Conditions: NAFLD
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 66
Healthy volunteers: yes

Brief summary:
This study is a phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of HM15211 in obese subjects with NAFLD

Detailed description:
This study will be single-blind and conducted in up to 6 cohorts comprising a total of up to 72 obese subjects with NAFLD. Each cohort will enroll subjects to ensure that at least 12 subjects per cohort will complete the study. Subjects will be randomized to investigational product (IP) or placebo in a 3:1 ratio via an Interactive Web Response System (IWRS). Per cohort (n=12 subjects), 9 subjects will be randomized to IP and 3 subjects to placebo. Cohorts may partially overlap after at least 9 subjects have completed 2-4 weeks of treatment (2 weeks of treatment is reached at Visit week 3) and a dose escalation decision has been made. Study drug will be administered weekly over a period of 12 weeks.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: HM15211 intervention 2: Placebo of HM15211
Intervention descriptions: intervention 1: A sterile solution of HM15211 contained in pre-filled syringes intervention 2: A sterile, matching solution in pre-filled syringes

Protocol document:
Prot_000.pdf: 
Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
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Page 1 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
Clinical Development HM15211 
Clinical Study Protocol HM-TRIA-102 
A PHASE 1 STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF MULTIPLE DOSES OF 
HM15211 IN OBESE SUBJECTS WITH NAFLD 
 
Sponsor: 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu 
Seoul, 05545 
Korea 
Sponsor Contact: 
Seungjae Baek, MD, PhD  
Executive Director of Clinical Science and 
Pharmacovigilance  
Telephone: +82-2-410-9039 
Clinical Research 
Organization: 
ProSciento, Inc. 
855 3rd Avenue, 
Chula Vista, CA, 91911 
USA 
Authors: 
Marcus Hompesch, MD (ProSciento, Inc.), Jae Duk Choi, 
PhD (Hanmi Pharm. Co., Ltd) 
Document type: 
Clinical Study Protocol 
IND number: 
137766 
Version number: 
V5.0 
Development phase: 
1 
Release date: 
02-Jul-2019 
 
Statement of Confidentiality 
This document contains ProSciento, Inc. and Hanmi Pharmaceutical Co., Ltd privileged or 
confidential information and is provided to you as an investigator, potential investigator, sponsor, 
or consultant, solely for review by you, your staff, and applicable institutional review board(s). 
The information is not to be disclosed to others without written authorization from ProSciento, 
Inc. and Hanmi Pharmaceutical Co., Ltd. 


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1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided. 
1.2 
Approval 
Representatives of Sponsor and Coordinating Principal Investigator will sign the 
agreement on the protocol. Signatures of the responsible Investigator’s at all participating 
sites will be collected in a separate protocol approval document. 
1.3 
Document History 
Version 
Revision 
Date 
Revision Description 
1.0 
27-Sep-2018 
Original Document 
2.0 
(Amendment 1) 
25-Oct-2018 
 
1. Dose Escalation in Part 1 of the Study: 
The starting dose of the study drug for cohort  
1-1 in Part 1 will be 0.01 mg/kg. The proposed 
dose for cohort 1-2 will be 0.02 mg/kg and the 
dose for cohort 1-3 will not exceed 0.04 mg/kg, 
but dose escalation will not exceed a two-fold 
increase between doses/cohorts. 
Section 2.0 Study Summary/Part 1, section 4.5 
Dose Escalation Algorithm.  
2. Administrative Changes/ Correction of 
Typographical Errors: 
2.1 Addition of coagulation to SOEs. 
2.2 Addition of footnote to SOEs. 
2.3 Correction of typo in header of SOE for Part  
Section 16.0 Appendix A. 
 2.4 Update of exclusion criterion # 24 in Part 2, 
as a part of the sentence was inadvertently 
deleted. 
Section 2.0 Study Summary/Part 2, section 7.4 
Part 2 Exclusion Criteria 
2.5 Typo in measurement period for ABPM 
Section 2.0 Study Summary 
2.6 Typo in email address on Investigator 
Approval Page 
Section  1.2 Approval 


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3.0 
(Amendment 2) 
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1. Adjustment and Addition of Parameter for 
Laboratory Analysis: 
Additional parameters will be analyzed to 
expand the assessment of the drug. 
CRP: Parameter will be added for analysis from 
blood samples taken on Day 3 in  
Part 1/Cohort 3 and in Part 2 of the study. For 
subjects who already participated in Part 1/ 
Cohort 1 or 2, back-up samples may be used for 
analysis.  
hs-CRP: Analysis of hs-CRP in Part 2 of the 
study will not be performed. 
Beta-hydroxybutyrate (BHB): Parameter will be 
added as exploratory endpoint and blood 
samples will be collected on Day 1 (pre-dose), 
Day 57 and Day 85 for Part 1/Cohort 3 and Part 
2. For subjects who already participated in Part 
1/Cohort 1 or 2, back-up samples may be used 
for analysis. 
Adiponectin: Parameter will be added as 
exploratory endpoint and blood samples will be 
taken on Day 1, Day 57 and Day 85 for Part 
1/Cohort 3 and Part 2. For subjects who already 
participated in Part 1/Cohort 1 or 2, back-up 
samples may be used for analysis. 
Section 2.0 Study Summary, sections 5.1.2 and 
5.2.2 Exploratory Objectives and Endpoints, 
section 6.2 Study Description, section 9.1.17 
Laboratory Pharmacodynamic Assessments, 
Table 9-2 and Table 9-3 Clinical Laboratory 
Assessments, section 9.1.22 Blood Volume, 
Table 12-1 and Table 12-2 Study Endpoints, 
Table 16-1 and Table 16-2 Schedule of Events. 
2. Change of Sponsor Contact 
Change of name and title of the person 
authorized to sign the protocol and the protocol 
amendments for the sponsor.  
Title Page, Sponsor Protocol Approval Page 
3. Incorporation of Administrative Letter # 1, 
dated 14 Nov 2018: 
Clarification of body weight measurement on  
Day -1. 


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Section 4.5 Dose Escalation Algorithm and 
section 16.0 Appendix A in Table 16-1 and 16-2 
4. Incorporation of Administrative Letter # 2, 
dated 03 Dec 2018: 
Correction of typographical error and 
alignment/clarification of procedures and 
injection of study drug on outpatient visits. 
Section 2.0 Study Summary and section 6.2 
Study Description 
5. Incorporation of Administrative Letter # 3, 
dated 25 Jan 2019: 
a) Clarification to measurement of temperature 
in order to allow for oral and aural assessments. 
Section 6.2 Study Design, section 9.1.6 Vital 
signs 
b) Adjustment of language for immunogenicity 
sampling to align with the SOE and to clarify 
that sampling will be performed 30 min prior to 
dosing on Day 1, and post the first dosing on 
Day 22,50, 78, 85 and 99. Post first dose 
samples will be taken at the same time point of 
safety blood sampling or collection of other 
blood samples. 
Section 9.1.20 Immunogenicity Assessments 
c) Clarification around the measurement of 
blood pressure on Day 4 and 81. Blood pressure 
is to be taken prior to the PK sample, and is 
independent from the disconnection from the 
ABPM. 
Section 9.1.6 Vital signs 
6. Addition of example parameters for the 
assessment of heart rate variability (HRV) 
SDANN and SDNN index added. 
Section 3.0 List of Abbreviations, Table 12-1, 
Table 12-2, section 12.2.5 Safety Analysis and 
Endpoints 
7. Correction of typographical errors and 
formatting 
5.1. Row “Week 3, Day 15” stated 2nd instead of 
3rd dosing. 
Table 9-3 PK Sampling Schedule 
5.2. Rows “Week” and “Day” were adjusted to 


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include Day 77 to Week 11. 
5.3. Row “PK Sampling”: X mark deleted on 
Day 79, as PK sampling follows the PK 
Sampling Schedule in section 9.1.16. 
Section 16.0 Appendix A in Table 16-1 and 16-2 
4.0 
(Amendment 3) 
09-Apr-2019 1. Up to 3 additional cohorts may be added to 
Part 1 of the study. Cohort 1-4 will proceed 
with a dose of HM15211 of 0.06 mg/kg body 
weight. 
Based on prediction from PK data for the second 
cohort, geometric mean weekly AUC0-t will not 
exceed PK exposure limit determined in 
toxicology studies. Therefore, this protocol will 
be amended to enroll up to 3 additional cohorts 
to increase the dose of the study drug in 
increments. The increments will be determined 
at dose escalation meetings, up to a maximum of 
0.12 mg/kg. Cohort 1-4 will proceed with a dose 
of 0.06 mg/kg 
Section 4.4 Rationale for Starting and Maximum 
Dose, 4.5 Dose Escalation Algorithm, 6.1 Study 
Design ,6.4 Study Discontinuation and Stopping 
Criteria,  
2. Addition of up to 2 study sites 
As up to 3 additional cohorts, with up to n=36 
additional subjects are added, up to 2 additional 
sites may be included in the study, if needed in 
order to fulfill enrollment needs. 
Section 2.0 Study Summary 
3. Addition of PK sampling timepoints starting 
with cohorts 1-3 (at week 12) 
Four (4) additional samples will be collected. 
Blood volume will be adjusted. 
Section 9.1.16 Pharmacokinetic Assessments 
and Schedule, section 9.1.22 Blood Volume  
4. Prolongation of In-house Period 2 
Due to the added PK sampling timepoint on Day 
82, subjects in cohort 1-4 will not be released 
home on Day 81 but will stay overnight for the 
collection of the PK sample in the morning of 
Day 82. The extended In-house Period is 


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optional for subjects that are already 
participating in cohort 1-3. 
Section 2.0 Study Summary, 6.2 Study 
Description, Section 16.0 Appendix A in Table 
16-3 Table 16-4 
5. Extension of ABPM and Holter monitoring 
Period 
Due to the added PK sampling timepoints 
around Tmax, a consecutive extension of ABPM 
and Holter monitoring until Day 5 in week 1 and 
until Day 82 in week 12 will be added. 
Section 2.0 Study Summary, 6.2 Study 
Description, section 9.1.6 Vital signs, section 
9.1.11 ECG Procedure, Section 9.1.14 ABPM, 
Section 16.0 Appendix A in Table 16-3 and 
Table 16-4 
6. Adjustment of ECG timepoint 
Due to the extended ABPM and Holter 
monitoring period until Day 5 and Day 82, the 
ECG measurements are moved from Day 4 to 
Day 5 and from Day 81 to Day 82 as well, as 
they are supposed to be conducted after the 
ambulatory devices have been removed. 
Section 9.1.11 ECG Procedure, Section 16.0 
Appendix A in Table 16-2, 16-3 and 16-4 
7. Part 2 of the study will not be conducted 
Description of Part 2 and language referring to 
Study Part 2, will be deleted. Language in other 
parts of the protocol will be adjusted to reflect 
the changes, such as subject number, etc. As 
there is only one study part left, the specification 
“Part 1” will be deleted. 
Title of the study, section 2.0 Study Summary, 
section 4.2 Rationale for the Proposed Study, 
section 4.5 Dose Escalation Algorithm, section 
5.0 Study Objectives Part 2, 6.1 Study Design, 
6.2 Study Description, 6.3 Rationale for Study 
Design and Endpoints, 7.0 Part 2 Inclusion and 
Exclusion Criteria, 8.6 Randomization and 
Blinding, 9.1.8 Procedures for Clinical 
Laboratory Samples, 9.1.17 Laboratory 
Pharmacodynamic Assessments, 9.1.18 MRI-


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PDFF, 9.1.19 VCTE, 9.1.22 Blood Volume, 12.0 
Statistical Methods 
8. Modification of Dose Escalation Stopping 
Criteria 
Dose Escalation Stopping Criteria were modified 
for gastrointestinal (GI) criteria (emesis/ 
vomiting), as it is anticipated that the GI 
tolerability will be dose limiting. 
Section 6.4 Study Discontinuation and Stopping 
Criteria 
9. Addition of HbA1c as Parameter to 
Exploratory Endpoints 
Section 2.0 Study Summary, section 5.1.2 
Exploratory Objectives and Endpoint, 9.1.17 
Laboratory Pharmacodynamic Assessments 
10. Adjustment of Rescreening Requirements 
Allowing subjects who would otherwise qualify 
not be limited to 1 rescreen. Subjects who have 
screen failed due to out of window may be 
rescreened with CRO approval.  
Section 9.1.2 Screening 
11. Clarification around serum hCG pregnancy 
test 
If FSH level in postmenopausal women is not 
corresponding to the stated postmenopausal 
status, a serum hCG pregnancy test may be 
performed out of the screening sample, if sampel 
is within stability range. 
Section 9.1.9 Contraception 
12. Clarification of Immunogenicity Sampling 
In order to correct current inconsistencies of 
sampling volumes with actual sampling 
instructions, the section of the immunogenicity 
sampling will only reference the 
Immunogenicity Sample and Shipping 
Instructions. 
Section 9.1.20 Immunogenicity Assessments 
13. Clarification of the timing for the tolerability 
assessment 
Specification of the timepoints for the 
assessment of injection site reactions to 


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differentiate between dosing days and non-
dosing days are inserted. 
Section 9.1.21 Tolerability Assessment 
14. Clarification of Language 
a) Clarification of language for check-in criteria. 
Section 9.1.12 Check-in Procedure 
b) Clarification of timepoint for body weight 
measurement through addition of a footnote. 
Section 16.0 Appendix A in Table 16-1 and 16-2 
15. Formatting Adjustments 
Section 9.1.21 Tolerability Assessments 
16. Adjustment of language for the responsibility 
of statistical services. 
Adjustment of language to reflect that statistical 
services have already been delegated to 
Pharmapace, Inc.. 
Section 12.1 Statistical and Analytical Plans 
5.0 
(Amendment 4) 
02Jul-2019 
1. Three additional exploratory objectives and 
endpoints added to the study 
a) Changes in liver steatosis and liver stiffness 
assessed by FibroScan® (VCTE), determined 
as absolute and percent change from baseline 
in controlled attenuation parameter (CAP) 
and liver stiffness measurements (LSM) 
An additional FibroScan assessment will be 
performed on Day 85 for subjects participating 
in Cohort 1-4 and up, to assess a change from 
baseline assessment after 12 weeks of treatment.  
Section 2.0 Study Summary, section 5.1.2 
Exploratory Objectives and Endpoints, 6.2 Study 
Description, 9.1.19 VCTE, and 16.0 Appendix A 
in Table 16-4 and 16-5. 
b) Changes in visceral fat volume, determined 
by absolute and relative percent change 
assessed by MRI 
For subjects participating in cohort 1-5 and up, 
assessment of visceral fat will be performed at 
Screening, and after 8 and 12 weeks of treatment 
via MRI. 
Section 2.0 Study Summary, section 5.1.2 
Exploratory Objectives and Endpoints, 6.2 Study 


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Description, 9.1.18 MRI/MRI-PDFF 
 
c) Waist circumference/waist measurement 
The measurement of the waist circumference is 
stated in the protocol in 2 different ways, as 
waist circumference and as waist measurement. 
In order to avoid confusion and to be consistent 
throughout the protocol, only the term waist 
circumference will be used.  
Measurements of waist circumference at Day 85 
will be added for cohorts 1-3 and up, and will be 
performed at Screening, Day 85 and at the 
Follow-up Visit. 
Section 9.1.5 Height, Weight, BMI and Waist 
Circumference and 16.0 Appendix A in Tables 
16-1 to 16-5. 






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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION .......................................................... 2 
1.1 
Contacts ................................................................................................... 2 
1.2 
Approval .................................................................................................. 2 
1.3 
Document History .................................................................................... 2 
2.0 
STUDY SUMMARY ................................................................................... 16 
3.0 
LIST OF ABBREVIATIONS ...................................................................... 28 
4.0 
INTRODUCTION ....................................................................................... 31 
4.1 
Background ............................................................................................ 31 
4.2 
Rationale for the Proposed Study............................................................ 32 
4.3 
Summary of Pre-Clinical/Clinical Studies .............................................. 32 
4.4 
Rationale for Starting and Maximum Dose ............................................. 33 
4.5 
Dose Escalation Algorithm ..................................................................... 34 
5.0 
STUDY OBJECTIVES ................................................................................ 36 
5.1.1 
Primary Objectives and Endpoints ............................................. 36 
5.1.2 
Exploratory Objectives and Endpoints ....................................... 37 
6.0 
STUDY DESIGN AND DESCRIPTION ..................................................... 39 
6.1 
Study Design .......................................................................................... 39 
6.2 
Study Description ................................................................................... 40 
6.3 
Rationale for Study Design and Endpoints.............................................. 43 
6.4 
Study Discontinuation and Stopping Criteria .......................................... 43 
6.4.1 
Dose Escalation Criteria ............................................................ 43 
6.4.2 
Dose Escalation Stopping Criteria ............................................. 44 
6.4.3 
Criteria for Early Termination of the Study ................................ 44 
6.4.4 
Criteria for Early Termination of Individual Subjects................. 45 
7.0 
STUDY POPULATION .............................................................................. 46 
7.1 
Inclusion Criteria .................................................................................... 46 
7.2 
Exclusion Criteria................................................................................... 46 
7.3 
Prohibited Medications ........................................................................... 48 
7.4 
Check in Criteria .................................................................................... 50 
8.0 
STUDY MATERIALS ................................................................................. 51 
8.1 
Investigational Products (IPs) ................................................................. 51 
8.1.1 
HM15211 .................................................................................. 51 
8.1.2 
Placebo ...................................................................................... 51 
8.2 
Packaging, and Labeling of Investigational Products .............................. 51 


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8.3 
Storage and Drug Accountability of Investigational Products ................. 51 
8.4 
Dose Regimen ........................................................................................ 52 
8.5 
Overdose ................................................................................................ 52 
8.6 
Randomization and Blinding .................................................................. 52 
8.7 
Breaking of Blinded Code ...................................................................... 53 
9.0 
STUDY PLAN............................................................................................. 54 
9.1 
Study Procedures .................................................................................... 54 
9.1.1 
Informed Consent and HIPAA Release ...................................... 54 
9.1.2 
Screening................................................................................... 54 
9.1.3 
Demographics and Medical History ........................................... 55 
9.1.4 
Physical Examination ................................................................ 55 
9.1.5 
Height, Weight, BMI and Waist Circumference ......................... 55 
9.1.6 
Vital Signs ................................................................................. 55 
9.1.7 
Concomitant Illness and Therapy ............................................... 56 
9.1.8 
Procedures for Clinical Laboratory Samples .............................. 56 
9.1.9 
Contraception ............................................................................ 62 
9.1.10 
Pregnancy .................................................................................. 63 
9.1.11 
ECG Procedure .......................................................................... 63 
9.1.12 
Check-in Procedure ................................................................... 64 
9.1.13 
Standardized Meals ................................................................... 64 
9.1.14 
ABPM ....................................................................................... 65 
9.1.15 
Holter Monitoring ...................................................................... 65 
9.1.16 
Pharmacokinetic Assessments and Schedule .............................. 66 
9.1.17 
Laboratory Pharmacodynamic Assessments ............................... 67 
9.1.18 
MRI/MRI-PDFF ........................................................................ 68 
9.1.19 
VCTE ........................................................................................ 68 
9.1.20 
Immunogenicity Assessments .................................................... 69 
9.1.21 
Tolerability Assessments ........................................................... 69 
9.1.22 
Blood Volume ........................................................................... 70 
10.0 
ADVERSE EVENTS ................................................................................... 71 
10.1 
Definitions ............................................................................................. 71 
10.1.1 
Adverse Event (AE)................................................................... 71 
10.1.2 
Treatment Emergent Adverse Event (TEAE) ............................. 71 
10.1.3 
Adverse Events of Special Interest (AESI) ................................. 71 
10.1.4 
Clinical Laboratory Event .......................................................... 71 
10.1.5 
Adverse Reaction ...................................................................... 72 


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10.1.6 
Suspected Adverse Reaction ...................................................... 72 
10.1.7 
Unexpected Adverse Event/ Unexpected Suspected Adverse 
Reaction .................................................................................... 72 
10.1.8 
Serious Adverse Event (SAE)/ Serious Suspected Adverse 
Reaction .................................................................................... 72 
10.1.9 
Life-Threatening Adverse Event/Life-Threatening Suspected 
Adverse Reaction ...................................................................... 73 
10.2 
Severity of AEs ...................................................................................... 73 
10.3 
Relationship to Study Treatment............................................................. 73 
10.4 
Procedures.............................................................................................. 74 
10.4.1 
Collection and Recording of AEs ............................................... 74 
10.4.2 
Collection and Reporting of SAEs and AESIs ............................ 74 
10.5 
Anticipated Adverse Events ................................................................... 75 
10.6 
Follow-up of AEs and SAEs ................................................................... 75 
10.6.1 
Safety Reporting to IRBs or IECs, and Regulatory Authorities .. 76 
11.0 
DATA HANDLING AND MANAGEMENT .............................................. 77 
11.1 
Data Management .................................................................................. 77 
11.2 
CRFs (Electronic)................................................................................... 77 
11.2.1 
Clinical Data Management Workflow ........................................ 77 
11.2.2 
Data Entry of eCRFs.................................................................. 78 
11.2.3 
Corrections to eCRFs ................................................................. 78 
11.2.4 
PI Approval of eCRF Data ......................................................... 78 
11.3 
Retention of Documents ......................................................................... 78 
12.0 
STATISTICAL METHODS ........................................................................ 79 
12.1 
Statistical and Analytical Plans ............................................................... 79 
12.2 
Study Endpoints ..................................................................................... 79 
12.2.1 
Analysis Sets ............................................................................. 82 
12.2.2 
Analysis of Demographics and Other Baseline Characteristics ... 82 
12.2.3 
Analysis of the Pharmacokinetic Endpoints ............................... 82 
12.2.4 
Analysis of the Pharmacodynamic Endpoints............................. 82 
12.2.5 
Safety Analysis and Endpoints ................................................... 83 
12.3 
Interim Analysis ..................................................................................... 83 
12.4 
Determination of Sample Size ................................................................ 83 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................. 84 
13.1 
Monitoring ............................................................................................. 84 
13.2 
Protocol Deviations ................................................................................ 84 


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14.0 
ETHICAL ASPECTS OF THE STUDY ...................................................... 85 
14.1 
Institutional Review Board and/or Independent Ethics Committee .......... 85 
14.2 
Regulatory Authorities ........................................................................... 85 
14.3 
Responsibilities of the Investigator ......................................................... 85 
14.4 
Informed Consent ................................................................................... 86 
14.5 
Subject Confidentiality ........................................................................... 86 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy .............. 87 
14.7 
Insurance and Compensation for Injury .................................................. 87 
15.0 
REFERENCES ............................................................................................ 88 
16.0 
APPENDIX A .............................................................................................. 89 
17.0 
APPENDIX B ............................................................................................ 104 
 
LIST OF IN-TEXT TABLES 
Table 4-1 Treatment Allocation and Dose Escalation (NAFLD) .............................. 34 
Table 7-1 Prohibited Medications ............................................................................ 49 
Table 9-1 Clinical Laboratory Assessments at Screening ......................................... 57 
Table 9-2 Clinical Laboratory Assessments during the Study ................................... 59 
Table 9-3 PK Sampling Schedule for cohorts 1-1 and 1-2 ........................................ 66 
Table 9-4 PK Sampling Schedule starting from cohort 1-3 ....................................... 67 
Table 12-1 Study Endpoints ..................................................................................... 79 
Table 16-1 Schedule of Events Cohorts 1-1 and 1-2 ................................................. 89 
Table 16-2 Schedule of Events, Cohort 1-3 (not including Day 82) .......................... 92 
Table 16-3 Schedule of Events, starting with Cohort 1-3 (including Day 82) ........... 95 
Table 16-4 Schedule of Events, Cohort 1-4 .............................................................. 98 
Table 16-5 Schedule of Events, Cohort 1-5 and up ................................................ 101 
 
LIST OF IN-TEXT FIGURES 
Figure 4-1 Dose Escalation Schematic ..................................................................... 35 
 


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STUDY SUMMARY 
Name of Study 
Drug 
HM15211 
Protocol 
Number 
HM-TRIA-102 
Protocol Title  
 
A PHASE 1 STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF MULTIPLE DOSES OF 
HM15211 IN OBESE SUBJECTS WITH NAFLD  
Study Overview 
The study will include up to 6 cohorts with 12 obese subjects with 
nonalcoholic fatty liver disease (NAFLD) each (up to total n=72), 
to assess safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) of HM15211 compared to placebo. Study 
drug will be administered weekly over a period of 12 weeks.  
Phase of 
Development 
1 
Number of 
Study Sites 
Up to 8 sites 
Subjects 
Obese Subjects with NAFLD in Part 1 
Number of 
Subjects 
Approximately up to 72 subjects, divided in up to 6 cohorts with 
12 subjects per cohort.  
Route of 
Administration 
All study drugs will be administered by subcutaneous (SC) 
injection into the abdominal wall on a weekly basis. 
Duration of 
Participation 
The duration of participation in this study including Screening, 
Treatment and Follow-up will be approximately 23 weeks for each 
subject including 12 weeks of treatment period. 
Primary 
Objectives and 
Endpoints 
To assess safety and tolerability of HM15211 after administration 
of multiple SC doses in obese subjects with NAFLD by: 
x Incidence of adverse events (AEs) (cardiovascular [CV] 
events, rash/inflammatory dermatitis and other skin 
disorders, gastrointestinal [GI] events, and gallstone 
formation [cholelithiasis] will be managed following 
separate AE guidance document) 
x Incidence of clinical lab abnormalities (including serum 
amylase, serum lipase, coagulation, thyroid stimulating 
hormone (TSH), serum calcitonin) 


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x Immunogenicity (Anti-drug antibodies [ADAbs], 
neutralizing antibodies [nAbs], anti-polyethylene glycol 
antibodies [anti-PEG]) 
x Incidence and severity of clinical findings on physical 
examination 
x Change from baseline in vital signs (blood pressure [BP], 
heart rate [HR], respiratory rate, and temperature]);  
BP assessed by 24-hour ambulatory blood pressure 
monitoring (ABPM); 
HR assessed by 24-hour ambulatory electrocardiography 
monitoring (Holter ECG; central reader) 
x Change from baseline in 12-lead ECG parameters; the 
primary ECG endpoint will be QTcF 
x Injection site reactions 
To assess the pharmacokinetic (PK) profile of HM15211 after 
administration of multiple SC doses in obese subjects with 
NAFLD by, but not limited to: 
x Maximum concentration (Cmax) 
x Time to reach Cmax (tmax) 
x Trough plasma concentration (Ctrough) 
x Area under the concentration-time curve (AUC), eg, 
AUC0-t at steady state 
x Terminal elimination rate constant (kel) 
x Terminal half-life (t1/2) 
x Apparent clearance (CL/F) 
x Apparent volume of distribution (Vz/F) 
To assess a reduction of liver fat after administration of multiple 
doses in obese subjects with NAFLD by: 
x Absolute and % changes of fat on magnetic resonance 
imaging-estimated proton density fat fraction (MRI-PDFF) 
Exploratory 
Objectives and 
Endpoints 
To assess additional PD properties of HM15211 after multiple SC 
doses in comparison to placebo by: 
x Incretins / metabolic hormones 
o Glucagon-like peptide-1 (GLP-1) 


