled to the appropriate groups based on the classification as 
defined in the Food and Drug Administration (FDA) draft guidance for industry, 
“Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and 
Impact on Dosing and Labeling” (2020).1 Subjects with normal renal function and subjects with 
renal impairment will be classified based on the estimated glomerular filtration rate (eGFR) 
calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(2021).  
• 
eGFR(mL/min/1.73m2) = 142 x min (Scr/κ, 1)α x max (Scr/κ, 1)-1.200 x 0.9938Age x 1.012 
[if female] 
where: Scr = serum creatinine in mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.241 (female) or -0.302 (male) 
min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 
max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 
Age (years) 
Subject screening for participation in this study will be conducted within 28 days prior to IP 
dosing on Day 1. The mean of the eGFR obtained from two screening visits will be used for 
group assignment. Second baseline eGFR sample will be taken during the screening period, that 
are at least 3 days but no more than 14 days apart from the first eGFR assessment. All subjects 
must have stable renal function to enter the study which is defined as ≤ 25% difference between 
2 measurements of eGFR during the screening period. Subjects will be selected and categorized 
according to their eGFR as shown in Table 5. Investigator and medical monitor should sign off 
the eligibility check form and the document should be submitted to the sponsor before dosing the 
subject. 
Table 5. Renal Function Categories by eGFR ranges 
Cohort 
Renal Impairment 
eGFR 
(mL/min/1.73m2) 
Number of Subjects 
1 
Normal 
≥ 90 
8 
2 
Severe 
< 30 
8 


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3 
Moderate 
≥ 30 to < 60 
8 
4 
Mild 
≥ 60 to < 90 
8 
Approximately 16 subjects will be enrolled in Part 1; 8 subjects with severe renal impairment 
(Cohort 2) and approximately 8 with normal renal function (Cohort 1). The 8 subjects of Cohort 
2 will be recruited first. After the end of recruitment of Cohort 2, the demographics will be 
pooled to determine an average value for age and weight which will be used as a reference value 
for Cohort 1. The subjects with normal renal function in Cohort 1 will be recruited later such that 
each subject’s age is within ±10 years and weight is within ±15 kg of the mean of the Cohort 2. 
An attempt will be made to maintain a similar male/female ratio between Cohort 1 and Cohort 2. 
Care will be taken when recruiting the subjects with normal renal function such that the entire 
group is not younger and of lower body weight than the impaired subjects.  
Part 2 will be conducted if the point estimate of geometric mean ratio (GMR) of AUC0-∞ for the 
severe renal impairment group (Cohort 2) compared to the control group (Cohort 1) 
 
Based on whether the decision criterion to proceed to Part 2 is met, up to 8 subjects with 
moderate renal impairment (Cohort 3) and 8 subjects with mild renal impairment (Cohort 4), 
matched for demographic character to control group will be enrolled.  
For both Parts 1 and 2, subjects who withdraw from the study for non-safety related reasons and 
who are considered to be non-evaluable with respect to the primary objective may be replaced at 
the discretion of the sponsor but the maximum number of meaningfully evaluable patients will 
be not more than planned 8. 
Each subject will receive a single dose of either HM15912 administered SC in the abdomen on 
the Day 1. Blood samples will be collected from subjects to determine PK of HM15912 up to 29 
days post-dose.  
Subjects will be confined to the unit PK sampling and safety assessments (as specified in the 
Table 2). Inpatient period will be approximately 8 days, with admission to the Clinical Research 
Unit (CRU) on Day -1, dosing on Day 1 and discharge in the Day 8. After completion of study 
procedures on Day 2, if subjects request to discharge, they may be discharged from the CRU, on 
their desired date, at the discretion of Investigator. If subjects discharge earlier than Day 8 and 
based on the subject’s request, Day 3, 4, 5, 6, and 7 procedures can be done in outpatient visit. 
These outpatient visit could be replaced to nurse home visit at the discretion of investigator. 
After the inpatient period, outpatient visits will take place on Day 10, 15, 22 and 29 for the 
collection of PK samples and safety assessments. On Day 10, if subjects request, outpatient visit 
could be replaced with nurse home visit upon the investigator’s discretion. Day 29 follow up 
visit will mark the end of study visit. 
Physical examinations, supine 12-lead electrocardiogram (ECG), vital sign measurements, and 
clinical laboratory tests will be conducted and AEs will be monitored throughout the study to 
assess safety.  


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4.2. 
Scientific Rationale for Study Design 
This study is designed to evaluate the PK of HM15912 in subjects with renal impairment, based 
on recommendations given in the FDA draft guidance1 for industry. Pharmacokinetic studies of 
investigational products intended for chronic use and with a molecular weight less than 69 kDa 
are recommended by global regulatory agencies. The molecular weight of HM15912 is 
approximately 57 kDa, and a subset of the target population may have renal impairment. As a 
result, the present study is being conducted to determine whether renal impairment affects 
HM15912 PK. The findings from this study will be used to develop dosing recommendations for 
patients with renal impairment.  
When the drug is substantially eliminated by the kidney (ie, if the fraction of dose excreted 
unchanged in the urine is at least 30%), a dedicated renal impairment study is recommended. The 
full pharmacokinetic study design of renal function is to include subjects with varying degrees of 
renal impairment, including mild, moderate and severe impairment, with corresponding matched 
control subjects. However, if renal elimination is a minor route of elimination of the drug, then a 
reduced study design which includes only severe impairment and matched control subjects is 
warranted for consideration. To investigate the effect of renal clearance on the pharmacokinetic 
properties of HM15912, a pharmacokinetic study was conducted in male sham and 
nephrectomized rats. In this study, impaired renal function didn’t impact pharmacokinetic 
properties of HM15912. These data indicate that the renal pathway might not be the main 
elimination route of HM15912, and impaired renal function did not affect the pharmacokinetic 
properties of HM15912. Overall, these results indicate that a full PK study design as outlined by 
FDA and the European Medicines Agency (EMA) guidances1,2 on studies with subjects with 
renal impairment is not warranted, and a reduced design can be applied. Therefore, the proposed 
study will assess the effect of HM15912 only in subjects with severe renal function and 
demographically matched subjects with normal renal function. If the study results confirm that 
severe renal impairment does not alter PK to an extent that warrants dosage adjustment, no 
further study is warranted. If the results do not strongly support such a conclusion, Part 2 will be 
conducted in subjects with mild and moderate renal impairment. 
4.3. 
Justification for Dose 
The planned dose of HM15912 for this study is 0.5 mg/kg. In the first in human SAD study 
(HM-GLP2-101) with healthy subjects, HM15912 doses of 0.05, 0.1, 0.5, 1.0 and 1.5 mg/kg 
were investigated. Safety results of doses up to 1.5 mg/kg suggested that HM15912 was safe and 
well-tolerated and no dose-limiting safety findings were noted during the Phase 1 study. This 
dose selection also takes into account safety considerations for subjects with severe renal 
impairment in whom an increase in exposure of HM15912 may be observed. In study HM-
GLP2-101, 0.5mg/kg doses of HM15912 led to Cmax of 3,740 ng/ml and AUC0-∞ of 1,237,890 
ng∙h/ml. 1.5mg/kg doses of HM15912 led to Cmax of 9,463 ng/ml and AUC0-∞ of 3,609,894 
ng∙h/ml. GMR of AUC0-∞ for the dose 1.5mg/kg to dose of 0.5mg/kg, the ratio was 
approximately 3.0 and the ratio of Cmax was 2.5. Thus, based on the safety data of prior study, 
with the single dose of 0.5 mg/kg, exposure increases up to 2.5 fold if observed, will not likely to 
pose any safety risks. 


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HM15912 is currently undergoing evaluation in clinical trials with SBS patients; therefore, the 
clinical dose has not yet been established. However, in the SAD study, dose of 0.5 mg/kg was 
sufficient to increase intestinal enterocyte mass. The fasting plasma citrulline levels which is a 
biomarker for intestinal enterocyte mass, increased from dose 0.5 mg/kg, and the values between 
0.5 mg/kg and 1.5 mg/kg tended to be overlapped and saturated. Thus, 0.5 mg/kg dose is selected 
for this study on the grounds that it is minimum effective dose and close to the clinical dose so as 
to enable prediction of pharmacokinetic at the clinical dose. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all periods of the 
study including the last scheduled procedure shown in the Schedule of Activities. The end of the 
study is defined as the date of the last visit of the last subject in the study or last scheduled 
procedure for the last subject in the trial globally. 
4.5. 
Study Termination 
Monitoring of subject safety data will be performed by the sponsor and medical monitor. Study 
conduct may be interrupted or terminated by the sponsor at any time if there appears to be an 
undue risk to the study subjects’ health or well-being after a thorough review of all clinical, 
laboratory, PK, and other available safety data.  
 


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Subjects who meet all the following criteria at screening will be eligible to participate in the 
clinical study. Note: Subjects not eligible because of laboratory result(s) may have the laboratory 
test(s) (hematology, clinical chemistry including liver function tests, and ECG) repeated once 
during the screening period at the discretion of the investigator to determine eligibility. 
5.1.1. 
All Subjects  
1. Subjects voluntarily agree to participate in this study and sign an IRB-approved informed 
consent prior to performing any of the Screening visit procedures. 
2. Males and females ≥ 18 and ≤ 80 years of age at the Screening visit  
3. Body mass index (BMI) of ≥17.5 to ≤40.0kg/m2 
4. 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. 
5. 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 contraceptive methods from the 
Screening visit and for a period of 60 days after the dose of IP. Acceptable methods of 
contraception for males are the use of condoms together with spermicidal 
foam/gel/film/cream/suppository. Effective contraceptives for the female partner include: 
surgical sterilization (e.g., bilateral tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy), hormonal contraception, intrauterine 
contraception/device or barrier methods (female condom, diaphragm, sponge, cervical 
cap) together with spermicidal foam/gel/film/cream/suppository. The adequacy of other 
methods of contraception will be assessed on a case-by-case basis by the Principal 
Investigator. 
5.1.2. 
Additional Inclusion Criteria for Subjects with Normal Renal Function (Cohort 
1) 
1. No clinically relevant abnormalities identified by a detailed medical history, full physical 
examination, including BP and heart rate measurement, 12 -lead ECG and clinical 
laboratory tests.  
2. Normal renal function (eGFR ≥ 90 mL/min/1.73m2) at Screening based on the CKD-EPI 
equation.  
3. Demographically comparable to the group of subjects with impaired renal function. 


