Clinical trial NCT04167553
Conditions: Obese With Comorbidities Overweight With Comorbidities Type2 Diabetes
Sponsor: Hanmi Pharmaceutical Company Limited
Start date: 2019-08-30; Completion date: 2020-12-09
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The planned period of each cohort is 22 weeks including subject screening, treatments for 12 weeks, and follow up period.

Detailed description:
The current Phase I study was a two-part study. Part 1 was designed to assess the safety, PK, and pharmacodynamics (PD) after repeated doses of HM15136 in obese or overweight subjects with comorbidities (i.e., dyslipidemia and/or hypertension). Part 2 was designed to assess the safety, PK, and PD after repeated doses of HM15136 in obese or overweight subjects with T2DM and comorbidities (i.e., dyslipidemia and/or

Arms: arm 1: HM15136 0.02mg/kg, 0.04mg/kg, 0.06mg/kg arm 2: Matching placebo: 0.02mg/kg, 0.04mg/kg, 0.06mg/kg
Interventions: intervention 1: HM15136 intervention 2: Placebo
Intervention descriptions: intervention 1: In Part 1, approximately 36 subjects, divided into 3 cohorts with 12 subjects (HM15136 group 9 subjects, placebo group 3 subjects) per cohort. In Part 2, approximately 66 subjects, in up to 4 cohort with 30 subjects for cohort 4 (HM15136 group 15 subjects, placebo group 15 subjects) and 12 subjects per cohorts 5-7 (HM15136 group 9 subjects, placebo group 3 subjects). Cohorts 6 and 7 are optional.

In the end of study, Part 2 of the study consisted of 2 cohorts comprising 16 subjects total. intervention 2: In Part 1, approximately 36 subjects, divided into 3 cohorts with 12 subjects (HM15136 group 9 subjects, placebo group 3 subjects) per cohort. In Part 2, approximately 66 subjects, in up to 4 cohort with 30 subjects for cohort 4 (HM15136 group 15 subjects, placebo group 15 subjects) and 12 subjects per cohorts 5-7 (HM15136 group 9 subjects, placebo group 3 subjects). Cohorts 6 and 7 are optional.

In the end of study, Part 2 of the study consisted of 2 cohorts comprising 16 subjects total.

Protocol documents:
Prot_000.pdf: 
 
Page 1 / 127 
CONFIDENTIAL 
 
 
Protocol 
 
 
A Phase 1, study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple doses of HM15136 in obese or overweight 
subjects with comorbidities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Confidential: This Clinical trial is carried out in accordance with the ICH (International Council of 
Harmonization) guideline E6 (R2), protocol and other applicable regulations for GCP (Good clinical practice), 
all of the information contained in this protocol is provided for Hanmi Pharm.Co., Ltd., cannot be disclosed to 
any third party without the prior written consent of Hanmi Pharm.Co., Ltd. 
 
Protocol No. 
HM-GCG-102 
Version No. (Date) 
ver. 6.0 (29 OCT 2020) 
Investigational product 
Test product: HM15136 
Comparator: Placebo 
Indication 
obese or overweight subjects with 
comorbidities 
Study Phase 
Phase 1 
Sponsor 
Hanmi Pharm.Co., Ltd. 


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CONFIDENTIAL 
 
[REVISION HISTORY]  
No 
Version No. 
Version Date 
Revision comments 
1 
Version 1.0 
23/JULY/2019 
Initial development 
2 
Version 2.0 
28/AUGUST/2019 
1. Change of Stopping Criteria for Dose Escalation /  
Establishing a Data Monitoring Committee (DMC) 
An independent DMC will be established to make dosing 
and cohort escalation assessments and recommendations.  
Section Study Summary, section Abbreviations and 
Definitions, section 5.1 Number of Subjects, section 6.2 
Study Design, section 6.3.4 Confirmation of Dosage and 
Escalation, section 6.4.2  Randomization No., section 6.5 
Blinding and Unblinding, section 7.3 Dose Escalation Study 
Stopping Criteria, section 9.2 Dosage, Method, Period of 
Investigational Product 
2. Addition of a Protocol Version to the Protocol Agreement 
Pages 
Section Sponsor Signature page and Investigator signature 
page 
3. Correction of language around the study drug and other 
compounds 
Specification that the study drug is a long-acting glucagon 
analogue and correction of terminology, as the term 
glucagon analogue and GLP-1 RA are used interchangeably 
in the introductory sections of the protocol. 
Section 3.1 Background, section 3.2 Background of Currently 
Used Treatments 
4. Incorporation of Administrative Letter #1 from 01Aug2019 
Clarifying that FPG laboratory assessment is not included in 
clinical chemistry, subject birth date can be obtained in full 
and age will only be assessed at Screening, no drug or 
alcohol testing at Day 8, study drug will be destroyed at end 
of study, and SMBG procedure will be extended to Day 5 
(and is not performed via YSI).   
Section Study Flow, section 10.2.2 Assessment Variable, 
section 10.2.1 Assessment items per visit, Synopsis, section 
5.2 Inclusion Criteria, section 8.5.3 Inventory Management 
and Record 
5. Correction of Typographical and Grammatical Errors/ 
Formatting 
Errors will be adjusted throughout the protocol for better 
clarity. 
Throughout various sections of the protocol 
6. Clarification around assessment of ECG 
ECG readings may be assessed by 'qualified Investigator' 
instead of 'qualified physician'. 
Section 10.2.2 Assessment Variable 
7. Allowing the Retesting of Screening Laboratory Parameter 
Laboratory parameters that are out of range during 
screening, may be retested per Investigator discretion. 


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CONFIDENTIAL 
Section 10.1.1 Scheduled Visit 
8.
Distribution of Diet Diaries on Study Day 8 
Diet diaries will be distributed on the last day of
hospitalization period 1/ in-house period 1 to document
diet at home.
Section Study Flow, section 10.2.1 Assessment Items per
Visit
9.
Clarification around SAE/AESI reporting
Details on SAE/AESI report preparation will be stated in the
Safety Monitoring Plan (SMP).
Section 10.4.7 SAE and AESI Reporting
10. Adjustment of Language for Hospitalization and In-house
Periods
Clarification of wording in order to differentiate between
hospitalization due to an adverse event and in-house
periods of the study.
Throughout various sections of the protocol
11. Clarification of Metformin use for Subjects with T2DM in
Part 2 of the Study
Per inclusion criterion # 4, subjects with T2DM on stable
treatment for 3 months with metformin are allowed. In
order to avoid confusion with the exclusion criteria # 5 and
# 7, metformin will be added as allowed.
Section Study Summary, section 5.3 Exclusion Criteria
12. Clarification around Medical History
The term “reproductive history” will be taken out, as the
term medical history covers the also the reproductive
system.
Section 10.2.2 Assessment Variable
3 
Version 3.0 
17/DECEMBER/2019 
1.
Data Monitoring Committee (DMC) Meeting for Cohort 3 
An independent DMC will meet after the 9th subject’s visit
on Day 29 in Cohort 3. The next dose level for the
subsequent cohort (Cohort 4 in Part 2) will be based on the
safety, tolerability, available PD, and available PK data
obtained.
Section Study Summary, section 6.2 Study Design, section
6.3.4 Confirmation of Dosage and Escalation, 7.3 Dose
Escalation Study Stopping Criteria, section 9 Clinical Trial
Methods and Adminsitration Plan
2.
Adjustment of Cohorts in Part 2 
Part 2 will be adjusted and will be combined as Cohort 4,
only enrolling subjects with T2DM.
Section Study Summary, Section 3.6. Rationale of Clinical
Trial, section 5.1 Number of Subjects, section 5.2 Inclusion
Criteria, section 5.4.2 Subject’s Withdrawal, Replacement
and Discontinuation, section 6.2 Study Design, section 6.3.1 
Selection of Subjects in Test Group, section 6.3.4 
Confirmation of Dosage and Escalation, section 6.4.2 
Randomization No., section 9 Clinical Trial Methods and


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CONFIDENTIAL 
 
Adminsitration Plan, section 9.2 Dosage, Method, Period of 
Investigational Product 
3. Adjustment of Number for Subjects in Part 2 
Thirty (30) subjects instead of 18 subjects for cohort 4 and 
18 subjects for cohort 5 will be included in one combined 
cohort. Randomization will still be performed as planned, in 
a ratio of 1:1 for IP and placebo. 
Section Study Summary, section 5.1 Number of Subjects, 
section 6.2 Study Design, section 6.3.4 Confirmation of 
Dosage and Escalation, section 6.4.2 Randomization No., 
section 9.2 Dosage, Method, Period of Investigational 
Product, section 11.3.2 Confirmation of sample size 
4. Change of Principal Investigator (PI) 
The PI for this study will change to Dr Bridgette Franey. 
Section 
Protocol 
Agreement, 
section 
2.2 
Principal 
Investigator  
5. Reduce the Collection Frequency of Blood Samples for Part 
2 of the Study 
The number of blood sampling timepoints for the 
assessment of the safety laboratory parameters will be 
reduced during the In-house periods for Part 2 of the study, 
in order to reduce the overall blood volume for the subjects. 
Samples will be taken on Days 1 (pre-dose), 3 and 8 and 
Days 78 (pre-dose), 80 and 82. 
Section Study Flow, section 10.2 Enrollment and Clinical 
Evaluations 
6. Incorporation of Administrative Letter #2 from 06Sep2019 
Clarifying that the assessment of MRI/MRI-PDFF stated for 
Day -1, may be performed while the Screening Calcitonin 
result is still pending. All other eligibility criteria for the 
subject, including lab results must be approved by the 
Investigator.  
Section Study Flow, section Assessment variable10.2.2 
Assessment Variable 
7. Adjustment of Timepoints for the 7-Point Glucose Profiles 
Time point of 15 minutes before the sleep (± 30 minutes) 
has been changed to 15 minutes before the evening snack 
(± 10 minutes), to capture glucose prior to the snack and to 
have an adequate assessment window prior to the snack. 
Section Study Flow, section 10.2 Assessment Variable 
8. Adjustment of Contraception 
a) Male subjects with a pregnant female partner  at 
signing of informed consent, may be included in the study, 
as semen cannot lead to conception. 
b) Adjustment of language for acceptable contraceptive 
methods for consistency between female subjects, 
participating in the study and female partners of male 
subjects. 
Section 10.2.3 Restrictions 


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CONFIDENTIAL 
 
9. Clarification of Inconsistency for Liver Fat Threshold 
Threshold for liver fat on Day -1 is stated as greater than 
10% and as equal to / greater than 10% throughout the 
protocol. Adjustments are made to consistently state equal 
to / greater than ϭϬй;шϭϬ %). 
Section Study Flow, section 10.2.1 Assessment items per 
visit, section 10.2.2 Assessment Variable 
10. Reduction 
of 
Measurement 
Timepoints 
for 
the 
Assessment of Subject’s Height 
The height of a subjects will only be assessed once at 
screening, as a change in the adult population is not 
expected during the study. 
Section Study Flow, section 10.2.2 Assessment Variable 
11. Adjustment of parameters for medical review  
Amino acid labs will not undergo a medical review as these 
are not needed for safety evaluation of the subjects. 
Section 11.2.7 Endpoints 
12. Clarification of Wording 
The word “enrollment” will be replaced with the word 
“screening” in section 6.4.1, as enrollment is suggestive of 
inclusion after randomization. 
Section 6.4.1 Screening No. 
13. Clarification around the term “prescription” 
The Investigator will determine the final eligibility for 
receiving IP and will not literally write out a prescription 
for investigational products. Section 8.5.2 Prescription will 
be renamed to Release of IP. 
Section 8.5.2 Release of IP 
14. Adjustment of Language for Recording of AEs and SAEs 
Per section 10.4.2, concomitant conditions that exist prior 
to signing the informed consent form (ICF) are not 
considered adverse events unless they worsen during the 
study. The pre-existing conditions are recorded as part of 
the subject's medical history. Therefore, sentence in section 
10.2.2 (9) will be adjusted for consistency. 
Section 10.2.2 Assessment Variable, section 10.4.2 
Definition of AE 
15. Clarification of Time Window for Assessment of Injection 
Site Reactions 
A window of 30 minutes is stated for all assessment time 
points, but the hospitalization visits have been omitted. A 
window of 30 minutes has been added for consistency.  
Section 10.2.2 Assessment Variable 
16. Correction of Wording for Consistency 
The term "Hospitalization Visit“ wil be exchanged with the 
term "In-house Period“ for consistency throughout the 
protocol. 
Section 10.2.2 Assessment Variable 
17. Dose Escalation Stopping Criteria 


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As stopping criteria are assessed under blinded conditions, 
criterion #7 is Changed from HM 15136 to IP. 
Section 7.3 Dose Escalation and Stopping Criteria 
18. Clarification around number of Visits 
Subjects will participate in 2 in-house periods  and 16 
outpatient visits, including follow-up visits.  
Section 10.1 Visit Schedule 
19. Title/Function of sponsor signatory person adjusted 
Sponsor signature page 
20. Correction of Unblinding Process 
Only the Principal Investigator can perform  unblinding via 
IWRS. 
Section 6.5 Blinding and Unblinding 
21. Correction of Typographical Errors/ Formatting 
Errors will be adjusted throughout the protocol for better 
clarity. 
Throughout various sections of the protocol 
4 
Version 4.0 
20/FEBRUARY/2020 
1. Conduct of an Interim Analysis 
An interim analysis will be performed, after Part 1 of the 
study has been completed. For this analysis, unblinding will 
occur after database lock for Part 1, and data from all 
healthy subjects (i.e. data from completed cohorts 1-3) will 
be analyzed to have data for the healthy subjects available 
in a timely manner. The study will proceed as planned with 
diabetic subjects in Part 2 in a blinded fashion. Validity or 
integrity of data will not be compromised through the 
interim analysis, as the study will be performed as planned 
and no changes will be made upon the results /outcome of 
the interim analysis. 
Section Study Summary, section 6.5 Blinding and 
Unblinding, section 11.3.1 Interim Analysis 
2. Clarification around Timepoint for Statistical Analysis Plan 
(SAP) 
SAP will be provided prior to the first database lock, prior to 
the interim analysis. 
Section 11.1 General Considerations 
3. Change 
and 
Clarification 
of 
Language 
around  
Contraception 
a) Male subjects are required to use a valid contraceptive 
method, female partner of male subjects should be 
encouraged to use  a valid method of contraception. 
b) The word “contraception“ was inadvertently used 
instead of the word “conception“, when the  section 
about contraception for male subjects with a pregnant 
female partner was adjusted in the last amendment. 
Section Study Summary, section 5.2 Inclusion Criteria, 
section 10.2.3 Restrictions, Section Revision History for 
Protocol Version 3.0 (Change No 8: Adjustment of 
Contraception) 