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o Gastric inhibitory peptide (GIP) 
o Glucagon 
o Fibroblast growth factor 21 (FGF21) 
o Leptin 
x Body weight and body mass index (BMI) 
x Waist circumference 
x Serum lipid profile and particles  
o Total cholesterol 
o Low-density lipoprotein (LDL), LDL-C, LDL-P 
(particles),  
o High-density lipoprotein (HDL), HDL-C, HDL-P 
(particles) 
o Very low-density lipoprotein (VLDL), VLDL-C, 
VLDL-P (particles) 
o Triglycerides 
o Free Fatty Acids (FFAs) 
x Amino acid profile  
x Inflammatory markers 
o Adiponectin 
x Bone metabolism parameters 
o Fasting carboxy-terminal crosslinked telopeptide of 
type 1 collagen (CTX-1) 
o Osteocalcin (OC) 
o Procollagen type 1 N-terminal propeptide (P1NP) 
x Glucose metabolism parameters: 
o Fasting plasma glucose (FPG) 
o Fasting insulin, fasting C-peptide 
o HbA1c 
x Ketone bodies: 
o Beta-hydroxybutyrate (BHB) 
x Changes in liver steatosis and liver stiffness assessed by 
FibroScan® (VCTE), determined as absolute and percent 
change from baseline in controlled attenuation parameter 
(CAP) and liver stiffness measurements (LSM) 
x Changes in visceral fat volume, determined by absolute 
and relative percent change assessed by MRI imaging 


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Summary of 
Study Design 
 
The study includes a randomized, single-blind, placebo-controlled, 
multiple-ascending dose study to investigate the safety, 
tolerability, and PK of SC administration of HM15211 in 
approximately up to 72 (n=12/cohort) obese subjects with 
NAFLD.  
To assess the effect of multiple SC doses of HM15211 in obese 
subjects on: 
1. Change in % liver fat, assessed by MRI-PDFF in obese 
subjects with pre-existing % liver fat >10% (determined by 
MRI-PDFF). 
The study will be conducted in up to 6 dosing cohorts that might 
partially overlap, enrolling 12 subjects per cohort. Subjects will be 
randomized to HM15211 or placebo in a ratio of 3:1 (9 on active, 
3 on placebo). 
Dose escalation to the next dose will proceed based on safety and 
tolerability and available PK data. After 2-4 weeks treatments of at 
least 3/4 (n=9) active participating subjects of previous dose, 
safety and available blinded PK/PD data will be reviewed to 
decide on beginning the next cohort. If dose escalation is stopped, 
dose de-escalation may occur in additional cohorts, to further 
refine clinically relevant dose levels. 
Screening: 
A Screening Visit will be performed up to 44 days prior to the first 
dosing to identify subjects for the study. All screening evaluations 
except MRI-PDFF will be performed.  
Only eligible subjects will undergo an MRI-PDFF for the 
assessment of liver fat within 30 days of randomization. Subjects 
who meet the inclusion criteria of >10% liver fat will proceed with 
the study and will be invited for the In-house Period 1. 
For subjects in cohort 1-5 and up: Only eligible subjects will 
undergo an MRI/MRI-PDFF for the assessment of liver fat and 
visceral fat within 30 days of randomization. Subjects who meet 
the inclusion criteria of >10% liver fat will proceed with the study 
and will be invited for the In-house Period 1. 
In-house Period 1: 
Day -2: Subjects will check in to the clinic in the morning on Day 
-2 for a 10-day In-house Period. They will receive standardized 
meals throughout their inpatient stay. Subjects will be connected 
to an ABPM system, and overnight measurements will be taken to 


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familiarize the subjects with the device. ABPM measurements will 
continue throughout Day 5. Only 24-hour monitoring data from 
Day -1 will be used for the baseline monitoring evaluation. 
Day -1: In the morning, subjects will be connected to a Holter 
ECG for 24-hour measurements and will continue these until Day 
5. Only 24-hour monitoring data from Day -1 will be used for the 
baseline monitoring evaluation. 
Subjects will be randomized to a weekly SC injection of 
HM15211 or placebo. 
Day 1: The active study drug or placebo, will be administered in 
the morning at approximately 08:00 hours (t=0), SC into the 
abdominal wall by qualified study staff. Measurements of vital 
signs, sampling for PK at pre-dose and 8 hours after dosing, and 
pre-dose sampling for laboratory parameters including 
incretins/metabolic hormones, lipid profiles and particles, amino 
acid panel, inflammatory marker, glucose metabolism parameters, 
ketone bodies and evaluations for safety parameters will be 
performed. 
ABPM and Holter ECG monitoring will be continued until the 
morning of Day 5 for the post-dose evaluation. 
Subjects will continue to stay in-house for safety evaluations and 
PK. They will be released from the clinical research unit (CRU) on 
Day 8, after the second dose of the weekly study drug is 
administered. They will return for multiple outpatient visits. 
Outpatient Visits: 
Subjects will return to the CRU every week (Days 10, 15, 22, 29, 
36, 43, 50, 57, 64, 71) in order to undergo assessments as 
described in the SOE. Subjects will receive the injection of the 
study drug in an outpatient fashion to ensure compliance on days 
15, 22, 29, 36, 43, 50, 57, 64 and 71. 
MRI/MRI-PDFF: Subjects will undergo an MRI/MRI-PDFF 
assessment during week 8, as close as possible to Day 57, but prior 
to the Day 57 (week 9) Dosing. 
During all outpatient visits, blood samples for PK analysis, 
exploratory endpoints and safety assessments as stated in the SOE 
will occur. 
In-house Period 2: 


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Day 77: Subjects will check in to the clinic in the morning on Day 
77 for a 5-day In-house Period. They will receive standardized 
meals throughout their inpatient stay. Subjects will be connected 
to an ABPM system, and overnight measurements will be taken to 
familiarize the subjects with the device. ABPM measurements will 
continue throughout Day 82. 
Day 78 to Day 82: In the morning, subjects will be connected to a 
Holter ECG for 24-hour measurements and will continue these 
until Day 82. A sample for the assessment of PK will be collected 
pre-dose for PKtrough. Study drug will be administered. 
Measurements of vital signs, sampling for PK and sampling for 
laboratory parameters and evaluations for parameters for safety 
parameters will be performed. 
Subjects will continue to stay in-house for safety evaluations and 
PK. They will be disconnected from Holter monitoring and ABPM 
on Day 82 and will be released home in the morning of Day 82, 
after the PK sample has been collected. 
For subjects participating in cohort 1-3, the in-house stay until day 
82 is optional. These subjects will continue to stay in-house for 
safety evaluations and PK until Day 81, after they are 
disconnected from Holter monitoring and ABPM. 
Subjects will undergo an MRI/MRI-PDFF assessment to assess 
liver fat during week 12, as close as possible to Day 85. For 
subjects in cohort 1-5 and up, visceral fat will be assessed 
additionally during the imaging procedure. 
Outpatient Visits: 
Subjects will return to the CRU during elimination phase of the 
drug on Days 85 and 99. On Day 85, measurements of vital signs, 
sampling for laboratory parameters including incretins/metabolic 
hormones, lipid profiles and particles, amino acid panel, bone 
metabolism parameters, glucose metabolism parameters, 
inflammatory marker, ketone bodies, local injection site 
evaluation, and evaluations for safety parameters will be 
performed for the assessment after 12 weeks of dosing. For 
subjects in cohort 1-4 and up, a FibroScan assessment will be 
performed additionally.  
On Day 99, sampling for PK, PD and safety will be performed as 
stated in the SOE. 
Follow-up Visit: 


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A follow-up visit will take place on Day 113 (± 2) to collect final 
safety assessments and the last PK sample. 
Treatment 
Sample Treatment Schedule: 
Cohorts 
Number of 
Subjects 
Treatment Period 
Cohort 1-1 
N=9 
HM15211 0.01 mg/kg 
N=3 
Matching Placebo 
Cohort 1-2 
N=9 
HM15211 0.02 mg/kg 
N=3 
Matching Placebo 
Cohort 1-3 
N=9 
HM15211 0.04 mg/kg 
N=3 
Matching Placebo 
Cohort 1-4 
N=9 
HM15211 0.06 mg/kg 
N=3 
Matching Placebo 
Cohort 1-5 
N=9 
HM15211 X mg/kg 
N=3 
Matching Placebo 
Cohort 1-6 
N=9 
HM15211 0.12 mg/kg 
N=3 
Matching Placebo 
 
Inclusion 
Criteria 
Subjects who meet all criteria at Screening will be included in the 
study:  
1. Adults ≥ 18 to ≤ 65 years. 
2. Body mass index (BMI) ≥ 30 kg/m2, with stable body 
weight by history for 3 months (defined as change < 5%). 
3. Waist circumference ≤ 57 inches. 
4. Fasting Plasma Glucose < 7 mmol/L (126 mg/dL). 
5. HbA1c < 6.5%. 
6. CAP ≥ 300 dB/m by FibroScan. (Subjects with matching 
results within 30 days prior to screening don’t need to 
undergo this procedure). Subjects with CAP 275-299 dB/m 
may proceed to MRI with CRO approval pending review 
of medical history and lab data. 
7. Liver fat by MRI-PDFF ≥ 10%. 


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8. Female subjects must be non-pregnant and non-lactating. 
Females of child bearing potential must use highly 
effective contraceptive methods, stable at least 2 months 
prior to the screening.  
9. Male subjects must be surgically sterile, abstinent or if 
engaged in sexual relations of child-bearing potential, the 
subject and his partner must use an acceptable method of 
contraception.  
10. Ability and willingness to comply with all protocol 
procedures (e.g., correct handling of investigational 
product, compliance to visit schedule and dietary advice, 
and complete trial-related questionnaires). 
Exclusion 
Criteria 
Subjects who meet any of the following criteria will be excluded 
from the study:  
1. Subjects with a history of or active chronic liver disease 
due to alcohol, auto-immune, HIV, HBV or active HCV-
infection or NASH disease. 
2. Any history of clinically significant chronic liver disease 
including esophageal varices, ascites, encephalopathy or 
any hospitalization for treatment of chronic liver disease; 
or Model for End Stage Liver Disease (MELD) ≥ 10.  
3. Previous surgical treatment for obesity (bariatric surgery, 
gastric banding, etc.) or any other gastrointestinal surgery 
that may induce malabsorption, history of bowel resection 
> 20 cm, any malabsorption disorder, severe gastroparesis, 
any GI procedure for weight loss (including LAP-
BAND®), as well as clinically significant gastrointestinal 
disorders (e.g. peptic ulcers, severe gastrointestinal reflux 
disease [GERD]) at Screening.  
4. Pacemaker, implanted electronic devices, metal fragments, 
aneurysm clips in the brain that could interfere with the 
MRI examination. 
5. Use of any prohibited concomitant medication (as listed in 
the table Prohibited Medication below) from time points 
specified until completion of the study. 
6. Uncontrolled hypertension, defined as systolic blood 
pressure >150 mmHg and/or diastolic blood pressure ≥ 100 
mmHg at screening (reading may be repeated on a 
different day). (Subjects with uncontrolled hypertension 


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may be rescreened after 3 months, following initiation or 
adjustment of antihypertensive therapy). 
7. Any weight control treatment within 3 months prior to 
Screening. 
8. Participation in an investigational study within 30 days 
prior to dosing or 5 half-lives within the last dose of 
investigational product whichever is longer. 
9. Personal history or current diagnosis of acute or chronic 
pancreatitis or factors for pancreatitis, such as a history of 
cholelithiasis (without cholecystectomy) or alcohol abuse.  
10. History of major depression, anxiety, suicidal behavior or 
attempts, or other psychiatric disorder (within 2 years of 
screening), requiring medical treatment, including selective 
serotonin reuptake inhibitors (SSRIs), serotonin 
norepinephrine reuptake inhibitors (SNRIs), 
antipsychotics, lithium. 
11. History of any major surgery within 6 months prior to 
screening. 
12. History of any serious adverse reaction or hypersensitivity 
to study drugs components. 
13. History or current diagnosis of heart disease, defined as 
symptomatic heart failure (New York Heart Association 
class III or IV), myocardial infarction, unstable angina 
requiring medication, transient ischemic attack, cerebral 
infarct, or cerebral hemorrhage or invasive cardiovascular 
procedure, such as coronary artery bypass graft surgery 
(CABG), or angioplasty/percutaneous coronary 
intervention (PCI) within 6 months of screening. (A 
diagnostic cardiac catheterization without any intervention 
does not exclude the subject.) 
14. Presence of clinically significant ECG findings (eg, QTcF 
> 450 msec for males, QTcF > 470 msec for females, 
LBBB) at Screening, or cardiac arrhythmia requiring 
medical or surgical treatment within 6 months prior to 
screening. 
15. Personal or family history of medullary thyroid carcinoma 
(MTC) or a genetic condition that predispose to MTC (ie, 
multiple endocrine neoplasia type 2). 


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16. Abnormal laboratory results: 
a) for fasting triglycerides >1000 mg/dL. Elevated values 
may be repeated once on a separate day. 
b) for pancreatic function, suggestive of pancreatic 
impairment (eg, amylase and lipase >3 x ULN). 
c) for calcitonin levels > 20 pg/mL. 
d) Transaminases (AST, ALT) > 3X ULN. 
17. History of renal disease or abnormal kidney function tests 
at Screening (glomerular filtration rate [GFR] < 60 
mL/min/1.73m2 as estimated using the MDRD equation).  
18. History of any active infection, other than mild viral illness 
within 30 days prior to dosing as judged by the 
Investigator. 
19. History of alcohol or illicit drug abuse as judged by the 
Investigator within approximately 1 year. Average daily 
drinking of ≥ 4 units/day for men and ≥ 3 units/day for 
women or are unwilling to stop alcohol consumption from 
24 hours prior to each check-in for in-house and outpatient 
visits and throughout the in-house periods until discharged 
from the clinical research unit (CRU) and are unwilling to 
limit alcohol consumption during outpatient periods. 
Positive alcohol test at Screening. (One unit of alcohol 
equals about 250 mL of beer, 90 mL of wine, or 25 mL of 
spirits). 
20. Daily use of more than 10 cigarettes/day, or 2 cigars/day, 
or equivalent use of any tobacco product within 6 weeks 
prior to Screening.  
21. Frequent use of marijuana within 6 weeks, or clinically 
under the effect at Screening, as per Investigator 
evaluation. 
22. Positive test for hepatitis B surface antigen (HBsAg), 
hepatitis C antibody (HCV Ab), or human 
immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) 
antibody. 
23. Any anticipated procedures (eg, surgery), that might 
interfere with the compliance or completion of the study. 
24. Presence of clinically significant physical exam, ECG or 
laboratory finding at screening that, in the opinion of the 


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Investigator, may interfere with any aspect of study 
conduct or interpretation of results. 
25. Donation or loss of > 500 mL of blood or blood product 
within 56 days of dosing. 
26. Mental incapacity, unwillingness or language barriers 
precluding adequate understanding or cooperation  
27. Is employed by Hanmi or ProSciento (permanent, 
temporary contract worker, or designee responsible for the 
conduct of the study) or is immediate family of Hanmi or 
ProSciento, defined as a spouse, parent, sibling, or child, 
whether biological or legally adopted. 
Prohibited 
Medication 
Medication or 
Class 
Indication/Reason 
From time point specified 
until the end of the study 
Antihypertensive 
medication  
Hypertension 
Excluded unless on stable 
dose for at least 3months 
prior to screening 
Statins 
Hyperlipidemia 
Excluded unless on stable 
dose for at least 3 months 
prior to screening 
Oral or systemic 
long-acting 
corticosteroids 
Eg, chronic or acute 
non-infectious 
inflammatory 
conditions, auto-immune 
diseases 
Within 3 months prior to 
screening 
Antacids, 
anticholinergics, 
antispasmodics 
(eg, modafinil, 
phenytoin), 5HT3 
antagonists, 
dopamine 
antagonists, or 
opiates, 
antiemetics  
Reduction/modification 
of GI motility 
Within 2 weeks prior to 
screening 


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Orlistat, lorcaserin, 
sibutramine, etc., 
including over-the-
counter and herbal 
supplements, or 
any medication 
with a labelled 
indication for 
weight loss or gain 
Weight control 
treatment 
Within 3 months prior to 
screening. 
Any anti-diabetic 
medication 
Diabetes 
Any prior treatment 
Selective serotonin 
reuptake inhibitors 
(SSRIs), serotonin 
norepinephrine 
reuptake inhibitors 
(SNRIs), 
antipsychotics, 
lithium.  
Depression, anxiety, 
psychiatric disorders 
 
 
Current treatment 
Use of SSRIs and 
SNRIs (including 
bupropion) 
For reasons other than 
active psychiatric 
indications (eg, 
migraine, weight loss, 
smoking cessation) 
Within 3-month prior to 
screening. 
 
Statistical 
Methods 
Data analyses will follow a statistical analysis plan (SAP). 
PK and PD assessments for all dose groups will be analyzed using 
descriptive and comparative statistical methods. 
No formal sample size calculation will be performed. Safety and 
tolerability of the study drug will be assessed based on adverse 
events, laboratory parameters, physical examination, vital signs, 
and ECG parameters throughout the duration of the study. Safety 
analysis will involve examination of the descriptive statistics and 
individual subject listings for any effects of study treatment on 
clinical tolerability and safety. 
 


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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABPM 
Ambulatory blood pressure measurement 
ADAbs 
Anti-drug antibodies  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Anti-PEG 
Anti-polyethylene glycol antibody 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BG 
Blood glucose 
BHB 
Beta-hydroxybutyrate 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
BP 
Blood pressure 
BW 
Body weight 
CDM 
Clinical data management 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Cmax 
Maximum concentration  
CRF 
Case report form 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
CV 
Coefficient of variation 
DFT 
Deviation from target 
DMP 
Data management plan 
ECG  
Electrocardiogram 
eCRF 
Electronic CRF 
FDA 
Food and Drug Administration 
FFA 
Free fatty acid 
FGF 
Fibroblast growth factor  
FPG 
Fasting plasma glucose 
FSFV 
First subject first visit 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GIP 
Glucose dependent insulinotropic polypeptide/ gastric 
inhibitory peptide 
GLP-1 
Glucagon-like peptide 
HbA1C 
Glycosylated hemoglobin 
HbsAg 
Hepatitis B surface antigen 


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HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRV 
Heart rate variability 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
lb 
Pound 
LBBB 
Left brunch bundle block 
LDL 
Low-density lipoprotein 
LS mean 
Least square mean 
LSM 
Liver stiffness measurement 
Mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
Mg 
Milligram 
MRI-PDFF 
Magnetic resonance imaging-estimated proton density fat 
fraction 
nAbs 
Neutralizing antibodies  
NAFLD 
Nonalcoholic fatty liver disease  
NASH 
Nonalcoholic steatohepatitis 
NCA 
Non-compartmental analysis 
NDA 
New Drug Application 
nmol 
nanomol 
NN 
Normal to normal  
PD 
Pharmacodynamics 
PE 
Physical examination 
PEG 
Polyethylene glycol 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
RR 
Respiration rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SDANN 
Standard deviation of the 5-minute average NN interval 
SDNN 
Standard deviation of all normal intervals 


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SDNN index 
Mean of standard deviations of all NN intervals for all 5 min 
segments of the entire recording. 
SOE 
Schedule of event 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to maximum serum concentration (in concentration 
time curve) 
TSH 
Thyroid-stimulating hormone 
U 
Unit 
ULN 
Upper limit of normal 
US 
United States  
USP 
Unites States Pharmacopeia 
VCTE 
vibration controlled transient elastography 
VLDL 
Very low-density lipoprotein 
Vz/F 
Apparent volume of distribution at terminal phase 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Excess weight has become an epidemic disease and impairs the health of more than 1.9 
billion adults, of whom 650 million are obese, defined by a. BMI of ≥ 30kg/m2. This 
represents about 13% of the world’s adult population.1 
Obesity impacts many organ systems. One affected system is the cardiovascular system, 
with an increased prevalence of heart failure, hypertension and coronary heart disease. 
Obstructive sleep apnea and asthma are also common in the obese. Non-alcoholic fatty 
liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), is on the rise 
and may soon become the leading cause of cirrhosis and hepatocellular carcinoma 
globally. Psychosocial and psychiatric consequences of obesity are also increasing.2 
Dual agonists have been developed that co-target the glucagon and glucagon like peptide  
(GLP-1) receptors for obesity treatment.3 Additionally, triple agonists, which have added 
a gastric inhibitory polypeptide receptor (GIPR) agonist to the combination, are under 
development in early phase clinical studies. 
HM15211 is a novel long-acting triple incretin agonist. It is a chemical conjugate of a 
chimeric peptide (GLP-1/Glucagon/GIP triple agonist; named TA15211) and human 
immunoglobulin G4 Fc fragment (named HMC001) linked via a bifunctional Maleimide-
Polyethylene glycol- Aldehyde (MAL-PEG-ALD) linker molecule.  
TA15211 is produced by chemical synthesis and the quality of TA15211 is controlled by 
complying with in-house specification. The HMC001 moiety was derived from the 
constant region of human immunoglobulin G4 fragment and produced in the transformed 
E. coli as an inclusion body. The inclusion body was purified after successive refolding 
and purification steps, and the quality of HMC001 was controlled by in-house 
specification. Human immunoglobulin G4 Fc fragment (HMC001) was chosen as the 
stabilizing agent because it is the most prevalent blood protein and has an in vivo half-life 
of several weeks without effector functions including antibody dependent cellular toxicity 
(ADCC) and complement dependent cytotoxicity (CDC). The linker is a 10 kDa 
polyethylene glycol (PEG) with bifunctional reactive groups (maleimide aldehyde 
reactive groups at individual ends, MAL-PEG-ALD). The conjugation of TA15211 and 
HMC001 is carried out through the formation of a thioether and amine bond between 
hetero-bifunctional MAL-PEG-ALD, Cys40 in TA15211, and the N-terminal amino acid 
in HMC001. 
HM15211 is a long-acting GLP-1/Glucagon/GIP triple agonist with an extended half-life 
through reduced renal clearance and possibly by vascular endothelial recycling via FcRn 
binding. HM15211 showed triple-agonistic properties with potent glucagon activity in 
addition to balanced GLP-1 and GIP activity.  
According to series of in vivo pharmacologic studies, HM15211 can be an attractive 
treatment option for obese patients based on its potent body weight loss efficacy from 


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energy intake inhibition and energy expenditure enhancement. Glucagon activity 
provides potent body weight loss primarily from fat mass reduction as shown in efficacy 
studies in diet-induced obesity (DIO) mice. Furthermore, GLP-1/GIP activities negate a 
possible hyperglycemic risk as demonstrated in intra-peritoneal glucose tolerance test 
(ipGTT) studies in normal and DIO mice.  
Above all, liver preferential distribution, and subsequent hepatic lipid metabolism 
improvement, renders HM15211 a suitable therapeutic option for NASH and hepatic 
fibrosis. Therefore, HM15211 is expected to have favorable therapeutic profiles in both 
obesity and NASH as well as convenience in its weekly clinical dosing regimen. 
For further information please refer to the Investigator’s brochure (IB). 
4.2 
Rationale for the Proposed Study 
The aim of this multiple ascending dose study is to investigate safety and tolerability of 
the drug as well as the PK and PD profiles in obese subjects with NAFLD. Up to 6 
cohorts in obese subjects with NAFLD will compare HM15211 to placebo.  
Adverse effects observed in the ongoing single ascending dose study (HM-TRIA-101), 
include so far GI events of nausea and vomiting. The management of any cardiac event, 
dermatitis, cholelithiasis and GI events will follow a specific adverse event management 
plan as provided in section 17.0. 
Based on the pre-clinical data and the conducted single ascending dose study (HM-TRIA-
101), the intended potential target populations will ensure that a robust and relevant set of 
safety, PK and PD data can be generated. 
4.3 
Summary of Pre-Clinical/Clinical Studies 
In vitro activity of HM15211 was evaluated using respective receptors, human GLP-1 
receptor (hGLP-1R), human glucagon receptor (hGlucagonR), and human GIP receptor 
(hGIPR). HM15211 showed dose-dependent activation of all three receptors with potent 
glucagon activity in addition to balanced GLP-1 and GIP activity. Simultaneous 
activation of three incretin receptors could provide synergistic metabolic benefits on body 
weight loss and lipid profile improvement whilst avoiding hyperglycemic risk.  
Further in vitro studies confirmed that since HM15211 includes an aglycosylated Fc 
moiety derived from human IgG4, there are minimal immune-mediated effector 
functions. In addition, due to Fc moiety, HM15211 retained pH-dependent FcRn binding 
property, which is essential for vascular endothelial recycling. 
In vivo pharmacology studies using obese mice showed that HM15211 enables potent 
body weight loss from both food intake inhibition and enhanced energy expenditure. The 
body weight loss was mainly from fat mass reduction, along with lowered serum lipid 
profile. Glucagon action increased energy expenditure and thus enhanced body weight 
loss; hyperglycemic risk by glucagon was effectively buffered by actions of GLP-1/GIP. 
In NASH-induced models, HM15211 effectively reduced hepatic triglycerides (TG), 