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A. The body weight of each subject will be within ±15kg of the mean body weight of 
the severe renal impairment group (Cohort 2). 
B. The age of each subject will be within ±10 years of the mean age of the severe renal 
impairment group (Cohort 2). 
C. Attempts will be made to ensure that the male-to-female distribution in Cohort 1 is 
comparable to that in Cohort 2; cohorts cannot comprise entirely of any one gender 
D. Other demographic characteristics, such as race and ethnicity, matched as closely as 
possible to the renal impairment cohort 
5.1.3. 
Additional Inclusion Criteria for Subjects with Impaired Renal Function 
(Cohort 2, Cohort 3 [if applicable] and Cohort 4 [if applicable]) 
1. Good general health commensurate with the population with chronic kidney disease 
(renal impairment). “Health” is defined as no clinically relevant abnormalities identified 
by a detailed medical history, full physical examination, measurement of heart rate and 
12-lead ECG as well as clinical laboratory tests (except serum creatinine and eGFR). 
Hypertension, diabetes mellitus, hyperparathyroidism, ischemic heart disease and other 
common co-morbidities in this population are possible exemptions, as long as, in the 
opinion of the investigator, the subject is medically stable, is on a stable drug regimen 
and can abide by the meals and dietary restrictions. 
2. Meet the following eGFR criteria during the screening period based on the CKD-EPI 
equation: 
A. Severe renal impairment: eGFR < 30 mL/min/1.73m2, but not requiring 
hemodialysis. 
B. Moderate renal impairment (Part 2 only): 30 mL/min/1.73m2 ≤ eGFR < 60 
mL/min/1.73m2 
C. Mild renal impairment (Part 2 only): 60 mL/min/1.73m2 ≤ eGFR < 90 
mL/min/1.73m2 
D. The difference of eGFR values obtained from the two screening visits should not be 
more than 25% 
3. Any form of renal impairment except acute nephritic syndrome (subjects with history of 
previous nephritic syndrome but in remission can be included). 
4. Stable drug regimen, which means no change in medication within 3 months prior to the 
dose of IP, for the management of individual subject’s medical history; on a case-by-case 
basis, with input from the sponsor and medical monitor; subjects receiving fluctuating 
concomitant medication/treatment may be considered if the underlying disease is under 
control. 
5.2. 
Exclusion Criteria  
Subjects who meet any of the following criteria will not be eligible to participate in the study: 


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5.2.1. 
All Subjects 
1. Renal transplant recipients or subjects requiring hemodialysis and peritoneal dialysis 
2. Subject with a history or presence of any psychiatric disorder that, in the opinion of the 
Investigator, might confound the results of the study or pose additional risk in 
administering the IP to the subject 
3. Has participated in an interventional clinical trial (investigational or marketed product) 
within 1 month of screening or 5 half-lives of the drug under investigation (whichever 
comes first), or plans to participate in another clinical trial 
4. Subject with a history of any serious adverse events, hypersensitivity reactions, or 
intolerance to IP components 
5. Subject who has any clinically significant history of allergic conditions (including drug 
allergies, asthma, eczema, or anaphylactic reactions, but excluding treatment not 
required, asymptomatic, seasonal allergies) prior to IP administration 
6. Subject with a history of any major surgery within 6 months prior to the Screening visit 
7. Subject with symptomatic heart failure (New York Heart Association class III or IV)) 
8. Subjects with clinically significant infections within the past 30 days those requiring 
hospitalization, or as judged by the Investigator 
9. Evidence of any viral (including COVID-19), bacterial (including upper respiratory 
infection), or fungal (noncutaneous) infection within 1 week prior to the Screening visit 
10. History of known colon polyps (if resected, the subject can be allowed to participate in 
the study) or family history of familial adenomatous polyposis 
11. 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) 
12. Subject with the existence of any surgical or medical condition that, in the judgment of 
the Investigator, might interfere with the absorption, distribution, metabolism or 
excretion of the IP 
13. Any clinically significant abnormality at screening identified on ECG that in the opinion 
of the investigator would affect the subject’s ability to participate in the trial or cardiac 
arrhythmia requiring any treatment among medical or surgical treatment, device 
implantation and catheter ablation within 6 months prior to screening 
14. Subject who has done a full blood donation within 60 days before the Screening visit, 
who has done apheresis within 1 month before the Screening visit or who has received 
blood products 
15. Subject who has a history of alcohol, illicit drug or recreational drug abuse as judged by 
the Investigator within 6 weeks prior to the Screening visit 
16. Subject who has a positive urine drug test (e.g., cocaine, amphetamines, barbiturates, 
opiates, benzodiazepines, cannabinoids) at the Screening visit or on Day -1, except for 
prescribed medications as judged by the Investigator 


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17. 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 CRU 
18. Subject who is unwilling to abstain from vigorous exercise from 48 hours prior to 
admission until the Follow-up visit 
19. 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 
20. Subject who is deemed by the Investigator to be inappropriate in conducting the clinical 
study 
5.2.2. 
Additional exclusion Criteria for Subjects with Normal Renal Function (Cohort 
1) 
1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease 
(including drug allergies, but excluding treatment not required, asymptomatic, seasonal 
allergies at the time of dosing). 
2. Subject who has a mean BP ≥ 140mmHg (systolic) or ≥ 90mmHg (diastolic). After at 
least 5 minutes of supine rest, measurements will be taken for 2 consecutive times at 
least 2 minutes apart. If mean of the 2 BP is ≥ 140mmHg (systolic) or ≥ 90mmHg 
(diastolic), the BP should be repeated 1 more time and the average of the 3 BP values 
should be used to determine the subject’s eligibility. 
3.  Subject who has a baseline corrected QT interval using the Fridericia formula QTcF 
>450 msec in males or QTcF > 470 msec in females 
5.2.3. 
Additional Exclusion Criteria for Subjects with Impaired Renal Function 
(Cohort 2, Cohort 3 [if applicable] and Cohort 4 [if applicable]) 
1. Subject with clinically significant active diseases that may affect the safety of the subject 
or that may affect the pharmacokinetics of HM15912 (including drug allergies, but 
excluding treatment not required, asymptomatic, seasonal allergies at time of dosing). 
Subjects with any significant hepatic, cardiac, or pulmonary disease or subjects who are 
clinically nephrotic. Hypertension, diabetes mellitus, hyperparathyroidism, ischemic 
heart disease, etc. is not cause for exclusion as long as the subject is medically stable and 
any drugs that are administered for these conditions are not expected to interfere with the 
PK of HM15912. 
2. Subject who has a mean BP ≥ 180 mm Hg (systolic) or ≥ 120 mm Hg (diastolic) After at 
least 5minutes of supine rest, measurements will be taken for 2 consecutive times at least 
2 minutes apart. If mean of the 2 BP is ≥ 180mm Hg (systolic) or ≥ 120mmHg 


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(diastolic), the BP should be repeated 1 more time and the average of the 3 BP values 
should be used to determine the subject’s eligibility. 
3.  Subject who has a baseline corrected QT interval using the Fridericia formula QTcF > 
480 msec 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
1. Abstain from all food and drink (except water) at least 4 hours prior to any safety 
laboratory evaluations. 
2. Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before the 
start of study intervention until after the final dose. 
3. Water consumption will also be limited for 1 hour before dosing and for approximately 2 
hours after dosing, after which time, water is allowed ad libitum. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
1. Abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola 
drinks, and chocolate) for 24 hours before the start of dosing until after collection of the 
final PK and/or PD sample. 
2. Abstain from alcohol for 24 hours before the start of dosing until after collection of the 
final PK and/or PD sample. 
3. Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
unit. 
5.3.3. 
Activity 
Subjects will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Subjects should refrain from unusual physical training before 
participating in the study and maintain usual lifestyle during study participation. 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., 
watching television, reading). 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 


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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. If a subject does not meet all inclusion criteria or meets one or more exclusion 
criterion, the subject may rescreen for the study once after discussion with the investigator and 
medical monitor. In the event that the subject is rescreened, a new informed consent form (ICF) 
must be signed, a new screening number assigned, and all screening procedures repeated. 


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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
medical device(s) intended to be administered to a study subject according to the study protocol. 
6.1. 
Study Drug Administered 
The study drug HM15912 is a chemical conjugate of a GLP-2 analog and a human IgG4 Fc 
fragment linked via a flexible bifunctional polyethylene glycol linker. Details of investigational 
product are provided in Table 6. 
Table 6. Study Drug (HM15912) 
Investigational 
Product 
HM15912 
Type 
Drug 
Dose 
Formulation 
Injection 
Identity of 
Study Drug 
HM15912 will be provided as a sterile, clear, and colorless solution and free 
of visible particles in prefilled syringe (PFS). The concentration of HM15912 
is 125 mg/mL as protein and the charged volume is 0.55 mL including 0.05 
mL overfill. The needle is covered with a needle shield. 
Dosage 
Level(s) 
0.5mg/kg, once 
Route of 
Administration Subcutaneous 
Site of 
Administration Abdominal wall 
Use 
Experimental 
Sourcing 
HM15912 will be manufactured and supplied by Hanmi Pharm. Co., Ltd. The 
sponsor should pack the study drug so that it is not contaminated or 
deteriorated during transportation or storage. 
Packaging and 
Labeling 
The study drug will be labeled and packaged according to local legal 
requirement and applicable health authority requirements.  