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CONFIDENTIAL 
 
4. Clarification of Language around Confirmation of Eligibility 
After the screening visit has been performed and all 
laboratory values are available, eligibility of subjects will be 
determined via in/exclusion criteria prior to the first in-
house period. This is stated under section 3) already. For 
better clarity and to avoid redundancy, language in section 
2) has been deleted or moved to section 3).  
Section 10.1.1 Scheduled Visit 
5. Rescheduling of In-house Period 
At check-in for the In-house Period 1, subjects will not be 
allowed to check in if they meet any of the  
criteria/variables, but the in-house period may be 
rescheduled per Investigator discretion. 
Section Study Flow, Section 10.1.1 Scheduled Visit 
6. Optional Consulting with Medical Monitor added 
The investigator may consult with the Medical Monitor 
about retesting of abnormal laboratory results at Screening 
and medical conditions that could interfere with the study 
results at check-in. 
Section 10.1.1 Scheduled Visit 
7. Clarification on exclusion criterion #2 
Use of anticoagulants are excluded. The use of 
acetylsalicylic acid (e.g., Bayer® Aspirin) in a low dose of 81 
mg/day 
taken 
prophylactically 
is 
not 
considered 
anticoagulation therapy for the purposes of this protocol. 
Section Study Summary, section 5.3 Exclusion Criteria, 
section 9.3 Past Medication and Concomitant Medication 
8. Correction of Typographical Errors 
Errors will be adjusted throughout the protocol for better 
clarity. 
Throughout various sections of the protocol 
5 
Version 5.0 
20/MAY/2020 
A - PROTOCOL AMENDMENT - COVID-19 
Modifications to this study are made due to the COVID-19 
outbreak, in order to follow public health orders and the FDA 
guidance on “Conduct of Clinical Trials of Medical Products 
during COVID-19 Pandemic”. The amendment will provide an 
option to continue the use of the investigational product and the 
monitoring of subjects throughout this period and the 
completion of the study. 
Modifications may affect Part 1 of the study, and may apply to 
subjects that are enrolled in Cohort 3. 
Modifications may affect all subjects in Part 2 of the study 
All modification stated under this section may only be used as 
long as needed under COVID restrictions. As soon as 
restrictions are terminated or widened, the original protocol 
language will be followed. In case additional adjustments need 
to be made, they will be stated in the Operations Manual.  
The following modifications will be made: 


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1. In-house Periods 1 and 2 will be modified to Outpatient 
Day Visits (OPD).  
Specific OPD visits may be performed as telephone (phone) 
visits to generate information/assessments in order to 
reduce the in-person visits. Depending on start of 
enrollment and according to actual visit day, a site visit may 
be combined with a phone visit to keep the schedule for the 
following visits. On combined visit days, specific data might 
be collected only once at that visit (e.g., assessment of 7-
point profile is stated for Day 3 and Day 4, but if Visit is 
combined on one day, only one 7-point profile might be 
available). 
Section Study Flow, section 9.3 Past Medication and 
Concomitant Medication, section 10.1 Visit Schedule, 10.1.1 
Scheduled Visit, section 10.2.1 Assessment Items per Visit 
2. Visit windows will be added/allowed 
This will accommodate for limited site access and to 
continue the assessments as stated per protocol. 
Section Study Flow, section PK Sampling Schedule, section  
10.2.1 Assessment Items per Visit 
3. Randomization may be performed on Day -2 
Due to change in visit schedule, randomization may be 
performed on site on Day -2.  
Section Study Flow, section 6.4.2 Randomization No. 
4. ABPM and Holter monitoring modifications 
ABPM and Holter monitoring will be continued as stated in 
the protocol for the safety of the subjects but will be moved 
to an outpatient setting. Subjects will therefore be provided 
with personal instructions on site and instructions to take 
home for use and care of the devices.  
Section 10.1.1 Scheduled Visit, section 10.2.1 Assessment 
Items per Visit 
5. Body temperature measurement will be replaced by vital 
sign assessment 
Measurements of tympanic temperature assessment may 
be decreased to 1x/day during the visit at the site in order 
to shorten the in-person visit and therefore, it will be 
assessed during the assessment of vital signs. 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit, section 10.2.2 Assessment Variable 
6. Seven (7)-point glucose profiles may be performed by 
subjects 
Subjects will be instructed on site and will be provided with 
instructions to take home and a diary to record their results. 
This will ensure glucose results can be recorded, in case 
data can’t be retrieved from the glucometer at the site visit. 
Additionally, as visits (OPV and phone visits on the next day) 
may be combined into one visit, only one 7-point profiles 
will be available per combined visit.  


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Section Study Flow, section 10.2.1 Assessment Items per 
Visit 
7. Fasting glucose assessments may be performed by 
subjects 
Subjects may perform fasting glucose at home with 
glucometer in case the visit at the site was modified to a 
phone visit. Therefore, fasting glucose may be assessed by 
fasting capillary blood glucose (FBG) instead of fasting 
plasma glucose (FPG) as stated in the protocol.  
Section Study Flow, section 10.2.1 Assessment Items per 
Visit 
8. Assessment of Injection Site 
Subjects may perform the assessment of the injection site 
at home in case the visit at the site was modified to a phone 
visit.  
Section 10.2.2 Assessment Variable 
9. 12-lead ECG timepoints may be modified 
Time points may be reduced or moved to the modified visits 
schedule. 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit 
10. Abbreviated Physical Examination 
Time points of assessment may be reduced, as some visits 
are modified to phone visits. 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit 
11. Vital Signs 
Time points of assessment may be reduced, as some visits 
are modified to phone visits. 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit 
12. Diet Education and Diary Distribution and Review 
Modifications 
As subjects will not be in-house and will not receive 
standardized meals for this period, the diet education as 
well as diet diary distribution and review will be started with 
the first OPV day. 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit, section 10.2.2 Assessment Variable 
13. Fasting insulin, Fasting C-peptide assessment timepoints 
may be reduced 
Due to the modified visits schedule, some samples may not 
be collected on phone visit days. 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit 
14. PK Sampling Schedule may be modified 
Number and timepoints of PK assessments may be adjusted 
and/or reduced to accommodate the modified visit 
schedule. The modified PK sampling schedule will not affect 
the primary endpoints of this study. 


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Section Study Flow, section PK Sampling Schedule, section 
10.2.1 Assessment Items per Visit 
15. MRI/MRI-PDFF assessment 
MRI/MRI-PDFF assessment will depend on the restrictions 
of the MRI center due to the COVID-19 restrictions. If 
MRI/MRI-PDFF assessment is not possible during the stated 
time period, due to COVID- restrictions, MRI/MRI-PDFF may 
be performed later than Day 85, but prior to the last Visit 
on Day 113. If assessment is not possible, the missing 
assessment will be documented in the CRFs (specific 
information will be captured that explains the basis of the 
missing data due to COVID-19). 
Section Study Flow, section 10.2.1 Assessment Items per 
Visit, section 10.2.2 Assessment Variable 
16. Pregnancy Test in Urine 
Pregnancy test in urine is adjusted to modified visit 
schedule and will take place on Day 78. 
Section Study Flow, section 10.2.3 Restrictions 
17. Clinical Study Monitoring 
In case on-site monitoring visits might no longer be 
possible, the use of central and remote monitoring 
programs to maintain oversight of clinical sites may be 
considered. 
Section 13.7 Monitoring and Auditing 
18. Availability of Standardized Meals 
Standardized meals and/or catering may be limited or not 
be available and may be skipped or exchanged with snack 
bags. 
Section 9.2 Dosage, Method, Period of Investigational 
Product, section 10.2.3 Restrictions 
B- General Changes and Adjustments  
1. Adjustment of Cohorts in Part 2 
Part 2 will be adjusted, and 3 additional cohorts may be 
added with already approved dose levels. Dose levels were 
already tested in Part 1 (conducted in healthy subjects) and 
approved by the iDMC for Part 2. The additional cohorts 
(Cohorts 5-7) will enroll subjects with T2DM. 
Section Study Summary, section 5.1 Number of Subjects, 
section 6.2 Study Design, section 6.3.4 Confirmation of 
Dosage and Escalation, section 6.4.2 Randomization No., 
section 9 Clinical Trial Methods and Administration Plan, 
section 9.2 Dosage, Method, Period of Investigational 
Product 
2. Dose Levels for Cohorts 5-7 
The maximum dose level for Cohorts 5-7 will not exceed 
0.06 mg/kg (tentative dose for Cohort 5 may be 0.02 mg/kg, 
tentative dose may be 0.04 mg/kg for Cohort 6). This dose 
level has been previously approved for subjects with T2DM. 


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Therefore, the decision to proceed to the next cohort/dose 
level will be made per review of safety data by Sponsor, 
Investigator and Medical Monitor during a Data Review 
Meeting (DRM), after the 9th subject’s visit on Day 43 (6 
weeks after dosing), and additional DMC meetings will not 
take place. 
Section Study Summary, section 5.1 Number of Subjects, 
section 6.2 Study Design, section 6.3.4 Confirmation of 
Dosage and Escalation, section 6.4.2 Randomization No., 
section 9 Clinical Trial Methods and Administration Plan, 
section 9.2 Dosage, Method, Period of Investigational 
Product 
3. Dose Escalation for Cohorts 5-7 and DMC Meetings for 
Cohorts 5-7 
A dose level of 0.06 mg/kg has been previously approved 
for subjects with T2DM by the DMC. Therefore, the decision 
to proceed to the next cohort/dose level for Cohorts 5-7 will 
be made per DRM of Sponsor, Investigator and Medical 
Monitor, and additional meetings with independent DMC 
will not take place. 
After the 9th subject’s visit on day 43 of each cohort 
(Cohorts 5 and 6), a DRM will assess the safety and will 
make dosing and cohort escalation assessments. 
Section Study Summary, section 6.2 Study Design, section 
6.3.4 Confirmation of Dosage and Escalation 
4. Adjustment of Number for Subjects in Part 2 
Up to 36 additional subjects may be added to Part 2 of the 
study, 12 subjects for each additional cohort (Cohorts 5-7). 
Randomization will be performed as planned, in a ratio of 
3:1 for IP and placebo (n=9 active, n=3 placebo). 
Section Study Summary, section 5.1 Number of Subjects, 
section 6.2 Study Design, section 6.3.4 Confirmation of 
Dosage and Escalation, section 6.4.2 Randomization No., 
section 9.2 Dosage, Method, Period of Investigational 
Product 
5. Adjustments to Cohort 4 
Enrollment of new subjects into Cohort 4 will be postponed 
and the cohort may be terminated with a lower number of 
subjects than planned. Therefore, the maximum allowed 
number of subjects in Cohort 4 will not be reached, and the 
number will include already enrolled and dosed subjects. 
Subjects who are currently active in Cohort 4 will continue 
with the study as planned. 
After additional cohorts with a lower dose level have been 
performed, the dose level from the current Cohort 4 may 
be continued. This dose level will then be further evaluated 
in a new Cohort (Cohort 7). 
Section Study Summary, section 6.2 Study Design 
6. Interim Analysis/Unblinding and Data Base Lock 


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Adjustment of analyses. The analyses for each part will be 
performed separately, once each part is complete and the 
data base for each part has been locked. Due to COVID-19 
outbreak, an interim analysis based on partially validated 
data for Part 1 will be performed for administrative purpose 
prior to database lock of Part 1.  
Section Study Summary, section 6.5 Blinding and 
Unblinding, 11.3.1 Interim Analysis 
7. Adjustment of Exclusion Criterion #27 
History of any active infection, including any active COVID-
19 infection even if mild, will be excluded. 
Section Study Summary/Exclusion Criteria, section 5.3 
Exclusion Criteria 
8. Clarification of PK Sample Analysis 
Adjustment made in order to be consistent with the actual 
analysis as stated in the PK Lab Manual, samples are 
analyzed using serum and not plasma. 
Section Study Summary, section 10.3.1 Primary Endpoints 
9. Missing HbA1c added 
HbA1c added to list of assessments as stated in SOE for 
consistency throughout the protocol. 
Section 10.2.1 Assessment items per visit, Day -2 
10. Discontinuation of Subjects 
Subjects may be withdrawn from the study, in case 
compliance of IP dosing is <70%. 
Section 5.4.2 Subject’s Withdrawal, Replacement and 
Discontinuation  
11. Clarification of Wording 
As the informed consent form (ICF) is not included in the 
protocol as an Appendix, the reference to it will be deleted. 
Section 13.2 Informed Consent 
6 
Version 6.0 
29/OCT/2020 
1. Change of Timepoint for Dose Escalation from Cohort 5 to 
Cohort 6/Addition of another Data Review meeting (DRM) 
The decision to proceed to the next cohort/dose level for 
Cohorts 5 will be made per DRM. Per DRM for Cohort 5 
(after the 9th subject’s visit on day 43 of Cohorts 5) a dose 
escalation to Cohort 6 will not proceed at this timepoint and 
another DRM will be held after all of the 12 subjects in 
Cohort 5 have completed the final study visit (F/U Visit) on 
Day 113, to assess the safety data and to make a decision to 
escalate to Cohort 6 or not. 
The conduct of cohorts 6 and 7 are optional. 
Section Study Summary, section 5.1 Number of Subjects, 
Section 6.2 Study Design, section 6.3.4 Confirmation of 
Dosage and Escalation, section 7.3 Dose Escalation and 
Study Stopping Criteria, section 9 Clinical Trial Methods and 
Administration Plan, section 9.2 Dosage, Method, Period of 
Investigational Product, section 11.3.2 Confirmation of 
Sample Size 


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CONFIDENTIAL 
 
2. Clarification on hCG 
assessment 
for 
women of 
childbearing potential at Screening 
Women of childbearing potential do not need to have a 
serum hCG test at Screening, as urine hCG test will be 
assessed at Screening.  
A serum hCG test will only be performed for women are 
either sterile but do not have medical records or for women 
who are postmenopaual, but postmenopausal status can’t 
be confirmed by FSH test.   
Section 10.2.3 Restrictions/Contraception 
3. Clarification of End of Treatment (EOT) Visit 
Language adjusted to clarify that EOT visit is not mandatory. 
Section 10.1 Visit Schedule 
4. Clarification on timepoint of Injection Site Reaction (ISR) 
Assessment 
ISRs should be evaluated in the morning, at the time of last 
IP administration within a window of ±30 minutes of dosing 
time. 
Section 10.2.2 Assessment Variable 
 






 
Page 16 / 127 
CONFIDENTIAL 
 
[STUDY SUMMARY] 
Title 
A Phase 1, study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple doses of HM15136 in obese or 
overweight subjects with comorbidities 
Protocol No. 
HM-GCG-102 
Study Phase 
Phase 1 
Sponsor 
Hanmi Pharmaceutical Co., Ltd. 
Study site and investigator 
Single site study at ProSciento, Inc. 
Study duration 
The planned period of each cohort is 22 weeks including subject 
screening, treatments for 12 weeks, and follow-up period.  
Target subjects 
Obese subjects or overweight subjects with comorbidities 
No of target subjects 
Overall, approximately 102 subjects will participate in this study. 
In Part 1, approximately 36 subjects, divided into 3 cohorts with 12 
subjects (HM15136 group 9 subjects, placebo group 3 subjects) per 
cohort.  
In Part 2, approximately 66 subjects, in up to 4 cohort with 30 subjects 
for cohort 4 (HM15136 group 15 subjects, placebo group 15 subjects) and 
12 subjects per cohorts 5-7 (HM15136 group 9 subjects, placebo group 3 
subjects). 
Cohorts 6 and 7 are optional. 
Primary Clinical Trial Objectives 
and Endpoints 
To assess safety and tolerability of HM15136 after multiple subcutaneous 
(SC) doses for 12 weeks. 
 