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oxidative stress and inflammatory markers. Furthermore, HM15211-treated animals 
showed significant reduction in NAFLD activity score and hepatic fibrogenic markers, 
suggesting HM15211 is an effective pharmacotherapy for NASH with hepatic fibrosis. 
Safety pharmacology studies were conducted to evaluate the effects on the 
cardiovascular, respiratory, central nervous systems and in vitro hERG channel assay. No 
significant effect was observed in the safety pharmacology studies and in vitro human 
ether-a go-go related gene (hERG) channel assay.  
In pharmacokinetic studies, HM15211 exhibited a prolonged half-life (t½) after 
subcutaneous (SC) or intravenous (IV) dosing, which ranged from approximately 42.7 to 
85.6 hours in mice, 74.7 to 86.0 hours in rats, and 35.7 to 79.7 hours in dogs, indicating 
that HM15211 is a long acting triple-agonist. HM15211 is preferentially distributed in the 
liver, making HM15211 a favorable treatment option for dysfunction in lipid metabolism 
specifically in the liver. 
The toxicity studies of HM15211, repeat dose toxicity up to 4 weeks in rats and monkeys, 
and in vitro genotoxicity studies, were conducted. Local tolerance of HM15211 was 
investigated in 4-week repeated rat and monkey studies. Additional studies were 
conducted with HMC001 (inactive ingredient) in rat and monkey up to 4 weeks repeat 
dose toxicity studies.  
No target organ was identified during the 4 weeks repeat dose toxicity studies of 
HM15211. All changes were completely or partially reversible during the recovery 
period.  
The majority of findings were related to fasting effect or pharmacological effect of 
glucagon. No adverse test article-related findings at the injection sites were noted. No 
adverse events were observed in HMC001 studies.  
Treatment emergent adverse events observed in the HM-TRIA-101 study and thought to 
be related to study drug are primarily gastrointestinal, specifically nausea and vomiting.  
Most GI adverse events were mild in severity; no cardiac or drug-related dermatologic 
adverse events have been noted up to this point. 
4.4 
Rationale for Starting and Maximum Dose 
Doses up to 0.12 mg/kg were evaluated in the single dose HM-TRIA-101 study. The 
steady state weekly AUC (AUC168SS) after multiple dosing can be approximated to the 
AUCinf after single dosing.  From the HM-TRIA-101 study, the maximum AUCinf after 
single dosing in the 0.12 mg/kg group was 126,281 ng*h/mL. In the 13 week rat 
toxicology study, the AUC168 exposure during the 13th week was 297,000 ng*h/mL at the 
rat NOAEL dose of 0.4 mg/kg. At the highest proposed dose in this study, the ratio would 
be (297,000/126,281) = 2.4  
Moreover, clinical issues including skin lesions, gastrointestinal adverse events (nausea 
and vomiting) and an elevation in fasting plasma glucose are known to occur as 


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exaggerated pharmacology with glucagon agonists such as HM15211. All of these 
clinical signs and symptoms are easily monitored, and are reversible. 
4.5 
Dose Escalation Algorithm 
The proposed dose escalation algorithm may include the following steps: 
Table 4-1 Treatment Allocation and Dose Escalation (NAFLD) 
Cohorts 
Number of Subjects 
Treatment Period 
Cohort 1-1 
N=9 
HM15211 0.01 mg/kg 
N=3 
Matching Placebo 
Cohort 1-2 
N=9 
HM15211 0.02 mg/kg 
N=3 
Matching Placebo 
Cohort 1-3 
N=9 
HM15211 0.04 mg/kg 
N=3 
Matching Placebo 
Cohort 1-4 
N=9 
HM15211 0.06 mg/kg 
N=3 
Matching Placebo 
Cohort 1-5 
N=9 
HM15211 X mg/kg 
N=3 
Matching Placebo 
Cohort 1-6 
N=9 
HM15211 0.12 mg/kg 
N=3 
Matching Placebo 
 
Additional cohorts may be added if necessary, to provide sufficient data. Proposed doses 
for cohort 1-2 and 1-3 and 1-4 may be adjusted but will not exceed the doses stated in the 
table. 
Each subject will be randomized to HM15211 or placebo according to the table above. 
The dose for the weekly dosing in cohort 1-1 will be 0.01 mg/kg, based on the body 
weight measured prior to the first dosing on Day -1. For dose calculation and rounding, 
please refer to the Operations Manual/Pharmacy Manual. 
After at least ¾ (n=9) of the subjects participating in one cohort have completed 2-4 
weeks of treatment (2 weeks of treatment is reached at Visit week 3), an interim data 
review meeting will be held which may include a dose escalation decision. Safety and 
available blinded PK and/or PD data will be reviewed, and predictions based on results 


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from the previous study and PK/PD data modelling will be used for a dose decision/ dose 
escalation decision for the subsequent cohort. The dose decision will be made by the 
Sponsor, medical monitor and the coordinating Principal Investigator. Dose escalation 
will not exceed a 2-fold increase. If there are no safety concerns, the next cohort may 
start and may partially overlap with the previous one. An additional data review meeting 
may be held at the end of the completed cohort.  The maximum dose for cohort 1-3 will 
not exceed 0.04 mg/kg. The dose for cohort 1-4 will be 0.06 mg/kg. The maximum dose 
for the study will not exceed 0.12 mg/kg. 
Following the dose escalation decision, the procedures for the subsequent cohorts will be 
identical to those described above. Therefore, all cohorts could be performed in parallel.   
The blind of the study will be maintained throughout. If dose escalation is stopped, dose 
de-escalation may occur for additional cohorts, to further refine the dose. 
Figure 4-1 Dose Escalation Schematic 
 
Optional adjustments 
Optional adjustments to the number of cohorts: 
If the first 3 cohorts do not provide sufficient data for the dose selection, optional cohorts 
may be added. The optional cohorts may proceed with a higher dose or a lower dose. If 
deemed appropriate, another cohort with the repetition of the same dose may be 
conducted. 
Optional adjustments to the study visits and sampling schedule: 
Depending on the safety and tolerability and/or on available PK/PD results of the first 
cohorts, additional study visits might be performed, or existing visit schedule or PK/PD 
sampling schedule may be adjusted/rescheduled for following cohorts.  


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5.0 
STUDY OBJECTIVES 
5.1.1 Primary Objectives and Endpoints 
To assess safety and tolerability of HM15211 after administration of multiple SC doses in 
obese subjects with NAFLD by: 
x Incidence of adverse events (AEs) (cardiovascular [CV] events, 
rash/inflammatory dermatitis and other skin disorders, gastrointestinal [GI] 
events, and gallstone formation [cholelithiasis] will be managed following 
separate AE guidance document) 
x Incidence of clinical lab abnormalities (including serum amylase, serum lipase, 
coagulation, thyroid stimulating hormone (TSH), serum calcitonin) 
x Immunogenicity (Anti-drug antibodies [ADAbs], neutralizing antibodies [nAbs], 
anti-polyethylene glycol antibodies [anti-PEG]) 
x Incidence and severity of clinical findings on physical examination 
x Change from baseline in vital signs (blood pressure [BP], heart rate [HR], 
respiratory rate, and temperature]);  
BP assessed by 24-hour ambulatory blood pressure monitoring (ABPM); 
HR assessed by 24-hour ambulatory electrocardiography monitoring (Holter 
ECG; central reader) 
x Change from baseline in 12-lead ECG parameters; the primary ECG endpoint will 
be QTcF 
x Injection site reactions 
To assess the pharmacokinetic (PK) profile of HM15211 after administration of multiple 
SC doses in obese subjects with NAFLD by, but not limited to: 
x Maximum concentration (Cmax) 
x Time to reach Cmax (tmax) 
x Trough plasma concentration (Ctrough) 
x Area under the concentration-time curve (AUC), eg, AUC0-t at steady state 
x Terminal elimination rate constant (kel) 
x Terminal half-life (t1/2) 
x Apparent clearance (CL/F) 
x Apparent volume of distribution (Vz/F) 
To assess a reduction of liver fat after administration of multiple doses in obese subjects 
with NAFLD by: 


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x Absolute and % changes of fat on magnetic resonance imaging-estimated proton 
density fat fraction (MRI-PDFF) 
5.1.2 Exploratory Objectives and Endpoints 
To assess additional PD properties of HM15211 after multiple SC doses in comparison to 
placebo by: 
x Incretins / metabolic hormones 
o Glucagon-like peptide-1 (GLP-1) 
o Gastric inhibitory peptide (GIP) 
o Glucagon 
o Fibroblast growth factor 21 (FGF21) 
o Leptin 
x Body weight and body mass index (BMI) 
x Waist circumference 
x Serum lipid profile and particles  
o Total cholesterol 
o Low-density lipoprotein (LDL), LDL-C, LDL-P (particles),  
o High-density lipoprotein (HDL), HDL-C, HDL-P (particles) 
o Very low-density lipoprotein (VLDL), VLDL-C, VLDL-P (particles) 
o Triglyceride 
o Free Fatty Acids (FFAs) 
x Amino acid profile  
x Inflammatory marker 
o Adiponectin 
x Bone metabolism parameters 
o Fasting carboxy-terminal crosslinked telopeptide of type 1 collagen 
 (CTX-1) 
o Osteocalcin (OC) 
o Procollagen type 1 N-terminal propeptide (P1NP) 
x Glucose metabolism parameters: 
o Fasting plasma glucose (FPG) 
o Fasting insulin, fasting C-peptide 
o HbA1c 
x Ketone bodies  
o Beta-hydroxybutyrate 


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x Changes in liver steatosis and liver stiffness assessed by FibroScan® (VCTE), 
determined as absolute and percent change from baseline in controlled attenuation 
parameter (CAP) and liver stiffness measurements (LSM) 
x Changes in visceral fat volume, determined by absolute and relative percent 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a randomized, placebo-controlled, multiple-ascending dose study to investigate 
the safety, tolerability, PK and PD of SC administration of HM15211, conducted in 1 
part. 
This study will be single-blind and conducted in up to 6 cohorts comprising a total of up 
to 72 obese subjects with NAFLD. Each cohort will enroll subjects to ensure that at least 
12 subjects per cohort will complete the study. Subjects will be randomized to 
investigational product (IP) or placebo in a 3:1 ratio via an Interactive Web Response 
System (IWRS). Per cohort (n=12 subjects), 9 subjects will be randomized to IP and 3 
subjects to placebo. Cohorts may partially overlap after at least 9 subjects have completed 
2-4 weeks of treatment (2 weeks of treatment is reached at Visit week 3) and a dose 
escalation decision has been made. Study drug will be administered weekly over a period 
of 12 weeks.  
Based on available safety, tolerability, and PK data of each cohort, and following a safety 
review and dose escalation meeting between the investigator and the sponsor, dose 
escalation to the next cohort may proceed. Cohorts will start in sequential order but may 
overlap partially during execution. Replacement of dropouts and withdrawals may take 
place.  
Each subject will undergo a screening visit, 2 in-house/ treatment periods and multiple 
outpatient visits. A final follow-up visit that will conclude subject study participation. 
The duration of participation in this study including Screening, Treatment and Follow-up 
will be approximately 23 weeks for each subject including 12 weeks of treatment period. 
 
Figure 6-1 Study Design Schematic Cohorts 1-1 to 1-3 
 
 
 


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Figure 6-2 Study Design Schematic Cohort 1-4 and up 
 
*Day 82 is optional for subjects in cohort 1-3 
6.2 
Study Description 
Each subject will undergo the following procedures during the study: 
Screening Visit: 
Before the screening takes place, potential subjects for the trial will be provided with 
written and oral information about the trial and the procedures involved. Subjects must 
sign the informed consent form (ICF) prior to entering the study. Please see section 9.1.1 
for further details.  
The screening visit will be performed up to 44 days prior to the first dosing day, to 
identify eligible subjects for the study. All assessments performed at the screening visit 
are stated in Table 16-1 and will be recorded in the electronic case report form (eCRF). 
Please see section 9.1.2 and 11.2 for further details.  
Subjects’ screening lab parameters and VCTE (CAP) scores will be evaluated to identify 
subjects who are likely to have a liver fat content of > 10% at MRI-PDFF. Depending on 
the outcome/results of these values, the subjects will proceed to MRI/MRI-PDFF. For 
further details on parameters and outcome for the determination to proceed to MRI/MRI-
PDFF see the Operations Manual. Subjects who are not able to proceed to MRI-PDFF 
will be recorded as screening failures. 
In-house Period 1: 
Day -2: Subjects will check in to the clinic in the morning of Day -2 for a 10-day in-
house period. They will receive standardized meals throughout their in-house stay. A 12-
lead standard ECG will be performed. Subjects will be connected to an ABPM system for 
measurement of blood pressure (BP), and measurements will be started overnight on Day 
-2 to familiarize the subjects with the device. Measurements will continue until the 
morning of Day 5.  


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Day -1: In the morning of Day -1, subjects will get connected to a Holter ECG for 
continued measurement of the heart rate activity until the morning of Day 5.  
Only 24-hour monitoring data from Day -1 to Day 1 will be used for the monitoring 
evaluation as baseline assessments for ABPM and Holter ECG monitoring. For 
measuring timepoints, please see sections 9.1.14 and 9.1.15. 
Subjects will be randomized to weekly SC injections of HM15211 or placebo. 
Randomization will take place as close to the drug administration as possible. 
Day 1: On Day 1, after an ≥ 10 h overnight fast, subjects will be dosed with HM15211or 
placebo at approximately 08:00 hours (t=0), through SC injection into the abdominal wall 
by qualified study staff. Measurements of vital signs,  blood sampling for PK at pre-dose 
and 8 hours after dosing and sampling for laboratory parameters including 
incretins/metabolic hormones, lipid profiles and particles, amino acid panel, bone 
metabolism parameters, glucose metabolism parameters, ketone bodies, local injection 
site evaluation, and evaluations for safety parameters will be performed, at timepoints 
stated in Table 16-1. 
ABPM and Holter ECG monitoring will be continued until the morning of Day 5 for the 
post-dose evaluation. 
Subjects will continue to stay in-house for safety evaluations, PK and PD assessments as 
stated in the SOE. They will be released from the CRU in the morning of Day 8, after the 
second dose of the weekly study drug is administered. They will return for multiple 
outpatient visits. 
Outpatient Visits: 
Subjects will return to the CRU every week (Days 10, 15, 22, 29, 36, 43, 50, 57, 64, 71) 
in order to undergo assessments as described in Table 16-1. Subjects will receive the 
injection of the study drug in an outpatient fashion to ensure compliance on Days 15, 22, 
29, 36, 43, 50, 57, 64 and 71. 
MRI/MRI-PDFF: Subjects will undergo an MRI-PDFF assessment during week 8, as 
close as possible to Day 57, but prior to the Day 57 (week 9) Dosing. 
During all outpatient visits, blood samples for PK analysis, exploratory endpoints and 
safety assessments will be performed as stated in the Table 16-1. 
In-house Period 2: 
Day 77: Subjects will check in to the clinic in the morning on Day 77 for a 5-day In-
house Period. They will receive standardized meals throughout their inpatient stay. 
Subjects will be connected to an ABPM system, and overnight measurements will be 
taken to familiarize the subjects with the device. ABPM measurements will continue 
throughout Day 82.  
Day 78 to 82: In the morning of Day 78, subjects will get connected to a Holter ECG for 
24-hour measurements and will continue these until Day 82. Sample for the assessment 


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of PK will be collected pre-dose for PKtrough. Study drug will be administered. 
Measurements of vital signs, sampling for PK, sampling for laboratory parameters and 
evaluations for safety parameters will be performed as stated in the SOE 
Subjects will continue to stay in-house for safety evaluations and PK. They will be 
disconnected from Holter monitoring and ABPM on Day 82 and will be released home in 
the morning of Day 82, after the PK sample has been collected. 
For subjects participating in cohort 1-3, the in-house stay until day 82 is optional. These 
subjects will continue to stay in-house for safety evaluations, PD and PK until Day 81, 
after they are disconnected from Holter monitoring and ABPM. 
Subjects will undergo an MRI/MRI-PDFF assessment to assess liver fat during week 12, 
as close as possible to Day 85. For subjects in cohort 1-5 and up, visceral fat will be 
assessed additionally during the imaging procedure. 
Outpatient Visits: 
Subjects will return to the CRU during elimination phase of the drug on Days 85 and 99. 
On Day 85, measurements of vital signs, sampling for laboratory parameters including 
incretins/metabolic hormones, lipid profiles and particles, amino acid panel, bone 
metabolism parameters, glucose metabolism parameters, inflammatory markers, ketone 
bodies, local injection site evaluation, and evaluations for safety parameters will be 
performed for the assessment after 12 weeks of dosing. For subjects in cohort 1-4 and up, 
a FibroScan assessment will be performed additionally, as stated in the SOE.  
On Day 99, sampling for PK, PD and safety will be performed as stated in the SOE. 
Follow-up Visit: 
A Follow-up Visit will be performed on Day 113 (± 2) to collect final safety assessments 
and the last PK sample. Please see Table 16-1 Schedule of Events for details. 
Sampling and Assessment: 
Time points for study procedures and sample collection are specified in the Table 16-1. 
Safety assessments will occur throughout the duration of the study, including monitoring 
of adverse events (AEs), clinical laboratory tests (eg, chemistry, hematology, 
coagulation, amylase, lipase and urinalysis), vital signs measurements (blood pressure, 
heart rate, respiration rate, and aural/oral temperature), 12-lead electrocardiograms 
(ECGs), ABPM, Holter ECG monitoring, and physical examinations. 
Local tolerability assessments will be performed by injection site inspection at specific 
time-points as stated in the Table 16-1. 
Immunogenicity samples for assessment of ADAbs, nAbs and anti-PEG will be taken 
prior to first dosing on Day 1, on Days 22, 50, 78, 85 and 99 as stated in the Table 16-1.  
The PK samples will be taken in accordance with the PK sampling schedule in section 
9.1.16. Sampling may be adjusted based on the results of the SDRM. 


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The PD samples will be taken in accordance with the PD sampling schedule in section 
9.1.17. Sampling time points may be adjusted based on the results of the SDRM. 
 
Follow-up Visit: 
A follow-up visit will take place on Day 113 (± 2) in order to collect final safety 
assessments and the last PK sample. 
6.3 
Rationale for Study Design and Endpoints  
This MAD study will assess the safety and tolerability, PK and PD of HM15211 in obese 
subjects with NAFLD compared to placebo.  
Cohorts will be assessed in ascending order, but may overlap, to determine a clinically 
appropriate dose for the subjects and will include the comparison with placebo. 
Randomization is used to avoid bias introduced through an association between study 
drug allocation order and subject characteristics. 
A single-blind design has been chosen to avoid bias and to maintain the blind between 
the administration of the study drug and placebo for subjects and clinical staff. 
Obese subjects with NAFLD will participate in the study, as these subjects are an 
important target population for the novel triple agonist. Enrollment criteria will favor the 
target population. Liver fat will be determined by MRI-PDFF and body mass index of ≥ 
30 kg/m2. 
Measurements for the assessment of cardiovascular events will start right after dosing and 
will continue until Day 5. 
The proposed PK endpoints are well-established, commonly used parameters to 
characterize pharmacological profiles of drugs. For the PK endpoints, blood samples for 
determination of HM15211 will be analyzed using a validated assay. 
This is an exploratory study. No formal sample size calculation and no statistical 
hypothesis testing will be performed. 
6.4 
Study Discontinuation and Stopping Criteria 
6.4.1 Dose Escalation Criteria 
Dose decision algorithms: 
x The primary tolerability criterion for decision-making will be emesis/vomiting  
(= GI tolerability). 
x As emesis has been shown to be associated with pharmacological doses of GLP-1 
agonists and glucagon, the severity of emesis is defined as follows for this study: 


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o Moderate: 3 to 5 episodes in 24 hours (individual episodes separated by at 
least 5 min) 
o Severe: ≥ 6 episodes in 24 hours (individual episodes separated by at least 
5 min) or requiring iv fluids 
6.4.2 Dose Escalation Stopping Criteria 
Dose escalation will be stopped if one of the following conditions apply: 
x 50% or more of the subjects in the cohort have experienced moderate or severe 
emesis; 
x 25% or more of the subjects in the cohort have experienced severe emesis; 
x Death of a subject in one cohort, at any time, that is considered related to the IP, 
judged by the Investigator; 
x One (1) or more of the subjects in a cohort have experienced a serious adverse event 
(SAE), that is considered related to the IP, judged by the Investigator, following 
discussion with the medical monitor and breaking the blind; 
x Two (2) or more of the subjects in a cohort have experienced severe or medically 
significant adverse events (eg, common terminology criteria for adverse events 
[CTCAE] ≥ grade 3 may be used as a grading scale at the discretion of Investigator), 
that is considered related to the IP, judged by the Investigator; 
x Two (2) or more of the subjects in a cohort have experienced moderate adverse events 
for more than 7 days (eg, common terminology criteria for adverse events [CTCAE] 
≥ grade 2 may be used as a grading scale at the discretion of Investigator), that is 
considered related to the IP, judged by the Investigator; 
x Two (2) or more subjects receiving HM15211 develop similar clinically significant 
laboratory, significant ECG or vital signs abnormalities, or severe AEs in the same 
organ class, indicating dose-limiting intolerance. Dose escalation may proceed if after 
review of the data by the Investigator and discussion with Sponsor, it is concluded 
that the events are not drug related; 
x It is determined that the limit of safety and/or tolerability has been reached. Decision 
will be made between Sponsor and the Coordinating Investigator. 
x All dose escalation and stopping decisions will be made following a discussion 
between the Coordinating Investigator and Sponsor. 
6.4.3 Criteria for Early Termination of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied  


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x Violation of Good Clinical Practice (GCP) that compromises the ability to achieve the 
primary study objectives or compromises subject safety. 
x Failure to meet expected enrollment goals 
x Administrative Reasons 
In case that the Sponsor, an institutional review board (IRB)/ independent ethics 
committee (IEC), or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the Sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension. 
6.4.4 Criteria for Early Termination of Individual Subjects 
Subjects may withdraw their consent to participate in the study at any time. 
If a subject withdraws consent, the date and reason for consent withdrawal should be 
documented. Subjects will be encouraged to remain in the clinic for safety assessments 
until the Investigator deems that it is safe for the subject to be discharged. Subject data 
will be included in the analysis up to the date of the consent withdrawal. 
x AE or SAE that requires discontinuation at the discretion of the Investigator 
x Protocol violation: If protocol violation or concurrent illness occurs, which, in the 
clinical judgment of the Investigator or after discussion with the Sponsor, may 
invalidate the study by interfering pharmacokinetically or pharmacodynamically with 
the investigational products, subject will be withdrawn by the Investigator. 
x Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 
x Voluntary withdrawal of consent (mandatory removal from study) 
x Discretion of Investigator (document reason on CRF) 
x Subject becomes pregnant or begins breastfeeding (mandatory) 
x Study discontinuation by Sponsor 
Wherever possible, the tests and evaluations, including those listed for the Follow-up 
Visit should be performed for all subjects who discontinue prior to the completion of the 
study. 
In the event the Investigator determines to terminate a subject participation in the Clinical 
Study, the Investigator must notify the Sponsor of such decision and rationale 
immediately in writing. In all cases, the appropriate IRB/IEC and other applicable 
regulatory authorities shall be informed. 


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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria  
Subjects who meet all criteria at Screening will be included in the study:  
1. Adults ≥ 18 to ≤ 65 years. 
2. Body mass index (BMI) ≥ 30 kg/m2, with stable body weight by history for 3 
months (defined as change < 5%). 
3. Waist circumference ≤ 57 inches. 
4. Fasting Plasma Glucose < 7 mmol/L (126 mg/dL). 
5. HbA1c < 6.5%. 
6. CAP ≥ 300 dB/m by FibroScan. (Subjects with matching results within 30 days 
prior to screening don’t need to undergo this procedure).  Subjects with CAP 275-
299 dB/m may proceed to MRI with CRO approval pending review of medical 
history and lab data. 
7. Liver fat by MRI-PDFF ≥ 10%. 
8. Female subjects must be non-pregnant and non-lactating. Females of child 
bearing potential must use highly effective contraceptive methods, stable at least 2 
months prior to the screening. Male subjects must be surgically sterile, abstinent 
or if engaged in sexual relations of child-bearing potential, the subject and his 
partner must use an acceptable method of contraception.  
9. Ability and willingness to comply with all protocol procedures (e.g., correct 
handling of investigational product, compliance to visit schedule and dietary 
advice, and complete trial-related questionnaires). 
7.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study:  
1. Subjects with a history of or active chronic liver disease due to alcohol, auto-
immune, HIV, HBV or active HCV-infection or NASH disease. 
2. Any history of clinically significant chronic liver disease including esophageal 
varices, ascites, encephalopathy or any hospitalization for treatment of chronic 
liver disease; or Model for End Stage Liver Disease (MELD) ≥ 10. 
3. Previous surgical treatment for obesity (bariatric surgery, gastric banding, etc.) or 
any other gastrointestinal surgery that may induce malabsorption, history of 
bowel resection > 20 cm, any malabsorption disorder, severe gastroparesis, any 
GI procedure for weight loss (including LAP-BAND®), as well as clinically 
significant gastrointestinal disorders (e.g. peptic ulcers, severe gastrointestinal 
reflux disease [GERD]) at Screening.  


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4. Pacemaker, implanted electronic devices, metal fragments, aneurysm clips in the 
brain that could interfere with the MRI examination. 
5. Use of any prohibited concomitant medication (as listed in the table Prohibited 
Medication below) from time points specified until completion of the study. 
6. Uncontrolled hypertension, defined as systolic blood pressure >150 mmHg and/or 
diastolic blood pressure ≥ 100 mmHg at screening (reading may be repeated on a 
different day). (Subjects with uncontrolled hypertension may be rescreened after 3 
months, following initiation or adjustment of antihypertensive therapy). 
7. Any weight control treatment within 3 months prior to Screening. 
8. Participation in an investigational study within 30 days prior to dosing or 5 half-
lives within the last dose of investigational product whichever is longer. 
9. Personal history or current diagnosis of acute or chronic pancreatitis or factors for 
pancreatitis, such as a history of cholelithiasis (without cholecystectomy) or 
alcohol abuse.  
10. History of major depression, anxiety, suicidal behavior or attempts, or other 
psychiatric disorder (within 2 years of screening), requiring medical treatment, 
including selective serotonin reuptake inhibitors (SSRIs), serotonin 
norepinephrine reuptake inhibitors (SNRIs), antipsychotics, lithium. 
11. History of any major surgery within 6 months prior to screening. 
12. History of any serious adverse reaction or hypersensitivity to study drugs 
components. 
13. History or current diagnosis of heart disease, defined as symptomatic heart failure 
(New York Heart Association class III or IV), myocardial infarction, unstable 
angina requiring medication, transient ischemic attack, cerebral infarct, or 
cerebral hemorrhage or invasive cardiovascular procedure, such as coronary 
artery bypass graft surgery (CABG), or angioplasty/percutaneous coronary 
intervention (PCI) within 6 months of screening. (A diagnostic cardiac 
catheterization without any intervention does not exclude the subject.) 
14. Presence of clinically significant ECG findings (eg, QTcF > 450 msec for males, 
QTcF > 470 msec for females, LBBB) at Screening, or cardiac arrhythmia 
requiring medical or surgical treatment within 6 months prior to screening. 
15. Personal or family history of medullary thyroid carcinoma (MTC) or a genetic 
condition that predispose to MTC (ie, multiple endocrine neoplasia type 2). 
16. Abnormal laboratory results: 
a) for fasting triglycerides >1000 mg/dL. Elevated values may be repeated once 
on a separate day. 
b) for pancreatic function, suggestive of pancreatic impairment (eg, amylase and 
lipase >3 x ULN). 