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6.2. 
Preparation/Handling/Storage/Accountability 
1. All supplies of study drug 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 the 
carton until ready for use). Avoid shaking HM15912 syringes during storage and 
handling. The instructions of how to proceed in case temperature deviations are observed 
(i.e., excursions above or below the allowed temperature range) are provided in the 
Pharmacy Manual. 
2. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
3. Only subjects enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff. 
4. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
5. Further guidance and information for the destruction and final disposition of unused 
study interventions are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. 
6.4. 
Study Drug Compliance 
Subjects will be administered study drug at the study center by the investigator or trained, 
qualified personnel designated by the principal investigator, under medical supervision at a 
scheduled timepoint. The date and time of the dose administered will be recorded in the source 
documents and recorded in the electronic case report form (eCRF). Deviation from the 
prescribed dosage regimen or planned dosing procedures should be recorded in the eCRF.  
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the subject is receiving at 
the time of enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose, frequency and route of administration  


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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Subjects must abstain from taking prescription or nonprescription drugs (including vitamins and 
dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the study drug administration until Day 29, 
unless, in the opinion of the investigator and sponsor, the medication will not interfere with the 
study. 
Since the mechanism of action of study drug may increase absorption of orally administered 
drugs (e.g., motility medications, warfarin, benzodiazepines, phenothiazines, and thyroid 
medications), consideration is advised when modifying concomitant oral medication regimens. 
Down-titration of concomitant medications should be considered when drugs, including those 
with a narrow therapeutic range or those requiring titration, are given at dosages that are higher 
than usual. Investigators should monitor all subjects carefully, since some of them have not 
previously been treated with a GLP-2 analog. 
The GLP-1, other GLP-2 analogs (teduglutide or similar drug), and DPP-4 inhibitors are not 
allowed to be used by the subjects during the course of the study. Other concomitant medication 
may be considered on a case-by-case basis by the Investigator in consultation with the Medical 
Monitor if required. 
6.5.1. 
Subjects with Normal Renal Function (Cohort 1) 
In general, subjects will abstain from all concomitant treatments (prescription or over-the-
counter [OTC] medications) as described in the Exclusion Criteria section of the protocol, except 
for the treatment of AEs.  
Limited use of nonprescription medications that are not believed to affect subject safety or the 
overall results of the study may be permitted on a case-by-case basis after approval by the 
sponsor or medical monitor.  
6.5.2. 
Subjects with Impaired Renal Function (Cohort 2, Cohort 3 [if applicable] and 
Cohort 4 [if applicable]) 
Subjects are permitted to be on stable doses of background medications (including herbal 
supplements) if they are considered necessary for the welfare of the study subjects (i.e., standard 
therapy for the underlying disease), are not contraindicated with the study drug and are unlikely 
to interfere with the PK of the study drug. Whenever possible, attempts must be made to not alter 
the doses and regimens of the concomitant medications after Day 1 and until the end of study. 
6.6. 
Intervention After the End of the Study 
No interventions are planned after the end of the study. 


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7. 
Discontinuation of Study Intervention and Subject 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a subject to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the subject 
will remain in the study to be evaluated for AEs. See the Schedule of assessments (SoA) (Section 
1.2) for data to be collected at the time of discontinuation of study intervention and follow-up 
and for any further evaluations that need to be completed. 
As any new study drug may have unexpected AEs, the following potential toxicities for 
HM15912 should be considered while making a decision to put the study drug on temporary hold 
or permanently discontinue. The details on grading and management for these toxicities are 
provided in Appendix 5.  
• 
cardiovascular toxicity 
• 
rash/inflammatory dermatitis and other skin disorders 
• 
liver toxicity 
• 
gastrointestinal events 
Other reasons for discontinuation of study drug include the following: 
• 
subject request 
• 
safety concern 
• 
pregnancy  
• 
lost to follow up 
• 
death 
• 
decision by sponsor or investigator 
• 
protocol-specified criteria 
7.2. 
Subject Discontinuation/Withdrawal from the Study 
• 
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.2). See SoA (Section 1.2) for data 
to be collected at the time of study discontinuation and for any further evaluations that 
need to be completed. 


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• 
At the early discontinuation visit, every effort must be made to complete scheduled 
assessments. However, lack of completion of all or any of the early 
discontinuation/withdrawal procedures will not be viewed as protocol deviations so 
long as the subject’s safety was preserved. 
• 
The subject will be permanently discontinued both from the study intervention and from 
the study at that time. 
• 
If the subject withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Study Subject Replacement 
• 
For both Parts 1 and 2, subjects who withdraw from the study for non-safety related 
reasons and who are considered to be non-evaluable with respect to the primary 
objective may be replaced at the discretion of the sponsor but the maximum number of 
meaningfully evaluable patients will be not more than planned 8. 
7.4. 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• 
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8. 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the SoA (Section 1.2). Protocol 
waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with medical monitor or the sponsor 
immediately upon occurrence or awareness to determine if the subject should continue 
or discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.2), is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Section 1.2). 
• 
The maximum amount of blood collected from each subject over the duration of the 
study will be in line with local regulations. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples. 
8.1. 
Efficacy Assessments 
Efficacy is not assessed in this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.2). All 
clinically significant abnormalities from the safety assessments will be recorded as AEs. 
8.2.1. 
Physical Examinations 
• 
A full physical examination will include, at a minimum, assessments of general 
appearance Skin, Head, Ears, Eyes, Nose and throat, Cardiovascular, Respiratory, 
Gastrointestinal and Neurological, Lymph nodes, Extremities, Musculoskeletal and 
Psychiatric systems.  
• 
A brief physical examination will include, at a minimum, assessments of the skin, 
respiratory, cardiovascular system, and abdomen (liver and spleen). 
• 
Height, Weight and BMI will also be measured according to the SoA (Section 1.2). And 
BMI will be calculated using Height assessed at the screening. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 


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8.2.2. 
Vital Signs 
• 
Tympanic body temperature, heart rate, respiratory rate, and blood pressure will be 
assessed. 
• 
Blood pressure and heart rate will be measured after the subject has been lying down or 
sitting to rest for ≥ 5 minutes in a quiet setting without distractions. Blood pressure and 
heart rate will be measured at 2 consecutive times at least 2 minutes apart. Each 
measurement and the mean value will be recorded on the eCRF. Completely automated 
devices will be used. Manual techniques will be used only if an automated device is not 
available. 
8.2.3. 
Electrocardiograms 
• 
A 12 lead ECG will be obtained at scheduled timepoints in the SoA (Section 1.2) using 
an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and 
QTc intervals. Additional ECGs will be performed for cause as needed to evaluate AEs. 
• 
The 12-lead ECGs will be performed after the subject has been resting supine for ≥ 5 
minutes. 
• 
A triplicate 12-lead ECGs will be performed at screening period and Day1. At all other 
times, however, single 12-lead ECGs will be performed as outlined in the SoA (Section 
1.2). 
• 
Limited to Day 1, ECGs will be performed at predose and at 4 hours postdose, and a 
±30-minute assessment window is allowed for measurement 4 hours postdose. 
• 
The 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. 
• 
Investigator’s assessment of clinical significance (‘abnormal, not clinically significant’ 
or ‘abnormal, clinically significant’) will be recorded in the eCRF. Centralized ECG 
vendor will be used for ECG measurement and independent reading. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.2) for the timing and frequency. Blood sample collection, processing, and 
shipping details will be outlined in a separate laboratory manual. 
• 
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the subject's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or up to last follow-up visit should be repeated until the values 


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return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.2). 
o If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE), then the results 
must be recorded as narration in the eCRF. 
8.2.5. 
Injection Site Assessment 
Injection site assessments will be performed at the timepoints specified in the SoA (Section 1.2).  
• After administration of study drug, the injection site will be marked with a pen. The local 
reaction from the injection site will be evaluated quantitatively using a Draize scale or 
similar scale. If an injection site reaction like pain on palpation, itching, erythema, edema, 
induration is observed, it must be recorded as an AE. 
• Erythema will be evaluated as follows: 
o 0 – no erythema 
o 1 – very slight erythema (barely perceptible) 
o 2 – well-defined erythema 
o 3 – moderate-to-severe erythema 
o 4 – severe erythema (beet redness) to slight eschar formations (injuries in depth) 
• Edema will be evaluated as follows: 
o 0 – no edema  
o 1 – very slight edema (barely perceptible) 
o 2 – slight edema (edges of area well defined by definite raising) 
o 3 – moderate edema (raised approximately 1 mm)  
o 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. The diameter 
of the affected area will be measured with a paper measuring tape in centimeters and the 
condition of the injection site will be recorded. Digital photography will be used to 
document all positive injection site reactions.  


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• 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. 
8.3. 
Adverse Events and Serious Adverse Events 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the subject to discontinue the study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AE and SAEs will be collected from the signing of the ICF until the last visit at the time 
points specified in the SoA (Section 1.2). 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study drug or study participation, the investigator must promptly notify the 
sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in Section 8.3.7), 
will be followed until resolution, stabilization, the event is otherwise explained, or the subject is 
lost to follow-up (as defined in Section 7.4). Further information on follow-up procedures is 
provided in Appendix 10.3. 
The Investigator must record follow-up information. Follow-up information is reported in the 
eCRF as with initial AE/SAEs. Follow-up questions to Investigators regarding SAEs are queried 
directly to the Investigator. 


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Follow-up information must be reported according to the following: 
• SAEs: All SAEs must be followed until the outcome of the events is 
“recovered/resolved”, “recovered/resolved with sequelae”, or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer, or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the subject has completed the follow-up period 
and is expected by the Investigator to recover. 
The SAE follow-up information should only include new (e.g., corrections or additional) 
information and must be reported within 24 hours of receipt of the information. This is also the 
case for previously non-serious AEs which subsequently become SAEs. 
• Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved”, or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer, or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome of “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when subject has completed 
the follow-up period and is expected by the Investigator to recover. 
If a potential hypersensitivity reaction is observed, additional blood samples may be required to 
further characterize the potential hypersensitivity reaction. If anaphylactic shock is suspected, 
blood samples may be taken for the measurement of tryptase. In this case, a blood sample should 
be taken 3 to 4 hours after the event and again approximately 1 to 2 weeks later to determine 
tryptase baseline levels. In addition, assessments for elevated histamine levels may be 
considered. 
The Investigator must ensure that the worst-case severity and seriousness of an event is kept 
throughout the study, i.e., if the severity of an AE changes over time then it should be reported as 
a single AE with the most severity. A worsening of an unresolved AE must be reported as follow 
up with re-assessment of severity and/or seriousness of the event. 
If an AE is resolved and reappears later then it should be reported as a new AE. 
 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
study drug under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to 


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safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects will be collected after the start of study drug and until last follow-up visit. All 
subjects must be instructed to notify the Investigator immediately if she or his partner 
becomes pregnant or suspects to be pregnant during the study. 
• 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported 
using the SAE form. 
8.3.6. 
Cardiovascular and Death Events 
The guidance for AEs indicating cardiovascular toxicity is provided in Appendix 5. 
8.3.7. Adverse Events of Special Interest  
In this study, the following events are to be regarded as adverse events of special interest 
(AESIs) should they occur: neoplasms (malignant and benign), suspicion of liver injury, and 
cholecystitis. 
If the event is reported as an SAE, the timelines for SAE reporting apply. If the event is reported 
as non-serious AE, it should be reported on the dedicated eCRF page within 24 hours of 
Investigator’s first knowledge. 
The event-specific information that needs to be captured in addition to the standard AE 
information is presented in the subsections below. 
8.3.7.1. 
Neoplasms 
Information on histopathology (date of examination and results), imaging (if imaging is 
performed), TNM staging, history of cancer (for the subject and the subject’s family), treatment 