To evaluate the 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 of HM15136 [Appendix]. 
 
To evaluate the incidence of clinical lab abnormalities: 
including serum amylase, serum lipase, coagulation, thyroid 
stimulating hormone (TSH), serum calcitonin. Only for females, LH 
(Luteinizing hormone) and FSH (follicle stimulating hormone) are 
additionally included. 
 
To evaluate the immunogenicity: 
Anti-drug antibodies (ADAbs), neutralizing antibodies (nAbs), anti-
polyethylene glycol antibodies (anti-PEG) 
 
Evaluation of clinically significant findings and incidence in physical 
examination 
 
Change from baseline in vital signs: 
Supine position blood pressure (BP), heart rate (HR), respiratory 
rate, and tympanic temperature 
 
Changes of blood pressure (BP) and heart rate: 
BP assessed by 24-hour ambulatory blood pressure monitoring 
(ABPM); 
HR assessed by 24-hour ambulatory electrocardiography 
monitoring (Holter ECG; central reader) 
 
Change from baseline in 12-lead ECG parameters: 


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CONFIDENTIAL 
 
the primary ECG endpoint will be QTcF 
 
Injection site reactions  
 
To assess the pharmacokinetic (PK) profile of HM15136 after 
administration of multiple subcutaneous (SC) doses in obese subjects by, 
but not limited to: 
 
Cmax: Maximum concentration 
 
Tmax: Time to reach Cmax 
 
Ctrough: Trough serum concentration 
 
AUC: Area under the concentration-time curve 
Ex.) AUC0-t: AUC at steady state during the period of injection 
(AUC0-t at steady state) 
 
Kel: Terminal elimination rate constant 
 
t1/2: Terminal half-life 
 
CL/F: Apparent clearance 
 
Vz/F: Apparent volume of distribution 
Exploratory 
Objectives 
and 
Endpoints 
To evaluate the pharmacodynamics (PD) properties of HM15136 after 
multiple subcutaneous (SC) doses 
 
Incretins / metabolic hormones 
1) Glucagon-like peptide-1 (GLP-1) 
2) Gastric inhibitory polypeptide (GIP) 
3) Glucagon 
4) Fibroblast growth factor 21 (FGF 21) 
5) Leptin 
 
Serum lipid profiles 
1) Total cholesterol 
2) Low-density lipoprotein (LDL) 
3) High-density lipoprotein (HDL) 
4) Very low-density lipoprotein (VLDL) 
5) Triglycerides 
6) Free fatty acids (FFAs) 
 
Amino-acid profile 
 
Glucose metabolism parameter 
1) Fasting plasma glucose (FPG) 
2) Fasting insulin, Fasting C-peptide 
3) 7-point Self-monitoring of blood glucose (SMBG) 
4) HbA1c 
5) Fructosamine 
6) Glycated albumin 
 
Insulin resistance 
- 
Homeostatic Model Assessment for Insulin Resistance 
(HOMA-IR) 
 
Insulin secretion function 
- 
Homeostatic Model Assessment for ɴCell Function (HOMA-ɴͿ 
 
Assessment of absolute and percent (%) changes of liver fat via 
MRI-PDFF (Magnetic resonance imaging-estimated proton density 


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Page 18 / 127 
CONFIDENTIAL 
 
fat fraction) 
(However, assessment of liver fat via MRI-PDFF will only be 
performed on day 85, if the liver fat on MRI PDFF prior to dosing ш 
10%) 
 
Changes in visceral fat volume, determined by absolute and 
relative percent change assessed by MRI 
 
Body weight 
 
Body mass index (BMI) 
 
Waist circumference 
 
Hip circumference 
 
Waist-to-hip ratio (WHR) 
 
Temperature (tympanic) 
 
Inflammatory markers 
1) High-sensitive C-reactive protein (hs-CRP) 
2) Adiponectin 
 
Ketone body 
- 
ɴ-hydroxybutyrate 
Study Design 
This is a double-blind, randomized, placebo controlled, multiple 
ascending dose (MAD) study to investigate the safety, tolerability, PD, and 
PK of the subcutaneous (SC) administration of HM15136 in obese 
subjects or overweight subjects with co-morbidities. 
This study will be conducted in Part 1 and 2. In part 1, enrolling 12 
subjects per cohort (HM15136 group 9 subjects, placebo group 3 
subjects) will participate, and 3 cohorts will proceed sequentially, but 
may overlap during the conduct. In part 2, enrolling 30 subjects in cohort 
4 (HM15136 group 15 subjects, placebo group 15 subjects) will 
participate, and up to 3 additional cohorts may proceed with 12 subjects 
per cohorts 5-7 (HM15136 group 9 subjects, placebo group 3 subjects). 
12 subjects per cohort assigned to Part 1 and Part 2 will be randomized 
to HM15136 and placebo in a ratio of 3:1, and 30 subjects per cohort 4 
assigned to Part 2 will be randomized to HM15136 and placebo in a ratio 
of 1:1. The final analysis for each part will be performed separately once 
each part is complete. Due to COVID-19 outbreak, an interim analysis 
based on partially validated data for Part 1 will be performed for 
administrative purpose prior to database lock of Part 1. 
After Cohort 1 randomization is completed, the DMC will assess the 
safety and will make dosing and cohort escalation assessments and 
recommendations to decide whether subjects can be randomized into 
Cohort 2. Details will be defined in the DMC charter. 
Dose escalation from cohort 2 to next dose level for the subsequent 
Cohort 3 will be based on the safety, tolerability, available PD, and 
available PK data obtained from cohort 1 and through the 9th subject’s 
visit on Day 29 in cohort 2. An independent Data Monitoring Committee 
(DMC) will assess the safety and will make dosing and cohort escalation 
assessments and recommendations.  


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CONFIDENTIAL 
 
The next dose level for the subsequent cohort (Cohort 4 in Part 2) will be 
based on the safety, tolerability, available PD, and available PK data 
obtained from cohort 1, 2 and through the 9th subject’s visit on Day 29 
in cohort 3. An independent Data Monitoring Committee (DMC) will 
assess the safety and will make dosing and cohort escalation assessments 
and recommendations.  
If dose escalation is stopped, dose de-escalation may occur in subsequent 
cohorts, to further refine clinically relevant dose levels. 
The dose of cohorts 3 and 4 can be adjusted, but may not be over the 
planned dose of 0.08 mg/kg. The escalated dose should not be more than 
2 times over the dose of the previous cohort.  
In part 2, after the review of the safety data, obtained by the 9th subject’s 
visit on Day 29 of Cohort 3 (in Part 1), cohort 4 can proceed with a dose 
of ч 0.08 mg/kg dose, which is the planned maximum dose.  
A DMC will assess the safety and will make dosing and cohort escalation 
assessments and recommendations for the study progress of Part 2. After 
the review of the safety data in Part 1, Part 2 may or may not proceed. 
Cohort 4 may be conducted with a lower number of subjects. 
Cohort 5 may start immediately and may overlap with the conduct of 
subjects in Cohort 4. 
In Part 2, dose escalation from cohort 5 to the subsequent Cohort 6 will 
be made after Data Review Meetings (DRM), held by Sponsor, 
Investigator and Medical Monitor, and the safety data obtained from the 
9th subject’s visit on Day 43 (=after 6 weeks of dosing) have been 
reviewed. Additionally, a second DRM will be held and safety data from 
the 12th subject’s final visit on Day 113 _(=F/U Visit) will be reviewed to 
dose escalate.  
Dose escalation from cohort 6 to the subsequent cohort 7 will follow the 
same dose escalation scheme and DRM(s) of the previous cohort. 
Cohorts 6 and Cohort 7 may be conducted at doses of 0.04 mg/kg and at 
0.06 mg/kg respectively upon approval by the Investigator, Medical 
Monitor, and the Sponsor, if the safety is demonstrated in Cohort 5. 
If sufficient safety data are collected after cohort 5 or cohort 6 have been 
completed, no additional cohorts will be conducted, and sponsor may 
choose to complete study. 
 
Inclusion criteria 
At the screening visit, subjects who meet all of the following criteria are 
considered eligible for participation in the study. 
1) 
Male or Female subjects 
2) 
ŐĞш18 ƚŽчϲϱǇĞĂƌƐ at Screening visit. 
3) 
Body Mass Index (BMI) ш30 kg/m2 or 27 kg/m2 ш with presence of 
comorbidities (Subjects in Part 1: dyslipidemia and or hypertension 
except for Type 2 (T2) DM, T2DM subjects in Part 2: dyslipidemia 
and/or hypertension with T2DM) with/without medication 
treatment and have had stable weight for 3 months (weight changes 
less than 5%). Untreated dyslipidemia is defined as LDL шϭϲϬŵŐͬĚ>͕


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Page 20 / 127 
CONFIDENTIAL 
 
or TriglyceƌŝĚĞшϭϱϬŵŐͬĚ>͕Žƌ,>фϰϬŵŐͬĚ>ĨŽƌŵĂůĞĂŶĚфϱϬ
mg/dL for female, untreated hypertension is defined as Systolic 
ůŽŽĚWƌĞƐƐƵƌĞшϭϰϬŽƌŝĂƐƚŽůŝĐůŽŽĚWƌĞƐƐƵƌĞшϵϬŵŵ,Ő͘  
4) 
The criteria for HbA1c and FPG are as below; 
£ Subjects in Part 1: ‘FPG < 5.6 mmol/L (100 mg/dL)’ and ‘< HbA1c 
< 5.7%’ (But, if the result is out of the reference range at the 
screening visit, it can be tested again on another day by 
laboratory analysis.) 
¤ Subjects in Part 2 with DM: Subjects diagnosed as type 2 DM, 
with HbA1c ч 9% and stable treatment for 3 months by 
Metformin only.  
5) 
Female subjects must be non-pregnant and non-lactating. Females 
of childbearing potential must use highly effective contraceptive 
methods, stable at least 2 months prior to the screening. 
Male subjects should be surgically sterile (at least 1 year after 
vasectomy) or sterilized from the screening visit to 60 days after 
administration of IP, or if the male subject has a sexual relationship 
with a female partner of childbearing potential, the male subject is 
required, and the female partner should be encouraged to use a 
valid contraceptive method (e.g., condom, spermicidal form/gel/ 
film/cream suppository combination, etc.) during the study period. 
6) 
Subjects who agree to participate this study voluntarily and to give 
written informed consent. 
Exclusion Criteria 
Subjects who meet at least one of the following criteria are considered 
not eligible for participation in the study. 
1) 
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 LAPBAND®), as well as clinically significant 
gastrointestinal disorders (e.g. peptic ulcers, severe GERD) at 
Screening. 
2) 
Use of antacids, anticoagulants, or drugs that directly modify 
gastrointestinal (GI) motility, including antacids anticholinergics, 
anticonvulsants, serotonin type 3 (5HT3) antagonists, dopamine 
antagonists, opiates; anticoagulation within 2 weeks of screening; 
(But, it is not limited to the above listed drugs.)  The use of 
acetylsalicyclic acid (e.g., Bayer® Aspirin) 81 mg/day taken 
prophylactically is not considered anticoagulation therapy for the 
purposes of this protocol. 
3) 
Uncontrolled hypertension, defined as systolic blood pressure > 160 
ŵŵ,ŐĂŶĚͬŽƌĚŝĂƐƚŽůŝĐďůŽŽĚƉƌĞƐƐƵƌĞшϭϬϬŵŵ,ŐĂƚƐĐƌĞĞŶŝŶŐ 
(independent of subjects being on antihypertensive medication or 
not). But, if the results are out of the reference range at the 
screening visit, they can be tested again on another day. Subjects 
with uncontrolled hypertension may be rescreened after 3 months, 
following initiation or adjustment of antihypertensive therapy.) 