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c) for calcitonin levels > 20 pg/mL. 
d) Transaminases (AST, ALT) > 3X ULN 
17. History of renal disease or abnormal kidney function tests at Screening 
(glomerular filtration rate [GFR] < 60 mL/min/1.73m2 as estimated using the 
MDRD equation).  
18. History of any active infection, other than mild viral illness within 30 days prior 
to dosing as judged by the Investigator. 
19. History of alcohol or illicit drug abuse as judged by the Investigator within 
approximately 1 year. Average daily drinking of ≥ 4 units/day for men and ≥ 3 
units/day for women or are unwilling to stop alcohol consumption from 24 hours 
prior to each check-in for in-house and outpatient visits and throughout the in-
house periods until discharged from the clinical research unit (CRU) and are 
unwilling to limit alcohol consumption during outpatient periods. Positive alcohol 
test at Screening. (One unit of alcohol equals about 250 mL of beer, 90 mL of 
wine, or 25 mL of spirits). 
20. Daily use of more than 10 cigarettes/day, or 2 cigars/day, or equivalent use of any 
tobacco product within 6 weeks prior to Screening.  
21. Frequent use of marijuana within 6 weeks, or clinically under the effect at 
Screening, as per Investigator evaluation. 
22. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV 
Ab), or human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) 
antibody. 
23. Any anticipated procedures (eg, surgery), that might interfere with the compliance 
or completion of the study. 
24. Presence of clinically significant physical exam, ECG or laboratory finding at 
screening that, in the opinion of the Investigator, may interfere with any aspect of 
study conduct or interpretation of results. 
25. Donation or loss of > 500 mL of blood or blood product within 56 days of dosing. 
26. Mental incapacity, unwillingness or language barriers precluding adequate 
understanding or cooperation  
27. Is employed by Hanmi or ProSciento (permanent, temporary contract worker, or 
designee responsible for the conduct of the study) or is immediate family of 
Hanmi or ProSciento, defined as a spouse, parent, sibling, or child, whether 
biological or legally adopted. 
7.3 
Prohibited Medications 
Use of the agents listed in Table 7-1 (prescription or nonprescription) is prohibited from 
the time points specified until completion of all study activities. 


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Table 7-1 Prohibited Medications 
Medication or Class 
Indication/Reason 
From time point specified 
until the end of the study 
Antihypertensive 
medication  
Hypertension 
Excluded unless on stable 
dose for at least 3 months 
prior to screening 
Statins 
Hyperlipidemia 
Excluded unless on stable 
dose for at least 3 months 
prior to screening 
Oral or systemic long-
acting corticosteroids 
Eg, chronic or acute 
non-infectious 
inflammatory 
conditions, auto-
immune diseases 
Within 3 months prior to 
screening 
Antacids, 
anticholinergics, 
antispasmodics (eg, 
modafinil, 
phenytoin), 5HT3 
antagonists, dopamine 
antagonists, or opiates, 
antiemetics  
Reduction/modification 
of GI motility 
Within 2 weeks prior to 
screening 
Orlistat, lorcaserin, 
sibutramine, etc., 
including over-the-
counter and herbal 
supplements, or any 
medication with a 
labelled indication for 
weight loss or gain 
Weight control 
treatment 
Within 3 months prior to 
screening. 
Any anti-diabetic 
medication 
Diabetes 
Any prior treatment 
Selective serotonin 
reuptake inhibitors 
(SSRIs), serotonin 
norepinephrine 
reuptake inhibitors 
(SNRIs), 
antipsychotics, lithium.  
Depression, anxiety, 
psychiatric disorders 
 
 
Current treatment 
Use of SSRIs and 
SNRIs (including 
bupropion) 
For reasons other than 
active psychiatric 
indications (eg, 
migraine, weight loss, 
smoking cessation) 
Within 3-month prior to 
screening. 
 


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7.4 
Check in Criteria 
Subjects will be educated about influencing factors, such as to refrain from strenuous 
exercise throughout the entire course of the study, to avoid alcohol and herbal 
supplements, (especially 24 hours prior to dosing), caffeinated drinks (caffeine containing 
food and beverages 24 hours prior to dosing), smoking or medication and 
illness/infection. 
At check-in for any in patient period(s) and outpatient visit(s), a subject will not be 
allowed to check in if they meet any of the following criteria and the treatment period 
may be rescheduled one time per Investigator discretion. The Sponsor will be notified 
about the rescheduling in a timely manner. 
1. Positive alcohol breath test. 
2. Positive urine drug screen test. 
3. Positive urine pregnancy test in female subjects.  
4. Any use of medicine other than any allowed concomitant medications within the 
last 24 hours. 
5. Any medical condition that could interfere with the study, as judged by the 
Investigator. 


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8.0 
STUDY MATERIALS 
8.1 
Investigational Products (IPs) 
8.1.1 HM15211 
A sterile solution of HM15211 contained in 0.52 mL pre-filled syringes will be provided. 
The concentration of HM15211 is 10 mg/mL as protein. HM15211 is manufactured by 
Hanmi Pharmaceuticals, Seoul, South Korea.  
8.1.2 Placebo 
Placebo is a sterile, matching solution (all components except drug substance) and free of 
visible particles. Placebo solution will be supplied in 0.52 mL pre-filled syringes by 
Hanmi Pharmaceuticals, Seoul, South Korea. Storage: 2 ℃ to 8 ℃. 
8.2 
Packaging, and Labeling of Investigational Products 
The Sponsor or designee will provide the Investigator with the labeled IPs in accordance 
with specific country regulatory requirements. 
The IP will be packaged and shipped to the clinical research unit (CRU) in an open label 
manner. Hanmi will prepare each syringe and place them in an independent paper 
box/carton. 
For details please see the Operations Manual. 
8.3 
Storage and Drug Accountability of Investigational Products 
All clinical material will be kept in an appropriate, limited-access, secure location. 
The investigational product, and its storage and preparation instructions, will be provided 
by the Sponsor. The IP must be stored securely at 2 ℃ to 8 ℃ (36 °F to 46 °F) and should 
not be exposed to excessive heat and never be frozen. It should be protected from direct 
sunlight and therefore should be kept in its carton until ready to be used.  
HM15211 is stable at room temperature up to 4 hours. 
The study staff is required to document the receipt, dispensing, and return/destruction of 
Study Drugs and supplies provided by or on behalf of the Sponsor. The CRU will destroy 
all used syringes of HM15211 and placebo at the CRU by the end of the study. Unused 
syringes of HM15211 and placebo will be processed as requested by the Sponsor by the 
end of the study.  
The Investigator or Investigator’s authorized staff must ensure the availability of proper 
storage conditions. The temperature of all study drugs will be monitored over 24 hours a 
day, 7 days a week (24/7). In case of incorrect storage, the Sponsor and monitor must be 
contacted without delay. 
No study drugs may be dispensed to any person not enrolled in the study.  


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8.4 
Dose Regimen 
The IPs, HM15211 or placebo will be administered after an ≥ 10 h overnight fast, by 
qualified staff while subjects are in the CRU. The products will be administered weekly 
by SC injection into a lifted skin fold of the abdominal wall. The injection needle should 
be placed at a 45° to 90° angle and kept in the skin fold for 5-10 seconds. Aim is to dose 
at approximately the same clock time (eg, at approximately 08:00 h) for all subjects. The 
actual clock time of dosing is defined as t=0. The actual time of each dosing will be 
recorded in the source documents and on the eCRFs.  
Subjects who miss a dose by > 1 day, must be approved by the medical monitor before 
they continue with the study. 
8.5 
Overdose 
If a study medication error occurs, it should be documented as Protocol Deviation. A 
brief description should be provided in the deviation, including whether the subject was 
symptomatic (list symptoms) or asymptomatic and whether the event accidental or 
intentional. 
Dosing details should be captured on the Dosing Case Report Form. If the subject takes a 
dose of IP that exceeds protocol specifications and the subject is symptomatic, then the 
symptom(s) should be documented as an AE and be reported.  
Should an overdose occur, the Investigator or designee should contact the Sponsor or 
designee within 24 hours.  
8.6 
Randomization and Blinding 
Subjects who meet all inclusion and exclusion criteria or check-in criteria will be 
assigned a subject randomization number via an Interactive Web Response System 
(IWRS). The system will randomize in a 3:1 ratio to HM15211 or placebo. 
Randomization will continue until a total of up to 72 subjects have completed the study 
(or until 12 subjects per cohort have completed the study). 
If a subject fails to start dosing, or if a subject can’t be randomized, the reason will be 
entered into the screening disposition page. The IWRS must be notified within 2 days 
that the subject was not randomized. 
In the event of an emergency, e.g. when it becomes necessary for the investigator to 
know which study drug the subject is taking, the subject code can be broken by the 
investigator, preferably after consultation with the medical monitor. Emergency code 
breaks can be performed using the IWRS, see section 8.7.  
As the study is single-blind, subjects and the clinical staff caring for the subjects are 
blinded to treatment. Staff involved in the data management, statistical analyses and staff 
from Pharmaceutical Services who are responsible for preparing the IP, will be 
unblinded. Unblinded staff will not be involved in the subjects’ care. 


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After all subjects in one cohort have completed the Follow-up Visit, necessary steps to 
start with the data analysis may be taken. Data may be unblinded and data analysis for the 
completed cohort may start. 
8.7 
Breaking of Blinded Code 
The code for a subject may be broken in a medical emergency, if knowing the identity of 
the treatment allocation would influence the treatment decision of the subject or if 
demanded by the subject. The emergency code break can be performed using the IWRS. 
Whenever a code is broken, the person breaking the code must record the time, date, and 
reason as well as his/her initials in the source documents. During un-blinding procedure 
in case of medical emergency, it should be ensured that no study personnel is unblinded 
to other subjects. Study site personnel and Sponsor personnel directly associated with the 
conduct of the study will not be unblinded. 
If the study site needs to break the code, the sponsor should, if possible, be contacted 
prior to breaking the blind. In all cases, the Trial Monitor must be notified within 24 
hours after an emergency unblinding. 
All codes (whether broken or not) must be kept throughout the trial period. 
Accountability of all broken or unbroken codes (hard copy or electronic) will be 
performed at or after trial closure and will be maintained in the Trial Investigator’s File 
(TIF) at the site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
9.1.1 Informed Consent and HIPAA Release 
Written informed consent will be obtained from each subject prior to performing any 
study-specific evaluations. The HIPAA release is embedded in the informed consent 
document. The informed consent document is subject to review and approval by the 
Sponsor and will be approved by a qualified IRB. The IRB-approved document must 
contain, at minimum, the eight basic elements of informed consent set forth in applicable 
law. Only the most recently IRB-approved informed consent document must be used to 
consent prospective study subjects. The Investigator (according to applicable regulatory 
requirements), or a person designated by the Investigator and under the Investigator’s 
responsibility, will fully inform the potential study subject of all pertinent aspects of the 
Clinical Study, including written information given approval/favorable opinion by the 
IRB/IEC.  
 
Prior to the potential subject’s participation in the Clinical Study, the written informed 
consent form must be signed, name filled in and personally dated by the subject and by 
the person who conducted the informed consent discussion, and by the Investigator. One 
copy of the signed and dated informed consent document will be given to the subject and 
the original retained by the Investigator/CRU. 
9.1.2 Screening 
Investigators must account for all subjects who sign informed consent forms. 
Screening number will be provided and will include a 3-digit site number followed by 3-
digit sequential number (i.e. 101 001). 
The Investigator will keep a Subject Screening and Enrollment Log at the investigational 
site. Subjects who have screen failed due to laboratory abnormalities may be allowed to 
re-screen once at the discretion of the Investigator. Subjects who have screen failed due 
to out of window may be rescreened with CRO approval. A new screening number will 
be assigned. 
If subjects are fasting (only water for ≥10 hours), all screening laboratory assessments 
may be done on the same day. If subjects are not fasting, they will be invited to return for 
a second screening visit to complete any missing screening procedures. 
Subjects screening lab parameter and VCTE (CAP) will be evaluated to identify subjects 
who are likely to have a liver fat content of > 10% at MRI-PDFF. Depending on the 
outcome/results of these values, the subjects will proceed to MRI/MRI-PDFF or not. For 
further details on parameters and outcome for the determination to proceed to MRI-PDFF 
see the Operations Manual. 
Subjects MELD score will be calculated according to the following formula: 


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MELD(i) = 0.957 × ln(Cr) + 0.378 × ln(bilirubin) + 1.120 × ln(INR) + 0.643 
Then, round to the tenth decimal place and multiply by 10. For further details see the 
Operations Manual. 
Subjects who meet all inclusion criteria and none of the exclusion criteria are eligible for 
this study and will be invited for the in-house period. Subjects will be instructed on 
influencing factors, such as refraining from strenuous exercise throughout the entire 
course of the study, restrictions on of alcohol and herbal supplements during the study, 
caffeinated drinks, smoking or medication and illness/infection as stated in section 7.4. 
9.1.3 Demographics and Medical History 
Demographic information and medical history, including smoking status, alcohol 
consumption and medication history will be obtained at Screening.  
9.1.4 Physical Examination 
The baseline physical examination will consist of the following body systems: (1) eyes; 
(2) ears, nose, throat, neck, thyroid; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system, mouth; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) central and peripheral nervous system and (10) lymph nodes. 
An abbreviated physical exam (based on symptoms and including examination of 
cardiovascular, respiratory, and gastrointestinal system) will be performed by the 
Investigator (or a qualified physician at the CRU) at time points indicated in the Table 
16-1. A complete physical examination may be performed in case the subjects have 
symptoms or at the discretion of the Investigator. 
9.1.5 Height, Weight, BMI and Waist Circumference  
Height (without shoes) will be measured once, during the Screening visit. 
Weight (without shoes) will be measured fasting in the morning, with light clothing and 
post void at time points indicated in the Table 16-1.  
BMI (kg/m2) will be calculated from height and weight. 
Waist circumference (inches) will be measured at Screening, Day 85 and at Follow-up 
Visit. 
9.1.6 Vital Signs 
Vital signs will include body temperature (aural or oral), supine blood pressure (supine 
BP after 5 minutes resting), respiration rate and pulse rate (after 5 minutes resting). The 
method of temperature (aural or oral) should be consistent throughout the study per 
subject from baseline through end of study. Vital sign measurements will be performed at 
days indicated in the Table 16-1. Vital signs measurements will be performed at PK 


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sampling timepoints (as stated in the PK sampling schedule), and the vital sign should be 
measured before PK sample is collected. 
Body temperature: Assessments will be performed as stated in the Table 16-1. 
Measurements may be taken more frequently, if deemed necessary by the Investigator. 
Measurement on Day -1 will be performed as baseline assessment. Measurements will 
continue throughout the study. Timepoints must not interfere with ABPM measurement 
timepoints. 
Blood pressure: 
Supine assessments will be performed. Measurements will be taken at Screening. 
Measurements on Day -2 and day 77 will be taken prior to connecting the subjects to the 
ABPM. Measurements on Day 4, 5, 81 and 82 will be taken prior to the PK sample. 
Measurements will be performed on the arm that is not connected to the ABPM system. 
Timepoints must not interfere with the ABPM measurements. 
Pulse rate and respiration rate: Assessments will be performed as stated in the Table 16-1 
at timepoints for blood pressure measurements.  
9.1.7 Concomitant Illness and Therapy 
Concomitant therapy is any medication given in addition to the investigational product 
(including over-the-counter medications, herbal medications, and vitamin supplements) 
administered between screening and follow-up.  
Concomitant illness is any significant medical condition or disease that is present at study 
start (signing of informed consent). This includes clinically significant laboratory, 
electrocardiogram (ECG), or physical examination abnormalities noted at Screening 
examination. 
Details of all concomitant illnesses and therapies must be recorded at study entry and 
must be recorded on the subject’s CRF. Any changes in concomitant medication must be 
recorded at each visit. If the change influences the subject’s eligibility to continue in the 
study, the Sponsor must be informed. The information collected for each concomitant 
medication includes, at a minimum, start date, stop date or continuing, and indication.  
AEs related to administration of these therapies or procedures must also be documented 
on the appropriate CRF. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. 
Laboratory samples (Table 9-1) will be taken as described in the Schedule of Events. 


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Table 9-1 Clinical Laboratory Assessments at Screening 
Hematology 
Serum Chemistry 
Urinalysis 
CBC with Differential: 
Hematocrit 
Hemoglobin 
Mean Corpuscular Volume 
(MCV) 
Mean Corpuscular Hemoglobin 
(MCH) 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
Red Cell Distribution Width 
(RDW) 
Percentage and Absolute 
Differential Counts 
Platelet Count 
Red Blood Cell Count (RBC) 
White Blood Cell Count (WBC) 
 
Hepatic Function Panel: 
Alanine Aminotransferase 
(ALT/SGPT) 
Alkaline Phosphatase, Serum 
Aspartate Aminotransferase 
(AST/SGOT) 
Bilirubin, Direct 
Bilirubin, Total 
Protein, Total, Serum 
Gamma Glutamyl Transferase, 
Serum 
Renal Function Panel: 
Albumin, Serum 
BUN 
BUN: Creatinine Ratio 
Calcium, Serum 
Carbon Dioxide, Total 
Chloride, Serum 
Creatinine, Serum 
Phosphorus, Serum 
Potassium, Serum 
Sodium, Serum 
Lipid Panel: 
Cholesterol, Total 
High-Density Lipoprotein (HDL) 
Cholesterol 
Low-Density Lipoprotein (LDL) 
Cholesterol (Calculated) 
Triglycerides 
Very Low-Density Lipoprotein 
(VLDL) Cholesterol (Calculated) 
Additional Parameters: 
Amylase 
Lipase 
Calcitonin 
Alpha-2 Macroglobulin 
Lactic Acid Dehydrogenase 
(LDH) 
Magnesium 
Uric Acid 
Free Fatty Acid (FFA) 
C-reactive protein (CRP) 
Routine urinalysis with 
microscopic examination on 
positives(a): 
Color 
Appearance, 
Specific Gravity 
PH 
Protein 
Glucose 
Ketones 
Occult Blood 
Leukocyte Esterase 
Nitrite 
Bilirubin 
Urobilinogen 
 
Diagnostic Screening 
Serum/Plasma/Whole Blood 
Urine 
Breath 


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Viral Serology: 
HBsAg 
Anti-HCV 
Anti-HIV-1 
Anti-HIV-2 
 
Coagulation: 
Partial thromboplastin time  
(PTT) 
PT 
International normalized ratio 
(INR) 
 
Thyroid-stimulating hormone 
(TSH)(b) 
 
HbA1c 
Serum Insulin 
FPG 
 
Drug Screen Profile 
Urine drug screen (12 panel) via 
commercial kit at the site. 
 
Female Subjects Only 
human chorionic gonadotropin 
(hCG) performed at Screening. 
Follicle-stimulating hormone 
(FSH) test for postmenopausal 
women (defined as amenorrheic 
female subjects <60 years of age 
and not surgically sterile) at 
Screening. 
Urine pregnancy testing via 
commercial kit at the site will at 
timepoints stated in the Schedule 
of Events. Urine pregnancy 
testing may be performed per 
Investigator’s discretion at 
additional timepoints during the 
study, if there is reason to 
believe the subject might be 
pregnant. 
 
Alcohol breath test at 
timepoints stated in the SOE at 
the site 
 
(a) Microscopic analysis should be performed only if urine evaluations are abnormal. 
(b) In the event of abnormal TSH, Free T3/T4 may be collected at Investigator discretion. 
 


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Table 9-2 Clinical Laboratory Assessments during the Study  
Hematology 
Serum Chemistry 
Urinalysis 
CBC with Differential: 
Hematocrit 
Hemoglobin 
Mean Corpuscular Volume 
(MCV) 
Mean Corpuscular Hemoglobin 
(MCH) 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
Red Cell Distribution Width 
(RDW) 
Percentage and Absolute 
Differential Counts 
Platelet Count 
Red Blood Cell Count (RBC) 
White Blood Cell Count (WBC) 
 
Hepatic Function Panel: 
Alanine Aminotransferase 
(ALT/SGPT) 
Alkaline Phosphatase, Serum 
Aspartate Aminotransferase 
(AST/SGOT) 
Bilirubin, Direct 
Bilirubin, Total 
Protein, Total, Serum 
Gamma Glutamyl Transferase, 
Serum 
Renal Function Panel: 
Albumin, Serum 
BUN 
BUN: Creatinine Ratio 
Calcium, Serum 
Carbon Dioxide, Total 
Chloride, Serum 
Creatinine, Serum 
Phosphorus, Serum 
Potassium, Serum 
Sodium, Serum 
 
Additional Parameters: 
Amylase 
Lipase 
Lactic Acid Dehydrogenase 
(LDH) 
Magnesium 
Uric Acid 
C-reactive protein (CRP) 
Routine urinalysis with 
microscopic examination on 
positives(a): 
Color 
Appearance, 
Specific Gravity 
PH 
Protein 
Glucose 
Ketones 
Occult Blood 
Leukocyte Esterase 
Nitrite 
Bilirubin 
Urobilinogen 
 
Serum/Plasma/Whole Blood 
Urine 
Breath 
Lipid profile and particles: 
Cholesterol, Total 
HDL-C (Cholesterol) 
HDL-P (Particles) 
LDL-C 
LDL-P 
VLDL-C 
VLDL-P 
Triglycerides 
FFA 
 
Thyroid-stimulating hormone 
(TSH)(b) 
 
Coagulation: 
Drug Screen Profile 
12 panel urine drug screen as stated 
in the SOE via commercial kit at 
the site. 
 
Female Subjects Only 
Urine pregnancy testing via 
commercial kit at site will be 
performed at timepoints stated in 
the SOE. Urine pregnancy testing 
may be performed per 
Investigator’s discretion at 
additional timepoints during the 
study, if there is reason to believe 
the subject might be pregnant. 
Alcohol breath test at 
timepoints stated in the SOE 
at the site. 


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Partial Thromboplastin Time  
(PTT) 
PT 
International Normalized Ratio 
(INR) 
 
Amino acid panel: 
Taurine 
Aspartate 
Hydroxyproline 
Threonine 
Serine 
Asparagine 
Glutamate 
Glutamine 
Sarcosine 
Alpha-Aminoadipate 
Proline 
Glycine 
Alanine 
Citrulline 
Alpha-Aminobutyrate 
Valine 
Cystine 
Methionine 
Homocitrulline 
Cystathionine 
Alloisoleucine 
Isoleucine 
Leucine 
Tyrosine 
Phenylalanine 
Argininosuccinate 
Beta-Alanine 
Beta-Aminoisobutyrate 
Homocysteine 
Gamma-Aminobutyrate 
Tryptophan 
Hydroxylysine 
Ornithine 
Lysine 
Histidine 
Arginine 
 
Incretins: 
GLP-1 
GIP 
Glucagon 
FGF21 
Leptin 
 
 
Aspartate


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Glucose Metabolism 
Parameter: 
FPG 
Fasting Insulin 
Fasting C-Peptide 
HbA1c 
 
Inflammatory Biomarker: 
Adiponectin 
 
Bone Metabolism Parameter: 
CTX-1 
OC 
P1NP 
 
Ketone bodies: 
BHB 
 
Immunogenicity Parameter: 
ADAbs 
nAbs 
anti -PEG 
 
Additional Parameters: 
Calcitonin 
 
(a) Microscopic analysis should be performed only if urine evaluations are abnormal. 
(b) In the event of abnormal TSH, Free T3/T4 may be collected at Investigator discretion. 
 


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The responsible laboratory will perform all necessary laboratory tests listed above. 
Specialty labs may be responsible for specific PD parameter. The results of safety 
laboratory tests will be sent to the appropriate Investigator or designee, who is 
responsible for reviewing these results. All laboratory safety data will be faxed or 
transferred electronically. 
Laboratory reports must be signed and dated by the Investigator or designee indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. 
All clinically significant laboratory abnormalities must be recorded as an AE. A clinically 
significant laboratory abnormality may be verified by retesting and may be followed 
upon discretion of the Investigator. 
9.1.9 Contraception 
Females must be non-pregnant and non-lactating, and either surgically sterile (eg, tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-
menopausal for >12 months. If females’ sterility or postmenopausal status is confirmed, 
no pregnancy testing is required during the study. The site will make an effort to retrieve 
medical records to document the sterility, however, the absence of records will not 
exclude the subject. In case that medical records cannot be obtained, serum pregnancy 
testing will be conducted at Screening, and urine pregnancy testing will be conducted 
throughout the study. Postmenopausal status will be confirmed through testing of FSH 
levels outside the normal range (as specified by responsible lab) at screening for 
amenorrheic female subjects < 60 years of age. 
Female subjects who state they are postmenopausal at the screening visit but have an 
FSH value that does not correspond with a postmenopausal FSH level, may have a serum 
hCG pregnancy test performed on a separate day. If screening sample is within stability 
range, the serum hCG pregnancy test may be performed out of the same sample. If test is 
negative and the subject agrees to be on a highly effective contraceptive method, subject 
may be enrolled in the study at the discretion of the Investigator. 
Female subjects of child-bearing potential must use highly effective contraceptive 
methods. Highly effective contraceptive methods are considered those with failure rate 
less than 1% undesired pregnancies per year, including hormonal intrauterine devices 
(coil), oral hormonal contraceptives, sexual abstinence, or a surgically sterilized partner. 
Oral hormonal contraceptives have to be taken at least 2 months prior to Screening until 
30 days after the last Follow-up Visit.  
During the course of the study, regular serum human chorionic gonadotropin (hCG) 
pregnancy tests will be performed for sterilized women, when medical records are not 
available. In addition to a negative serum hCG pregnancy test at Screening, subjects also 
must have a negative urine hCG pregnancy test at check-in to in-house periods. 