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received for this event, and an event narrative. Copies of images (if performed) could be stored at 
each site. A retrospective imaging review may be performed if deemed necessary. 
8.3.7.2. 
Suspicion of Liver Injury 
Suspicion of liver injury is defined as: 
• ALT or AST >3 times baseline value lasting more than 2 weeks*, or 
• ALT or AST >5 × upper limit of normal (ULN) and total bilirubin >2 × ULN*, or 
• ALT or AST >5 × ULN and International normalized ratio (INR) >1.5*, or 
• ALT or AST >5 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)*. 
* where no other etiology exists 
If liver injury is suspected, the tests should be repeated in 48 to 72 hours for evaluation of the 
event course/confirmation. Additional information will need to be provided by the site, e.g., 
physical examination, information on alcohol consumption, concomitant therapy (including 
herbals). 
The narrative of the event should include: 
• Clinical signs and symptoms and how they developed over time. Aspects such as 
abdominal pain, nausea, vomiting, jaundice, fever, rash, abdominal tenderness, 
hepatomegaly, splenomegaly, BP, peripheral edema, jugular venous distension, signs of 
ascites, and recent weight gain should be considered and described. 
• Information on relevant medical history, alcohol consumption, and relevant concomitant 
therapy (including herbals). 
• Laboratory tests (at local laboratory, if needed): as a minimum ALT, AST, bilirubin 
(direct and total) and INR. Other tests may be warranted as clinically indicated. 
• Imaging diagnostic (ultrasound/CT scan/MRI/other imaging modality). Copies of images 
(if performed) should be stored at each site. 
• Biopsy results (if performed). 
8.3.7.3. 
Cholecystitis 
The narrative of the event should include 
• 
Clinical signs and symptoms and how they developed over time. Aspects such pain 
(character of the pain including the anatomical region [e.g. sudden, after a large meal, in 
upper right or center abdomen] +/- irradiating pain to right shoulder or back), tenderness 
of the abdomen, nausea, vomiting, and fever should be considered and described. 
• 
Information on relevant medical history, alcohol consumption, and relevant concomitant 
therapy (including herbals). 


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• 
Laboratory tests (at local laboratory, if needed): liver function tests, including ALT, 
AST, bilirubin, and ALP. Other tests may be warranted as clinically indicated. 
• 
Imaging diagnostic (ultrasound/ CT scan/MRI/other imaging modality). Details such as 
the presence of gall bladder stones and common bile duct diameter should be reported, if 
available. 
8.4. 
Treatment of Overdose 
HM15912 will be administered once at the clinic, thus limiting the risk of overdose. For this 
study, any dose of study drug greater than the recommended dose for the assigned cohort will be 
considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. Standard symptomatic support 
measures should be used in the case of excessive pharmacological effects or overdose. No 
antidotes are available. 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities until study 
drug can no longer be detected systemically. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
8.5. 
Pharmacokinetics 
• Serum samples will be collected for measurement of serum concentrations of study drug as 
specified in the Table 2.  
• If PK data are available indicating that other timepoints would be more advantageous, the 
timing of sample collection for PK analysis may be adjusted between cohorts. Details of 
the collection, handling, and transport of blood samples are separately summarized in the 
laboratory manual. The blood for the sample will be processed and the serum analyzed 
using a fully validated method.  
• The actual date and time (24-hour clock time) of each sample will be recorded. 
• Samples collected for analyses of study drug serum concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study.  
8.7. 
Genetics 
Genetics are not evaluated in this study. 


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8.8. 
Immunogenicity Assessments 
Antibodies to study drug including ADAs, Neutralizing antibodies (Nabs), and anti-PEG 
antibodies will be evaluated in serum samples collected from all subjects according to the SoA 
(Section 1.2). Additionally, serum samples may be collected at the final visit from subjects who 
discontinued study drug or were withdrawn from the study. These samples will be tested by the 
sponsor or sponsor’s designee. Detailed sampling method and volume will be indicated in 
separate documents (i.e., Lab Procedure Manual). 
The serum samples will be analyzed using a tiered approach (screening, confirmation, and 
titration of confirmed ADA positive samples), followed by characterization of ADA-positive 
samples for in vitro HM15912-neutralizing potential and cross-reactivity to the major metabolite 
(HM15912) and GLP-2. Results will not be revealed to the sites. 
The detection and characterization of antibodies to study drug will be performed using a 
validated assay method by or under the supervision of the sponsor. All samples collected for 
detection of antibodies to study drug will also be evaluated for study drug serum concentration to 
enable interpretation of the antibody data. Antibodies may be further characterized and/or 
evaluated for their ability to neutralize the activity of study drug.  
Samples may be stored for a maximum of 5 years (or according to local regulations) following 
the last subject’s last visit for the study at a facility selected by the sponsor to enable further 
analysis of immune responses to study drug. Sponsor could destroy stored sample before the 5 
years without notification if there is no longer need to store.  
8.9. 
 Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 


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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The study is not powered for formal hypothesis testing. As such there are no hypotheses for 
testing. 
9.2. 
Sample Size Determination 
The planned sample size of 8 subjects for each cohort is selected to characterize the effect of 
renal impairment on the PK of HM15912 based on FDA and EMA guideline rather than 
calculated with consideration of statistical requirements. With 8 subjects for each cohort (renal 
impairment cohort and normal renal function cohort), half width of two-sided 90% confidence 
interval of natural log scaled AUC0-∞ difference between two cohorts is
 
 
 
 
As stated in the study design part, approximately 16 subjects will be enrolled in Part 1 (8 subjects 
with severe renal impairment and approximately 8 subjects with normal renal function). If Part 2 
is conducted, 8 subjects with moderate renal impairment and 8 subjects with mild renal 
impairment will be enrolled. 
9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Safety Population 
All subjects who received any amount of HM15912. All analyses 
other than that specified will be performed based on safety 
population. 
PK Population 
All subjects who have at least one evaluable HM15912 serum 
concentration after receiving any amount of HM15912 without 
important protocol deviations or events (i.e. significantly affect 
the PK of study drug).  
PK parameter analyses will be conducted with PK population. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock (DBL) and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary/exploratory endpoints. Any changes from the 
analyses planned in SAP will be detailed in the Clinical Study Report (CSR). 


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9.4.1. General considerations 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation (SD), minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints unless other specified. Where appropriately, 
change from baseline will also be summarized. Baseline values will be defined as the most recent 
non-missing measurements collected prior to the first study drug administration. The data 
summaries will be presented by cohort. Individual subject data used for the analysis will be 
listed. 
Pharmacokinetic parameter will be calculated using WinNonlin®  or any available software for 
the pharmacokinetic analysis, and the other analysis will be performed using SAS version 9.4 (or 
above). 
9.4.2. 
Pharmacokinetic Analyses 
Summary of PK concentration and PK parameter will be presented for PK population, and all 
available individual data will be listed for safety population. 
PK concentration will be summarized using mean, SD, min, median, max, geometric mean, and 
geometric CV (%) by planned timepoint, and the concentration-time profiles will be depicted 
appropriately. 
PK parameters of HM15912 following single dose administration will be derived from the 
concentration-time profiles as detailed below tables. PK parameters will be derived by non-
compartmental analysis based on actual PK sampling times. In the case that actual PK sampling 
times are not available, nominal PK sampling time will be used in the derivation of PK 
parameters. 
 
Primary endpoint 
Parameter 
Description 
AUC0-∞ *  
Area under the serum concentration-time profile from time zero 
extrapolated to infinite time. 
Cmax 
Maximum serum concentration 
* As data permit 
 
Exploratory endpoint  
Parameter 
Description 
tmax 
Time to maximum serum concentration 
t1/2 * 
Elimination half-life 


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Vd/F * 
Volume of distribution 
CL/F  * 
Clearance 
λz  * 
First order rate constant associated with the terminal (log-linear) 
portion of the curve 
AUClast 
Area under the concentration-time curve from time zero to the 
last observable concentration 
AUC%Extrap 
Percentage of AUC0-∞ due to extrapolation from Tlast to infinity 
* As data permit 
 
After Part 1, PK parameter of HM15912 from severe renal impairment group (Cohort 2) will be 
estimated and compared to control group (Cohort 1). A one-way analysis of variance (ANOVA) 
will be used to compare log transformed PK parameter. The estimates of mean difference and 
corresponding 90% confidence intervals (CI), as well as each exponentiation of estimates will be 
presented to provide the estimates of geometric mean ratio. After statistical or clinical evaluation 
of results from Part 1, whether to proceed to Part 2 will be further discussed. 
If Part 2 is conducted, same analysis with Part 1 will be implemented to compare of each 
moderate (Cohort 3) or mild (Cohort 4) renal impairment subjects and normal renal function 
subjects in Cohort 1. In case the demographics of the moderate or mild renal impairment group 
compared to the normal renal function group are not within the criteria specified in the protocol, 
it will be considered to add that demographic information as a covariate of ANOVA. If needed, 
further evaluation to characterize the relationship between renal function and PK parameter will 
be explored. 
9.4.3. 
 Safety Analyses 
All safety analyses will be performed in the safety population.  
AE analyses will focus on TEAEs which are defined as any AE that begins, or worsens in 
severity on or after the date of first study drug administration until the last follow up visit. 
Incidence of TEAEs will be summarized using System Organ Class (SOC) and Preferred Term 
(PT) of MedDRA coding dictionary. Additional summary of TEAEs by maximum severity using 
NCI-CTCAE version 5.0 will also be presented. Incidence of treatment related AEs (TRAEs), 
AESIs, SAEs or TEAEs leading to death also be summarized respectively. Injection site 
reactions will be documented as AEs. Additional summary for the quantitative assessment will 
be provided. All AEs, including those occurred between informed consent and first study drug 
administration, will be provided in a listing. 
The results of laboratory tests, vital signs and 12-lead ECG will be summarized descriptive 
statistics for the actual value and the change from baseline by planned time point. Frequency 
analyses also be performed as appropriately. If applicable, the shift tables for the investigator’s 


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abnormality assessment between baseline and post-baseline will be present. Abnormal physical 
examination findings will be reported as a list. 
Immunogenicity test results will be listed by subject and summarized. 
9.5. 
Interim Analyses  
No formal interim analysis will be conducted for this study. 
9.6. 
Data Monitoring Committee (DMC) 
Not applicable. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
• 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the stud. 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study. 