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CONFIDENTIAL 
 
4) 
Uncontrolled dyslipidemia, defined as fasting triglycerides (TG)  
> 500 mg/dL and/or fasting low density lipoprotein (LDL) cholesterol 
>200 mg/dL at Screening (independent of subjects being on lipid 
lowering medication or not). 
5) 
Use of any drugs that are known to interfere with glucose or insulin 
metabolism, within 3 months prior to screening except for 
metformin for T2DM subjects in part 2: oral or parenteral 
corticosteroids or topiramate, monoamine oxidase (MAO) 
inhibitors, growth hormone (But, it is not limited to the above listed 
drugs.) 
6) 
Subjects who are currently diagnosed with type 1 DM or who have 
such medical history  
7) 
Subjects diagnosed with type 2 DM, who have a treatment history 
of relevant drugs like sulfonylurea, thiazolidinediones, GLP-1 
receptor agonist, SGLT2 inhibitor, insulin and DPP-4 inhibitors within 
3 months before screening visit. Stable metformin therapy is 
allowed. 
8) 
Any weight control treatment, including over-the-counterdrugs, 
herbal medications and supplements, or any medication with a 
labelled indication for weight loss or weight gain within 3 months 
prior to screening. 
9) 
Participation in another investigational study within 1 month prior 
to enrollment or 5 half-lives within the last dose of investigational 
product (IP), whichever is longer. 
10) Serum calcitonin levels > 20 pg/mL at the screening. 
11) 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. 
12) Personal history of cancer diagnosis prior to screening visit, if it is 
likely to impact the study results as judged by the investigator. 
13) History of major depression, anxiety, 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. 
(Use of SSRIs and SNRIs and bupropion for reasons other than active 
psychiatric indications [eg, migraine, weight loss, smoking cessation] 
must meet a 3-month wash out.)  
14) History of significant suicidal ideation or suicidal behavior/attempts. 
15) History of any major surgery within 6 months prior to screening. 
16) Subjects who are unable to handle noise or isolation circumstances 
in testing devices or have any contraindication for MRI test (e.g., 
pacemaker, iron implant in body, metal pieces, clips of cerebral 
aneurysm as well as those things in the body that can be impacted 
by the magnetic field.). 
17) History of any serious adverse reaction or hypersensitivity to study 
drugs components, or have contraindication diseases (e.g., 
pheochromocytoma, insulinoma, glucagonoma). 
18) 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, 


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CONFIDENTIAL 
 
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) 
19) Cardiac arrhythmia requiring medical or surgical treatment within 6 
months prior to screening. 
20) Personal or family history of medullary thyroid carcinoma (MTC) or 
a genetic condition that predispose to MTC (ie, multiple endocrine 
neoplasia type 2).  
21) Anemia findings of hemoglobin < 13 g/dL in male or < 12 g/dL in 
female in clinical laboratory results. 
22) Abnormal laboratory results for thyroid stimulating hormone (TSH) 
(> 1.5 x ULN or < 0.4 mIU/L) at screening. 
23) Clinically significant abnormal hepatic function tests suggestive of 
hepatic impairment (eg, ALT and/or AST >2 x ULN). 
24) Clinically significant abnormal pancreatic function tests suggestive 
of pancreatic impairment (eg, amylase and/or lipase >3 x ULN). 
25) 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). 
26) Female who is pregnant or breast-feeding, or has a positive 
pregnancy test at screening or Day -2. 
27) History of any active infection, including any active COVID-19 
infection even if mild, within 30 days prior to dosing (except mild 
viral illness, such as common cold), as judged by the investigator. 
28) Use of a very-low calorie (1,000 kcal/day) liquid weight loss diet 
within 6 months prior to screening 
29) History of alcohol or illicit drug abuse as judged by the Investigator 
within approximately 1 year.  
30) 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. (Subjects must be able to abstain from smoking during 
the confinement period.) 
31) Use of debauchery drug (e.g., marijuana) within 6 weeks prior to 
screening or clinically under the effect at screening, as per 
Investigator evaluation. 
32) Subject has positive urine drug test (e.g., cocaine, amphetamines, 
barbiturates, opiates, benzodiazepines, cannabinoids) at Screening 
or Day -2. 
33) Known history of or positive test for hepatitis B surface antigen 
(HBsAg), hepatitis C antibody (HCVAb), or human immunodeficiency 
virus type 1 (HIV-1) or type 2 (HIV-2) antibody. 
34) Any anticipated procedures (eg, surgery), that might interfere with 
the compliance or completion of the study. 
35) Presence of clinically significant physical, laboratory, or ECG findings 
(eg, QTcF > 450 msec for males, QTcF > 470 msec for females, LBBB) 
at screening that, in the opinion of the Investigator, may interfere 
with any aspect of study conduct, results or interpretation of results. 


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CONFIDENTIAL 
 
36) Donation of whole blood (400 mL) within 60 days, or donation of 
blood components (500 mL) or receiving transfusion of blood 
products within 14 days prior to screening. 
37) Unwillingness to participate, involuntary participation or language 
barriers precluding adequate understanding or cooperation. 
38) Is employed by Hanmi (permanent, temporary contract worker, or 
designee responsible for the conduct of the study) or is immediate 
family of Hanmi staff (defined as a spouse, parent, sibling, or child, 
whether biological or legally adopted.). 
Investigational product 
Test product: HM15136, pre-filled syringe with a clear or almost colorless 
transparent sterile solution. The concentration is 10 mg/mL as a protein 
and the total amount is 0.52 mL. 
Comparator: Placebo, pre-filled syringe with clear sterile solution in 
place, colorless or almost colorless. 
Administration and dosage 
Administration group and dosage 
[Part 1] 
Cohorts 
Number of 
Subjects 
Treatment 
Cohort 1 
N=9 
HM15136 0.02-mg/kg 
N=3 
Placebo 
Cohort 2 
N=9 
HM15136 0.0ϰ-mg/kg 
N=3 
Placebo 
Cohort 3* 
N=9 
HM15136 ч0.08-mg/kg 
N=3 
Placebo 
* Dosage of Cohort 3 can be adjusted, but cannot be over the dosage 
presented in the table. The escalated dose should not be over twice the 
dose of the previous cohort. 
 
[Part 2] 
Cohorts 
Number of Subjects 
Treatment 
Cohort 4 
(DM) 
N=15 
HM15136 0.06-mg/kg 
N=15 
Placebo 
Cohort 5 
(DM) 
N=9 
HM15136 0.02-mg/kg 
N=3 
Placebo 
Cohort 6 
(DM)** 
N=9 
HM15136 0.04-mg/kg 
N=3 
Placebo 
Cohort 7 
(DM)** 
N=9 
HM15136 0.06-mg/kg 
N=3 
Placebo 
* In part 2, if necessary, after the review of the safety data obtained by 


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Page 24 / 127 
CONFIDENTIAL 
 
the 9th subject’s visit on Day29 of Cohort 3 in Part 1, the cohort can 
proceed within the 0.08 mg/kg of dose, which is the planned maximum 
dose. 
The dose and study progress of Part 2 should be guided by the 
recommendation of the DMC. After the review of the safety data in Part 
1, Part 2 may or may not proceed. 
**The conduct of cohorts 6 and 7 is optional. 
Statistical Methods 
 
Data presentation/Descriptive statistics 
All demographics, safety, PK and PD data will be analyzed using 
appropriate descriptive and comparative statistical methods and will be 
summarized. PK data will also be presented as graphs. PK/PD relationship 
for HM15136’s exposure and exploratory endpoints can also be 
presented as graphs. 
 
Interim Analysis 
An interim analyss will be performed to aid in the planning of future 
studies in the development program. Due to COVID-19 outbreak, an 
interim analysis based on partially validated data for Part 1 will be 
performed for administrative purpose prior to database lock of Part 1.  
The final analysis for Part 1 will be performed after all healthy subjects in 
Part 1 (i.e., Cohorts 1-3) have been finalized. The final analysis for Part 2 
will be performed after all subjects in Part 2 (i.e., Cohorts 4-7) have been 
finalized.  
 
 
Determination of sample size 
This study determined the number of subjects without consideration of 
statistical validity. The number of subjects for the Part 1 will be 12 
(HM15136: placebo = 9:3) for each cohort, and for the Part 2 will be up 
to 66, 30 for cohort (HM15136: placebo = 15:15) and 12 for cohorts 5-7 
(HM15136: placebo = 9:3). This is consistent with the typical sample size 
used in the similar study to evaluate safety and PK. Therefore, 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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[STUDY FLOW] Part 1 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Administration IP 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure of Screening 
Informed consent process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/Exclusion criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication and 
medical history taking 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infection of HBV, HCV and 
Anti-body, infection of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (Urine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum FSH (Only 
Postmenopausal female) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug abuse urine screening 
and alcohol exhalation test 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Dietary education 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
Diet diary distribution 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
Diet diary review 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
Safety assessment 
TSH 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Amylase, lipase 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
LH, FSH (Only female) 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 26 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical 
examination 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
Vital sign2 
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 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
ABP monitoring4 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Holter monitoring4 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Clinical laboratory test 
(Hematological, Chemistry5, 
Blood coagulation, Urine 
analysis) 
X 
X 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
X 
X 
Other Safety assessment  
Concomitant medications 
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 
X 
X 
X 
X 
X 
Adverse events 
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 
X 
X 
X 
X 
X 
Injection site reactions 
 
 
 
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 
 
 
Pharmacodynamics (PD) assessment6 
MRI/MRI-PDFF7 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
 
 
Body weight, BMI 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tympanic temperature 
(2x/day)10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 27 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Waist circumference, Hip 
circumference, Waist-to-hip 
ratio (WHR) 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
X 
X 
X 
7-point Self-monitoring of 
blood glucose (SMBG)8 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Glucose measure (via YSI)11 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Fructosamine, glycated 
albumin 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Fasting plasma glucose (FPG) 
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 
X 
X 
X 
X 
X 
Fasting insulin, 
Fasting C-peptide 
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 
X 
X 
X 
HOMA-IR, HOMA-ɴ 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Incretins / metabolic 
hormones 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Amino-acid profile 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Serum lipid profiles 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Inflammatory markers 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
ɴ-hydroxybutyrate 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 28 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacokinetic (PK), Immunogenicity assessment 
Immunogenicity (ADAbs, 
nAbs, anti-PEG) 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
PK assessment9 
 
 
 
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 
1 Only that are eligible for in-house period and past medications (stated as #1-5 in section 10.1.1-3) in-house period. 
2 Sampling for PK assessment and V/S to be measured on the day should be conducted before each PK sampling (prior to the collection of Pre-dose Samples on Day 1 and Day 78). 
3 At the screening visit, a 12-lead ECG is conducted 1 time. All other 12-lead ECGs should be repeated 3 times. Additional measurements of the 12-lead ECG may be conducted during the following specified in-house period, 
which is also repeated 3 times. 
The ECG measurements are collected on Day -2 and Day 77 before the subject is connected to the ABP monitoring device and on the Day 5 and Day 82 after the subject is disconnected to the ABP monitoring device. 
4 Measurement time point may be adjusted after PK assessment.  
5 Serum ferritin in the chemistry laboratory test is measured on the Day 1 before the administration, Day 57, Day 85. 
6 All PD assessment endpoints are collected at the same time on fasting conditions at the time of PK Sample collection (Pre-dose Sample collection on Day 1 and Day 78). In the case of fasting conditions, the test subject 
should be kept in a state of being maintained for about 10 hours. 
7 MRI/MRI-PDFF assessment marked for Day -1 can be performed prior to Day -1, after subject’s eligibility for the study is confirmed (MRI may be performed while Screening calcitonin results are pending). MRI-PDFF 
measurements marked for Day 85 should be conducted as close as possible to the Day 85 of the 12th week before the Day 85 PK sampling, and on Day 85 of the MRI-PDFF measurement, the MRI-PDFF will only be 
performed if the MRI-PDFF on Day -1 showed equal or more than 10% liver fat. MRI assessment will be performed as close as possible to the Day 85 of the 12th week before the Day 85 PK sampling. 
8 The 7-point SMBG is measured 15 minutes before the meal (± 10 minutes), 2 hours after the meal starts (± 15 minutes), and 15 minutes before the evening snack (± 10 minutes)s. For the Day 1 and Day 78 of the test, 5 
times, except before and after breakfast, should be conducted. 
9 The time of PK sampling may be adjusted between cohorts if PK data showing that other time points are more advantageous can be obtained when the sample for pharmacokinetic analysis is collected. Specific PK sampling 
timeline for analysis follows the PK sampling schedule table. 
10 During the in-house periods, tympanic temperature will be measured 2 x /24 hours. 
11 FPG will be measured via YSI in addition to the FPG measure that is included in clinical laboratory assessments. The measurement of glucose via YSI should be performed for all subjects and for all outpatient visits.  
 