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Males must be surgically sterile (at least 1-year post vasectomy), abstinent or if engaged 
in sexual relations of child-bearing potential, the subject and his partner must be using an 
acceptable contraceptive method from screening and for a period of 30 days after the last 
Follow-up visit. Acceptable methods of contraception are the use of condoms together 
with spermicidal foam/gel/film/cream/suppository. In addition, they must be advised not 
to donate sperm during this period. Male subjects must also encourage their female 
partner to use effective contraception. Effective contraceptive for the female partner 
includes surgical sterilization (e.g., bilateral tubal ligation, 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. 
9.1.10 Pregnancy 
In the event a subject becomes pregnant during the study, she should be withdrawn. 
However, the subject will be encouraged to complete the post-treatment follow-up 
portion of the study to the extent that study procedures do not interfere with the 
pregnancy. 
In addition, any pregnancies in the partner of a male subject during the study or for 60 
days after the last dose should also be recorded.  
If the pregnancy occurs at any time during the study and the 60 days of last dose of active 
study medication, the pregnancy should be reported immediately to the Sponsor, using a 
pregnancy notification form. 
Study subjects will give consent on enrollment that the Investigator will report any 
pregnancy during the study to the Sponsor and that they will be asked to provide 
information about her pregnancy, delivery, and the health of her infant until age one 
month. Payment for all aspects of obstetrical care, child, or related care will be the 
subject’s responsibility.  
All reported pregnancies will be followed up to final outcome, using the pregnancy and 
pregnancy follow-up forms. The outcome, including any premature termination, will be 
reported to the Sponsor. An evaluation after the birth of the child may also be conducted. 
Pregnancy complications must be recorded as adverse event(s). If the infant has a 
congenital anomaly/birth defect this must be reported and followed up as a serious 
adverse event. 
9.1.11 ECG Procedure  
All ECG’s throughout this study will be performed as standard triplicate 12-lead ECG’s, 
except the ECG at Screening. ECG’s will be recorded after 5 minutes in a supine 
position. Only the Triplicate ECG’s will be recorded at least 1 minute apart from each 
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The Investigator (or designee) will interpret the ECG’s by use of an electronic 
measurement using the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal with clinical significance. ECG’s are performed 
according to the Table 16-1. The following parameters will be recorded from the 
subject’s ECG trace: heart rate, QT interval, PR interval, QRS interval, R-R interval, and 
QTcF (corrected) using the Fridericia correction (QTcF = QT ÷ cube root of the R-R 
interval [where R-R is the duration of the entire cardiac cycle]). 
When ECGs are to be collected at the same time point as a blood collection, ECGs should 
be collected first to avoid any artificially increased heart rates due to the blood collection. 
The mean value of the 3 baseline ECG measurements collected at Day -2 will serve as 
each subject’s baseline for all post-dose comparisons. ECG measurements are to be 
collected during screening and on Day -2 and 77 before subjects are connected to the 
ABPM device. Additionally, ECG measurements are taken on Day 5 and Day 82, after 
ambulatory devices (Holter and ABPM) are removed. 
In some cases, it may be appropriate to repeat abnormal ECGs. If a machine-read QTc 
value is prolonged, repeat measurements may not be necessary if the Investigator’s 
interpretation determines that the QTc value is in the acceptable range. 
9.1.12 Check-in Procedure 
All subjects will check in to the clinic in the morning for the In-house Periods 1 and 2. 
Eligibility will be confirmed, and the following will be assessed: 
1. Positive alcohol breath test. 
2. Positive urine drug screen. 
3. Positive urine pregnancy test for WOCBP.  
4. Any use of prescription or non-prescription medicine other than the allowed 
concomitant medications within the last 12 hours. 
5. Any medical condition that could interfere with glucose metabolism, as judged by the 
Investigator. 
Subjects who fulfill one or more of the stated criteria at check–in, will not be able to 
continue onto the treatment period. The treatment period will be rescheduled. Each 
treatment period may be rescheduled no more than twice. After that, the subject will be 
excluded from the study. Replacement of subjects for the dosing period may be permitted 
to enroll sufficient subjects into the study after discussion with Sponsor and Investigator. 
9.1.13 Standardized Meals 
During in-house period, subjects will receive standardized meals. The standardized 
weight maintaining meals will be provided using estimated BMR× activity factor of 1.5 
to determine daily caloric intake.  


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9.1.14 ABPM 
The 24-hour blood pressure will be measured by an ABPM device. A validated, reliable, 
automated, and accurate monitor will be used with a storage function. Blood pressure 
measurements will be started overnight on Day -2 to familiarize the subjects with the 
device. During this period, measurements will be taken every 2 hours until the morning 
of Day -1.  
The baseline assessment period will start in the morning of Day -1 until Day 1. 
Measurements will be taken hourly up to 14 hours and then 2-hourly until 24 hours. 
The post-dose assessment period will start in the morning of Day 1. Measurements will 
be taken hourly up to 14 hours and then 2-hourly until 24 hours every day (for every 24-
hour period), until the morning of Day 5.  
Additionally, subjects will be connected to the ABPM system again on Day 77. Blood 
pressure measurements will be started overnight on Day 77 to familiarize the subjects 
with the device. During this period, measurements will be taken every 2 hours until the 
morning of Day 78.  
The post-dose assessment period will start in the morning of Day 78. Measurements will 
be taken hourly up to 14 hours and then 2-hourly until 24 hours every day (for every 24-
hour period), until the morning of Day 82. 
Time points stated in the Table 16-1. Adequate cuff size will be documented for each 
subject, after determination of the patient’s non-dominant arm circumference. Subject’s 
bedtime and awakening will be recorded to divide the downloaded data into diurnal and 
nocturnal values. Depending on available PK and safety data, timepoints for 
measurements may be adjusted for the following cohorts. 
Specifications about the ABPM model will be described in the Operations Manual and 
ABPM Procedure Manual, as well as detailed instructions of blood pressure frequency, 
data management and medical review.  
9.1.15 Holter Monitoring 
24-hour heart rate activity will be continuously recorded with an ambulatory Holter 
monitoring system (eg, Mortara surveyor). Holter electrodes (12 lead, 3-channel 
placement) will be placed to the subject’s chest and will be attached to a small recording 
monitor. The Holter monitor will be carried in a pocket or small pouch. Subject’s 
activities or exercises will be recorded while wearing the monitor. 
Specifications about the Holter model will be described in the Operations Manual and 
Holter Procedure Manual, as well as detailed instructions of data management and 
medical review.  


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9.1.16 Pharmacokinetic Assessments and Schedule 
Blood for PK analysis of the study drugs will be collected at the time points indicated in 
the Table 16-1 Schedule of Events and follow the PK sampling schedule Table 9-3. One 
2-mL sample per scheduled time point will be collected to provide a minimum of 500 μL 
of serum for PK measurements and 500 μL of serum as a secondary back-up sample. 
Instructions for sample processing and shipment will be provided in the PK Sample and 
Shipping Instructions. Pre-dose sampling will be taken within 10 minutes before dosing. 
Dosing should occur at approximately 08:00 h on every dosing day. The actual time of 
PK sampling should not deviate from the nominal time by more than ± 5 minutes during 
the Inpatient Period, and by more than ± 2 days for the Elimination Period and Follow-up 
Visit. If Visit during elimination period or follow-up visits will be performed on a 
different day, the time point for the sampling will still be in the morning, preferably at the 
same time (at approximately 08:00h). The actual time of dosing, actual sampling dates 
and times should be recorded. 
Table 9-3 PK Sampling Schedule for cohorts 1-1 and 1-2 
PK sampling schedule 
Treatment Period 
Week 1 
Day 1 
Pre-dose 1st dosing 
8 h after 1st dosing 
Day 2 
24 h after 1st dosing 
Day 3 
48 h after 1st dosing 
Day 4 
72 h after 1st dosing 
Week 2 
Day 8 
Pre-dose 2nd dosing 
Day 10 
48 h after 2nd dosing 
Week 3 
Day 15 
Pre-dose 3rd dosing 
Week 4 
Day 22 
Pre-dose 4th dosing 
Week 5 
Day 29 
Pre-dose 5th dosing 
Week 6 
Day 36 
Pre-dose 6th dosing 
Week 8 
Day 50 
Pre-dose 8th dosing 
Week 9 
Day 57 
Pre-dose 9th dosing 
Week 12 
Day 78 
Pre-dose 12th dosing 
Day 80 
48 h after 12th dosing 
Day 81 
72 h after 12th dosing 
Elimination 
Period 
(±2) 
Week 13 
Day 85 
168 h after 12th dosing 
Week 15 
Day 99 
504 h after 12th dosing 
F/U (±2) 
Week 17 
Day 113 
840 h after 12th dosing 
 


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Table 9-4 PK Sampling Schedule starting from cohort 1-3 
PK sampling schedule 
Treatment Period 
Week 1 
Day 1 
Pre-dose 1st dosing 
8 h after 1st dosing 
Day 2 
24 h after 1st dosing 
Day 3 
48 h after 1st dosing 
Day 4 
72 h after 1st dosing 
Day 5*  
96 h after 1st dosing 
Week 2 
Day 8 
Pre-dose 2nd dosing 
Day 10 
48 h after 2nd dosing 
Week 3 
Day 15 
Pre-dose 3rd dosing 
Week 4 
Day 22 
Pre-dose 4th dosing 
Week 5 
Day 29 
Pre-dose 5th dosing 
Week 6 
Day 36 
Pre-dose 6th dosing 
Week 8 
Day 50 
Pre-dose 8th dosing 
Week 9 
Day 57 
Pre-dose 9th dosing 
Week 12 
Day 78 
Pre-dose 12th dosing 
8 h after 12th dosing  
Day 79 
24 h after 12th dosing 
Day 80 
48 h after 12th dosing 
Day 81 
72 h after 12th dosing 
Day 82** 
96 h after 12th dosing 
Elimination 
Period 
(±2) 
Week 13 
Day 85 
168 h after 12th dosing 
Week 15 
Day 99 
504 h after 12th dosing 
F/U (±2) 
Week 17 
Day 113 
840 h after 12th dosing 
*Sampling on Day 5 will start with Cohort 1-4 and will not be taken for cohort 1-3. 
** Sampling on Day 82 will be optional for cohort 1-3 but will be taken in cohort 1-4. 
 
Available PK data will be utilized for decision making in dose escalation meeting. Based 
on results, the PK sampling schedule may be adjusted. The total number of blood 
sampling events will not exceed the total number of blood sampling events originally 
planned. 
9.1.17 Laboratory Pharmacodynamic Assessments  
Blood for analyses of PD assessments will be collected at the time points indicated in the 
Table 16-1 and Table 16-2. Sampling for incretins/ metabolic hormones (GLP-1, GIP, 


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Glucagon, FGF21, Leptin), serum lipid profiles and particles (total cholesterol, LDL-C, 
LDL-P (particles), HDL-C, HDL-P (particles), VLDL-C, VLDL-P (particles), 
Triglyceride, Free Fatty Acids), amino acid profile (taurine, aspartate, hydroxyproline, 
threonine, serine, asparagine, glutamate, glutamine, sarcosine, alpha-aminoadipate, 
proline, glycine, alanine, citrulline, alpha-aminobutyrate, valine, cystine, methionine, 
homocitrulline, cystathionine, alloisoleucine, isoleucine, leucine, tyrosine, phenylalanine, 
argininosuccinate, beta-alanine, beta-aminoisobutyrate, homocystine, gamma-
aminobutyrate, tryptophan, hydroxylysine, ornithine, lysine, histidine, arginine),  glucose 
metabolism parameter (FPG, Fasting insulin, fasting c-peptide, HbA1c), inflammatory 
marker (Adiponectin), ketone bodies (BHB) and bone metabolism parameters (CTX-1, 
OC, P1NP) will be collected. 
Instructions for sample processing and shipment will be provided in the laboratory 
manual. All samples, including pre-dose sampling on Day 1 will be taken within 30 
minutes before dosing.  
9.1.18 MRI/MRI-PDFF 
Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) deems as a 
noninvasive, quantitative, and accurate measure of liver fat content/ hepatic steatosis 
grade in this study to identify the study population and assess the treatment response in 
subjects with NAFLD. For subjects in cohort 1-5 and up, the assessment of visceral fat 
will also be assessed via MRI imaging at Screening, during week 8 and week 12, together 
with the MRI-PDFF assessment. 
MRI-PDFF will be performed using a standardized imaging acquisition calibration 
protocol and the results a will be determined by central reader at screening (as baseline 
value) and during week 8 (close to Day 57 as possible, but prior to dosing on Day 57), 
and week 12 (close to Day 85 as possible, but after ABPM and Holter are disconnected 
on Day 82; but prior to the PK sampling on Day 85). 
For details please see the Operations Manual. 
9.1.19 VCTE 
One-dimensional vibration controlled transient elastography (VCTE) assessed via eg, 
FibroScan (EchoSens™, Paris, France) will be used in this study. 
At Screening, subjects will be examined with the FibroScan to assess the controlled 
attenuation parameter (CAP) in order to qualify for the inclusion in the study. 
For subjects participating in cohort 1-4 and up, FibroScan assessments will be performed 
on Day 85 to assess a change from baseline in CAP and LSM. 
It is a device, that uses non-invasive, one-dimensional vibration controlled transient 
elastography (VCTE). The device generates a low-frequency shear wave from a probe 
applied to the subject’s skin between the ribs. The speed of the wave spread is then 
measured between two points within the liver to allow the livers stiffness to be 


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quantified. The wave will travel more rapidly through stiff tissue. An examination using 
the FibroScan consists of ten signal acquisitions at a single point; the whole process lasts 
around 15 minutes. The results are instantly displayed on a screen and the value for 
stiffness can be matched to a fibrosis stage. 
For details please see the Operations Manual. 
9.1.20 Immunogenicity Assessments 
Blood samples will be acquired to determine ADAbs, nAbs and anti -PEG within 30 min 
prior to the first dosing on Day 1, post first dosing on Day 22, 50, 78, 85 and 99. Post 
first dose samples will be taken at the same time point of safety blood sampling or 
collection of other blood samples.  
Instructions for sample processing and shipment will be provided in the 
PK/Immunogenicity Sample and Shipping Instructions.  
9.1.21 Tolerability Assessments 
After injection of the study drug, the injection site will be marked with an indelible 
marker/pen. Assessment of study drug injection site will be performed within 30 minutes 
of pre-dose, at 4 and 12-hour post-dose on Day 1 with a window of ± 30 minutes. 
Assessment of study drug injections on the other dosing days will be performed at least 
30 minutes post-dose, and then daily during the in-house periods and at outpatient visits 
on non-dosing days in the morning, approximately at the time of the dosing on dosing 
days. Last injection site inspection will be performed on Day 85. 
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 and then will be 
evaluated using the following scale: 
Erythema will be evaluated as follows:    
•  0 – No erythema  
•  1 – Very slight erythema (barely perceptible)  
•  2 – Well-defined erythema  
•  3 – Moderate to severe erythema  
•  4 – Severe erythema (beet redness) to slight eschar formations (injuries in depth)  
Edema will be evaluated as follows:  
•  0 – No edema  
•  1 – Very slight edema (barely perceptible)  
•  2 – Slight edema (edges of area well defined by definite raising)  
•  3 – Moderate edema (raised approximately 1 mm)  


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•  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 centimeter 
(cm) and the condition of the injection site will be recorded. Digital photography will be 
used to document all positive injection site reactions. 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. 
Biopsies will be performed using a 4-mm punch biopsy centered on the injection site. 
The biopsy area will be anesthetized with lidocaine prior to the biopsy. Wound closure 
will be performed with Steristrips. If stitches are necessary to close the punch area, they 
will be removed approximately 2 weeks later. The time between injection and biopsy will 
be recorded. Microscopic and histological examination of the punch biopsies will be 
performed at a qualified lab. 
9.1.22 Blood Volume 
Total blood sampling volume for subjects will approximately be 435 mL for subjects 
participating in the study. 
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Event (AE) 
An AE is any undesirable and unintended medical event occurring to a subject in a 
clinical study, whether or not related to the study products. This includes events from the 
first study related activity after the subject has signed the informed consent and until post 
treatment follow-up period as defined in the protocol. The following should not be 
recorded as AEs, if recorded as medical history/concomitant illness on the CRF at 
screening: 
• 
Pre-planned procedure, unless the condition for which the procedure was planned 
has worsened from the first study related activity after the subject has signed the 
informed consent 
• 
Pre-existing conditions found as a result of screening procedures 
• 
Pre-existing events that has not worsened in intensity or frequency from baseline 
10.1.2 Treatment Emergent Adverse Event (TEAE) 
A treatment-emergent AE (TEAE) is defined as any clinically significant event not 
present before exposure to study drug or any event already present that worsens in either 
intensity or frequency after exposure to study drug. 
10.1.3 Adverse Events of Special Interest (AESI) 
AEs of special interest (AESI) are selected, non-serious adverse events. They will be 
reported to the sponsor within the same timeframe that applies to SAE, using SAE report 
form.   
AESIs in this study include the following: 
x Necrolytic migratory erythema 
x Cholelithiasis 
x Pancreatitis 
10.1.4 Clinical Laboratory Event 
A clinical laboratory AE is any clinically significant laboratory abnormality that suggests 
a disease and/or organ toxicity and is of a severity, which requires active management, 
(i.e. change of dose, discontinuation of study product, more frequent follow-up, or 
diagnostic investigation). 
A laboratory re-test and/or continued monitoring of an abnormal value is not considered 
an intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 


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10.1.5 Adverse Reaction 
An adverse reaction is defined as any adverse event caused by a drug. Adverse reactions 
are a subset of all suspected adverse reactions where there is reason to conclude that the 
drug caused the event. 
10.1.6 Suspected Adverse Reaction 
Suspected adverse reaction is defined as a subset of any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of IND 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lower degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
Reasonable possibility is given if: 
• 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure 
• 
One or more occurrences of an event, that is not commonly associated with drug 
exposure, but otherwise uncommon in the population exposed to the drug 
• 
An aggregate analysis of specific events observed in a clinical study that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
10.1.7 Unexpected Adverse Event/ Unexpected Suspected Adverse Reaction 
An unexpected AE/unexpected suspected adverse reaction is an AE or suspected adverse 
reaction that is not listed in the Investigator Brochure, as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation, or is not listed at the 
specificity or severity that has been observed; or, if an Investigator Brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
10.1.8 Serious Adverse Event (SAE)/ Serious Suspected Adverse Reaction 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is life threatening. 
x The term “life threatening” 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 that hypothetically 
might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization.  


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4. Results in persistent or significant disability/incapacity. 
5. Leads to a congenital anomaly/birth defect. 
6. Is an important medical event that satisfies any of the following: 
x May require intervention to prevent items 1 through 5 above. 
x May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
10.1.9 Life-Threatening Adverse Event/Life-Threatening Suspected Adverse 
Reaction 
A life-threatening AE/life-threatening suspected adverse reaction, in the view of either 
the Investigator or Sponsor, places the patient or suspect at immediate risk of death. It 
does not include an adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
The determination of whether an AE is life threatening can be based on the opinion of the 
Investigator or Sponsor. If either, the Sponsor or investigator believes that the event is 
serious or life threatening, the event must be considered serious and evaluated by the 
Sponsor for expedited reporting (21 CFR 312.32(a) and 312.32(c)(1)). 
10.2 
Severity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient, easily tolerated by the subject and does not 
affect the subject’s daily activities. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s 
usual daily activities. 
Severe: 
The event is incapacitating and causes considerable interference with 
the subject’s usual activities. 
10.3 
Relationship to Study Treatment 
The relationship of each AE to the study drug(s) will be assessed by the Investigator or 
Sub-Investigator on the basis of his/her clinical judgment and the following definitions: 
1= Related: 
The AE follows a reasonable temporal sequence from the study product administration 
and cannot be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, or concomitant medications). 
 
The AE follows a reasonable temporal sequence from the investigational product 
administration and represents a known reaction to the drug under study or other drugs in 
its class or is predicted by the known pharmacological properties of the drug. 
 


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The AE resolves with discontinuation of the investigational product and/or recurs with 
rechallenge, if applicable. 
 
If a relationship to an AE is not assessable, it should be recorded as Related. 
 
2 = Not Related: 
The AE does not follow a reasonable temporal sequence from investigational product 
administration or can be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications). 
10.4 
Procedures 
10.4.1 Collection and Recording of AEs 
Collection of all AEs (serious AEs and non-serious AEs) will commence from the time 
the subject signs the informed consent to participate in the study until the post-treatment 
follow-up visit. Throughout the in-house treatment period and outpatient visits, the 
Investigator will assess whether any subjective AEs have occurred. In order to avoid bias 
in eliciting AEs, a non-specific question, such as “How have you been feeling since your 
last visit?” may be asked. Subjects may report AEs occurring at any other time during the 
study. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored and given appropriate medical treatment at the 
discretion and judgement of the Investigator until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is 
a satisfactory explanation for the changes observed. All AEs will be documented in the 
AE page of the CRF, whether or not the Investigator concludes that the event is related to 
the drug treatment. The event term, start and stop dates, severity, action taken with study 
drug and outcome, will be documented, along with the Investigator’s opinion of the 
causal relationship between the event and the study drug.  
10.4.2 Collection and Reporting of SAEs and AESIs 
When an SAE and AESI occur, it should be reported according to the following 
procedure: 
An SAE form must be completed immediately or within 24 hours of first onset or 
notification of the event. The information should be completed as fully as possible but 
contain, at a minimum a short description of the event and the reason why the event is 
categorized as serious, subject identification number, Investigator’s name, name of the 
study medication and a causality assessment. 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
and AESIs (regardless of their relationship to study drug) should be reported to the 
Sponsor or a designated qualified vendor within 24 hours of the Study Center’s first 
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The collection of SAEs and AESIs will begin after the subject signs the informed consent 
form and stop at the end of the subject’s follow-up period. An Initial Serious Adverse 
Event Form should be completed, and a copy should be faxed to the Sponsor or 
designated qualified vendor. 
All serious and unexpected adverse event reporting will adhere to 21 CFR 312.32 for 
IND drugs and 21 CFR 314.80 for marketed drugs (15-day alerts). The Institutional 
Review Board (IRB) and all Investigators will be notified of the alert reports per FDA 
regulations. 
10.5 
Anticipated Adverse Events 
Normal precautions taken for a human study, including the provision of emergency 
equipment, will be taken during this study. Qualified and well-trained physicians and 
medical staff will instruct the subjects.  
In case any drug related AEs occur, they will be managed according to the AE guidance 
document in section 17.0. 
Procedure related AEs: 
The study procedures involve the use of adhesive to secure the placement medical 
equipment. The adhesive may cause an allergic reaction, redness, swelling or itching 
when in contact with the skin. 
Subjects will participate in several blood draws throughout the course of the study which 
have the potential to cause a venous line-vasovagal response, bruising, tenderness, and 
rarely infection. 
10.6 
Follow-up of AEs and SAEs 
All AEs should be followed up and subjects will be rendered appropriate medical care 
and treatment at the discretion of the Investigator until resolution or until the Investigator 
and Sponsor concludes that “further follow-up is not necessary”. If the AE has not 
resolved by the post-treatment follow-up visit, the stop date will be recorded as 
“ongoing.” 
All SAEs and AESIs should be followed up until resolution or permanent outcome of the 
event or until the Investigator and Sponsor judge that further follow-up is not necessary. 
If information is not available at the time of the first report and becomes available later, 
the Investigator should complete a follow-up SAE form at the earliest possible or provide 
other written documentation and fax it immediately within 24 hours of receipt of 
information to the Sponsor or designee. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent accordingly. 
All other non-serious AEs must be followed until the outcome of the event is 
“recovering” (for chronic conditions), or “recovered”, or until the end of the post-


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treatment follow-up stated in the protocol, whichever comes first, and until all queries 
related to these AE’s have been resolved. 
10.6.1 Safety Reporting to IRBs or IECs, and Regulatory Authorities 
The Sponsor or designated qualified vendor will be responsible for reporting all 
suspected unexpected serious adverse reactions (SUSARs) and any other applicable 
SAEs to regulatory authorities, Investigators, and IRBs or IECs, as applicable, in 
accordance with national regulations in the countries where the study is conducted.  
Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-
threatening events and 15 days for other SUSARs, unless otherwise required by national 
regulations.  
The Sponsor or designated qualified vendor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment 
of an investigational product or that would be sufficient to consider changes in the 
investigational product administration or in the overall conduct of the study. The 
investigational site will forward a copy of all expedited reports to his or her IRB or IEC 
in accordance with national regulations. 
Reporting responsibilities of Investigator under 21 CFR 312.64(b) and Sponsor under 21 
CFR 312.32(c)(1)(i) for serious and unexpected suspected adverse reactions will be 
followed. 


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11.0 
DATA HANDLING AND MANAGEMENT 
Clinical Data Management (CDM), is the responsibility of ProSciento. With permission 
of the Sponsor, CDM may be delegated under an agreement of transfer of responsibilities 
to a qualified vendor of ProSciento.  
11.1 
Data Management 
The full details of procedures for data handling will be documented in the Data 
Management Plan (DMP). 
AEs and medical history will be coded using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded 
using the World Health Organization (WHO) WHODrug Global.  
Unique numbers will identify the subject and the biological material obtained from the 
subject. Appropriate measures such as encryption or deletion will be enforced to protect 
the identity of human subjects in all presentations and publications as required by 
local/regional/national requirements. 
Data from screening failures will be entered into the database. 
Laboratory data from the central laboratory will be electronically transferred to 
ProSciento for database reconciliation purposes. The electronic laboratory data will be 
considered source data. In cases where sensitive non-PK laboratory data is transferred via 
non-secure electronic networks, data will be encrypted during transfer. 
The laboratory will provide one copy of the laboratory reports to the CRU staff. The staff 
will receive all laboratory data electronically or based on FAX reports directly from the 
laboratory. An Investigator must review, evaluate, sign and date the laboratory print-outs 
upon receipt. The signed print-out of the laboratory reports are source data. 
All other results, including PK, PD data, and laboratory tests will be transferred 
electronically to the responsible Data Management Unit.  
11.2 
CRFs (Electronic) 
11.2.1 Clinical Data Management Workflow 
Electronic CRFs will be developed by the CDM department, in collaboration with the 
clinical study team at ProSciento and statistician. CDM will document the process 
workflow in the DMP. After data entry, monitor(s) will source data verify (SDV) the 
eCRFs against the source documents. Queries may be issued to clarify the data entered. 
The PI will electronically sign the eCRFs after all data have been entered, all queries 
have been resolved and all external data has been reconciled with the eCRF data. If 
corrections and/or resolution of queries are required after PI approvals, those eCRFs 
affected by changes will be re-signed by the PI. The database may be locked after the PI 
approvals are completed. 