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• 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
• 
The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
ICF. 
• 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
10.1.4. 
Data Protection 
• 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
• 
The subject must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject who will be required to give consent for their data to be 
used as described in the informed consent  
• 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
After completion of the study, a clinical study report will be written by the sponsor following the 
guidance in ICH E3 and will be submitted in accordance with local regulations. 
10.1.6. 
Data Quality Assurance 
• 
All subject data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the 
eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 


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• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• 
Current Food and Drug Administration guidelines require records to be retained for a 
period of 2 years following the date a marketing application is approved for the drug, 
for the indication for which it is being investigated. If no application is filed or if the 
application for the investigated indication is not approved, documents will be kept until 
2 years after the investigation is discontinued and the FDA is notified. It is the sponsor’s 
responsibility to inform the contract research organization as to when essential 
documents are no longer needed to be retained. 
10.1.7. 
Source Documents 
• 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up 
10.1.9. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 7 will be performed by the central laboratory. 
• 
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study drug administration and/or response evaluation. 
If a local sample is required, it is important that the sample for central analysis is 
obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study drug administration decision or response evaluation, the results must be 
entered as narration in the eCRF. 
• 
The alcohol breath test will be performed according to the site’s SOP at designated time 
points as specified in the SoA (Section 1.2) 
• 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• 
Investigators must document their review of each laboratory safety report. 
Table 7: Protocol-Required Safety Laboratory Assessments 
Hematology 
Coagulation 
Clinical Chemistry 
Urinalysis 
• RBC count 
• WBC count 
(with differential) 
 Neutrophils 
 Eosinophils 
 Basophils 
 Lymphocytes 
 Monocytes 
• Platelet count 
• Hemoglobin 
• Hematocrit 
• RBC indices: 
• MCV 
• MCH 
• %Reticulocytes 
• PT (INR) 
• aPTT 
• Fasting plasma 
glucose 
• BUN 
• Creatinine 
• Potassium 
• Sodium  
• AST 
• ALT 
• GGT 
• Alkaline 
phosphatase 
• Total and direct 
bilirubin 
• Specific gravity 
• pH, glucose, 
protein, blood, 
ketones, bilirubin, 
urobilinogen, 
nitrite, leukocyte 
esterase by 
dipstick 
• Microscopic 
examination 
(if blood or protein 
is abnormal) 
• Pregnancy test 
Additional Tests 
• Immunogenicity (ADA, NAb, anti-PEG antibody) 


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Other Screening 
Tests 
• HbA1c 
• eGFR 
• Urine drug screen 
• Serum hCG pregnancy test 
• Serology (HIV antibody, HbsAg, and hepatitis C virus antibody) 
Abbreviations: ALT = alanine aminotransferase; aPTT =  activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; GGT = gamma-glutamyl transferase; 
HbA1c = hemoglobin A1c; HbsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HIV = human 
immunodeficiency virus; INR =  international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean 
corpuscular volume; PEG = polyethylene glycol; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell. 
 
 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study subject, 
temporally associated with the use of study drug, whether or not considered related to 
the study drug. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study drug. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE 
unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 


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• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical drug to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to sponsor in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested 
by regulatory authorities. In this case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before 
submission to regulatory authorities. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The CTCAE Version 5.0 Grades 1 through 5 are described below:  
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)a 


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• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADLb 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE. 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.Other measures to evaluate AEs and SAEs may be utilized 
(e.g., National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-
CTCAE]). 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration 
will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 


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• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor’s with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The investigator will submit any updated SAE data to sponsor within 24 hours of 
receipt of the information. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to Sponsor via an Electronic Data Collection Tool (Primary method) 
• The primary mechanism for reporting an SAE to sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor/SAE coordinator by telephone. 
• Contacts for SAE reporting can be found in safety management plan. 
 
SAE Reporting to Sponsor via Paper SAE form (Back-up method) 
• Facsimile transmission of the paper SAE form is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the paper SAE form within the designated reporting time frames. 
• Contacts for SAE reporting can be found in safety management plan. 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview. 
 
3. Postmenopausal female 
• A postmenopausal state is defined as >52 years of age and no menses for 12 months or 
more and/or as follicle-stimulating hormone (FSH) level >30 mIU/mL (as measured at 
site) without an alternative medical cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 


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Contraception Guidance: 
Females aged ≥12 years must have a negative urine/serum pregnancy test and must use an 
acceptable method of contraception, including abstinence, a barrier method (diaphragm or 
condom), Depo-Provera, or an oral contraceptive for the duration of the study 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This applies 
only to male subjects who receive study drug. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female Subjects who become pregnant 
• 
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a subject's 
pregnancy.  
• 
The subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the subject and the neonate and the information will 
be forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE unless there is a suspicion 
that the study drug may have interfered with the effectiveness of a contraceptive 
medication, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  


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• 
Any post-study pregnancy related SAE considered reasonably related to the study drug 
by the investigator will be reported to the sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study subjects, he 
or she may learn of an SAE through spontaneous reporting. 
• 
Any female subject who becomes pregnant while participating in the study will 
discontinue study drug or be withdrawn from the study. 
 
 
 


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10.5. 
Appendix 5: Adverse Event Guidance 
As any new study drug may have unexpected AEs, the following guidance is offered for potential 
toxicities for HM15912. The following diagnostic work-up and procedures are suggested actions 
and should be tailored to the clinical presentation as assessed by the investigator. 
1. Cardiovascular Toxicity 
Definitions: 
Signs and symptoms may include the following: chest pain, arrhythmia, palpitations, peripheral 
edema, progressive or acute dyspnea, pleural effusion, and fatigue. 
Diagnostic workup: 
At baseline: 
• Electrocardiogram 
• Cardiac biomarkers (creatine kinase-MB and troponin-I) 
Depending on presentation: 
• Inflammatory biomarkers (erythrocyte sedimentation rate, C-reactive protein, white blood 
cell count) 
• O2 saturation 
• B-type natriuretic peptide 
• Emergency room/hospital transfer 
• Cardiology consultation 
• Chest x-ray 
Additional testing to be guided by cardiology and may include the following: 
• Echocardiography 
• Stress test 
• Cardiac catheterization 
• Cardiac magnetic resonance imaging (MRI) 


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Gradinga 
Management 
G1: Asymptomatic abnormal cardiac 
biomarker testing, including abnormal ECG 
All grades (G1-G4) warrant workup and 
intervention given for potential cardiac 
compromise. 
Please consider the following: 
• Hold therapy and permanently discontinue 
after G1 
• Management of cardiac symptoms 
according to ACC/AHA guidelines 
• Transfer subject to the emergency room at 
the hospital for further evaluation and 
management for any grade >G1 
• Cardiology consultation 
G2: Mild symptoms consistent with 
cardiotoxicity with or without abnormal 
cardiac biomarkers 
G3: Moderate symptoms consistent with 
cardiotoxicity and/or clinically significant 
abnormal cardiac biomarkers 
G4: Moderate to severe decompensation, 
intravenous medication or intervention 
required, life-threatening conditions 
 
Qualifying statement: Treatment recommendations are based on local standards of care and the 
life-threatening nature of cardiovascular complications. Holding therapy is recommended for 
complication grades >G2. The appropriateness of re-challenging remains unknown. 
Abbreviations: ACC = American College of Cardiology; AHA = American Heart Association; CTCAE = Common Terminology 
Criteria for Adverse Events; ECG = electrocardiogram; G = grade. 
a Not associated with CTCAE grading system 


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2. Rash/Inflammatory Dermatitis and Other Skin Disorders 
Definitions: 
• Erythema multiforme major and minor (a targetoid reaction in the skin and mucous 
membranes, usually triggered by infections such as herpes simplex virus, but can be 
associated with an immune-related drug eruption; if progresses to erythema multiforme 
major, it can be a harbinger of severe cutaneous adverse reaction such as Stevens–Johnson 
syndrome) 
• Lichenoid (resembling the flat-topped, polygonal, and sometimes scaly or hypertrophic 
lesions of lichen planus) 
• Eczematous (inflammatory dermatitis characterized by pruritic, erythematous, scaly, or 
crusted papules or plaques on the skin, which is vulnerable to superinfection) 
• Psoriasiform (resembling the well-demarcated, erythematous, and scaly papules and 
plaques of psoriasis) 
• Morbilliform (a nonpustular, nonbullous measles-like exanthematous rash of the skin often 
referred to as ‘maculopapular’ and without systemic symptoms or laboratory abnormalities, 
excluding occasional isolated peripheral eosinophilia 
• Palmoplantar erythrodysaesthesia (hand-foot syndrome) (redness, 
numbness/burning/itching and superficial desquamation of the palms and soles) 
• Neutrophilic dermatoses (eg, sweet’s syndrome) 
• Others 
Diagnostic workup for skin disorders above and others which are considered to be possibly 
study drug-related: 
• Pertinent history and physical examination 
• Rule out any other etiology for the skin problem, such as an infection, an effect of another 
drug, or a skin condition linked to another systemic disease or unrelated primary skin 
disorder 
• If needed, consider a checkup including a blood cell count, liver, and kidney tests. 
• Directed serologic studies if an autoimmune condition is suspected, such as lupus or 
dermatomyositis: 
o a screening antinuclear antibody test, SSA/Anti-Ro, SS-B/Anti-La 
o if predominantly photodistributed/photosensitivity, antihistone, ds-DNA and other 
relevant serologies 
o consider expanding serologic studies or diagnostic work up if other autoimmune 
conditions are considered based on signs, symptoms 
• Dermatology consultation with or without skin biopsy 


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• Consider clinical monitoring with use of serial clinical photography, if IRB approved and 
subject has consented 
• Review full list of subject medications to rule out other drug-induced cause for skin lesion 
Grading 
Grading according to CTCAE criteria is a 
challenge for skin. Instead, severity may be 
based on body surface area, tolerability, 
morbidity, and duration. 
Management 
G1: Symptoms do not affect the quality of life 
or are controlled with topical regimen and/or 
oral antipruritics 
• Consider continuing therapy for mild 
localized reaction (eg, injection site 
erythema) 
• Consider treatment with topical emollients 
and/or mild-moderate potency topical 
corticosteroids 
• Counsel subjects to avoid skin irritants and 
sun exposure 
G2: Inflammatory reaction that affects quality 
of life and requires intervention based on 
diagnosis 
• Dermatology consultation for proper 
management plan 
• Consider holding therapy and monitor 
weekly for improvement. If not resolved, 
interrupt treatment until skin AE has 
reverted to G1. 
• Consider initiating prednisone (or 
equivalent) at 0.5 to 1 mg/kg/day and 
tapering over at 4 weeks 
• In addition, treat with topical emollients, 
oral antihistamines, and medium-to-high 
potency topical corticosteroids 
G3: As G2 but with failure to respond to 
indicated interventions for a G2 dermatitis. 
• Hold the therapy and consult with 
dermatology to determine appropriateness 
of management plan and resuming 
• Initiate oral prednisone or equivalent 
(0.5 to 1 mg/kg/day) and tapering over at 
least 4 weeks 
• Treat with topical emollients, oral 
antihistamines, and high potency topical 
corticosteroids 
Page 1 of 2 
Footnotes are provided on the last page of the table. 