 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 29 / 127 
CONFIDENTIAL 
 
 
[STUDY FLOW] Part 2 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Administration IP 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure of Screening 
Informed consent process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/Exclusion criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication and 
medical history taking 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infection of HBV, HCV and 
Anti-body, infection of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (Urine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum FSH (Only 
Postmenopausal female) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug abuse urine screening 
and alcohol exhalation test 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Dietary education 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
Diet diary distribution 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
Diet diary review 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
Safety assessment 
TSH 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Amylase, lipase 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 30 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
LH, FSH (Only female) 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical 
examination 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
Vital sign2 
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 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
ABP monitoring4 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Holter monitoring4 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Clinical laboratory test 
(Hematological, Chemistry5, 
Blood coagulation, Urine 
analysis) 
X 
 
 
X5 
 
X 
 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X5 
X 
X 
 
X 
 
X 
 
X 
X5 
X 
X 
Other Safety assessment  
Concomitant medications 
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 
X 
X 
X 
X 
X 
Adverse events 
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 
X 
X 
X 
X 
X 
Injection site reactions 
 
 
 
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 
 
 
Pharmacodynamics (PD) assessment6 
MRI/MRI-PDFF7 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
 
 
Body weight, BMI 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tympanic temperature 
(2x/day)10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 31 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Waist circumference, Hip 
circumference, Waist-to-hip 
ratio (WHR) 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
X 
X 
X 
7-point Self-monitoring of 
blood glucose (SMBG)8 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Glucose measure (via YSI)11 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Fructosamine, glycated 
albumin 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Fasting plasma glucose (FPG) 
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 
X 
X 
X 
X 
X 
Fasting insulin, 
Fasting C-peptide 
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 
X 
X 
X 
HOMA-IR, HOMA-ɴ 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Incretins / metabolic 
hormones 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Amino-acid profile 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Serum lipid profiles 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Inflammatory markers 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
ɴ-hydroxybutyrate 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 32 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
In-house Period 1 
OPD 
In-house Period 2 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 
17 
Visit(day) 
-35 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6-7 
8 
10 
11 
15 
17 
18 
22 
29 
36 
43 
50 
57 
64 
71 
77 
78 
79 
80 
81 
82 
85 99 113 
Visit window 
 
 
 
 
 
 
 
 
 
 
 
 
±1 
 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
 
 
±2 ±2 
±2 
Sequestered in clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacokinetic (PK), Immunogenicity assessment 
Immunogenicity (ADAbs, 
nAbs, anti-PEG) 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
PK assessment9 
 
 
 
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 
1 Only that are eligible for in-house period and past medications (stated as #1-5 in section 10.1.1-3) in-house period. 
2 Sampling for PK assessment and V/S to be measured on the day should be conducted before each PK sampling (prior to the collection of Pre-dose Samples on Day 1 and Day 78). 
3 At the screening visit, a 12-lead ECG is conducted 1 time. All other 12-lead ECGs should be repeated 3 times. Additional measurements of the 12-lead ECG may be conducted during the following specified in-house period, 
which is also repeated 3 times. 
The ECG measurements are collected on Day -2 and Day 77 before the subject is connected to the ABP monitoring device and on the Day 5 and Day 82 after the subject is disconnected to the ABP monitoring device. 
4 Measurement time point may be adjusted after PK assessment.  
5 Serum ferritin in the chemistry laboratory test is measured on the Day 1 before the administration, Day 57, Day 85. 
6 All PD assessment endpoints are collected at the same time on fasting conditions at the time of PK Sample collection (Pre-dose Sample collection on Day 1 and Day 78). In the case of fasting conditions, the test subject 
should be kept in a state of being maintained for about 10 hours. 
7 MRI/MRI-PDFF assessment marked for Day -1 can be performed prior to Day -1, after subject’s eligibility for the study is confirmed (MRI may be performed while Screening calcitonin results are pending). MRI-PDFF 
measurements marked for Day 85 should be conducted as close as possible to the Day 85 of the 12th week before the Day 85 PK sampling, and on Day 85 of the MRI-PDFF measurement, the MRI-PDFF will only be 
performed if the MRI-PDFF on Day -1 showed equal or more than 10% liver fat. MRI assessment will be performed as close as possible to the Day 85 of the 12th week before the Day 85 PK sampling. 
8 The 7-point SMBG is measured 15 minutes before the meal (± 10 minutes), 2 hours after the meal starts (± 15 minutes), and 15 minutes before the 15 minutes before the evening snack (± 10 minutes). For the Day 1 and Day 
78 of the test, 5 times, except before and after breakfast, should be conducted. 
9 The time of PK sampling may be adjusted between cohorts if PK data showing that other time points are more advantageous can be obtained when the sample for pharmacokinetic analysis is collected. Specific PK sampling 
timeline for analysis follows the PK sampling schedule table. 
10 During the in-house periods, tympanic temperature will be measured 2 x /24 hours. 
11 FPG will be measured via YSI in addition to the FPG measure that is included in clinical laboratory assessments. The measurement of glucose via YSI should be performed for all subjects and for all outpatient visits.  


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Page 33 / 127 
CONFIDENTIAL 
 
[STUDY FLOW] Parts 1 and 2 – COVID-19 Modification 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
OPD 
OPD 
OPD 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 17 
Phone visit (P) (assessments at 
home)11 
 
 
P 
 
P 
 
P 
 
P 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
 
P 
 
 
 
 
Visit(day) 
-35 to -3 
-211 
-111 
1 
211 
311 
411 
511 
611 
711 
8 
10 1111 15 
17 1811 22 
29 
36 43 
50 57 64 
71 7711 78 7911 8011 8111 8211 85 99 11
3 
Visit window 
 
±1 
±2 
 
±1 
±1 
±1 
±1 
±1 
±1 
 
±1 
±2 
±1 
±1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±1 
 
±1 
±1 
±1 
±1 
±2 ±2 ±2 
Administration IP 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure of Screening 
Informed consent process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/Exclusion criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication and medical 
history taking 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infection of HBV, HCV and Anti-
body, infection of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (Urine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Serum FSH (Only Postmenopausal 
female) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug abuse urine screening and 
alcohol exhalation test 
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 
Dietary education 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Diet diary distribution 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Diet diary review 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Safety assessment 
TSH 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Amylase, lipase 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Calcitonin 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 


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%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 34 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
OPD 
OPD 
OPD 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 17 
Phone visit (P) (assessments at 
home)11 
 
 
P 
 
P 
 
P 
 
P 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
 
P 
 
 
 
 
Visit(day) 
-35 to -3 
-211 
-111 
1 
211 
311 
411 
511 
611 
711 
8 
10 1111 15 
17 1811 22 
29 
36 43 
50 57 64 
71 7711 78 7911 8011 8111 8211 85 99 11
3 
Visit window 
 
±1 
±2 
 
±1 
±1 
±1 
±1 
±1 
±1 
 
±1 
±2 
±1 
±1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±1 
 
±1 
±1 
±1 
±1 
±2 ±2 ±2 
LH, FSH (Only female) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Vital sign2 
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 ECG3 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ABP monitoring4 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Instructions on ABPM at home 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Holter monitoring4 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Instructions on Holter monitoring at 
home 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory test 
(Hematological, Chemistry5, Blood 
coagulation, Urine analysis) 
X 
 
 
X5 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X5 
X 
X 
 
X 
 
X 
 
X 
X5 
X 
X 
Other Safety assessment  
Concomitant medications 
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 
X 
X 
X 
X 
X 
X 
Adverse events 
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 
X 
X 
X 
X 
X 
X 
Injection site reactions 
 
 
 
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 
X 
 
 
Pharmacodynamics (PD) assessment6 
MRI/MRI-PDFF7 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
 
 
Body weight, BMI 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 35 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
OPD 
OPD 
OPD 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 17 
Phone visit (P) (assessments at 
home)11 
 
 
P 
 
P 
 
P 
 
P 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
 
P 
 
 
 
 
Visit(day) 
-35 to -3 
-211 
-111 
1 
211 
311 
411 
511 
611 
711 
8 
10 1111 15 
17 1811 22 
29 
36 43 
50 57 64 
71 7711 78 7911 8011 8111 8211 85 99 11
3 
Visit window 
 
±1 
±2 
 
±1 
±1 
±1 
±1 
±1 
±1 
 
±1 
±2 
±1 
±1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±1 
 
±1 
±1 
±1 
±1 
±2 ±2 ±2 
Waist circumference, Hip 
circumference, Waist-to-hip ratio 
(WHR) 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
7-point Self-monitoring of blood 
glucose (SMBG)8,12 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Instructions on  
7-point SMBG and FPG at home 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
SMBG and fasting blood glucose 
(FPG) diary distribution 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
Glucose measure (via YSI)10,12 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
HbA1c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Fructosamine, glycated albumin 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Fasting plasma glucose (FPG) (per 
clinical lab assessment)9 12 
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 
FBG at home  
(via glucometer)12 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Fasting insulin, 
Fasting C-peptide 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
HOMA-IR, HOMA-ɴ 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Incretins / metabolic hormones 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Amino-acid profile 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 


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2TQVQEQN0Q*/)%)
 
 
Page 36 / 127 
CONFIDENTIAL 
 
Assessment 
V 1 
V 2 
V 3-15 
V 16 
V 17-19 
 
Screening 
OPD 
OPD 
OPD 
OPD (F/U) 
Visit(Week) 
-5 to -1 
 
 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
11 
12 
13 15 17 
Phone visit (P) (assessments at 
home)11 
 
 
P 
 
P 
 
P 
 
P 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
 
P 
 
 
 
 
Visit(day) 
-35 to -3 
-211 
-111 
1 
211 
311 
411 
511 
611 
711 
8 
10 1111 15 
17 1811 22 
29 
36 43 
50 57 64 
71 7711 78 7911 8011 8111 8211 85 99 11
3 
Visit window 
 
±1 
±2 
 
±1 
±1 
±1 
±1 
±1 
±1 
 
±1 
±2 
±1 
±1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±1 
 
±1 
±1 
±1 
±1 
±2 ±2 ±2 
Serum lipid profiles 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Inflammatory markers 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
ɴ-hydroxybutyrate 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Pharmacokinetic (PK), Immunogenicity assessment 
Immunogenicity (ADAbs, nAbs, anti-
PEG) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
PK assessment9 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
1 Only that are eligible for past medications (stated as #1-5 in section 10.1.1-3). 
2 Sampling for PK assessment and V/S to be measured on the day should be conducted before each PK sampling (prior to the collection of Pre-dose Samples on Day 1 and Day 78). 
3 At the screening visit, a 12-lead ECG is conducted 1 time. All other 12-lead ECGs should be repeated 3 times. Additional measurements of the 12-lead ECG may be conducted during the OPV days, which is also repeated 3 
times. The ECG measurements are collected on Day -2 and Day 78 before the subject is connected to the ABP monitoring device and on the Day 5 and Day 82 after the subject is disconnected to the ABP monitoring device. 
4 Measurement time point may be adjusted after PK assessment.  
5 Serum ferritin in the chemistry laboratory test is measured on the Day 1 , Day 57, Day 85. 
6 All PD assessment endpoints are collected at the same time on fasting conditions at the time of PK Sample collection (Pre-dose Sample collection on Day 1 and Day 78). In the case of fasting conditions, the test subject 
should be kept in a state of being maintained for about 10 hours. 
7 MRI/MRI-PDFF assessment marked for Day -2 can be performed  after subject’s eligibility for the study is confirmed (MRI may be performed while Screening calcitonin results are pending), but MRI must be completed 
prior to first dosing. MRI-PDFF measurements marked for Day 85 should be conducted as close as possible to the Day 85 of the 12th week before the Day 85 PK sampling, and on Day 85 of the MRI-PDFF measurement, the 
MRI-PDFF will only be performed if the MRI-PDFF prior to the first dosing showed equal or more than 10% liver fat. MRI assessment will be performed as close as possible to the Day 85 of the 12th week before the Day 85 
PK sampling. If MRI/MRI-PDFF assessment is not possible during the stated time period, due to COVID- restrictions, MRI/MRI-PDFF may be performed at a later timepoint, but prior to the last visit on Day 113. If MRI/MRI-
PDFF assessment is not possible due to restricted access of MRI center under COVID-19 restrictions, the missing assessment will be documented in the CRFs (specific information will be captured that explains the basis of 
the missing data due to COVID-19).The missing assessment will be documented as a protocol deviation (with reason due to COVID-19 stated). 


*CPOK2JCTOCEGWVKECN%Q.VF 
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Page 37 / 127 
CONFIDENTIAL 
 
8 The 7-point SMBG is measured 15 minutes before the meal (± 10 minutes), 2 hours after the meal starts (± 15 minutes), and 15 minutes before the 15 minutes before the evening snack (± 10 minutes). For the Day 1 and Day 
78 of the test, 5 times, except before and after breakfast, should be conducted. During OPD, subjects will perform SMBG at stated times. Measurements may partly be performed in the clinic and partly at home on that 
day. On days with a phone visit, subjects will only measure the 7-point profile at home. All meal-times and corresponding SMBG values will be recorded in a subject diary. 
9 The time of PK sampling may be adjusted between cohorts if PK data showing that other time points are more advantageous can be obtained when the sample for pharmacokinetic analysis is collected. Specific PK sampling 
timeline for analysis follows the PK sampling schedule table. 
10 FPG will be measured via YSI in addition to the FPG measure that is included in clinical laboratory assessments. The measurement of glucose via YSI should be performed for all subjects and for all outpatient visits. If OPV is 
adjusted to a phone visit, subjects will measure fasting glucose in the morning (prior to any breakfast). Capillary blood will be used for the fasting blood glucose assessment (FBG), which will be performed by subjects at home 
via glucometer instead of FPG with YSI at the site. Other fasting glucose measures are already covered by the assessment of the 7-point profiles. 
11 If OPVs and/or phone visits are not feasible on the specified visit days (only as an example, Day 1 being on a Monday and visit is therefore scheduled to take place on a weekend/holiday),visits can be moved within the visit 
window and OPV and phone visit (on day prior to OPV or day after OPV) can be combined into one visit (as example, combined visit for Day 5 and 6) to keep the schedule for the following visits. If the visit is moved/combined, 
all other visits between the corresponding dosing visits will be performed as scheduled, to ensure that weekly dosing can be performed as scheduled. 
12 -Summary of the various measurement methods that involve assessment of glucose: 
- 7-point SMBG will be measured on Day -1, 1, 2, 3, 4, 5, 78, 79, 80, and 81 (original time points kept, regardless of the changes in visit type). 
- FBG at home (via glucometer): Day 6, 7, and 77. 
- FPG at clinic (blood sample for LabCorp analysis): at every visit in the clinic (D-2, Day 1, 3, 5, 8, and all OPD V3-15 assessments, 78, 80, 82, 85, 99, and 113) 
- Glucose measure (via YSI): at every visit in the clinic. 
 