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After database lock, CDM study design documentation and locked eCRFs (PDF) will be 
created and will be provided to the Sponsor, if requested. 
11.2.2 Data Entry of eCRFs 
Data required for analyses and subject safety assessments will be entered from source 
documentation into eCRFs. Instructions for data entry will be provided in the eCRF 
Completion Guidelines, developed by the CDM department. All staff involved with 
entering data into the eCRFs will be trained prior to gaining access to the study database. 
11.2.3 Corrections to eCRFs 
Queries may be generated by the eCRF system during data entry, and queries may be 
generated by CDM staff, monitors, and other data reviewers during the course of the 
study. Only specific CRU personnel will be authorized to make corrections to the eCRFs; 
CDM will train personnel prior to granting access in the eCRF system. Corrections will 
be made directly in the eCRF – by modifying existing data, adding new data, or deleting 
data, as appropriate. All data corrections will be logged in the electronic audit trail. 
11.2.4 PI Approval of eCRF Data 
The Investigator or Investigator’s authorized staff must ensure that all information 
derived from source documentation is consistent with the source information and 
accurately reflected in the eCRFs. By electronically signing the eCRFs, the Investigator 
confirms that the information is complete and correct. 
11.3 
Retention of Documents 
At the completion of the study, all records created by and under the supervision of the 
Investigator should be maintained in accordance with the requirements of the regulatory 
authority guideline and the GCP Guideline. These will be available for inspection at any 
time by the Sponsor or the FDA. 
Clinical study documents are archived upon completion of the study and maintained for 
at least 15 years from the study closure or longer in accordance with local regulation and 
applicable regulatory authority guidelines, and the study sponsor will be notified prior to 
destruction of study records. 
Current FDA 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 
ProSciento as to when essential documents are no longer needed to be retained. 
 
 


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12.0 
STATISTICAL METHODS 
12.1 
Statistical and Analytical Plans 
Statistical services is delegated under an agreement of transfer of responsibilities to 
Pharmapace, Inc., a qualified vendor of the Sponsor. 
An SAP will be prepared that will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. It will also 
provide any changes or additions to the analyses that are not apparent in the protocol. 
Procedures for accounting for missing, unused, or spurious data will be discussed in 
detail in the SAP 
12.2 
Study Endpoints 
The study endpoints or derived parameters used to assess whether the study objectives 
have been met. The endpoints for this study are shown in Table 12-1. Additional 
endpoints may be added to the SAP as needed to address the needs of the study. 
Table 12-1 Study Endpoints 
Primary Endpoints (Safety Endpoints) 
Primary Endpoints 
Exploratory 
Endpoints 
To assess the safety 
of HM15211  
To assess the 
local tolerability 
of HM15211 
To assess the 
PK profiles of 
HM15211 
To assess the 
reduction of 
liver fat by 
MRI-PDFF 
To assess the PD 
properties of 
HM15211 
compared to 
placebo 
Adverse events 
Injection site 
reaction 
Cmax 
Absolute 
change from 
baseline 
Incretins / 
metabolic 
hormones 
-GLP-1 
-GIP 
-Glucagon 
-FGF21 
-Leptin 
Clinical laboratory 
abnormalities 
(including serum 
amylase, lipase, 
coagulation, TSH, 
calcitonin) 
 
tmax 
% change from 
baseline 
Body weight and 
BMI 
Immunogenicity 
(ADAbs, nAbs, 
anti-PEG) 
∙ 
Ctrough 
 
Lipid metabolism 
(Total cholesterol, -
-LDL, LDL-C, 
LDL-P 
-HDL, HDL-C, 
HDL-P 


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Primary Endpoints (Safety Endpoints) 
Primary Endpoints 
Exploratory 
Endpoints 
-VLDL, VLDL-C, 
VLDL-P 
-Triglycerides 
-FFA 
Clinical findings on 
physical 
examination 
 
AUC,  
eg., AUC0-t at 
s.teady state 
 
Amino acid profile 
Vital signs (BP, 
respiratory rate, 
temperature, and 
HR) 
 
kel 
 
Glucose 
metabolism 
parameters: 
-FPG 
-Fasting insulin 
-fasting C-peptide 
-HbA1c 
24-hour ABPM 
(Mean day- and 
night time 
systolic/diastolic 
BP) 
 
t1/2 
 
 
Bone metabolism 
parameters: 
-CTX-1 
-OC 
-P1NP 
 
24-hour Holter 
ECG (HR, HRV 
(e.g. mean heart 
rate, difference 
between day and 
night HR, mean 
NN intervals, 
SDNN, SDANN, 
SDNN index) 
 
CL/F 
 
 
Inflammatory 
markers: 
-Adiponectin 
12-lead ECG 
parameters (the 
primary ECG 
endpoint will be 
QTcF) 
 
Vz/F 
 
Ketone bodies: 
-BHB 
 
 
 
 
Waist 
circumference 
 
 
 
 
Changes in liver 
steatosis and liver 
stiffness assessed 
by FibroScan® 
(VCTE), 
determined as 
absolute and 


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Primary Endpoints (Safety Endpoints) 
Primary Endpoints 
Exploratory 
Endpoints 
percent change 
from baseline in 
controlled 
attenuation 
parameter (CAP) 
and liver stiffness 
measurements 
(LSM) 
 
 
 
 
Changes in visceral 
fat volume, 
determined by 
absolute and 
relative percent 
change assessed by 
MRI imaging 
 


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12.2.1 Analysis Sets 
12.2.1.1 Safety Set 
The Safety analysis set will include all subjects who received study medication (HM 
15211 or Placebo). The Safety analysis set will be used for demographic, baseline 
characteristics and safety summaries.  
12.2.1.2 Pharmacokinetic (PK) Analysis Set 
The PK analysis set will include all subjects who received HM 15211 or placebo with 
sufficient evaluable PK data appropriate for the evaluation of interest (without major 
protocol deviations or violations that would have an impact on the absorption, 
distribution, metabolism, or excretion of HM 15211). The PK analysis set will be used 
for analysis of PK endpoints. 
12.2.1.3 Pharmacodynamics (PD) Analysis Set 
The PD analysis set will include all subjects who received HM 15211 or placebo with 
sufficient evaluable PD data appropriate for the evaluation of interest (without major 
protocol deviations or violations that would have an impact on the PD of HM 15211). 
The PD analysis set will be used for analysis of PD endpoints. 
12.2.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects overall and 
by cohort and treatment. Summary statistics (e.g., number of subjects, mean, median, 
standard deviation, and range) will be generated for continuous variables (e.g., age and 
weight) and the number and percentage of subjects within each category will be 
presented for categorical variables (eg, gender, ethnicity, and race).   
12.2.3 Analysis of the Pharmacokinetic Endpoints 
The planned analyses will be described in more detail in the statistical analysis plan 
(SAP). 
The serum pharmacokinetic (PK) concentration profiles will be graphically presented.  
The PK endpoints will be derived from the individual serum HM15211 profiles during 
the elimination phase using the non-compartmental models. Ctrough will be derived from 
the pre-dosing PK samples on Day 78. The PK parameters will be summarized by dose.  
12.2.4 Analysis of the Pharmacodynamic Endpoints 
All PD parameters including but not limited to MRI-PDFF will be summarized using 
appropriate descriptive statistics (e.g., n, mean or geometric mean, CV, min, median, 
max) by treatment dose and collection day. The placebo group will be pooled across 
cohorts in the summary tables.   


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Exploratory PD parameters including but not limited to FPG, insulin, C-peptide, GCG, 
leptin, GLP1, GIP, FGF21, Leptin, as well as CRP, lipid profiles and particles, FFA, 
BMI, and body weight, etc. will be summarized by treatment dose. The placebo group 
will be pooled across cohorts in the summary tables. 
12.2.5 Safety Analysis and Endpoints 
Safety and tolerability of the study drugs will be assessed by collection and review of 
adverse events, tolerability, laboratory parameters, physical examination, vital signs, and 
ECG parameters throughout the duration of the study. Immunogenicity of HM15211 will 
be assessed by the development of ADAbs, nAbs and anti-PEG. 
Safety analysis will involve examination of the descriptive statistics and individual 
subject listings for any effects of study treatment on clinical tolerability and safety. 
Placebo patients will be pooled across cohorts in the safety analysis. 
The 24-hour blood pressure (day and night time systolic/diastolic BP) collected from 
ABPM, and 24-hour Holter ECG (HR, HRV [eg, difference between day and night HR, 
NN intervals, SDNN, SDANN, SDNN index]) will be summarized descriptively by 
treatment dose.  
All AEs will be coded using the most current MedDRA version. AEs will be summarized 
using preferred term and primary system organ class using the safety analysis set by 
treatment dose.  
Adverse event summaries will include the overall incidence (by system organ class and 
preferred term), events by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse events. Physical 
exam, vital signs, blood pressure assessed by ABPM, heart rate assessed by Holter ECG, 
12-lead ECG data, and laboratory parameters (hematology, chemistry, and urinalysis) 
will be summarized descriptively by treatment. 
12.3 
Interim Analysis 
No formal interim analysis is planned. 
12.4 
Determination of Sample Size 
Due to the exploratory nature of this study, a sample size of 12 subjects per cohort is 
empirically determined and consistent with typical sample sizes used for similar studies 
to assess PK and safety data. 
 


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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Monitoring 
The study will be monitored by ProSciento’s monitor. 
Monitoring visits to the study sites will be made periodically during the study to ensure 
that all aspects of the protocol and GCP are followed, CRFs are completed correctly, and 
drug accountability is monitored. The Monitor will visit the sites at least once before First 
Subject First Visit (FSFV) (Initiation Visit), at least once during the clinical part of the 
study, and at least once after Last Subject Last Visit (LSLV). Furthermore, the Monitor 
must be available for discussions by telephone.  
ProSciento may assign additional Clinical Research Associates (CRAs)/Monitors on an 
ad hoc basis for training purposes and to meet required timelines. In addition, if study 
timelines are modified for any reason, e.g., delays in recruitment or accelerated 
enrollment, ProSciento may use additional CRAs at its discretion to ensure study 
expectations are met. 
The Monitor must be given direct access to source documents, such as original 
documents, data, and records. Direct access includes permission to examine, analyze, 
verify any record(s) and report(s) that are important to evaluation of the clinical study. 
The study will be monitored to verify integrity and validity of the data. Monitoring will 
follow a Monitoring Plan. 
Additional QC monitoring of the clinical study for protocol and GCP compliance will be 
conducted periodically by qualified staff of ProSciento, Inc. 
13.2 
Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study subjects. Should other circumstances arise that 
will require deviation from protocol-specified procedures, unless there is an emergency 
or immediate need, the Investigator should contact the medical monitor and Sponsor to 
review and discuss the implications of the deviation and determine the appropriate course 
of action. Any deviation must be documented, stating the reason and date, the action 
taken, and the impact for the subject and/or the study. The documentation must be kept in 
the Investigator’s Study File and the Sponsor’s Study Master File. 


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14.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted in accordance with the Protocol, the International 
Conference on Harmonization (ICH), Guideline for Good Clinical Practice: Consolidated 
Guidance (E6) and applicable regulatory requirements including clinical research 
guidelines established by the Basic Principles defined in the U.S. 21 CFR Parts 50, 56, 
and 312 and the principles enunciated in the Declaration of Helsinki (revised version 
Fortaleza 2013).7,8 
14.1 
Institutional Review Board and/or Independent Ethics Committee 
Prior to commencement of the study, the protocol, any amendments, subject 
information/informed consent form, any other written information to be provided to the 
subject, subject recruitment procedures, information about payments and compensation 
available to subjects if not mentioned in the subject information, the Investigator’s 
current CV and/or other documentation evidencing qualifications, and other documents 
as required by the local Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) should be submitted. The submission letter should clearly identify (by study 
identification number, including version, title and/or date of the document) which 
documents have been submitted to the IEC/IRB. Written approval/favorable opinion must 
be obtained from IEC/IRB prior to commencement of the clinical study start. 
During the study, the Investigator must promptly report the following to the IEC/IRB: 
Updates to IB, unexpected SAEs where a causal relationship cannot be ruled out, 
substantial amendments to the protocol, non-substantial amendments, deviations to the 
protocol implemented to eliminate immediate hazards to the subjects, new information 
that may affect adversely the safety of the subjects or the conduct of the study (including 
new risk/benefit analysis in case it will have an impact on the planned follow-up of the 
subjects), annually written summaries of the study status and other documents as required 
by the local IEC/IRB. 
Substantial amendments must not be implemented before approval/favorable opinion, 
unless necessary to eliminate hazards to the subjects. 
The Investigator must maintain an accurate and complete record of all submissions made 
to the IEC/IRB. The records should be filed in the Investigator’s Study File and copies 
must be provided to the Sponsor.  
14.2 
Regulatory Authorities 
Regulatory Authorities will receive the Clinical Study Application, Protocol, 
Amendments to the Protocol, reports on SAEs and the Integrated Clinical Study Report 
according to national regulations. 
14.3 
Responsibilities of the Investigator 
The Investigator will conduct this clinical study in compliance with all applicable 
national, state, local or regional laws and regulatory requirements of the countries in 


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which the clinical study is performed. The Investigator will align his or her conduct in 
accordance with the “Responsibilities of the Investigator”. 
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the 
applicable local laws and regulations. The responsibilities imposed on Investigators by 
the FDA are summarized in the “Statement of Investigators” (Form FDA 1572), which 
must be completed and signed before the Investigator may participate in this study.  
14.4 
Informed Consent 
Once signed, the original informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the 
Investigator’s site file. The Investigator must document the date the subject signs the 
informed consent in the subject’s medical record. Copies of the signed informed consent 
form, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or 
the relevant subject’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised informed 
consent form. 
14.5 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Subject records will be kept private except when 
ordered by law. The following individuals will have access to study subject records: 
Principal Investigator and designees, study Sponsor, monitors and auditors, the FDA, 
other government offices and the IRB. 
Throughout this study, a subject’s source data will only be linked to the Sponsor’s 
clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, 
age, or date of birth, and subject initials may be used to verify the subject and accuracy of 
the subject’s unique identification number. 
The Investigator must agree to permit the Sponsor’s monitor or designee’s monitor, 
representatives from any regulatory authority, the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s source data or documents, including, 
but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process. The confidentiality 
of the verified data and the protection of the subjects must be respected during these 
inspections. 


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Copies of any subject source documents that are provided to the Sponsor must have 
certain personally identifiable information removed. 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy 
The Investigator will provide the Sponsor with truthful, accurate and complete test results 
and all data derived from the study. During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as 
required by law or regulation. Except as otherwise allowable in the clinical study site 
agreement, any public disclosure (including publicly accessible websites) related to the 
protocol or study results, other than study recruitment materials and/or advertisements, is 
the sole responsibility of the Sponsor. 
ProSciento or its designee will be responsible for preparing the Clinical Study Report. 
When all data has been fully analyzed, ProSciento or Sponsor will communicate the 
results of the Clinical Study to the Investigator(s).  
The Investigator or qualified designee agrees to use this information only and strictly in 
connection with this Clinical Study and must not use it for other purposes without the 
prior written permission from the Sponsor. Prior to any publication, the Sponsor must be 
given the opportunity to review and comment upon any manuscript, poster, or paper that 
contains data derived or generated from this study in order to be aware of all written and 
oral presentations of the data and does not imply any editorial review or restriction of the 
contents of the presentation or use. 
To ensure that information on clinical studies reaches the public in a timely manner and 
to comply with applicable law, regulation and guidance, this study may be registered on 
Clinicals.gov or other publicly accessible websites before study initiation.  
14.7 
Insurance and Compensation for Injury 
The Sponsor shall carry applicable insurance in the types and amounts necessary to cover 
its obligations herein in accordance with local laws and requirements and/or guidelines 
for conducting clinical studies in any country, unless others have shown negligence. The 
Sponsor renounces liability in the event of negligence or any other liability by the clinics 
or doctors conducting experiments or by persons for whom the said clinic or doctors are 
responsible. The Sponsor accepts liability in accordance with all applicable regulations 
per the Code of Federal Regulations (CFR) and all other applicable federal or state 
regulations. 
Each subject in the study must be insured in accordance with the regulations applicable to 
the study site where the subject is participating.  
If a subject becomes ill or injured due to an adverse event directly resulting from use of 
the study drug or a study procedure in the course of their participation in this Clinical 
Study, medical treatment will be provided. Sponsor will pay the costs of such treatment. 


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15.0 
REFERENCES 
1. Obesity and overweight fact sheet (2016). 
http://www.who.int/mediacentre/factsheets/fs311/en/ 
2. Finer N. Medical consequences of obesity (2003). Medicine, Vol 43: 2, pp 88-93 
3. Sanchez-Garrido MA, Brandt SJ, Clemmensen C et al (2017). GLP-1/glucagon 
receptor co-agonism for treatment of obesity. Diabetologia Vol 60, pp 1851-1861 
4. Choi IY, Lee JS, Kim JK, et al. (2017). Potent body weight loss and therapeutic 
efficacy in a NASH animal model by a novel long-acting GLP-1/GIP/Glucagon 
tri-agonist (HM15211). Diabetologia, Vol 60: Supplement 1, pp 1-564 
5. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers, Food and Drug 
Administration. Center for Drug Evaluation and Research, July 2005. 
6. European Medicines Agency guidance: Guidelines on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal 
Products, Committee for Medicinal Products for Human Use (CHMP), July 2007 
7. World Medical Association. Declaration of Helsinki. Ethical Principles for 
Medical Research Involving Human Subjects. 52nd WMA General Assembly, 
Edinburgh, Scotland, October 2000. Last amended with Note of Clarification on 
Paragraph 29 by the WMA General Assembly, Washington 2002.and Note of 
clarification on paragraph 30 by the WMA General assembly, Tokyo 2004 
8. International Conference on Harmonization. ICH Harmonized Tripartite 
Guideline. Good Clinical Practice. 01-May-1996 
 


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16.0 
APPENDIX A 
Table 16-1 Schedule of Events Cohorts 1-1 and 1-2 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 -2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING PROCEDURES 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior Medication  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated Glomerular Filtration Rate 
(eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
HBA1C, FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in Criteria to In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Urine Drug Screen & Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
SAFETY AND EXPLORATORY ASSESSMENTS 
Physical Examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Haematology, Chemistry, Coagulation, 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 


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Screen 
Admin 
Treatment Period 
Elimination 
FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 -2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Urinalysis  
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight12 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lipid Profile and Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Bone Metabolism Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENTS 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
OTHER SAFETY ASSESSMENTS 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility. 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from the 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection.  
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule in section 9.1.16. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 91 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel.  
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 
 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 92 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
Table 16-2 Schedule of Events, Cohort 1-3 (not including Day 82) 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 -2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING PROCEDURES 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior Medication  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated Glomerular Filtration Rate 
(eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
HBA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in Criteria to In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Urine Drug Screen & Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
SAFETY AND EXPLORATORY ASSESSMENTS 
Physical Examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 93 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 -2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Haematology, Chemistry, Coagulation, 
Urinalysis  
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight13 
X 
 
X 
X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lipid Profile and Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Bone Metabolism Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENTS 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
OTHER SAFETY ASSESSMENTS 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility. 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 4 and 81 after subject have been disconnected from the 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 94 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
6All incretins will be collected at the same time points together with the PK sample collection.  
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule in section 9.1.16. Cohort 3 will start to collect additional PK sample with start of Day 78.  
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel.  
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then 
daily during the in-house periods and at outpatient visits on non-dosing days in the morning, approximately at the time of the dosing on dosing days 
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 95 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
Table 16-3 Schedule of Events, starting with Cohort 1-3 (including Day 82) 
 
Screen 
Admin 
Treatment Period 
Elimination FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
82* 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING PROCEDURES 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior Medication  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated Glomerular Filtration Rate 
(eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HBA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in Criteria to In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Urine Drug Screen & Alcohol Breath 
Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
SAFETY AND EXPLORATORY ASSESSMENTS 
Physical Examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 96 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
 
Screen 
Admin 
Treatment Period 
Elimination FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
82* 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Haematology, Chemistry, Coagulation, 
Urinalysis  
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight13 
X 
 
X X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lipid Profile and Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Bone Metabolism Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Inflammatory Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENTS 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
OTHER SAFETY ASSESSMENTS 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility. 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 97 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from the 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection.  
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule in section 9.1.16. Cohort 1-3 will start to collect additional PK sample with start of Day 78. . 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits in the morning, approximately at the time of the dosing on non dosing days 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel.  
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
* Day 82 is optional for subjects already participating in cohort 1-3. 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 98 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
Table 16-4 Schedule of Events, Cohort 1-4 
 
Screen 
Admin 
Treatment Period 
Elimination FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING PROCEDURES 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior Medication  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated Glomerular Filtration Rate 
(eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HBA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Check-in Criteria to In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Urine Drug Screen & Alcohol Breath 
Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
SAFETY AND EXPLORATORY ASSESSMENTS 
Physical Examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 99 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
 
Screen 
Admin 
Treatment Period 
Elimination FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
12-lead ECG 
X4 
X4 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Haematology, Chemistry, Coagulation, 
Urinalysis  
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight13 
X 
 
X X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lipid Profile and Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Bone Metabolism Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Inflammatory Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENTS 
PK Sampling8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
OTHER SAFETY ASSESSMENTS 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility. 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 


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Clinical Study Protocol 
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Page 100 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from the 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection.  
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule in section 9.1.16. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits in the morning, approximately at the time of the dosing on non-dosing days 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel.  
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 


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Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
Table 16-5 Schedule of Events, Cohort 1-5 and up 
 
Screen 
Admin 
Treatment Period 
Elimination FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING PROCEDURES 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior Medication  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated Glomerular Filtration Rate 
(eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HBA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Check-in Criteria to In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Urine Drug Screen & Alcohol Breath 
Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
SAFETY AND EXPLORATORY ASSESSMENTS 
Physical Examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
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Page 102 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
 
Screen 
Admin 
Treatment Period 
Elimination FU 
In house Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
12-lead ECG 
X4 
X4 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Haematology, Chemistry, Coagulation, 
Urinalysis  
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight13 
X 
 
X X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lipid Profile and Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
MRI/MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Bone Metabolism Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Inflammatory Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENTS 
PK Sampling8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
OTHER SAFETY ASSESSMENTS 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility. 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 103 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from the 
ambulatory device. 
5Subjects will undergo an MRI/MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but 
prior to the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection.  
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule in section 9.1.16. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits in the morning, approximately at the time of the dosing on non-dosing days 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel.  
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
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Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
17.0 
APPENDIX B 
Adverse Event Guidance Document 
General Statement 
As any new investigational product may have unexpected adverse events, the following 
guidance is offered for potential, but unexpected, toxicities for HM15211. 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: 
chest pain, arrhythmia, palpitations, peripheral edema, progressive or acute dyspnea, 
pleural effusion, fatigue 
Diagnostic Workup: 
At baseline: 
• Electrocardiogram 
• Cardiac biomarkers (creatine kinase and troponin) 
 
Depending on presentation: 
• Inflammatory biomarkers (ESR, CRP, WBC count) 
•  O2 Saturation 
• BNP 
• Emergency room/hospital transfer 
• Cardiology consultation 
• Chest x-ray 
 
Additional testing to be guided by cardiology and may include: 
• Echocardiography 
• Stress test 
• Cardiac catheterization 
• Cardiac MRI 
 
 


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Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
Grading* 
Management 
G1: Asymptomatic abnormal cardiac biomarker 
testing, including abnormal ECG 
All grades warrant workup and intervention 
given potential for cardiac compromise 
Please consider the following: 
• Hold therapy and permanently discontinue 
after G1 
• Management of cardiac symptoms according to 
ACC/AHA guidelines 
• Transfer patient 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 greater than G2. The appropriateness of rechallenging remains unknown. 
* Not associated with CTCAE grading system 
 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 106 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
2. Rash/Inflammatory Dermatitis and Other Skin Disorders 
Definitions:  
x Erythema multiforme major and minor (a targetoid reaction in the skin and mucous 
membranes usually triggered by infections, such as Herpes Simplex Viruses, but can 
be associated with an immune-related drug eruption and if progresses to EM major, 
it can be a harbinger of SCAR, such as SJS)  
x Lichenoid (resembling the flat-topped, polygonal and sometimes scaly or 
hypertrophic lesions of lichen planus)  
x Eczematous (Inflammatory dermatitis characterized by pruritic, erythematous, scaly 
or crusted papules or plaques on the skin, which is vulnerable to superinfection) 
x  Psoriasiform (resembling the well-demarcated, erythematous and scaly papules and 
plaques of psoriasis)  
x Morbilliform (a non-pustular, non-bullous measles-like exanthematous rash of the 
skin often referred to as “maculopapular” and without systemic symptoms or lab 
abnormalities, excluding occasional isolated peripheral eosinophilia  
x Palmoplantar erythrodysaesthesia (PPE) (hand-foot syndrome) (redness, 
numbness/burning/itching and superficial desquamation of the palms and soles)  
x Neutrophilic dermatoses (e.g. sweet’s syndrome)  
x Others 
 
Diagnostic Workup for Skin Disorders above and Others Considered to be Possibly 
IP-related: 
• Pertinent history and physical exam 
• Rule out any other etiology of 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, a biological checkup including a blood cell count, liver and kidney tests 
• Directed serologic studies if an autoimmune condition is suspected, such as lupus or 
dermatomyositis: a screening antinuclear antibody test, SSA/Anti-Ro, SS-B/Anti-La if 
predominantly photodistributed/photosensitivity, anti-histone, ds-DNA and other 
relevant serologies. Consider expanding serologic studies or diagnostic work up if other 
autoimmune conditions are considered based on signs, symptoms. 
• Dermatology consultation with skin biopsy 
• Consider clinical monitoring with use of serial clinical photography, if IRB approved 
and subject has consented 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
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Page 107 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
• Review full list of patient medications to rule out other drug-induced cause for 
photosensitivity 
Grading 
Grading according to CTCAE criteria is a 
challenge for skin. Instead, severity may be 
based on BSA, tolerability, morbidity, and 
duration. 
Management 
G1: Symptoms do not affect the quality of life 
or controlled with topical regimen and/or oral 
antipruritic 
• Consider continuing therapy for mild localized 
reaction, e.g., injection site erythema 
• Consider treatment with topical emollients 
and/or mild-moderate potency topical 
corticosteroids 
• Counsel patients to avoid skin irritants and sun 
exposure 
G2: Inflammatory reaction that affects quality 
of life and requires intervention based on 
diagnosis. 
• Dermatology consultation with possible biopsy 
• Consider holding therapy and monitor weekly 
for improvement. If not resolved, interrupt 
treatment until skin AE has reverted to grade 1 
• Consider initiating prednisone (or equivalent) 
at 
dosing 1 mg/kg tapering over at 4 weeks 
In addition, treat with topical emollients, oral 
antihistamines and medium-to-high potency 
topical 
corticosteroids 
G3: As grade 2 but with failure to respond to 
indicated interventions for a grade 2 dermatitis. 
• Hold therapy and consult with dermatology to 
determine appropriateness of resuming 
• Treat with topical emollients, oral 
antihistamines and high potency topical 
corticosteroids 
• Initiate oral prednisone or equivalent  
(0.5-1 mg/kg/day) tapering over at least 4 weeks 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 108 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
G4: All severe rashes not manageable with prior 
intervention 
• Immediate hold therapy and consult 
dermatology to determine appropriateness of 
resuming therapy upon resolution of skin 
toxicity and once corticosteroids are reduced to 
prednisone (or equivalent) 10mg or less. 
• Systemic steroids: IV (methyl)prednisolone (or 
equivalent) dosed at 1–2mg/kg with slow 
tapering when the toxicity resolves 
• Monitor closely for progression to Severe 
Cutaneous Adverse Reaction 
• Should admit patient immediately with an 
urgent 
consult by dermatology 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 109 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
3. Gallstones (Cholelithiasis), Biliary Cholic or Cholecystitis 
Definition: 
Asymptomatic gallstones/ asymptomatic common bile duct stones: Stones that are found 
incidentally, as a result of imaging investigations unrelated to gallstone disease in people 
who have been completely symptom free for at least 12 months before diagnosis. 
Symptomatic gallstones/ symptomatic common bile duct stones: Stones found on 
gallbladder imaging, regardless of whether symptoms are being experienced currently or 
whether they occurred sometime in the 12 months before diagnosis. 
When should symptomatic gallbladder stones be suspected? 
The characteristic symptoms of gallbladder stones, i.e. episodic attacks of severe pain in 
the right upper abdominal quadrant or epigastrium for at least 15-30 minutes with 
radiation to the right back or shoulder and a positive reaction to analgesics, should be 
identified by medical history and physical examination 
 
• Diagnostic Workup for Symptoms Suggestive of Gallstone-related Disorders: 
• Liver function tests and ultrasound for suspected gallstone disease, and for individuals 
with abdominal or gastrointestinal symptoms that have been unresponsive to previous 
management. 
• Consider magnetic resonance cholangiopancreatography (MRCP) if ultrasound has not 
detected common bile duct stones but the: 
✓ bile duct is dilated and/or 
✓ liver function test results are abnormal. 
• Consider endoscopic ultrasound (EUS) if MRCP does not allow a diagnosis to be made. 
• Consider holding therapy and consulting gastroenterology. 
• Refer people for further investigations if conditions other than gallstone disease are 
suspected. 


Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 110 of 110 
Protocol No. HM-TRIA-102 
 
Version 5.0_02Jul2019 
4. Gastrointestinal Events 
Definition: Nausea and vomiting are anticipated adverse events with this protocol.  
The initial assessment needs to include consideration of other differentials including 
pancreatitis and cholelithiasis.  Laboratory assessments of amylase, lipase and liver 
function tests (ALT, AST, alkaline phosphatase, and bilirubin) or imaging 
(ultrasound, CT 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. 
 
 
 
• Hold therapy; resume therapy only if 
symptoms are fully resolved  
• Treat with antiemetic medication as indicated 
• Treat with IV fluid 
• Treat with parenteral nutrition if no oral intake 
sustained beyond 7 days 
G4: Life-threatening symptoms 
• Immediately discontinue therapy  
• Systemic IV fluids 
• Treat with antiemetic medication as indicated 
• Treat with parenteral nutrition 
• Should admit patient immediately with an 
urgent consult 
 

SAP_001.pdf: 
 
 
HM-TRIA-102 Statistical Analysis Plan 
   
 
Confidential 
 
 
 
 
Page 1 
 
 
 
 
Statistical Analysis Plan 
 
Protocol HM-TRIA-102 
 
A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Multiple Doses of HM15211 in Obese Subjects with NAFLD 
 
Phase I 
 
Original Protocol:  
Version 1.0: 27-Sep-2018 
Version 2.0: 25-Oct-2018 
Version 3:0: 13-Feb-2019 
Version 4.0: 09-Apr-2019 
Version 5.0: 02-Jul-2019 
 
 
 
 
 
 
 
 
Prepared by: 
________________________ 
 
 
Tim Lin, MS 
 
Senior Statistician, Statistics 
 
 
 
Pharmapace, Inc. 
 
 
 
 
 
 
 
Version: 
Final 
 
 
Date: 
March 23, 2020 
 
 
Tim Lin, MS
Pharmapace, Inc.
Senior Statistician, Statistics


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
 
Confidential 
 
 
 
 
Page 2 
 
 
 
 
Statistical Analysis Plan 
 
Protocol HM-TRIA-102 
 
A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Multiple Doses of HM15211 in Obese Subjects with NAFLD 
 
Phase I 
 
Original Protocol: 
   
Version 1.0: 
27-Sep-2018   
Version 2.0: 
25-Oct-2018   
Version 3:0: 13-Feb-2019   
Version 4.0: 09-Apr-2019   
Version 5.0: 02-Jul-2019 
  
 
 
 
 
 
 
 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
Date:  
 
OakPil Han 
Director of BioMetrics 
Hanmi Pharmaceutical Co., Ltd. 
 
 
OakPil Han
Director of BioMetrics
Hanmi Pharmaceutical Co., Ltd.


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
 
Confidential 
 
 
 
 
Page 3 
 
Table of Contents 
1. 
Introduction ............................................................................................................................. 9 
2. 
Study Overview ...................................................................................................................... 9 
2.1. 
Study Design .................................................................................................................... 9 
2.2. 
Randomization and Blinding .......................................................................................... 11 
2.3. 
Sample Size and Power .................................................................................................. 11 
2.4. 
Study Procedures and Visit Structure............................................................................. 11 
3. 
Study Objectives ................................................................................................................... 11 
3.1. 
Primary Objectives and Endpoints ................................................................................. 11 
3.1.1. 
Safety and Tolerability of HM15211 ...................................................................... 11 
3.1.2. 
Pharmacokinetics of HM15211 .............................................................................. 12 
3.1.3. 
Pharmacodynamics of HM15211 ........................................................................... 12 
3.2. 
Exploratory Objectives and Endpoints ........................................................................... 12 
4. 
Analysis Sets ......................................................................................................................... 13 
4.1. 
Safety Set........................................................................................................................ 13 
4.2. 
Pharmacokinetic Analysis Set ........................................................................................ 13 
4.3. 
Pharmacodynamic Analysis Set ..................................................................................... 14 
5. 
Study Subjects ....................................................................................................................... 14 
5.1. 
Subject Disposition ........................................................................................................ 14 
5.2. 
Demographic and Baseline Characteristics .................................................................... 14 
5.3. 
Medical History .............................................................................................................. 14 
5.4. 
Subject Eligibility and Withdrawal Criteria ................................................................... 14 
5.5. 
Exposure ......................................................................................................................... 14 
5.6. 
Concomitant Medication ................................................................................................ 15 
5.7. 
Protocol Deviations ........................................................................................................ 15 
6. 
Statistical Methods of Analysis ............................................................................................ 15 
6.1. 
General Considerations .................................................................................................. 15 
6.1.1. 
Statistical Notation and Presentation ...................................................................... 15 
6.1.2. 
Handling of Multiple Observations, Missing Observations or Out of Window 
Observations ......................................................................................................................... 16 
6.1.3. 
Handling of Missing or Partial Dates...................................................................... 16 
6.1.4. 
Handling of Outliers and Unquantifiable Measurements ....................................... 17 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
 
Confidential 
 
 
 
 
Page 4 
 
6.1.5. 
Study Baseline ........................................................................................................ 18 
6.2. 
Pharmacokinetic Analyses ............................................................................................. 18 
6.2.1. 
PK Concentration .................................................................................................... 18 
6.2.2. 
PK Parameters ......................................................................................................... 18 
6.2.3. 
Dose Proportionality ............................................................................................... 19 
6.3. 
Pharmacodynamic Analyses .......................................................................................... 20 
6.3.1. 
MRI-PDFF .............................................................................................................. 20 
6.4. 
Exploratory Analyses ..................................................................................................... 20 
6.4.1. 
Incretins Secretion .................................................................................................. 20 
6.4.2. 
Body Weight, Body Mass Index, and Waist Circumference .................................. 20 
6.4.3. 
Serum Lipid Profile and Particles ........................................................................... 20 
6.4.4. 
Amino Acids ........................................................................................................... 21 
6.4.5. 
Inflammatory Marker .............................................................................................. 21 
6.4.6. 
Bone Metabolism .................................................................................................... 21 
6.4.7. 
Glucose Metabolism ............................................................................................... 21 
6.4.8. 
Ketone Bodies ......................................................................................................... 21 
6.4.9. 
Liver Steatosis and Liver Stiffness ......................................................................... 21 
6.4.10. 
Visceral Fat Volume............................................................................................ 22 
6.5. 
Safety Analyses .............................................................................................................. 22 
6.5.1. 
Adverse Events ....................................................................................................... 22 
6.5.2. 
Clinical Laboratory Assessments ............................................................................ 22 
6.5.3. 
Immunogenicity ...................................................................................................... 22 
6.5.4. 
Physical Examination.............................................................................................. 23 
6.5.5. 
Vital Signs ............................................................................................................... 23 
6.5.6. 
24-Hour Ambulatory Blood Pressure Monitoring .................................................. 23 
6.5.7. 
24-Hour Holter ECG ............................................................................................... 23 
6.5.8. 
12-Lead Electrocardiograms ................................................................................... 23 
6.5.9. 
Injection Site Reactions .......................................................................................... 23 
7. 
Interim Analysis .................................................................................................................... 24 
8. 
Statistical Software ............................................................................................................... 24 
9. 
Changes to the Planned Analyses from Protocol .................................................................. 24 


 
 
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10. 
References .......................................................................................................................... 24 
11. 
Appendix ............................................................................................................................ 25 
 
 
 


 
 
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List of In-Text Tables and Figures 
Table 1: Treatment Allocation and Dose Escalation (NAFLD) ................................................... 10 
Table 2: Schedule of Events, Cohorts 1-1 and 1-2 ....................................................................... 25 
Table 3: Schedule of Events, Cohorts 1-3 (not including Day 82) ............................................... 28 
Table 4: Schedule of Events, Cohorts 1-3 (including Day 82) ..................................................... 31 
Table 5: Schedule of Events, Cohorts 1-4 .................................................................................... 34 
Table 6: Schedule of Events, Cohorts 1-5 and up ......................................................................... 37 
Table 7: PK Sampling Schedule for cohorts 1-1 and 1-2 ............................................................. 40 
Table 8: PK Sampling Schedule starting from cohort 1-3 ............................................................ 41 
 
Figure 1: Dose Escalation Schematic ........................................................................................... 10 
 
 
 


 
 
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List of Abbreviations 
Abbreviation 
Definition of Term 
_obs 
observed 
_pred 
predicted 
ADAbs 
Anti-drug antibodies 
Adj_RSq 
Adjusted r squared 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
anti-PEG 
Anti-polyethylene glycol antibodies 
ATC 
Anatomic Therapeutic Chemistry 
AUC 
Area under the concentration-time curve 
AUC0-168h SS 
Area under the concentration-time curve for HM15211 during steady 
state 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
BP 
Blood pressure 
CAP 
Controlled attenuation parameter 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Cmax 
Maximum concentration 
CSR 
Clinical study report 
Ctrough 
Trough serum concentration 
CTX-1 
Carboxy-terminal crosslinked telopeptide of 
type 1 collagen 
CV 
Cardiovascular 
CV% 
Coefficient of  variation 
ECG 
Electrocardiogram 
FFA 
Free fatty acid 
FGF21 
Fibroblast growth factor 21 
FPG 
Fasting plasma glucose 
GCG 
Glucagon 
GI 
Gastrointestinal 
GIP 
Gastric inhibitory peptide 
GLP-1 
Glucagon like peptide-1 
HA 
Hyaluronic acid 
HDL 
High-density lipid 
HDL-C 
High-density lipid cholesterol content 
HDL-P 
High-density lipid particles 
HR 
Heart rate 
IP 
Investigational product 
IWRS 
Interactive Web Response System 
kel 
Apparent elimination constant 
LDL 
Low-density lipid 
LDL-C 
Low-density lipid cholesterol content 


 
 
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Abbreviation 
Definition of Term 
LDL-P 
Low-density lipid particles 
LLOQ 
Lower limit of quantitation 
LS 
Least squares 
LSM 
Liver stiffness measurements 
max 
maximum 
MedDRA 
Medical dictionary for regulatory activities 
min 
minimum 
MRI-PDFF 
Magnetic resonance imaging-estimated proton density fat fraction 
n 
sample size 
nAbs 
Neutralizing antibodies 
NAFLD 
Non-alcoholic fatty liver disease 
NCA 
Non-compartmental analysis 
NN 
Normal to normal R-R intervals 
OC 
Osteocalcin 
P1NP 
Procollagen type 1 N-terminal propeptide 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetics 
PT 
Preferred term 
QTcF 
Fridericia’s corrected QT interval 
Rdnm 
Ratio of the dose normalized geometric means 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDANN 
Standard deviation of the 5-minute average NN interval 
SDNN index 
Mean of standard deviations of all NN intervals for all 5 min 
segments of the entire recording. 
SE 
Standard error 
SOC 
System organ class 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
TSH 
Thyroid stimulating hormone 
VCTE 
Vibration controlled transient elastography 
VLDL 
Very low-density lipid 
VLDL-C 
Very low-density lipid cholesterol content 
VLDL-P 
Very low-density lipid particles 
Vz/F 
Apparent volume of distribution at terminal 
WHO DDE 
World Health Organization drug dictionary enhanced 
 
 


 
 
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1. Introduction 
This document describes the statistical methods and data presentation in the analysis and 
summary of the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of 
HM15211 with Placebo as comparator in obese subjects with non-alcoholic fatty liver disease 
(NAFLD). This statistical analysis plan (SAP) was developed based on Hanmi Pharmaceutical 
Protocol HM-TRIA-102 (version 5.0 dated 02Jul2019).  
This SAP will be finalized prior to data analyses and before database lock. Any major 
differences between the statistical methods provided in the clinical study protocol and this SAP 
will be explained herein. Any major changes and deviations from this SAP to the final data 
analysis must be substantiated by sound statistical rationale and fully documented in the final 
clinical study report (CSR). 
2. Study Overview 
2.1. Study Design 
This is a randomized, placebo-controlled, multiple-ascending dose study to investigate the safety, 
tolerability, PK, and PD of subcutaneous (SC) administration of HM15211. 
This study will be single-blind and conducted in up to 6 cohorts comprising a total of up to 72 
obese subjects with NAFLD. Each cohort will enroll subjects to ensure that at least 12 subjects 
per cohort will complete the study. Subjects will be randomized to investigational product (IP) or 
placebo in a 3:1 ratio via an Interactive Web Response System (IWRS). Per cohort (n=12 
subjects), 9 subjects will be randomized to HM15211 and 3 subjects to placebo. Cohorts may 
partially overlap after at least 9 subjects have completed 2-4 weeks of treatment (2 weeks of 
treatment is reached at Visit week 3) and a dose escalation decision has been made. Study drug 
will be administered weekly over a period of 12 weeks. 
Based on the safety and available PK and PD data of each cohort, and following a safety review 
and dose escalation meeting between the investigator and the sponsor, dose escalation to the next 
cohort may proceed. Cohorts will start in sequential order but may overlap partially during 
execution. Replacement of dropouts and withdrawals may take place. 
Each subject will undergo a screening visit, 2 in-house/ treatment periods and multiple outpatient 
visits. A final follow-up visit that will conclude subject study participation. 
The duration of participation in this study including Screening, Treatment and Follow-up will be 
approximately 23 weeks for each subject including 12 weeks of treatment period. 


 
 
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Table 1: Treatment Allocation and Dose Escalation (NAFLD) 
Cohorts 
Number of Subjects 
Treatment 
Cohort 1-1 
N=9 
HM15211 0.01 mg/kg 
N=3 
Matching Placebo 
Cohort 1-2 
N=9 
HM15211 0.02 mg/kg 
N=3 
Matching Placebo 
Cohort 1-3 
N=9 
HM15211 0.04 mg/kg 
N=3 
Matching Placebo 
Cohort 1-4 
N=9 
HM15211 0.06 mg/kg 
N=3 
Matching Placebo 
Cohort 1-5 
N=9 
HM15211 0.08 mg/kg 
N=3 
Matching Placebo 
Cohort 1-6 
N=9 
HM15211 0.12 mg/kg 
N=3 
Matching Placebo 
Additional cohorts may be added if necessary, to provide sufficient data. Proposed doses for 
cohort 1-2 and 1-3 and 1-4 may be adjusted but will not exceed the doses stated in the table. 
Figure 1: Dose Escalation Schematic 
 


 
 
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2.2. Randomization and Blinding 
Subjects who meet all inclusion and exclusion criteria or check-in criteria will be assigned a 
subject randomization number via an IWRS. The system will randomize in a 3:1 ratio to 
HM15211 or placebo. Randomization will continue until a total of up to 72 subjects have 
completed the study (or until 12 subjects per cohort have completed the study). If a subject fails 
to start dosing, or if a subject can’t be randomized, the reason will be entered into the screening 
disposition page. The IWRS must be notified within 2 days that the subject was not randomized. 
In the event of an emergency, e.g. when it becomes necessary for the investigator to know which 
study drug the subject is taking, the subject code can be broken by the investigator, preferably 
after consultation with the medical monitor. Emergency code breaks can be performed using the 
IWRS, see section 8.7 in the protocol. As the study is single-blind, subjects and the clinical staff 
caring for the subjects are blinded to treatment. Staff involved in the data management, statistical 
analyses and staff from Pharmaceutical Services who are responsible for preparing the IP, will be 
unblinded. Unblinded staff will not be involved in the subjects’ care. 
After all subjects in one cohort have completed the Follow-up Visit, necessary steps to start with 
the data analysis may be taken. Data may be unblinded and data analysis for the completed 
cohort may start. 
2.3. Sample Size and Power 
Due to the exploratory nature of this study, a sample size of 12 subjects per cohort is empirically 
determined and consistent with typical sample sizes used for similar studies to assess PK and 
safety data. 
2.4. Study Procedures and Visit Structure 
In the appendix, Tables 2-6 describe the procedures and visit structure for this study for all 
Cohorts; Tables 7 and 8 describe the PK sampling schedules; the schedule of events and PK 
sampling schedules for each cohort can also be found in the clinical trial protocol. 
3. Study Objectives 
3.1. Primary Objectives and Endpoints 
3.1.1. Safety and Tolerability of HM15211 
To assess safety and tolerability of HM15211 after administration of multiple subcutaneous 
doses in obese subjects with NAFLD by: 
x Incidence of adverse events (AEs) (cardiovascular [CV] events, rash/inflammatory 
dermatitis and other skin disorders, gastrointestinal [GI] events, and gall stone formation 
[cholelithiasis] will be managed following separate AE guidance document). 
x Incidence of clinical lab abnormalities (including serum amylase, serum lipase, 
coagulation, thyroid stimulating hormone (TSH), serum calcitonin) 


 
 
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x Immunogenicity (Anti-drug antibodies [ADAbs], neutralizing antibodies [nAbs], anti-
polyethylene glycol antibodies [anti-PEG]) 
x Incidence and severity of clinical findings on physical examination 
x Change from baseline in vital signs (blood pressure [BP], heart rate [HR], respiratory 
rate, and temperature]);  
BP assessed by 24-hour ambulatory blood pressure monitoring (ABPM);  
HR assessed by 24-hour ambulatory electrocardiography monitoring (Holter ECG; 
central reader) 
x Change from baseline in 12-lead ECG parameters; the primary ECG endpoint will be 
QTcF 
x Injection site reactions. 
3.1.2. Pharmacokinetics of HM15211 
To assess the pharmacokinetic (PK) profile of HM15211 after administration of multiple SC 
doses in obese subjects with NAFLD by, but not limited to: 
x Maximum concentration (Cmax) 
x Time to reach Cmax (tmax) 
x Trough serum concentration (Ctrough) 
x Area under the concentration-time curve (AUC), eg, AUC0-t at steady state 
x Terminal elimination rate constant (kel) 
x Terminal half-life (t1/2) 
x Apparent clearance (CL/F) 
x Apparent volume of distribution (Vz/F) 
3.1.3. Pharmacodynamics of HM15211 
To assess a reduction of liver fat after administration of multiple doses in obese subjects with 
NAFLD by: 
x Absolute and % changes of fat on magnetic resonance imaging-estimated proton density 
fat fraction (MRI-PDFF) 
3.2. Exploratory Objectives and Endpoints 
To assess additional pharmacodynamic properties of HM15211 after multiple SC doses in 
comparison to placebo by: 
x Incretins/ metabolic hormones 
o Glucagon-like peptide-1 (GLP-1) 
o Gastric inhibitory peptide (GIP) 
o Glucagon 
o Fibroblast growth factor 21 (FGF21) 
o Leptin 


 
 
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x Body weight and body mass index (BMI) 
x Waist circumference  
x Serum lipid profile and particles 
o Total cholesterol 
o Low-density lipoprotein (LDL): LDL-C, LDL-P (particles) 
o High-density lipoprotein (HDL): HDL-C, HDL-P (particles) 
o Very low-density lipoprotein (VLDL): VLDL-C, VLDL-P (particles) 
o Triglycerides 
o Free Fatty Acids (FFAs) 
x Amino acid profile 
x Inflammatory marker 
o Adiponectin 
x Bone metabolism parameters 
o Fasting carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1) 
o Osteocalcin (OC) 
o Procollagen type 1 N-terminal propeptide (P1NP) 
x Glucose metabolism parameters: 
o Fasting plasma glucose (FPG) 
o Fasting insulin, fasting C-peptide 
o HbA1c 
x Ketone bodies 
o Beta-hydroxybutyrate 
x Changes in liver steatosis and liver stiffness assessed by FibroScan® (VCTE), determined 
as absolute and percent change from baseline in controlled attenuation parameter (CAP) 
and liver stiffness measurements (LSM) (For Cohort 4 and 5) 
x Changes in visceral fat volume, determined by absolute and relative percent change 
assessed by MRI imaging. (Will no longer be performed) 
4. Analysis Sets 
4.1. Safety Set 
The Safety analysis set will include all subjects who received study medication (HM15211 or 
Placebo). The Safety analysis set will be used for demographic, baseline characteristics and 
safety summaries. 
4.2. Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects who received HM15211 with evaluable PK data 
appropriate for the evaluation of interest (without important protocol deviations or violations that 
would have an impact on the absorption, distribution, metabolism, or excretion of HM15211). 
PK analysis set will be used for analysis of PK endpoints. 


 
 
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4.3. Pharmacodynamic Analysis Set 
The PD analysis set will include all subjects who received HM15211 or placebo with evaluable 
PD data appropriate for the evaluation of interest (without important protocol deviations or 
violations that would have an impact on the PD of HM15211). PD analysis set will be used for 
analysis of PD endpoints. 
5. Study Subjects 
Study subject data will be summarized by treatment and treatment overall, with pooled placebo 
using the Safety Set. 
5.1. Subject Disposition 
Subject disposition will be summarized for the Safety Set. Summary tables will be presented. 
5.2. Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for all subjects in the 
Safety Set. Demographic and baseline characteristics include, but are not limited to: age, sex, 
ethnicity, race, body weight, height, body mass index, smoking status at Screening, alcohol use 
at Screening, VCTE, Liver Fat via MRI-PDFF, CAP and LSM by FibroScan®, HbA1c, c-
peptide, insulin, fasting plasma glucose, total cholesterol, cholesterol and particles of HDL, LDL, 
and VLDL, triglycerides, Free Fatty Acids, creatinine, bilirubin, ALT, AST, GGT, and 
incretins/metabolic hormones. 
5.3. Medical History 
Medical history is any significant medical condition or disease that is present at study start 
(signing of informed consent). The medical history recorded through clinically significant 
laboratory, electrocardiogram (ECG), or physical examination (PE) abnormalities noted at 
Screening examination will be listed. 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
version 23.0) and summarized by System Organ Class (SOC) and Preferred Term (PT) for the 
Safety Set. Medical history will be listed. 
5.4. Subject Eligibility and Withdrawal Criteria 
Subject eligibility and subjects who meet withdrawal criteria will be presented in listings. 
5.5. Exposure 
Total study dose administrated (mg/kg) and number of administration by visit and overall will be 
summarized by treatment and treatment overall, with pooled placebo. Study drug administration 
information will be listed. 
 


 
 
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5.6. Concomitant Medication 
Concomitant medication is medication given in addition to the study medication (including over-
the-counter medications, herbal medications, and vitamin supplements) administered between 
screening and follow-up. Medication will be categorized into the three following types: 
x Prior concomitant medication is defined as any medications that start before the date of 
dosing of study medication and continue beyond that date.  
x New concomitant medication is defined as any medications that start after the date of 
dosing of study medication, including those started in the follow-up period.  
x Pre-treatment medication is defined as any non-study medication that stops before the 
date of dosing of study medication. 
The WHO Drug Global version B3, March 2020) will be used to categorize the verbatim 
descriptions of medications into the Anatomic Therapeutic Chemistry (ATC) classification 
system. Each verbatim name will be classified by anatomical main group (ATC level 1), 
therapeutic subgroup (ATC level 2), pharmacological subgroup (ATC level 3), chemical 
subgroup (ATC level 4), and trade name. 
The number and percentage of subjects receiving concomitant medications (including both prior 
and new concomitant medications) will be summarized by ATC classification (ATC level 2 and 
level 4) for the Safety Set. Pre-treatment medication administered during the study will only be 
listed. 
5.7. Protocol Deviations 
Protocol deviations may include the deviations from entry criteria, the study procedures, study 
medication intake/administration, or study restrictions, etc. Important protocol deviations will be 
identified prior to database lock and will be summarized for the Safety Set. Subjects with 
important protocol deviations that may impact the primary PK and PD endpoints will be 
excluded from the PK and PD Evaluable Sets. All deviations will be listed. 
6. Statistical Methods of Analysis 
6.1. General Considerations 
PK, PD, and Safety analyses will be performed with the PK Evaluable Set, PD Evaluable Set, 
and Safety Set, respectively. All data collected during the study for Safety Set will be included in 
data listings. 
6.1.1. Statistical Notation and Presentation 
The continuous variables will be summarized by number of observations (n), mean, standard 
deviation (SD), median, minimum (min), and maximum (max).  For categorical variables, the 
count and percentage of subjects in each category will be provided. For log-normal distributed 
data, geometric mean, standard error (SE) of the geometric mean, and coefficient of variation 


 
 
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(CV) will also be provided. The geometric mean is calculated as the exponential of the arithmetic 
mean calculated from data on a log scale. The CV is calculated as CV% = 100%∗
ݏݍݎݐ(exp(ߪଶ) −1), where σ is the SD of the data on the natural log scale.  
Minimum and maximum values will be rounded to the precision of the original value. Means, 
least squares (LS) means (if applicable), and medians will be rounded to 1 decimal place greater 
than the precision of the original value. SDs, SEs, and confidence intervals (CIs) will be rounded 
to 2 decimal places greater than the precision of the original value. Percentages for summarizing 
categorical data will be rounded to one decimal place. P-values, if needed, will be presented with 
4 decimal places and values less than 0.0001 will be presented as <.0001. 
All inferential statistical testing, if applicable, will be two-sided and conducted at the 0.05 
significance level, unless specified otherwise. No multiplicity adjustment is planned for this 
study. 
6.1.2. Handling of Multiple Observations, Missing Observations or Out of Window 
Observations 
If there are multiple measurements within the same scheduled visit which are scheduled to be 
collected once at each visit and are recorded as triplicate 12-lead ECG’s except the ECG at 
Screening, the average of the multiple measurements will be computed at each visit for all 
subjects and this averaged value will be used in all the analyses and summaries. 
On scheduled visits with missing assessments, unscheduled assessments within the visit window, 
if available, may be used for analysis. Assessments collected during scheduled visits that are 
outside the visit window can be used for analysis. A footnote will be added to tables where 
unscheduled visits are used to impute missing scheduled visits. 
For PK and PD data, if a blood sample was collected outside the protocol specified blood 
sampling time window, such data will still be included in data analysis, and the actual clock time 
will be used for PK and PD parameters calculations such as area under the curve (AUC). 
All values, scheduled or unscheduled, will be presented in data listings.  
6.1.3. Handling of Missing or Partial Dates 
In cases of incomplete dates for adverse events (AEs) or non-study medications, the missing 
component(s) will be assumed as the most conservative value(s) possible. The imputation rule 
aims to capture AEs with missing start dates as treatment-emergent AEs (TEAEs) in a 
conservative manner with the following algorithms: 
x If “day” is the only missing field, impute the “day” as the later one between the first day 
of the month and the dosing date if their “month” are the same. 