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Grading 
Grading according to CTCAE criteria is a 
challenge for skin. Instead, severity may be 
based on body surface area, tolerability, 
morbidity, and duration. 
Management 
G4: All severe rashes not manageable 
with prior intervention 
• Immediately hold therapy and urgently 
admit the subject with consultation to a 
dermatology specialist for proper 
management of skin lesion 
• For resuming the therapy upon the 
resolution of skin toxicity, the 
dermatologic consultation should be 
conducted when the corticosteroids are 
reduced to prednisone (or equivalent) 
10 mg or less 
• Systemic steroids: intravenous (methyl) 
prednisolone (or equivalent) at a dose of 
1 to 2 mg/kg with slow tapering when the 
toxicity resolves 
• Monitor closely for progression to severe 
cutaneous adverse reaction 
Page 2 of 2 
Abbreviation: AE = adverse event. 


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3. Liver Toxicity Monitoring Guideline 
Following evaluations should be undertaken if on treatment liver function tests (LFT) increase to 
either #1 or #2 below: 
1. If baseline LFTs are normal, further evaluation is needed if ALT or AST >3 x ULN 
2. If baseline LFTs are abnormal, further evaluation is needed if ALT or AST >2 x ULN 
Evaluations to be performed if trigger ALT/AST reached: 
Step 1: Repeat and confirm trigger ALT/AST elevation 
Step 2: If elevation confirmed, consider below in addition to hepatology/GI referral: 
1. Take history to evaluate for intercurrent infection/illness 
2. Obtain a history of new medications, new supplements, current alcohol use, recreational 
drug use, or new special diet started 
3. Obtain history of exposure to environmental chemical agents 
4. Rule out new liver diseases or biliary disease 
a) Acute hepatitis panel (HAV IgM, hepatitis B surface antigen, core IgM, HCV Ab or 
HCV RNA [better]) 
b) Antinuclear antibody, anti-smooth muscle antibody 
c) Iron, ferritin 
d) Abdominal ultrasound 
e) Gamma-glutamyl transferase 
f) 
Alcohol level 
g) Drug screen 
5. Monitor weekly LFTs until levels fall to baseline or new stable level is established 
6. Study drug status should be discussed with medical monitor 
Immediate study drug discontinuation 
1. If normal ALT/AST 
a) ALT or AST >5 x ULN 
b) ALT or AST >3 x ULN + total bilirubin >2 x ULN 
2. If abnormal baseline ALT/AST 
a) ALT or AST >5 x baseline 
b) ALT or AST >3 baseline and bilirubin >2 x baseline 
c) Absolute ALT or AST >500 


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4. Gastrointestinal Events 
Definition: 
Nausea and vomiting are anticipated AEs with this protocol. The initial assessment needs to 
include consideration of other differentials including pancreatitis and cholelithiasis. Laboratory 
assessments of amylase, lipase, and LFTs (ALT, AST, alkaline phosphatase, and bilirubin) or 
imaging (ultrasound, computed tomography, or MRI) should be considered and pursued if 
indicated. 
Severity of symptoms should be assessed as following: 
Grading 
(Not associated with CTCAE grading system) 
Management 
G1: Mild symptoms that do not interfere with 
quality of life 
• No intervention 
G2: Mild-to-moderate symptoms that may 
need intervention based on investigator 
• Patient observation 
• Consider initiating antiemetic medication 
G3: Moderate–to-severe symptoms that need 
medical intervention 
• Consider holding therapy: resume therapy 
only if symptoms are resolved to tolerate 
the therapy 
• Treatment with antiemetic medication and 
intravenous fluid as needed 
• Treat with parenteral nutrition if no oral 
intake sustained 
G4: Life-threatening symptoms 
• Immediately discontinue therapy 
• Systemic intravenous fluids 
• Treat with antiemetic medication as 
indicated 
• Treat with parenteral nutrition 
• Should admit subject immediately with an 
urgent consult 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events. 
 
 


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10.6. 
Appendix 6: Abbreviations 
Abbreviation  
or Specialist Term 
Explanation 
ADA  
Anti-drug antibody  
AE  
Adverse event  
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT  
Alanine aminotransferase  
ANOVA 
Analysis of variance 
Anti-PEG 
Anti-polyethylene glycol 
AST  
Aspartate aminotransferase  
AUC0-∞ 
Area under the concentration-time curve extrapolated to infinity 
AUClast 
Area under the concentration-time curve from time zero to the last 
observable concentration 
BMI 
Body mass index 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence intervals 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
Cmax 
Maximum serum concentration 
CKD-EPI 
Chronic kidney disease-epidemiology collaboration 
CRU 
Clinical research unit 
CSR 
Clinical Study Report 
CT  
Computerized tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
DBL 
Database lock 
DNA 
Deoxyribonucleic acid 
DPP-4  
Dipeptidyl peptidase-4  
ECG  
Electrocardiogram  


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Abbreviation  
or Specialist Term 
Explanation 
EMA 
European Medicines Agency 
eCRF  
Electronic case report form  
eGFR 
Estimated glomerular filtration rate 
FcRn 
Neonatal Fc receptor 
FDA 
Food and Drug Administration 
FSH  
Follicle-stimulating hormone  
GCP  
Good Clinical Practice  
GGT 
Gamma glutamyl Transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GLP-1 
Glucagon-like peptide 1 
GLP-2  
Glucagon-like peptide 2 
GMR 
Geometric mean ratio 
hCG  
Human chorionic gonadotropin  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF  
Informed consent form  
ICH  
International Council for Harmonisation  
IEC  
Independent Ethics Committee  
INR 
International normalized ratio 
IP 
Investigational product 
IRB  
Institutional Review Board  
MRI 
Magnetic resonance imaging 
NAb 
Neutralizing antibody 
NOAEL 
No observed adverse effect level  
PD 
Pharmacodynamic 


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Abbreviation  
or Specialist Term 
Explanation 
PEG 
Polyethylene glycol 
PK  
Pharmacokinetic 
PN/IV  
Parenteral nutrition/Intravenous fluid 
PT 
Prothrombin time 
RR 
Respiratory rate 
SAD 
Single ascending dose 
SAE  
Serious adverse event  
SAP  
Statistical Analysis Plan  
SBS 
Short bowel syndrome  
SBS-IF 
Short bowel syndrome-associated intestinal failure 
SC  
Subcutaneous  
SD  
Standard deviation  
SoA 
Schedule of assessments 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment emergent AE 
TRAE 
Treatment related AE 
tmax 
time to maximum serum concentration  
t1/2 
elimination half-life 
ULN  
Upper limit of normal  
Vd 
volume of distribution 
WOCBP 
Woman of Childbearing Potential 
 
 
 


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11. 
References 
1. Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function Study 
Design, Data Analysis, and Impact on Dosing and g. FDA Guidance, September 2020. 
2. Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with 
Decreased Renal Function. EMA Committee for Medicinal Products or Human use. 17 
December 2015. 
3. Wang P, Yang J, Zhang Y, Zhang L, Gao X, Wang X. Risk Factors for Renal Impairment 
in Adult Patients with Short Bowel Syndrome. Frontiers in Nutrition. 2021;7. 
4. Pironi L, Arends J, Bozzetti F, et al. ESPEN Guidelines on Chronic Intestinal Failure in 
Adults. Clinical Nutrition. 2016;35(2):247-307. 
5. O’Keefe SJD, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short 
Bowel Syndrome and Intestinal Failure: Consensus Definitions and Overview. Clinical 
Gastroenterology and Hepatology. 
6. Buchman AL, Moukarzel A, Ament ME, Gornbein J, Goodson B, Carlson C, et al. Serious 
Renal Impairment is Associated with Longterm Parenteral Nutrition. JPEN J Parent Enteral Nutr. 
(1993) 17:438-44. 
7. Ylinen E, Merras-Salmio L, Gunnar R, Jahnukainen T, Pakarinen MP. Intestinal Failure as a 
Significant Risk Factor for Renal Impairment in Children. Nutrition. (2018) 45:90-3. 
8. Rowland KJ, Brubaker PL. Life in the Crypt: A Role for Glucagon-like Peptide 2? Mol Cell 
Endocrinol. 2008;288(1-2):63-70. 
9. Leen JL, Izzo A, Upadhyay C, et al. Mechanism of Action of Glucagon-like Peptide-2 to 
Increase IGF-I mRNA in Intestinal Subepithelial Fibroblasts. Endocrinology. 2011;152(2):436-
446. 
10. Drucker DJ, Erlich P, Asa SL, Brubaker PL. Induction of Intestinal Epithelial Proliferation 
by Glucagon-like Peptide 2. Proc Natl Acad Sci USA. 1996;93:7911-7916. 
11. European medicines agency: EMA/CHMP/525255/2012 – Assessment report of Revestive®  
(teduglutide) 

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Statistical Analysis Plan V1.0 
 
 
 
 
 
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Statistical Analysis Plan 
Study Title 
An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability of HM15912 in Subjects with Renal Impairment 
and Matched Control Subjects with Normal Renal Function 
Protocol No 
HM-GLP2-102 
Version 
V1.0 
 