 


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Page 38 / 127 
CONFIDENTIAL 
 
[PK SAMPLING SCHEDULE]  
PK sampling schedule 
Time window 
Treatment 
period 
In-house 
Period 1 
Week 1 
Day 1 
Pre-dose 1st dosing 
-60 min 
8 h after 1st dosing 
±10 min 
Day 2 
24 h after 1st dosing 
±30 min 
Day 3 
48 h after 1st dosing 
±30 min 
Day 4 
72 h after 1st dosing 
±30 min 
Day 5 
96 h after 1st dosing 
±30 min 
Week 2 
Day 8 
Pre-dose 2nd dosing 
-60 min 
OPD 
Week 2 
Day 10 
48 h after 2nd dosing 
±30 min 
Day 11 
72 h after 2nd dosing 
±30 min 
Week 3 
Day 15 
Pre-dose 3rd dosing 
-60 min 
Day 17 
48 h after 3rd dosing 
±30 min 
Day 18 
72 h after 3rd dosing 
±30 min 
Week 4 
Day 22 
Pre-dose 4th dosing 
-60 min 
Week 5 
Day 29 
Pre-dose 5th dosing 
-60 min 
Week 6 
Day 36 
Pre-dose 6th dosing 
-60 min 
Week 7 
Day 43 
Pre-dose 7th dosing 
-60 min 
Week 8 
Day 50 
Pre-dose 8th dosing 
-60 min 
Week 9 
Day 57 
Pre-dose 9th dosing 
-60 min 
Week 10 
Day 64 
Pre-dose 10th dosing 
-60 min 
Week 11 
Day 71 
Pre-dose 11th dosing 
-60 min 
In-house 
Period 2 
Week 12 
Day 78 
Pre-dose 12th dosing 
-60 min 
8 h after 12th dosing 
±10 min 
Day 79 
24 h after 12th dosing 
±30 min 
Day 80 
48 h after 12th dosing 
±30 min 
Day 81 
72 h after 12th dosing 
±30 min 
Day 82 
96 h after 12th dosing 
±30 min 
F/U 
OPD 
Week 13 
Day 85 
168 h after 12th dosing 
±2 days 
Week 15 
Day 99 
504 h after 12th dosing 
±2 days 
Week 17 
Day 113 
840 h after 12th dosing 
±2 days 


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Page 39 / 127 
CONFIDENTIAL 
 
[PK SAMPLING SCHEDULE] PARTs 1 and 2 - COVID-19 Modification 
PK sampling schedule 
Time 
window 
Added 
Time 
window 
Treatment 
period 
OPD 
Week 1 
Day 1 
Pre-dose 1st dosing 
-60 min 
 
4 h after 1st dosing 
±10 min 
 
Day 3 
48 h after 1st dosing 
±30 min 
±1 day 
Day 5 
96 h after 1st dosing 
±30 min 
±1 day 
Week 2 
Day 8 
Pre-dose 2nd dosing 
-60 min 
 
Week 2 
Day 10 
48 h after 2nd dosing 
±30 min 
±1 day 
Day 11 
72 h after 2nd dosing 
±30 min 
±2 days 
Week 3 
Day 15 
Pre-dose 3rd dosing 
-60 min 
 
Day 17 
48 h after 3rd dosing 
±30 min 
±1 day 
Day 18 
72 h after 3rd dosing 
±30 min 
±2 days 
Week 4 
Day 22 
Pre-dose 4th dosing 
-60 min 
 
Week 5 
Day 29 
Pre-dose 5th dosing 
-60 min 
 
Week 6 
Day 36 
Pre-dose 6th dosing 
-60 min 
 
Week 7 
Day 43 
Pre-dose 7th dosing 
-60 min 
 
Week 8 
Day 50 
Pre-dose 8th dosing 
-60 min 
 
Week 9 
Day 57 
Pre-dose 9th dosing 
-60 min 
 
Week 10 
Day 64 
Pre-dose 10th dosing 
-60 min 
 
Week 11 
Day 71 
Pre-dose 11th dosing 
-60 min 
 
Week 12 
Day 78 
Pre-dose 12th dosing 
-60 min 
 
4 h after 12th dosing 
±10 min 
 
Day 80 
48 h after 12th dosing 
±30 min 
±1 day 
Day 82 
96 h after 12th dosing 
±30 min 
±1 day 
F/U 
OPD 
Week 13 
Day 85 
168 h after 12th dosing 
±2 days 
 
Week 15 
Day 99 
504 h after 12th dosing 
±2 days 
 
Week 17 
Day 113 
840 h after 12th dosing 
±2 days 
 
 
 
 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
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[ABBREVIATIONS AND DEFINITIONS]  
ABP 
Ambulatory blood pressure 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
anti-PEG 
Anti-polyethylene glycol 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC%extrap 
Percentage of AUCinf that is due to extrapolation beyond tlast  
AUC0-t 
Area under the concentration-time curve from predose (time 0) to the time of the last 
quantifiable concentration  
AUCinf 
Area under the concentration-time curve from predose (time 0) extrapolated to infinite time 
(AUC0-t + Clastͬʄz)  
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute  
BUN 
Blood urea nitrogen  
CFR 
Code of Federal Regulations  
CHI 
Congenital hyperinsulinism  
Cl 
Chloride  
CL/F 
Total body clearance  
Cmax 
Maximum concentration  
CO2 
Carbon Dioxide  
CRO 
Contract Research Organization 
Ctrough 
Trough plasma concentration  
CVA 
Cardiovascular accident  
DBP 
Diastolic blood pressure  
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram  


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 41 / 127 
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EDC 
Electronic data capture 
eGFR 
Estimated Glomerular filtration rate  
EMA 
European Medicines Agency  
FiH 
First-in-human 
FBS 
Fasting blood sugar 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice  
GFR 
Glomerular filtration rate  
GGT 
Gamma glutamyl transferase  
Hb 
Hemoglobin 
HbA1c 
Hemoglobin A1c  
HBsAg 
Hepatitis B surface antigen  
HCV ab 
Hepatitis C antibody  
HDL 
High-density lipoprotein  
hERG 
Human ether-a-go-go-related gene 
HIV 
Human immunodeficiency virus type 1  
HOMA-IR 
Homeostatic model assessment for insulin resistance  
HOMA- ɴ 
Homeostatic model assessment for ɴ Cell Function 
IB 
Investigator’s Brochure  
ICF 
Informed consent form  
ICH 
International Council for Harmonisation 
IMP 
Investigational medicinal product  
IND 
Investigational New Drug  
INR 
International normalized ratio  
IRB 
Institutional review board  
IUD 
Intrauterine contraceptive device  
IUS 
Intrauterine system  
Kel 
Terminal elimination rate constant  
LBBB 
Left bundle branch block  
LDH 
Lactate dehydrogenase  
LDL 
Low-density lipoprotein  
MAD 
Multiple ascending dose  


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 42 / 127 
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MAL-PEG-ALD 
Maleimide-polyethylene glycol-aldehyde  
MAO 
Monoamine oxidase  
MCH 
Mean corpuscular hemoglobin  
MCHC 
Mean corpuscular hemoglobin concentration  
MCV 
Mean corpuscular volume  
MDRD 
Modification of diet renal disease  
MedDRA 
Medical dictionary for regulatory activities  
MID 
Minimum intolerable dose  
MTC 
Medullary thyroid carcinoma  
MTD 
Maximum tolerated dose  
Nab 
Neutralizing antibodies  
NOAEL 
No observed adverse effect level  
NYHA 
New York heart association  
OTC 
Over-the-counter  
PCI 
Percutaneous coronary intervention  
PD 
Pharmacodynamics  
PE 
Physical examination 
PK 
Pharmacokinetics  
PR 
Pressure rate  
PT 
Preferred term  
PT 
Prothrombin time  
PTT 
Activated partial thromboplastin time  
PV 
Pharmacovigilance  
QTc 
QT interval corrected for heart rate  
QTcB 
QT interval corrected for heart rate using Bazett's correction  
QTcF 
QT interval corrected for heart rate using Fridericia's correction  
RBC 
Red blood cell  
RR 
Respiratory rate  
SAD 
Single ascending dose  
SAE 
Serious adverse event  
SID 
Subject identification  
SMBG 
Self-monitoring of blood glucose 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 43 / 127 
CONFIDENTIAL 
 
SNRIs 
Serotonin norepinephrine reuptake inhibitors  
SOC 
System organ class  
SOP 
Standard operating procedure  
SSRIs 
Selective serotonin reuptake inhibitors  
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal half-life  
Tmax 
Time to maximum serum concentration  
TEAE 
Treatment Emergent Adverse Event  
TSH 
Thyroid stimulation hormone  
ULN 
Upper limit of normal  
VLDL 
Very low-density lipoprotein  
Vz/F 
Apparent volume of distribution  
WBC 
White blood cell  
WHR 
Waist-Hip ratio  
ʄz 
Terminal elimination rate constant  
 
 
 


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 44 / 127 
CONFIDENTIAL 
 
Table of contents 
Sponsor Signature pag
Investigator signature page
[STUDY SUMMARY]
[STUDY FLOW] Part 1
[STUDY FLOW] Part 2
[STUDY FLOW] Parts 1 and 2 – COVID-19 Modification
[PK SAMPLING SCHEDULE]
[PK SAMPLING SCHEDULE] PARTs 1 and 2 - COVID-19 Modification
[ABBREVIATIONS AND DEFINITIONS]
Table of contents
1.
Clinical Trial Title and Phase
1.1.
Study Title
1.2.
Phase
2.
Information of Investigators, Sponsor
2.1.
Name and Address of the Institutions
2.2.
Principal Investigator
2.3.
Sponsor
3.
Introduction
3.1.
Background
3.2.
Background of Currently Used Treatments
3.3.
Investigational Product Profile
3.4.
Result of Nonclinical Experiences
3.5.
Result of Clinical Trial Experiences
3.6.
Rationale of Clinical Trial
3.7.
Risks Assessment
4.
Study Objectives
4.1.
Primary Objectives
4.2.
Exploratory Objectives
5.
Subject Selection
5.1.
Number of Subjects
5.2.
Inclusion Criteria
5.3.
Exclusion Criteria
5.4.
Withdrawal and Discontinuation Criteria
5.4.1.
Violation of Protocol


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 45 / 127 
CONFIDENTIAL 
 
5.4.2.
Subject’s Withdrawal, Replacement and Discontinuation
6.
Study Design
6.1.
Duration of Clinical Trial
6.2.
Study Design
6.3.
Rationale of Trial Design
6.3.1.
Selection of subjects in test group
6.3.2.
Selection of controlled Group
6.3.3.
Rationale of initiation and maximum dosage adjustments
6.3.4.
Confirmation of dosage and escalation
6.4.
Subjects Identification and Randomization
6.4.1.
Screening No.
6.4.2.
Randomization No.
6.5.
Blinding and Unblinding
7.
Completion and Early Discontinuation of the Clinical Trial
7.1.
Study Completion
7.2.
Study Discontinuation
7.3.
Dose Escalation and Study Stopping Criteria
8.
Information and Control of Investigational Product
8.1.
Test Product
8.2.
Comparator
8.3.
Dosage and Administration
8.4.
Drug Supply, Package, Labelling and Storage
8.5.
Manufacture, Prescription, Inventory Management and Disposal/Destruction
8.5.1.
Manufacture
8.5.2.
Release of IP
8.5.3.
Inventory Management and Record
9.
Clinical Trial Methods and Administration Plan
9.1.
Overall Clinical Trial Method
Dosage, Method, Period of Investigational product
9.2.
Past medication and Concomitant Medication
9.3.
Treatment Compliance
10.
Procedure and Assessment of Clinical Trial
10.1.
Visit Schedule
10.1.1.
Scheduled Visit
10.1.2.
Unscheduled Visit


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 46 / 127 
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10.2.
Enrollment and Clinical Evaluation
10.2.1.
Assessment items per visit
10.2.2.
Assessment variable
10.2.3.
Restrictions
10.2.4.
Handling of hypersensitivity
10.3.
Endpoints
10.3.1.
Primary endpoints
10.3.2.
Exploratory endpoints
10.4.
Safety assessment
10.4.1.
Adverse Event (AE)
10.4.2.
Definition of AE
10.4.3.
Recording of AE
10.4.4.
Severity of AE
10.4.5.
Causality with IP
10.4.6.
Seriousness
10.4.7.
SAEs and AESI Reporting
10.4.8.
Follow-up of AE
10.4.9.
SUSAR (Suspected unexpected serious adverse reaction)
10.5.
Pregnancy
10.6.
Safety Reporting to Institutional Review Boards (IRBs) or Independent Ethic Committees (IECs), 
and Regulatory Authorities
11.
Statistical analysis and statistical consideration
11.1.
General Considerations
11.1.1.
Population
11.1.2.
Handling of Missing Data
11.2.
Statistical Analysis
11.2.1.
General Principles of Statistical Analysis
11.2.2.
Protocol Deviation/Violation
11.2.3.
Subject participation status
11.2.4.
Demographics, Physical examination and Baseline characteristics
11.2.5.
Prior medication and concomitant medication and Administration of medication
11.2.6.
IP administration status
11.2.7.
Endpoints
11.3.
Statistical Analysis Timing and Decision for Sample Sizes
11.3.1.
Interim analysis


*CPOK2JCTOCEGWVKECN%Q.VF 
%NKPKECN5VWF[2TQVQEQN
2TQVQEQN0Q*/)%)
 
 
Page 47 / 127 
CONFIDENTIAL 
 
11.3.2.
Confirmation of sample sizes
12.
Data Management
12.1.
Data Recording
12.2.
Data Collection
12.3.
Data Access
12.4.
Data Protection and Storage
13.
Ethical considerations and administrative procedures
13.1.
Ethical Considerations
13.2.
Informed Consent
13.3.
IND (Investigational New Drug) Approval
13.4.
Case Report Form (CRF)
13.5.
Confidentiality
13.6.
Knowledge of Protocol
13.7.
Monitoring and Auditing
13.8.
Recording and Dissemination of Results
13.8.1.
Recording
13.8.2.
Dissemination
13.9.
Protocol Amendment
14.
Other considerations to conduct the clinical trial
14.1.
Institution
14.2.
Investigator
14.3.
Subinvestigator
15.
References
[Appendix] Adverse Event Guidance of HM15136
 
 
 


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1. Clinical Trial Title and Phase  
1.1. Study Title 
A Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses 
of HM15136 in obese subjects or overweight subjects with co-morbidities. 
 