 
 
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x If “day” and “month” are the only missing fields, impute the “day” and “month” as the 
later one between January 1 of the year or the dosing date if the “year” is the same as the 
dose date. 
x If “day”, “month”, and “year” are all missing, to be conservative, the event will be 
assumed to occur post-dose on the same day as the first dose administration day.   
Concomitant medications with partial or missing start dates are assumed to have started prior to 
the dosing of the study medication. Non-study medications with missing or partial dates will be 
imputed similarly. 
Date imputation will only be used for computational purposes; e.g., treatment-emergent status or 
identifying concomitant medications. Actual data values, as they appear in the clinical database, 
will be shown in the data listings. 
6.1.4. Handling of Outliers and Unquantifiable Measurements 
Prior to database lock, PK data will be reviewed by the principal investigator, pharmacokinetic 
scientists, consulting scientists, data management representatives, statisticians, and the sponsor to 
assess whether individual concentration values are inconsistent with other values from the same 
subject or if there are errors with the samples. The pharmacokineticist will provide input that will 
determine whether the sample result is plausible given the PK profile of the subject. Such values 
may be re-analyzed or may be removed from the analysis prior to calculation of PK parameters 
at the discretion of the pharmacokineticist. Determination of data points subject to re-analysis or 
removal from determination of PK parameters (i.e., implausible data) will be documented prior 
to database lock. Appropriate representatives will also review PK and PD parameter results and a 
determination of plausibility will be made. Individual subject results deemed implausible may be 
removed prior to summarization of PK and PD parameter results by treatment. Removal of 
individual subject PK/PD parameter results will be documented. 
The following rules will be applied when blood samples are assayed as below the limit of 
quantitation (BLQ) or if individual concentration results are deemed implausible prior to 
database lock: 
x For graphical presentations of the individual subject data: BLQ and values deemed 
implausible will not be displayed but will be flagged for reference and retained in the 
data as assayed. 
x If any values are deemed implausible, final decisions and rationale will be documented in 
the pre-database lock meeting minutes.  
For the calculation of summary statistics of concentrations or derivation of PK and PD 
parameters: values that are BLQ and values deemed implausible will be set to missing. 


 
 
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6.1.5. Study Baseline 
%aseline will be defined as the last non-missing observation obtained prior to the administration 
of the study drug. 
6.2. Pharmacokinetic Analyses 
6.2.1. PK Concentration 
Concentration of HM15211 will be summarized descriptively by treatment group. Line plots of 
HM15211 individual subject concentration overlaid with the mean concentration for each cohort 
will be plotted separately. In addition, a line plot of the HM15211 mean concentration by 
treatment group will be plotted.  
6.2.2. PK Parameters 
The following PK parameters will be derived using non-compartmental analysis and summarized 
by treatment group for the PK Analysis Set. 
x Maximum concentration (Cmax) is defined as the maximum HM15211 concentration 
measured after SC dose. Will be calculated for Week 1 (1st dose) and Week 12 (12th 
dose): 
o Cmax  (Week 1)  
o Cmax  (Week 12) 
x Time to reach Cmax (Tmax) is defined as the time from initial injection to time of Cmax. 
Will be calculated for Week 1 (1st dose) and Week 12 (12th dose): 
o Tmax (Week 1) 
o Tmax (Week 12) 
x Ctrough, the trough serum concentration is defined as the minimum HM15211 
concentration just prior to next dose administration. Will be calculated for Week 1 (pre 
1st dose) and Week 12 (pre 12th dose): 
o Ctrough pre-dose on Day 1 (Week 1)  
o Ctrough pre-dose on Day 78 (Week 12) 
x Area under the concentration-time curve for HM15211, AUC0-168h after 1st and 12th 
dosing (steady state), will be calculated by linear trapezoidal method. 
o AUC0-168h (Week 1) and AUC0-inf (Week 1) 
o AUC0-168h (Week 12) 
x kel, first-order terminal elimination rate constant, calculated by linear regression of time 
vs. log concentration curve in the terminal phase.  For kel to be acceptable, it shall be 
determined over a time interval equal to at least 1.5 x t½ kel, with at least three different 
time points in the terminal phase for the regression analysis, and the coefficient of 


 
 
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determination Adj_RSq shall be ≥0.8.  If at least one of these three conditions is not 
fulfilled, the parameters depending on kel (e.g., the terminal half-life t1/2 kel, CL and Vz) 
shall be flagged as not reliable if calculated and listed. They will generally be excluded 
from descriptive statistics and statistical testing procedures, unless otherwise judged by 
the pharmacokineticist in charge of PK analysis. Will be calculated for Week 1 (1st dose) 
and Week 12 (12th dose): 
o kel (Week 1) 
o kel (Week 12) 
x Apparent terminal half-life t1/2 will be determined from equation ln2/ kel. Will be 
calculated for Week 1 (1st dose) and Week 12 (12th dose). 
o t1/2 (Week 1) 
o t1/2 (Week 12) 
x Apparent clearance divided by bioavailability (CL/F). Will be calculated for Week 1 (1st 
dose) and Week 12 (12th dose). 
o CL/F (Week 1) 
o CL/F (Week 12) 
x Apparent volume of distribution at terminal phase divided by bioavailability (Vz/F). Will 
be calculated for Week 1 (1st dose) and Week 12 (12th dose). 
o Vz/F (Week 1) 
o Vz/F (Week 12) 
x Accumulation ratio (AR). Will be calculated for Week 1 (1st dose) and Week 12 (12th 
dose). 
Box plots of Cmax and AUC0-168h SS for each cohort may be generated.   
6.2.3. Dose Proportionality 
The power model will be used to analyze the dose proportionality in Cmax and AUC0-168h SS of 
HM15211. The estimate of the ratio of the dose normalized geometric means (mg/kg), Rdnm, and 
the corresponding 90% CI will be derived. 
The power model is defined as follows:  
 
Where 
ܲܭ௜ is the PK parameter (Cmax or AUC0-168h) observation for the subject i.  
α is the population intercept. 
β is the population slope. 
log(ܲܭ௜) = α + (β) * log(dosei) + Ɛi 


 
 
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Ɛi is the random error; Ɛi ~ N(0, ߪఌ
ଶ) and independent.    
The assumption for the Power Model is that the underlying relationship between log(PK 
parameter) and log(dose) is linear. The dose proportionality corresponds to the ratio of dose-
normalized geometric means (Rdnm), which is defined as ratio of the predicted geometric mean of 
the highest dose relative to the predicted geometric mean of the lowest dose. The dose 
proportionality would be declared when the 90% CI for the Rdnm falls entirely within the limit of 
0.8 to 1.25. 
6.3. Pharmacodynamic Analyses 
6.3.1. MRI-PDFF 
The observed values, change from baseline, and the percent change from baseline of liver fat on 
magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) will be 
summarized descriptively by treatment group, visit, and time point. 
A mixed model repeated measures analysis will be performed with the change from baseline in 
liver fat as the dependent variable, treatment group, analysis time point and the interaction 
between treatment group and analysis time point as factors, and the baseline of the dependent 
variable as a covariate. Repeated measures on each subject, at each visit week, will assume an 
unstructured covariance structure. If the model fails to converge, other covariance structures will 
be considered and selected based on model fit as determined by Akaike information criterion. 
The LS mean, SE of LS mean and 95% confidence interval will be presented by treatment group 
for each post baseline analysis time point. The LS mean difference from pooled placebo, SE of 
the LS mean difference from pooled placebo, and the 95% confidence interval will be presented 
by active treatment group for each post baseline analysis time point. 
6.4. Exploratory Analyses 
6.4.1. Incretins Secretion 
Observed values and the change from baseline for parameters related to incretins secretion, such 
as GLP-1, GIP, GCG, FGF21, and leptin will be summarized descriptively by treatment group, 
visit, and time point. MMRM analysis that will be specified similarly to the analysis of MRI-
PDFF will be used. 
6.4.2. Body Weight, Body Mass Index, and Waist Circumference 
The observed values, the change from baseline, and the percent change from baseline in body 
weight and waist circumference will be summarized by treatment group and visit. Observed 
values and change from baseline for BMI will be summarized similarly. MMRM analysis that 
will be specified similarly to the analysis of MRI-PDFF will be used. 
6.4.3. Serum Lipid Profile and Particles 
Observed values and the change from baseline for parameters related to lipid metabolism, such 
as total cholesterol, LDL-C, LDL-P, HDL-C, HDL-P, VLDL-C, VLDL-P, triglycerides, and 


 
 
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FFAs, will be summarized descriptively by treatment group and visit. MMRM analysis that will 
be specified similarly to the analysis of MRI-PDFF will be used. 
6.4.4. Amino Acids 
Observed values and the change from baseline for amino acids will be summarized descriptively 
by treatment group and visit. MMRM analysis that will be specified similarly to the analysis of 
MRI-PDFF will be used. 
6.4.5. Inflammatory Marker 
Observed values and the change from baseline for adiponectin will be summarized descriptively 
by treatment group and visit. MMRM analysis that will be specified similarly to the analysis of 
MRI-PDFF will be used. 
6.4.6. Bone Metabolism 
Observed values and the change from baseline for CTX-1, OC, and P1NP will be summarized 
descriptively by treatment group and visit. MMRM analysis that will be specified similarly to the 
analysis of MRI-PDFF will be used. 
6.4.7. Glucose Metabolism 
Observed values and the change from baseline for parameters related to glucose metabolism, 
such as FPG, fasting insulin, fasting C-peptide, and HbA1c will be summarized descriptively by 
treatment group, visit and time point. MMRM analysis that will be specified similarly to the 
analysis of MRI-PDFF will be used. 
6.4.8. Ketone Bodies 
Observed values and the change from baseline for beta-hydroxybutyrate will be summarized 
descriptively by treatment group and visit. MMRM analysis that will be specified similarly to the 
analysis of MRI-PDFF will be used. 
6.4.9. Liver Steatosis and Liver Stiffness 
Observed values and the absolute and percent change from baseline for CAP and LSM will be 
summarized descriptively by treatment group and visit. For Cohorts 4 and up, an analysis of 
covariance (ANCOVA) model with treatment as factor and baseline CAP (or LSM) value as a 
covariate will be performed to evaluate the change from baseline in CAP and LSM in each 
treatment group versus the pooled placebo group. The LS mean difference from pooled placebo, 
SE of the LS mean difference from pooled placebo, and the 95% confidence interval will be 
derived by treatment group for the single post-baseline visit. If data are not normally distributed 
based on the Shapiro-Wilks normality test, the Wilcoxon-Mann-Whitney test will be performed 
to analyze the change from baseline in CAP and LSM for each active treatment group versus the 
pooled placebo group. The Hodges-Lehmann estimator of the median and its 95% confidence 
interval will be provided. 


 
 
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6.4.10. Visceral Fat Volume 
Visceral Fat Volume will no longer be collected or analyzed. 
6.5. Safety Analyses 
Safety data will be summarized by treatment, with pooled placebo. All safety data will be listed. 
6.5.1. Adverse Events 
Adverse events (AEs) will be coded using MedDRA, version 23.0. AEs will be summarized for 
the Safety Set. 
AEs with onset on or after the date of informed consent but before the date of dosing of study 
medication will be considered pre-treatment AEs. Pre-treatment AE will be listed only.  
AEs with onset date/time on or after receiving the dosing of study medication, or pre-existing 
AEs that increase severity on or after receiving the dosing of study medication will be considered 
as TEAE.  
TEAEs will be summarized by SOC and PT, and by SOC, PT, and maximum severity by 
treatment group, with pooled placebo. TEAEs that are related to study medication per 
investigator’s decision, TEAEs leading to study discontinuation, TEAEs that are serious 
(treatment-emergent SAEs) and adverse events of special interest (such as necrolytic migratory 
erythema, cholelithiasis and pancreatitis) will be summarized similarly. 
AEs with missing severity will not be imputed. AEs with missing relationship will be imputed as 
related. 
6.5.2. Clinical Laboratory Assessments 
All hematology, clinical chemistry, and urinalysis results (including serum amylase, serum 
lipase, coagulation, thyroid stimulating hormone (TSH), serum calcitonin) will be summarized. 
Laboratory assessments that are outside of normal ranges and/or with potential clinical 
importance will be summarized and flagged in the listings. Shift tables of hematology, clinical 
chemistry, and urinalysis results will be generated to summarize the normal and abnormal 
(abnormal high and abnormal low) status changes from baseline.  
6.5.3. Immunogenicity 
Anti-drug antibodies (ADAbs, anti-HM15211 antibodies) will be summarized categorically, 
displaying the tier 1 (putative positive and negative) and tier 2 (positive and negative) tests by 
treatment group with positive tests further summarized by tier 3 absolute titer values and domain 
specificity. Tier 3 neutralizing antibody (nAbs) results will be summarized with ADAbs data in 
the same table. 


 
 
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In a separate table, anti-polyethylene glycol antibodies (anti-PEG) will be summarized 
categorically, displaying the screening result and specificity. The Anti-PEG specificity test will 
only be performed for samples where the titer increased more than 4 times compared to Day 1. 
6.5.4. Physical Examination 
The clinical findings on PE will have their incidence and severity listed. 
6.5.5. Vital Signs 
Observed vital sign values (blood pressure, heart rate, respiratory rate, and temperature) at each 
day and change from baseline at each post-baseline day will be summarized. 
6.5.6. 24-Hour Ambulatory Blood Pressure Monitoring 
Mean daytime (10:00 to 20:00) and nighttime (00:00-6:00) systolic and diastolic BP will be 
summarized for each day from Day -2 to Day 4 (Fagard 2008). 
6.5.7. 24-Hour Holter ECG 
Observed values from 24-Hour Holter ECG will be summarized by time point for each day from 
Day -1 to Day 4. Parameters calculated over the entire day such as mean HR, mean difference 
between day and night HR, mean NN intervals, pNN50, RMS SD, SDANN and SDNN index 
will be summarized by day.  
Heart Rate Variability will be assessed by the following parameters: 
x Percentage Greater than 50 msec (PRR_GT50), aka pNN50, the percentage of successive 
differences in RR values greater than 50 milliseconds (can be increases or decreases) 
during the time period. 
x RMS SD, the square root of the mean of the squares of successive differences between 
the RR values during the time period. 
x Magid SD, also known as SDNN index, the average of five-minute period standard 
deviations of the RR intervals during the time period. 
x Kleiger SD, also known as SDANN, standard deviation of all five-minute average RR 
intervals during the time period. 
6.5.8. 12-Lead Electrocardiograms 
Observed and change from baseline values of QTcF and other ECG parameters will be 
summarized. Status of 12-lead ECG parameters, normal, abnormal not clinically significant, and 
abnormal clinically significant, and their shifts from baseline will be summarized. 
6.5.9. Injection Site Reactions 
The number and percentage of subjects with any injection site reactions will be summarized by 
treatment group for the entire in-house period and by visit and time point within in-house period. 
The number and percentage of subjects with specific site reactions such as pain on palpation, 


 
 
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itching, erythema, edema, induration and other will be summarized by visit, time point, and 
Draize scale. In addition, diameter of affected areas will be summarized descriptively by visit 
and time point.  
7. Interim Analysis 
No interim analysis is planned. 
8. Statistical Software 
All statistical analyses will be performed using SAS® version 9.4. All PK and PD parameters 
will be derived with standard NCA methods using WinNonlin v5.2 or higher and/or SAS® 
version 9.4. 
9. Changes to the Planned Analyses from Protocol 
Visceral Fat Volume will no longer be collected or analyzed.  Cohort 1-6 was not conducted. 
10. References 
Fagard RH, Celis H, Lutgarde T, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. 
Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular 
events in hypertension. Hypertension. 2008; 51: 55-61. 


 
 
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11. Appendix 
Table 2: Schedule of Events, Cohorts 1-1 and 1-2 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior 
Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated Glomerular 
Filtration Rate (eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test 
(TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
HBA1C, FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in Criteria to In-
house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Urine Drug Screen & 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Safety and Exploratory Assessments 
Physical Examination 
(PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 


 
 
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Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Hematology, 
Chemistry, 
Coagulation, Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
CRP10
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight12 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic Assessments 
Lipid Profile and 
Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Bone Metabolism 
Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism 
Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory 
Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic and Immunogenicity Assessments 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
Other Safety Assessments 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site 
Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection. 


 
 
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7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel. 
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection. 
12Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 


 
 
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Table 3: Schedule of Events, Cohorts 1-3 (not including Day 82) 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Prior 
Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated Glomerular 
Filtration Rate (eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Test 
(TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
HBA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in Criteria to In-
house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Urine Drug Screen & 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Safety and Exploratory Assessments 
Physical Examination 
(PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 


 
 
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Page 29 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Hematology, 
Chemistry, 
Coagulation, Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
CRP10
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight12 
X 
 
X 
X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Pharmacodynamic Assessments 
Lipid Profile and 
Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Bone Metabolism 
Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism 
Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory 
Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic and Immunogenicity Assessments 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
Other Safety Assessments 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site 
Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 4 and 81 after subject have been disconnected from 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection. 
7Subjects need to be in fasting condition for collection. 


 
 
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8PK sampling will follow the PK sampling schedule. Cohort 3 will start to collect additional PK sample with start of Day 78. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits on non-dosing days in the morning, approximately at the time of the dosing on dosing days. 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel. 
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 


 
 
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Table 4: Schedule of Events, Cohorts 1-3 (including Day 82) 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82* 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Prior 
Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and 
Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated 
Glomerular Filtration 
Rate (eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function 
Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HBA1C
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 
Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in Criteria to 
In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Urine Drug Screen & 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Safety and Exploratory Assessments 
Physical Examination 
(PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 32 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82* 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology, 
Chemistry, 
Coagulation, 
Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight12 
X 
 
X 
X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Pharmacodynamic Assessments 
Lipid Profile and 
Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Bone Metabolism 
Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism 
Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Inflammatory 
Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic and Immunogenicity Assessments 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Other Safety Assessments 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site 
Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 33 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection. 
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule. Cohort 3 will start to collect additional PK sample with start of Day 78. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits on non-dosing days in the morning, approximately at the time of the dosing on dosing days. 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel. 
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
*Day 82 is optional for subjects already participating in cohort 1-3. 
 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 34 
Table 5: Schedule of Events, Cohorts 1-4 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Prior 
Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and 
Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated 
Glomerular Filtration 
Rate (eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function 
Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HBA1C
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 
Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Check-in Criteria to 
In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Urine Drug Screen & 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Safety and Exploratory Assessments 
Physical Examination 
(PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 35 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology, 
Chemistry, 
Coagulation, 
Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight12 
X 
 
X 
X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Pharmacodynamic Assessments 
Lipid Profile and 
Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Bone Metabolism 
Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism 
Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Inflammatory 
Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic and Immunogenicity Assessments 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Other Safety Assessments 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site 
Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 36 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from 
ambulatory device. 
5Subjects will undergo an MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but prior to 
the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection. 
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule. 
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits on non-dosing days in the morning, approximately at the time of the dosing on dosing days. 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel. 
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 37 
Table 6: Schedule of Events, Cohorts 1-5 and up 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dosing 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Prior 
Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and 
Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Estimated 
Glomerular Filtration 
Rate (eGFR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function 
Test (TSH) 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HBA1C
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-2 
Macroglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCTE (FibroScan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Check-in Criteria to 
In-house Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Urine Drug Screen & 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Safety and Exploratory Assessments 
Physical Examination 
(PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 38 
 
Screen 
Admin 
Treatment Period 
Elimination 
FU 
In House Period 1 
Outpatient Visit 
In house Period 2 
Outpatient Visit 
Week 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
15 
17 
Day 
-44 to -
3 
-2 
-1 
1 
2-3 
4 
5-7 
8 
10 
15 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 
99 
113 
Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±2 
±2 
12-lead ECG 
X4 
X4 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X4 
 
 
 
 
X 
 
 
 
Holter Monitoring 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
ABPM 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology, 
Chemistry, 
Coagulation, 
Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
CRP10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase, Lipase 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Body Weight12 
X 
 
X 
X12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
BMI Calculation 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Pharmacodynamic Assessments 
Lipid Profile and 
Particles 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
MRI/MRI-PDFF5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Amino Acid Panel 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Incretins6 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Bone Metabolism 
Parameters 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Glucose Metabolism 
Parameters7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Inflammatory 
Biomarkers11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Ketone Bodies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic and Immunogenicity Assessments 
PK Sampling8 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Other Safety Assessments 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site 
Tolerability 
 
 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1Confirmation of eligibility 
2Serum pregnancy test only at screening, urine pregnancy tests at all other time points 
3Measurements of vital signs on PK sampling days will follow the PK sampling schedule and should be measured prior to every PK sample. 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 39 
4ECG at screening not triplicate. ECG measurements are to be collected on Day-2 and 77 before subjects are connected to the ABPM and on Day 5 and 82 after subject have been disconnected from 
ambulatory device. 
5Subjects will undergo an MRI/MRI-PDFF assessment during week 8, as close as possible to Day 57, but prior to the Day 57 (week 9) Dosing and during week 12, as close as possible to Day 85, but 
prior to the Day 85 PK sampling (week 13). 
6All incretins will be collected at the same time points together with the PK sample collection. 
7Subjects need to be in fasting condition for collection. 
8PK sampling will follow the PK sampling schedule.  
9Injection site will be inspected pre-dose, at 4 and 12-hour post-dose on Day 1. Assessment of injection site on the other dosing days at least 30 minutes post-dose, and then daily during the in-house 
periods and at outpatient visits on non-dosing days in the morning, approximately at the time of the dosing on dosing days. 
10CRP only, on Day 3. CRP is also measured at SCR/D1/D8/D15/D29/D36/D57/D78/D85/D99 in chemistry panel. 
11Inflammatory biomarkers will be collected at the same time points together with the PK sample collection.  
12To be measured prior to dosing. 
13Weight to be collected in the morning, fasting and post void. On all dosing days, weight should be measured pre-dose. 
 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 40 
Table 7: PK Sampling Schedule for cohorts 1-1 and 1-2 
PK sampling schedule 
Treatment Period 
Week 1 
Day 1 
Pre-dose 1st dosing 
8 h after 1st dosing 
Day 2 
24 h after 1st dosing 
Day 3 
48 h after 1st dosing 
Day 4 
72 h after 1st dosing 
Week 2 
Day 8 
Pre-dose 2nd dosing 
Day 10 
48 h after 2nd dosing 
Week 3 
Day 15 
Pre-dose 3rd dosing 
Week 4 
Day 22 
Pre-dose 4th dosing 
Week 5 
Day 29 
Pre-dose 5th dosing 
Week 6 
Day 36 
Pre-dose 6th dosing 
Week 8 
Day 50 
Pre-dose 8th dosing 
Week 9 
Day 57 
Pre-dose 9th dosing 
Week 12 
Day 78 
Pre-dose 12th dosing 
8 h after 12th dosing 
Day 80 
48 h after 12th dosing 
Day 81 
72 h after 12th dosing 
Elimination Period (±2) 
Week 13 
Day 85 
168 h after 12th dosing 
Week 15 
Day 99 
504 h after 12th dosing 
F/U (±2) 
Week 17 
Day 113 
840 h after 12th dosing 


 
 
HM-TRIA-102 Statistical Analysis Plan 
   
Confidential 
 
 
 
 
 
 
Page 41 
Table 8: PK Sampling Schedule starting from cohort 1-3 
PK sampling schedule 
Treatment Period 
Week 1 
Day 1 
Pre-dose 1st dosing 
8 h after 1st dosing 
Day 2 
24 h after 1st dosing 
Day 3 
48 h after 1st dosing 
Day 4 
72 h after 1st dosing 
Day 5* 
96 h after 1st dosing 
Week 2 
Day 8 
Pre-dose 2nd dosing 
Day 10 
48 h after 2nd dosing 
Week 3 
Day 15 
Pre-dose 3rd dosing 
Week 4 
Day 22 
Pre-dose 4th dosing 
Week 5 
Day 29 
Pre-dose 5th dosing 
Week 6 
Day 36 
Pre-dose 6th dosing 
Week 8 
Day 50 
Pre-dose 8th dosing 
Week 9 
Day 57 
Pre-dose 9th dosing 
Week 12 
Day 78 
Pre-dose 12th dosing 
8 h after 12th dosing 
Day 80 
48 h after 12th dosing 
Day 81 
72 h after 12th dosing 
Day 82** 
96 h after 12th dosing 
Elimination Period (±2) 
Week 13 
Day 85 
168 h after 12th dosing 
Week 15 
Day 99 
504 h after 12th dosing 
F/U (±2) 
Week 17 
Day 113 
840 h after 12th dosing 
*Sampling on Day 5 will start with Cohort 1-4 and will not be taken for cohort 1-3. 
**Sampling on Day 82 will be optional for cohort 1-3 but will be taken in cohort 1-4.