 


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Revision History 
Approval Date 
Version 
Prepared by 
Comment 
05 Sep 2023 
V1.0 
 
Initial document 
 
 


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Table of Contents 
1 
INTRODUCTION ............................................................................................................ 8 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 8 
3 
INVESTIGATIONAL PLAN ............................................................................................. 9 
3.1 
Overall Study Design and Plan .............................................................................. 9 
3.2 
Treatment Plan .................................................................................................... 11 
3.3 
Analysis Schedule ............................................................................................... 11 
4 
DETERMINATION OF SAMPLE SIZE .......................................................................... 11 
5 
ANALYSIS SET ............................................................................................................ 11 
6 
ESTIMAND ................................................................................................................... 12 
6.1 
Estimand for the Primary Objective ...................................................................... 12 
6.2 
Estimand for the Secondary Objective ................................................................. 13 
7 
GENERAL STATISTICAL CONSIDERATION ............................................................... 14 
7.1 
Summary and Representation of Data ................................................................. 14 
7.2 
Baseline ............................................................................................................... 15 
7.3 
Repeat and Unscheduled Data ............................................................................ 15 
7.4 
Handling of Missing Data ..................................................................................... 15 
7.5 
Study Day ............................................................................................................ 15 
7.6 
End of Study ........................................................................................................ 16 
7.7 
Software .............................................................................................................. 16 
8 
CHANGE FROM PROTOCOL ...................................................................................... 16 
9 
STATISTICAL METHODS............................................................................................. 16 
9.1 
Study Subjects ..................................................................................................... 16 
9.2 
Efficacy Evaluation .............................................................................................. 17 
9.3 
Safety Analysis .................................................................................................... 19 
10 INTERIM ANALYSIS ..................................................................................................... 22 
11 SAS PROCEDURES .................................................................................................... 22 
12 REFERENCES ............................................................................................................. 24 
13 APPENDICES............................................................................................................... 25 
13.1 
Schedule of Assessments ................................................................................. 25 
13.2 
List of Tables, Figures, and Listings .................................................................. 28 
 
 
 


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Abbreviations 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANOVA 
Analysis of variance 
anti-PEG 
Anti-polyethylene glycol 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area under the serum concentration-time profile 
AUC%Extrap 
Percentage of AUC0-∞ due to extrapolation from tlast to infinity 
AUC0-∞ 
AUC from time zero extrapolated to infinite time 
AUClast 
AUC from time zero to the last observable concentration 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
Clearance 
CM 
Concomitant medication 
Cmax 
Maximum serum concentration 
CRU 
Clinical research unit 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GMR 
Geometric mean ratio 
HR 
Heart rate 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 


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IPD 
Important protocol deviation 
MedDRA 
Medical Dictionary for Regulatory Activities 
N/A 
Not available 
NAb 
Neutralizing antibody 
NCA 
Non-compartmental analysis 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PD 
Protocol deviation 
PK 
Pharmacokinetics 
PT 
Preferred term 
QTcF 
QT interval corrected using Fridericia’s correction 
RR 
Respiratory rate 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
t½ 
Elimination half life 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
tmax 
Time to maximum serum concentration 
TRAE 
Treatment-related adverse event 
Vd/F 
Volume of distribution 
λz 
First order rate constant associated with the terminal (log-linear) portion of 
the curve 
 
 
 








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from CRU, all the remaining procedures will be conducted by outpatient visit.  
b. If subjects discharge earlier than Day 8 based on the subject’s request, Day 3, 4, 5, 6, and 7 procedures can be 
done in outpatient visits.  
3.2 Treatment Plan 
The study drug, HM15912 0.5mg/kg, will be administered once by the authorized site staff via 
SC injection into abdominal wall. 
3.3 Analysis Schedule 
After all subjects in Cohort 1 and Cohort 2 have completed all scheduled procedures, 
preliminary analysis will be conducted to decide whether to proceed to Part 2, or not. Part 2 
will be conducted if the point estimate of GMR of AUC0-∞ for the severe renal impairment group 
(Cohort 2) compared to the control group (Cohort 1)
 
If the decision criterion to proceed to Part 2 is met, final analysis will be conducted after all 
subjects who are enrolled in the Part 2 complete or discontinue the study. However, if the 
decision criterion to proceed to Part 2 is not met, final analysis will be conducted follow up with 
preliminary analysis. 
4 
DETERMINATION OF SAMPLE SIZE 
The planned sample size of 8 subjects for each cohort is selected to characterize the effect of 
renal impairment on the PK of HM15912 based on FDA and European Medicines Agency (EMA) 
guideline rather than calculated with consideration of statistical requirements. With 8 subjects 
for each cohort (renal impairment cohort and normal renal function cohort), half width of two-
sided 90% confidence interval of natural log scaled AUC0-∞ difference between two cohorts is 
0.2260 with consideration of between-subject standard deviation, 0.257, from the previous 
phase I study result of HM15912. This provides the 90% confidence interval (0.798, 1.254) for 
a geometric mean ratio of 1.0. 
As stated in the study design part, approximately 16 subjects will be enrolled in Part 1 (8 
subjects with severe renal impairment and approximately 8 subjects with normal renal function). 
If Part 2 is conducted, 8 subjects with moderate renal impairment and 8 subjects with mild 
renal impairment will be enrolled. 
5 
ANALYSIS SET 
An analysis populations classification will be discussed to decide which subjects and/or data 
will be excluded from certain analyses. The decisions will be made before the database lock 
and will be documented and approved. 
In this study, the following populations are defined. 
Table 3 Analysis Set Definition 








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the by-subject listing for Screened population. Each subject’s cohort information and defined 
analysis population will be presented for all listings.  
7.2 Baseline 
The baseline value is defined as the last non-missing measurements collected prior to the first 
study drug administration. Repeat and unscheduled assessments will be included in the 
derivation of the baseline values. Change from baseline and percent change from baseline will 
be calculated as below only when the both baseline and post-baseline values are available in 
each subjects. 
• 
Change from Baseline = Post-baseline – Baseline 
• 
Percent Change from Baseline (%) = (Post-baseline – Baseline) / Baseline * 100 
 
7.3 Repeat and Unscheduled Data 
Values collected at scheduled study visits/time points will be presented in summary tables. If 
a repeat assessment was performed, the result from the original assessment will be presented 
as the result at the specific visit and time point. All collected data will be included in the data 
listings. 
7.4 Handling of Missing Data 
Except as stated below, there will be no imputation of missing values, and all data will be 
included in the by-subject listings as it is. 
7.4.1 Missing or Partial Dates 
In general, missing or partial date will not be imputed except for classification of Treatment 
Emergent Adverse Event (TEAE) or Concomitant Medication (CM). If the start and/or stop date 
are partial, the dates will be compared as far as possible with the date of first study drug 
administration. However, if the missing or partial date interrupts classification, adverse events 
or medication will be treated as TEAE or CM. 
7.4.2 Missing Assessment of Adverse Event 
If the assessment of the severity or relationship to study drug is missing for the AEs, the event 
will be classified as ‘Severe (or Grade 3)’ or ‘Related’, respectively, for summary purposes.  
7.5 Study Day 
The study day of an event is defined as the relative day of the event starting with the date of 
the first study drug administration (reference date) as Day 1. The date preceding first study 
drug administration is designated as study day -1 (there will be no Day 0). 
• 
If the date of event is before the study drug administration, then:               


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Study Day = (Date of event - Date of first study drug administration) 
• 
If the date of event is on or after the study drug administration, then:            
Study Day = (Date of event - Date of first study drug administration) + 1 
 
Study days will only be calculated for events with complete dates and will be undefined for the 
end date of ongoing events at the end of the study. 
7.6 End of Study 
A subject is considered to have completed the study if subject has completed all periods of the 
study including the last scheduled procedure shown in the Schedule of Assessments. The end 
of the study is defined as the date of the last visit of the last subject in the study or last 
scheduled procedure for the last subject in the trial globally. 
7.7 Software 
PK parameters will be derived with standard non-compartmental analysis (NCA) methods 
using PKanalix® version 2023 (application of the MonolixSuiteTM for NCA) or any available 
software for the PK analysis, and the other analysis will be performed using SAS® version 9.4 
or higher. 
All analyzed tables, listings, and figures will be generated using SAS® Version 9.4 or higher. 
8 
CHANGE FROM PROTOCOL 
There is no change from protocol. 
9 
STATISTICAL METHODS 
9.1 Study Subjects 
9.1.1 Disposition of Subjects and Analysis Population 
For screened population, subject disposition at the end of screening and at the end of study 
will be summarized including the reason of termination from each study milestone. The number 
of screened subjects will be used as denominator for the summary of end of screening status, 
and the number of screening completed subjects will be used as denominator for the summary 
of end of study status. 
The summary of subjects who included / excluded in each analysis population (i.e., Safety 
population and PK population) and the reason for exclusion will be provided. 
9.1.2 Protocol Deviation 
A full list of protocol deviations (PD) for the study will be reviewed prior to database lock, and 
the important protocol deviations will be identified. 