1.2. Phase 
Phase 1 


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2. Information of Investigators, Sponsor 
2.1. Name and Address of the Institutions 
Institutions 
Address 
Tel. 
ProSciento, 
Inc. 
855 3rd Avenue, Chula Vista, CA, 91911, USA 
 
 
 
2.2. Principal Investigator 
Bridgette Boggess Franey, MD, FAAFP 
 
2.3. Sponsor 
Sponsor 
CEO 
Address 
Tel. 
Hanmi Pharm. Co., Ltd. 
Jong Su, Woo 
Se Chang, Kwon 
14, Wiryeseong-daero, Songpa-gu, Seoul, 
Korea, Hanmi Tower 
02-410-9114 
 


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3. Introduction 
3.1. Background 
Obesity emerged as an issue of priority in public health in the 21st century. According to a survey conducted in 
the United States in 2000, approximately 30% of the adult population was obese with the body mass index (BMI) 
ш30 kg/m2 and 35% was overweight with BMI 25-29.9 kg/m2, indicating a 50-60% or higher increase compared 
to 20 years ago. In Korea, a 2005 National Health and Nutrition Examination Survey showed that 34.9% of the 
adult population was obese with шBMI 25 kg/m2, suggesting a persistent increase from 32.7% in 2001 (2). 
In addition, according to a recent report of the Korean Society for the Study of Obesity, while the percentage of 
obesity patients in Korea between 2009 and 2013 was 31.8%, decreasing from 2001, the percentage of obese or 
overweight patients with BMI ш25-30 kg/m2 in men rose greatly 35.8% in 2009 to 37.6% 2013 (8). 
Such persistent increase in obesity is attributed to primary causes such as excessive caloric intake, reduced 
physical activities and lack of sleep, as well as endocrine disorders, genetic diseases (e.g.: Prader-Willi syndrome, 
Laurence-Moon-Biedl syndrome, Alstrom syndrome and Cohen syndrome) and effects of a drug (8). 
Being obese is not merely a problem of gaining weight but it leads to cardiovascular diseases such as type 2 
diabetes, dyslipidemia and hypertension, as well as musculoskeletal diseases such as osteoarthritis, and 
gastrointestinal, respiratory, endocrine and metabolic disorders and blood tumor, threatening health of mankind 
and also posing a continuously growing economic loss to society (1, 2, 8). 
For such reasons, research on obesity treatment in ongoing. Initially, non-drug therapy such as diet, exercise, 
behavioral therapy is attempted to treat obesity and when such efforts are not effective after 3~6 months, drug 
treatment or even surgery is considered (3, 8). 
Drug treatment is roughly categorized into fat absorption inhibitors, appetite suppressants, and unapproved 
medications with reported weight reduction effects even though they have not been approved for weight loss 
or maintenance. Orlistat, an active ingredient of a fat absorption inhibitor was approved by the United States 
Food and Drug Administration (US FDA) in 1999 and a low dose formulation was approved as an over-the-counter 
medication in 2007. In Korea, 120 mg and 60 mg are approved and commercially available as prescription 
medication. Appetite suppressants reduce appetite by stimulating the central nervous system and promoting 
norepinephrine secretion, and Phentermine or Mazindol are contained as an active ingredient. While drug 
combination represents another treatment option, it is not used frequently for safety reasons arising from 
concurrent use (3). 
In addition, with reports on weight loss effects of a glucagon-like peptide receptor agonist (GLP-1 RA) 
subcutaneous injection used for diabetes treatment, the US FDA approved up to 3.0 mg once weekly regimen in 
obesity in December 2014 (1, 3). 
Hanmi Pharmaceutical is developing HM15136, a synthetic conjugate of a glucagon analogue (called GC15136) 
and a G4 Fc portion of human immunoglobulin (called HMC001) linked by a maleimide-polyethylene glycol-
aldehyde(MAL-PEG-ALD) bifunctional linker molecule. This product was designed as a novel therapeutic agent 
for congenital hyperinsulinism(CHI) which is a rare genetic disease characterized by inappropriately elevated 
serum insulin. Hanmi Pharmaceutical conducted an efficacy study in target animals for the treatment of 
hyperinsulinism. The result showed that the drug inhibits hyperinsulinism while also promoting appetite 
suppression and lipolysis, suggesting its potential effects in obesity. 
In vitro activity of HM15136 was evaluated using hGCGR/Chinese hamster ovary(CHO) cells. HM15136 raised the 
cyclical adenosine monophosphate level in cells in a dose dependent fashion and exhibited the maximum efficacy 
similar to natural glucagon, demonstrating its property as a complete agonist. In rat primary hepatocytes, 
HM15136 induced glucose production through both glycogenolysis and gluconeogenesis just like natural 
glucagon, suggesting that HM15136 actually has pharmacological properties similar to glucagon. In additional in 
vitro studies, HM15136 showed the minimal immune mediated effector function as it contains a non-
glycosylated Fc portion derived from human IgG4. Furthermore, HM15136 has a pH dependent FcRn binding 
property due to a Fc portion which is essential for vascular endothelial recirculation. 


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In vivo efficacy of HM15136 was evaluated by measuring the glycemic profile after single and repeated doses in 
acute and chronic hypoglycemia rat models. In vivo studies demonstrated that HM15136 rapidly reverses acute 
hypoglycemia as well as sustainably increasing the blood sugar level in rats that mimicked human CHI. 
Congenital hyperinsulinism is one of the most common diseases that cause serious and persistent hypoglycemia 
in newborns and infants. Insulin is a hormone that controls blood sugar levels in body and lowers the glycemic 
level when it is elevated after eating food. In patients with congenital hyperinsulinism, insulin does not play such 
a role and is secreted from the pancreas irrespective of the glycemic level. Consequently, patients experience 
hypoglycemia. HM15136, developed with an indication of congenital hyperinsulinism based on such mechanism, 
has hyperglycemic effects, an general action of glucagon, as well as appetite suppression and anti-obesity effects 
by activating hormone-sensitive lipase in adipocytes and promoting lipolysis as found in animal studies. 
Pharmacodynamic assessment in a hypoglycemic rat model observed a concentration dependent effect of 
HM15136 on weight loss which was estimated to be similar to the action of glucagon. Besides, different from 
previous technology, HM15136 overcame a short half-life, a shortcoming of previous biopharmaceuticals. 
Consequently, the duration of action in blood is extended and an equivalent or greater efficacy and effects are 
anticipated with a lower dose than previous doses applied to insulin products.  
 
3.2. Background of Currently Used Treatments 
Korean Society for the Study of Obesity recommends diet, exercise and behavioral therapy as initial treatment 
of obesity, and drug therapy when these approaches are not effective (3, 8). As drug treatment, fat absorption 
inhibitors, appetite suppressants and drug combination therapy, etc. were developed. Recently, application of a 
glucagon analogue used for diabetes treatment in obesity was approved, first in the United States and also in 
Korea in 2017. 
It is known that the lowered incretin response in type 2 diabetes can explain up to 60% of the change in the post-
prandial insulin response. GLP-1 RA is a therapeutic agent to prevent degradation of glucagon like peptide-1, a 
key incretin in human, by dipeptidyl peptidase-4(DPP-4) (6). It was reported that a GLP-1 RA is effective for weight 
loss by maintaining the incretin level in body (4). 
As of 2015, there are 5 clinical trials in the United States reporting on the use of a GLP_1 RA (liraglutide) for 
obesity, and clinical trials at various phases were performed to investigate its effects in obesity (7). 
Currently approved GLP-1 RAs include Exenatide, Liraglutide, Exenatide LAR, Lixisenatide, Albiglutide and 
Dulaglutide. Such GLP-1 RAs are designed to stimulate GLP-1 receptors, thereby increasing insulin secretion in 
response to oral and intravenous glucose to similar extents; this means the magnitude of the incretin effect 
should remain unchanged.  (5, 6). 
In this context, this clinical trial aims to investigate the effect of HM15136 after its administration in a small 
number of obese or overweight subjects and thereby to develop a therapeutic agent for obesity, based on a 
single dose clinical trial in healthy subjects (HM-GCG-101). This compound is differentiated from GLP-1 agents as 
it is a long-acting glucagon analogue and exhibits improved stability due to conjugation of a glucagon analogue 
with a Fc region of human immunoglobulin G4 by MAL-PEG-ALD.  
3.3. Investigational Product Profile 
Hanmi Pharmaceutical is developing HM15136, a synthetic conjugate of a glucagon analogue (called GC15136) 
and a G4 Fc portion of human immunoglobulin (called HMC001) linked by a maleimide-polyethylene glycol-
aldehyde (MAL-PEG-ALD) bifunctional linker molecule.  
This product was designed as a novel therapeutic agent for congenital hyperinsulinism (CHI) which is a rare 
genetic disease characterized by inappropriately elevated serum insulin.  
When the mechanism of insulin secretion or glycemic detection is dysfunctional, the pancreatic insulin secretion 
is not reduced even though the glycemic level drops. If left untreated, CHI can result in a brain damage or even 
death secondary to hypoglycemia.  
For such reasons, the effect of relieving hypoglycemia was observed in an acute and chronic hypoglycemia rat 
model that mimicked CHI, and it was also found that HM15136 has a concentration dependent weight loss 


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effect. In addition, single and repeated dose studies also noted the weight loss effect resulting from appetite 
suppression.  
Such action is attributable to a glucagon portion of HM15136. Previous glucagon products exhibit low solubility, 
limited stability in physiological pH and short duration of action, resulting in limited utility. In order to overcome 
such shortcomings, the sponsor developed HM15136, a novel glucagon analogue with a long duration of action. 
 
 
3.4. Result of Nonclinical Experiences 
<In vitro> 
In vitro activity of HM15136 was evaluated using hGCGR/Chinese hamster ovary(CHO) cells. HM15136 increased 
the cyclical adenosine monophosphate level in cells in a dose dependent fashion and exhibited the maximum 
efficacy similar to natural glucagon, demonstrating its property as a complete agonist.  
In rat primary hepatocytes, HM15136 induced glucose production through both glycogenolysis and 
gluconeogenesis just like natural glucagon, suggesting that HM15136 actually has pharmacological properties 
similar to glucagon.  
In additional in vitro studies, HM15136 exhibited the minimal immune mediated effector function as it contains 
a non-glycosylated Fc portion derived from human IgG4. Furthermore, HM15136 has a pH dependent FcRn 
binding property due to a Fc portion which is essential for vascular endothelial recirculation. 
 
<In vivo efficacy study> 
In vivo efficacy of HM15136 was evaluated by measuring the glycemic profile after single and repeated doses in 
acute and chronic hypoglycemia rat models. In vivo studies demonstrated that HM15136 rapidly reverses acute 
hypoglycemia as well as sustainably increasing blood sugar levels in rats that mimicked human CHI. 
Such findings were consistent with in vitro study results. HM15136 exhibits endogenous activities similar to that 
of glucagon in vivo also, indicating the therapeutic potential of HM15136 in CHI treatment. 
 
During pharmacodynamic assessment conducted in a hypoglycemia rat model, the concentration dependent 
effect of HM15136 in weight loss was confirmed which is estimated to be similar to a pharmacological action of 
glucagon. Furthermore, during a safety pharmacology study of HM15136, information on general behavioral 
profile, body temperature and body weight was collected for the general behavior (Irwin’s test) investigation, 
and of these, in terms of body weight, the weight loss effect was shown at intermediate (0.583 mg/kg) and the 
highest concentrations (1.750 mg/kg), and a repeated dose toxicity study also found a rapid weight loss effect in 
both female and male.  
Such findings were observed along with reduced food intake. Decreased appetite causes lipolysis and weight loss. 
This is estimated to be due to a pharmacological action of HM15136 in which glucagon acts directly on the liver 
to promote glycogenesis and glycogenolysis and thereby elevates sugar concentrations.  
 
<Safety pharmacology study> 
Effects on the cardiovascular system, respiratory system, central nervous system and in vitro human ether-a-go-
go-related gene(hERG) channel analysis were evaluated.  
No significant effect was observed in this study. 
 
<Pharmacokinetic (PK) study> 
Pharmacokinetic parameters were measured after subcutaneous administration in experimental animals. 
HM15136 had high bioavailability and long half-life (t1/2) which was approximately 32.3-56.2 hours in mice, 
approximately 40.9-54.8 hours in rats and 26.6-34.9 hours in dogs, indicating that HM15136 is a long acting 
glucagon analogue.  
HM15136 was found to be distributed mostly in the liver, a target organ of glucagon in gluconeogenesis. 
 


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<Toxicity study> 
Up to 13 weeks of repeated dose toxicity studies in rats and monkeys and an in vitro genotoxicity study were 
conducted. Local tolerance was investigated in a repeated dose toxicity study, and a key dose limiting factor was 
weight loss in rats and monkeys. 
In addition, no adverse event was observed in a toxicity study of HMC001. 
 
- 
No Observed Adverse Effect Level (NOAEL) 
The therapeutic safety margin at the no observed adverse effect level (NOAEL) was estimated as 4-fold in rats 
and 49-fold in monkeys, based on 0.02 mg/kg which is an expected starting clinical dose for human (NOAEL was 
0.5 mg/kg in rats and 3 mg/kg in monkeys. Human equivalent dose converted from an animal dose based on the 
body surface area was 0.08 mg/kg in rats and 0.97 mg/kg in monkeys). 
 
- 
4 week-repeated dose toxicity study 
Vulnerable target organ was not identified in a 4 week-repeated dose toxicity study. While all changes returned 
to normal during the recovery phase, atrophy of the thymus, spleen, pancreas, parotid salivary gland and 
mesenteric lymph node in monkeys persisted. Most of observed responses were related to the effect of fasting 
or pharmacological action of glucagon. There was no adverse finding related to the test chemical at the injection 
site. Anti-HM15136 antibody was detected in monkeys but not in rats. There was no difference in exposure by 
sex in 4 week-toxicity studies in rats and monkeys.  
 
- 
13 week-repeated dose toxicity study 
In a 13 week-repeated dose toxicity study in rats, reduced body weight and food intake were observed, and the 
relevant findings partially returned to normal after a 4 week- recovery phase. In some dose groups, reduced RBC 
and atrophy of multiple organs (lymphatic organs, intestine, adrenals, ovaries and vagina) was noted; such 
changes were due to an excessive pharmacological action of HM15136 and did not appear to represent adverse 
effects. In a 13 week-repeated dose toxicity study in monkeys, erythroid disturbance and atrophy of multiple 
organs (thymus, spleen, pancreas, salivary gland, lymph node and bone marrow) were observed; such changes 
were due to an excessive pharmacological action of HM15136 and did not represent adverse effects. 
 
- 
Genotoxicity study 
The compound was negative in genotoxic potential.  
 
For further details, see the Investigator Brochure (IB)(9). 
 
3.5. Result of Clinical Trial Experiences 
Safety, tolerability, pharmacokinetic and pharmacodynamic factors are under clinical evaluation in 8 subjects per 
cohort (investigational product : placebo = 6 : 2) with a total of 7 cohorts of healthy subjects (0.01, 0.02, 0.03, 
0.05, 0.08, 0.10, 0.12 mg/kg) by HM15136 dose (HM-GCG-101). Data is not available yet, but there was no 
significant safety issue to date.  
 
3.6. Rationale of Clinical Trial 
This clinical trial aims to evaluate safety, pharmacokinetics and pharmacodynamics after repeated dose in 
volunteers with dyslipidemia and/or hypertension in part 1 subjects and dyslipidemia and/or hypertension with 
type 2 diabetes in part 2 diabetes subject, among


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overweight volunteers with obesity or comorbidity, based on findings from a previous clinical trial in healthy 
volunteers (HM-GCG-101).