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Based on Safety population, the summary of protocol deviation will be provided by protocol 
deviation category and sub-category, with a focus on important protocol deviation. By-subject 
listing of all protocol deviations will be provided. 
9.2 Efficacy Evaluation 
9.2.1 Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the safety 
population and the PK population. Demographic and baseline characteristics include, but are 
not limited to: age, sex, race, ethnicity, weight, height, body mass index (BMI), and eGFR at 
baseline. BMI and eGFR at baseline will be calculated according to the formula below. 
• 
Baseline BMI (kg/m2) = Baseline weight (kg) / [Baseline height (cm) / 100]2 
• 
Baseline eGFR (mL/min/1.73m2) = The mean of the eGFR obtained from two 
screening visits 
 
9.2.2 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.1 or higher. Based on Safety population, the summary of medical history will be 
provided by System Organ Class (SOC) and Preferred Term (PT), with a focus on ongoing 
status. By-subject listing of all medical histories will be provided.  
9.2.3 Prior and Concomitant Medication 
Prior medication is defined as any medications that start and end before the first study drug 
administration. Concomitant medication is defined as any medications that were administered 
after the first study drug administration (including medications that start prior to dosing and 
continued after). 
The WHO Drug Global (B3) Version September, 2022 or higher will be used to categorize the 
verbatim descriptions of medications into the Anatomic Therapeutic Chemical (ATC) 
classification system.  
Prior and Concomitant medications will be summarized by ATC level 2 (therapeutic class) and 
preferred term for the Safety population. Subjects who used the same medication on multiple 
occasions will only be counted once in each specific category. 
By-subject listing will be provided with flags to distinguish the prior and concomitant 
medications. 
9.2.4 Extend of Exposure 
Detailed information for the study drug administration will be listed by subject for the Safety 
population. 
9.2.5 Pharmacokinetic Concentration 




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less than 3 after Cmax. 
In order to comparing the exposures among cohorts, box and whisker plots of Cmax, AUC0-∞ 
and AUClast will be generated. 
After Part 1, PK parameter of HM15912 from severe renal impairment group (Cohort 2) will be 
estimated and compared to control group (Cohort 1). A one-way analysis of variance (ANOVA) 
will be used to compare log transformed PK parameter. The estimates of mean difference 
(Cohort 2 – Cohort 1) and corresponding 90% confidence intervals (CI), as well as each 
exponentiation of estimates will be presented to provide the estimates of geometric mean ratio. 
After statistical or clinical evaluation of results from Part 1, whether to proceed to Part 2 will be 
further discussed.  
If Part 2 is conducted, the same analysis with Part 1 will be implemented to compare of each 
moderate (Cohort 3) or mild (Cohort 4) renal impairment subjects and normal renal function 
subjects in Cohort 1. In case the demographics (weight and age) of the moderate or mild renal 
impairment group compared to the normal renal function group are not within the criteria 
specified in the protocol, it will be considered to add that demographic information as a 
covariate of ANOVA. If needed, further evaluation to characterize the relationship between 
renal function and PK parameter will be explored. 
9.3 Safety Analysis 
Safety data will be summarized for the Safety population, and all safety data will be listed. 
9.3.1 Adverse Events 
All AEs will be coded using the MedDRA Version 25.1 or higher, and each AEs will be assessed 
by the investigator for relationship to the study drug (i.e., ‘Not-related’, ‘Related’) and severity 
using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE), Version 5.0. In this study, neoplasms (malignant and benign), suspicion of liver injury, 
and cholecystitis are treated as adverse events of special interests (AESIs). 
AE analyses will focus on treatment-emergent AEs (TEAEs) which are defined as any AE that 
begins, or worsens in severity on or after the date of first study drug administration until the 
last follow up visit. 
Summaries of TEAEs will include the following: 
• 
Overall summary of TEAEs 
• 
Incidence of TEAEs 
• 
Incidence of TEAEs with Maximum Severity 
• 
Incidence of Treatment-related AEs (TRAEs) 
• 
Incidence of TRAEs by Maximum Severity 
• 
Incidence of Treatment-emergent serious adverse event (TESAEs) 
• 
Incidence of Treatment-related TESAEs 
• 
Incidence of AEs of Special Interest (AESIs) 
 




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Any quantitative laboratory parameters that are given as '<xx' or '>xx' in the database will be 
replaced with the value without the sign (e.g., <2.2 will be imputed as 2.2) for the 
summarization purpose.  
Each laboratory test results will be evaluated by the investigator as ‘Normal’, ‘Abnormal, Not 
Clinically Significant’, or ‘Abnormal, Clinically Significant’. Shift tables will be generated 
showing the number and percentage of subjects with shifts from baseline to each post-baseline 
visit. 
All by-visit summary of laboratory test data will be provided based on the test results at 
scheduled visit, but all the data will be listed by subject regardless of measurements at 
scheduled or unscheduled. 
By-subject listing for all laboratory test data including the parameters which are not specified 
in the Table 9 (i.e., HbA1c, eGFR, serum hCG pregnancy test, serum FSH test, serology, urine 
drugs of abuse and alcohol breath test) will be provided as recorded in the raw data. 
9.3.3 Vital Signs 
Observed value and the changes from baseline value for vital signs measurements [tympanic 
body temperature, respiratory rate (RR), systolic blood pressure (SBP), diastolic blood 
pressure (DBP), and heart rate (HR)] will be summarized using descriptive statistics by 
scheduled visit. For summary of body temperature, Celsius degree will be used with the 
conversion formula as below: 
• 
Celsius degree (℃) = [Fahrenheit degree (℉) – 32] x 5 / 9 
 
For SBP, DBP, and HR which are measured greater than or equal to 2 consecutive times of 
each visit, mean value of consecutive measurements will be used for summarization. If there 
is missing data among the consecutive measurements, only the non-missing value will be used 
to calculate the mean value. 
Overall interpretation (‘Normal’, ‘Abnormal, Not Clinically Significant’, or ‘Abnormal, Clinically 
Significant’) for the vital signs will be summarized using shift table to compare the investigator’s 
evaluation between baseline and each post-baseline visit and timepoint. 
By-subjects listing for all vital signs data which is recorded and derived will be listed. 
9.3.4 Physical Examination 
Physical examination findings (‘Normal’, ‘Abnormal, Not Clinically Significant’, and ‘Abnormal, 
Clinically Significant’), height, weight, and BMI will be listed by subject. 
9.3.5 12-lead Electrocardiograms 
A triplicate 12-lead ECGs will be performed at screening period and Day 1. At all other times, 
however, single 12-lead ECGs will be performed. For the ECGs measurement taken in 
triplicate, mean of the triplicates measurements will be used as baseline and post-baseline 


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value of each visit and timepoint. If there is missing data among the triplicated measurements, 
only the non-missing value will be used to calculate the mean value. 
Automatically calculated HR, PR, QRS, QT, and corrected QT using the Fridericia correction 
formula (QTcF) will be used to summarize the observed value and change from baseline value 
by visit and timepoint. 
Additional categorical analysis for the QT and QTcF will also be performed based on categories 
as below: 
• 
Observed value: ≤450 ms, >450 and ≤480 ms, >480 and ≤500 ms, >500ms 
• 
Change from baseline value: ≤30 ms, >30 ms and ≤60 ms, >60 ms 
 
Overall interpretation (‘Normal’, ‘Abnormal, Not Clinically Significant’, or ‘Abnormal, Clinically 
Significant’) of 12-lead ECG will be summarized using shift table to compare the investigator’s 
evaluation between baseline and each post-baseline visit and timepoint. 
9.3.6 Immunogenicity 
Anti-drug antibodies (ADAs) will be summarized categorically, hierarchically displaying the 
positive and negative results from screening assay and confirmatory assay by scheduled visit 
and cohort. Confirmed positive ADAs 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 for the subjects who have ADA 
positive results from confirmatory assay, hierarchically displaying the positive and negative 
results from screening assay and confirmatory assay by scheduled visit and cohort. Cross-
reactivity for confirmed positive NAbs will be summarized by scheduled visit and cohort. 
Anti-polyethylene glycol (Anti-PEG) antibodies will be summarized categorically, displaying the 
positive and negative results from screening assay, confirmatory titer and specificity by 
scheduled visit and cohort. 
10 INTERIM ANALYSIS 
No formal interim analyses are planned for this study, but preliminary analysis will be 
conducted to decide whether proceed to Part 2 as stated in the section 3.3 of this SAP. 
11 SAS PROCEDURES 
One-way ANOVA to compare PK parameter between cohort: 
PROC MIXED DATA=data; 
CLASS cohort; 
MODEL lnpk = cohort / DDFM=KR; 
REPEATED / TYPE=UN SUBJECT=subjid GROUP=cohort; 
ESTIMATE 'Severe vs Normal' cohort -1 1 / CL ALPHA=0.1; 


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RUN; 
 
 


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12 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. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use, ICH Harmonised Guideline, Addendum on Estimands and Sensitivity 
Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials (E9 
(R1)), 20 November 2019. 
4. 
Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function - 
Study Design, Data Analysis, and Impact on Dosing. FDA Guidance, September 2020. 
5. 
Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients 
with Decreased Renal Function. EMA Committee for Medicinal Products for Human 
use, 17 December 2015. 






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a. Screening will consist of two CRU outpatient visits (Screening Visit 1 and 2) -between 3 to 14 days apart, with the 1st screening visit occurring within 28 days prior to IP 
administration (Day 1). At each screening visit, blood sample will be taken for the eGFR assessment. The 2nd screening visit is only to demonstrate stable renal function with 
eGFR ≤ 25% of the value obtained at Screening visit 1. Other screening procedures completed during the first visit do not need to be repeated except eGFR, adverse event 
assessment and physical examinations. 
b. 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. BMI will be calculated with the height measured at S1. 
c. Serum pregnancy tests at the Screening visit; serum or urine pregnancy tests at the Day -1 and Day 29. A woman is considered to have childbearing potential, following 
menarche and until becoming post-menopausal unless permanently sterile. 
d. After completion of study procedures on Day 2, if subjects request to discharge, subjects may be discharged from the CRU on their desired date, upon investigator’s discretion. 
If subjects discharge from CRU, all the remaining procedures scheduled for inpatient period will be conducted by outpatient visit. 
e. If subjects discharge earlier than Day 8 based on the subject’s request, Day 3, 4, 5, 6, and 7 procedures can be done in outpatient visits. 
f. On Day 8, urine drug test and alcohol screening will be performed only if subjects discharge earlier than Day 8. 
g. Supine BP and HR will be measured for 2 consecutive times, at least 2 minutes apart, after the subject has been recumbent and at rest ≥ 5 minutes, and mean values will be 
recorded. If abnormal, at the Screening visit, measurement will be repeated 1 more time and the average of the 3 BP values should be used to determine the subject’s eligibility. 
h. Samples for a chemistry test will be collected after at least 4 hours of fasting.  
i. The 2nd screening visit is only to demonstrate stable renal function with eGFR ≤25% of the value obtained at Screening visit 1. Other clinical laboratory tests except serum 
creatinine assessment, do not need to be repeated. 
j. The 12-lead ECGs will be performed after the subject has been resting supine for ≥ 5 minutes. A triplicate 12-lead ECGs will be performed at screening period and Day1. At all 
other times, however, single 12-lead ECGs will be performed. Limited to Day 1, ECGs will be performed at predose and at 4 hours postdose, and a ±30-minute assessment 
window is allowed for measurement 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. 
k. Injection site assessments will be performed at predose and at 4 and 12 hours postdose on Day 1. 
l. Full physical examination at Screening Visit 1 (S1); brief physical examination at all other time points. 
m. At the early discontinuation visit, every effort must be made to complete the assessments planned at Day 29.