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3.7. Risks Assessment 
Pharmacologic and pre-clinical data known for individual agonists suggest that the following toxicities are 
expected. 
 
Gastrointestinal system: Nausea, vomiting, gastrointestinal hypotonia, diarrhea, indigestion, weight 
loss, anorexia, dehydration, gastroesophageal reflux disease 
 
Metabolism: Hyperglycemia, hypoglycemia, body temperature change 
 
Cardiovascular system: Hypertension or hypotension (increased heart rate and inotropic action) 
 
Immune system: Systemic allergic reaction including anaphylaxis, angioedema, urticaria, dyspnea and 
hypotension 
 
General: Injection site reaction, pyrexia, abdominal pain, abdominal distension 
 
Laboratory: Hepatic dysfunction (transient elevation of aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]), bleeding and blood coagulation disorder, hypokalemia, elevated creatinine 
levels, anemia 
 
Nervous system: Agitation, dizziness, headache 
 
Skin legion: Necrolytic migratory erythema 
 
Changed salivation  
 
Diuresis 
 
 


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4. Study Objectives 
To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of HM15136 in 
obese subjects or overweight subjects with co-morbidities 
 
4.1. Primary Objectives 
 
To assess safety and tolerability of HM15136 after multiple subcutaneous (SC) doses. 
 
To assess the pharmacokinetic (PK) profile of HM15136 after administration of multiple SC doses. 
 
4.2. Exploratory Objectives 
 
To assess pharmacodynamics (PD) properties of HM15136 after multiple SC doses. 
 


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5. Subject Selection 
The subjects with obese or overweight with co-morbidities, should provide informed consent in writing based on 
the information, and should meet all of inclusion criteria and should not meet any exclusion criteria.  
 
5.1. Number of Subjects 
This study will be enrolled with 12 subjects in each cohort according to in/exclusion in Part 1, planned 3 cohorts. 
9 subjects randomized to the HM15136 group will be administered IP in each cohort, 3 subjects will receive 
placebo. In part 2, up to 66 subjects will be enrolled. Thirty (30) subjects in cohort 4 will be randomized to 
HM15136 or placebo in a ratio of 15:15, 12 subjects in each of the cohorts 5-7 in a ratio of 9:3. Part 2 will only be 
performed, if deemed necessary, after the safety data, obtained by the 9th subject’s visit on Day 29 of Cohort 3 
in Part 1, have been reviewed. 
An independent Data Monitoring Committee (DMC) will assess the safety and will make dosing and cohort 
escalation assessments and recommendations for the dose and study progress of Part 2. After the review of the 
safety data in Part 1, Part 2 may or may not proceed. 
 
[Part 1] 
 
Cohorts 
Number of Subjects 
Treatment 
Cohort 1 
N=9 
HM15136 0.02 mg/kg 
N=3 
Placebo 
Cohort 2 
N=9 
HM15136 0.04 mg/kg 
N=3 
Placebo 
Cohort 3* 
N=9 
HM15136 ч0.08 mg/kg 
N=3 
Placebo 
* Dosage of Cohort3 can be adjusted, but cannot be over the dosage presented in the table. 
The escalated dose should not be over twice the dose of the previous cohort. 
 
[Part 2] 
 
Cohorts 
Number of Subjects 
Treatment 
Cohort 4* 
(DM) 
N=15 
HM15136 0.06 mg/kg 
N=15 
Placebo 
Cohort 5 
(DM) 
N=9 
,DϭϱϭϯϲчϬ͘ϬϮ-mg/kg 
N=3 
Placebo 
Cohort 6** 
(DM) 
N=9 
,DϭϱϭϯϲчϬ͘Ϭϰ-mg/kg 
N=3 
Placebo 
Cohort 7** 
(DM) 
N=9 
,DϭϱϭϯϲчϬ͘Ϭϲ-mg/kg 
N=3 
Placebo 
* In part 2, enrolling 30 subjects per cohort 4, 15 subjects randomized to HM15136 group will be 
administered IP, (15 subjects will receive placebo).  
The dose and study progress of Part 2 should be guided by the recommendation of the DMC. After the 
review of the safety data in Part 1, Part 2 may not proceed. 


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** Cohorts 6 and 7 will be optional. 
 
5.2. Inclusion Criteria 
Subjects who meet all of the following criteria are considered eligible for participation in the study. 
 
1) 
Male or Female subjects 
2) 
ŐĞшϭ8 ƚŽчϲϱǇĞĂƌƐ at Screening visit. 
3) 
Body Mass Index (BMI) ш 30 kg/m2 or 27 kg/m2 ш with presence of comorbidities (Subjects in Part 1: 
dyslipidemia and or hypertension except for Type 2 (T2) DM, T2DM subjects in Part 2: dyslipidemia and/or 
hypertension with T2DM) with/without medication treatment and have had stable weight for 3 months 
(weight changes less than 5%), Untreated dyslipidemia is defined as LDL шϭϲϬŵŐͬĚ>͕ŽƌdƌŝŐůǇĐĞƌŝĚĞшϭϱϬ
mg/dL, or HDL < 40mg/dL for male and < 50 mg/dL for female, untreated hypertension is defined as Systolic 
ůŽŽĚWƌĞƐƐƵƌĞшϭϰϬŽƌŝĂƐƚŽůŝĐůŽŽĚWƌĞƐƐƵƌĞшϵϬŵŵ,Ő͘   - 
4) 
The criteria for HbA1c and FPG (Fasting Plasma Glucose) are as below. 
£ Subjects in Part 1: ‘FPG < 5.6 mmol/L (100 mg/dL)’ and ‘HbA1c < 5.7%’ (But, if the result is out of the 
reference range at the screening visit, it can be tested again on another day by laboratory analysis.) 
¤ Subjects in Part 2 with DM: the subjects diagnosed as type 2 DM, and stably treated with HbA1c ч 9% 
for 3 months by Metformin only.  
5) 
Female subjects must be non-pregnant and non-lactating. Females of childbearing potential must use highly 
effective contraceptive methods, stable at least 2 months prior to the screening. 
Male subjects should be surgically sterile (at least 1 year after vasectomy) or sterilized from the screening 
visit to 60 days after administration of IP, or if the male subject has a sexual relationship with a female 
partner of childbearing potential, the male subject is required, and the female partner should be encouraged 
to use a valid contraceptive method (e.g., condom, spermicidal form/gel/ film/cream suppository 
combination, etc.) during the study period. 
6) 
Subjects who agree to participate this study voluntarily and to give written informed consent. 
5.3. Exclusion Criteria 
Subjects who meet at least one of the following criteria are considered not eligible for participation in the study. 
 
1) 
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 LAPBAND®), as well as clinically significant 
gastrointestinal disorders (e.g. peptic ulcers, severe GERD) at Screening. 
2) 
Use of antacids, anticoagulants, or drugs that directly modify gastrointestinal (GI) motility, including 
antacids anticholinergics, anticonvulsants, serotonin type 3 (5HT3) antagonists, dopamine antagonists, 
opiates; anticoagulation within 2 weeks of screening;(But, it is not limited to the above listed drugs.)  The 
use of acetylsalicyclic acid (e.g., Bayer® Aspirin) 81 mg/day taken prophylactically is not considered 
anticoagulation therapy for the purposes of this protocol. 
3) 
Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg and/or diastolic blood pressure 
шϭϬϬŵŵ,ŐĂƚƐĐƌĞĞŶŝŶŐ 
(Independent of subjects being on antihypertensive medication or not, But, if the results are out of the 
reference range at the screening visit, they can be tested again on another day. Subjects with uncontrolled 
hypertension may be rescreened after 3 months, following initiation or adjustment of antihypertensive 
therapy.) 
4) 
Uncontrolled dyslipidemia, defined as fasting triglycerides (TG) > 500 mg/dL and/or fasting low density 
lipoprotein (LDL) cholesterol >200 mg/dL at Screening (independent of subjects being on lipid lowering 
medication or not). 


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5) 
Use of any drugs that are known to interfere with glucose or insulin metabolism, within 3 months prior to 
screening except for metformin for T2DM subjects in part 2: oral or parenteral corticosteroids or topiramate, 
monoamine oxidase (MAO) inhibitors, growth hormone 
(But, it is not limited to the above listed drugs.) 
6) 
Subjects who are currently diagnosed with type 1 DM or who have such medical history  
7) 
Subjects diagnosed with type 2 DM, who have a treatment history of relevant drugs like sulfonylurea, 
thiazolidinediones, GLP-1 receptor agonist, SGLT2 inhibitor, insulin and DPP-4 inhibitors within 3months 
before screening visit. Stable metformin therapy is allowed. 
8) 
Any weight control treatment, including over-the-counter drugs and herbal medications and supplements, 
or any medication with a labelled indication for weight loss or weight gain within 3 months prior to screening. 
9) 
Participation in another investigational study within 1 month prior to enrollment or 5 times of half-lives 
within the last dose of investigational product, whichever is longer. 
10) Serum calcitonin levels > 20 pg/mL at the screening. 
11) 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. 
12) Personal history of cancer diagnosis prior to screening visit, if it is likely to impact the study results as judged 
by the investigator. 
13) History of major depression, anxiety, 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. 
(Use of SSRIs and SNRIs and bupropion for reasons other than active psychiatric indications [eg, migraine, 
weight loss, smoking cessation] must meet a 3-month wash out.)  
14) History of significant suicidal ideation or suicidal behavior/attempts. 
15) History of any major surgery within 6 months prior to screening. 
16) Subjects who cannot cope with noise or isolation circumstances in testing devices or have any 
contraindication for MRI test (e.g., pacemaker, iron implant in body, metal pieces, clips of cerebral aneurysm 
as well as those things in the body that can be impacted by the magnetic field.). 
17) History of any serious adverse reaction or hypersensitivity to study drugs components, or have 
contraindication diseases (e.g., pheochromocytoma, insulinoma, glucagonoma). 
18) 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) 
19) Cardiac arrhythmia requiring medical or surgical treatment within 6 months prior to screening. 
20) Personal or family history of medullary thyroid carcinoma (MTC) or a genetic condition that predispose to 
MTC (ie, multiple endocrine neoplasia type 2).  
21) Anemia findings of hemoglobin < 13 g/dL in male or < 12 g/dL in female in clinical laboratory results. 
22) Abnormal laboratory results for thyroid stimulating hormone (TSH) (> 1.5 x ULN or < 0.4 mIU/L) at screening. 
23) Clinically significant abnormal hepatic function tests suggestive of hepatic impairment (eg, ALT and/or AST 
>2 x ULN). 
24) Clinically significant abnormal pancreatic function tests suggestive of pancreatic impairment (eg, amylase 
and/or lipase >3 x ULN). 
25) 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). 
26) Female who is pregnant or breast-feeding, or has a positive pregnancy test at screening or Day -2. 
27) History of any active infection, including any active COVID-19 infection even if mild, within 30 days prior to 
dosing (except mild viral illness, such as common cold), as judged by the investigator. 
28) Use of a very-low calorie (1,000 kcal/day) liquid weight loss diet within 6 months prior to screening 


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29) History of alcohol or illicit drug abuse as judged by the Investigator within approximately 1 year.  
30) 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. (Subjects must be able to abstain from smoking during the confinement period.) 
31) Use of debauchery drug (e.g., marijuana) within 6 weeks prior to screening or clinically under the effect at 
screening, as per Investigator evaluation. 
32) Subject has positive urine drug test (e.g., cocaine, amphetamines, barbiturates, opiates, benzodiazepines, 
cannabinoids) at Screening or Day -2. 
33) Known history of or positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCVAb), or 
human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) antibody. 
34) Any anticipated procedures (eg, surgery), that might interfere with the compliance or completion of the 
study. 
35) Presence of clinically significant physical, laboratory, or ECG findings (eg, QTcF > 450 msec for males, QTcF > 
470 msec for females, LBBB) at screening that, in the opinion of the Investigator, may interfere with any 
aspect of study conduct, results or interpretation of results. 
36) Donation of whole blood (400 mL) or blood components (500 mL) within 60 days, or received transfusion of 
blood products within 14 days prior to screening. 
37) Unwillingness to participate, involuntary participation or language barriers precluding adequate 
understanding or cooperation. 
38) Is employed by Hanmi (permanent, temporary contract worker, or designee responsible for the conduct of 
the study) or is immediate family of Hanmi staff (defined as a spouse, parent, sibling, or child, whether 
biological or legally adopted). 
 
5.4. Withdrawal and Discontinuation Criteria 
5.4.1. 
Violation of Protocol 
The investigator should report to Hanmi Pharm. Co., Ltd. as soon as possible if a subject violation has occurred, 
and determine whether the subject should continue to participate in the clinical trial or not. When a subject 
withdraws due to a violation of protocol, it has to be written in the CRF. Serious violations of the protocol include, 
but are not limited to: 
 
1) Violation of inclusion and exclusion criteria that may affect efficacy, safety, exploratory evaluation. 
2) Administration of prohibited medications or using prohibited therapies. 
3) Any other violation considered as a serious protocol violation  
 
5.4.2. 
Subject’s Withdrawal, Replacement and Discontinuation 
The subject may withdraw his/her consent to participate in the clinical trial at any time for any reason without 
any disadvantage or impact on future medical care. Although the subject is not required to state the reasons for 
withdrawing consent to participate in the clinical trial, the reasons for withdrawal must be recorded in all cases. 
If the randomization code for the subject is broken, the date, time and reason must be recorded. Subject’s 
participation may be terminated before completion of the study. 
Subjects who have received IP but for whatever reason cannot participate in the entire study period are classified 
as 'withdrawals‘. 
If the subject requests the study discontinuation or consent withdrawal or the investigator judges that the 
subject should be discontinued, the subject may be withdrawn at any time. If the study would be discontinued 
or withdrawn, the results of the study obtained prior to that point in time may be reviewed for final evaluation 
if assessible. 
 
The reasons for the withdrawals or discontinuation of individual subjects are as follows. 
 


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1) If the subject who is healthy in Part 1 has a FPG exceeding 10 mmol/L (180 mg/dL). Subjects FPG should 
be re-tested and FPG must be confirmed by a morning plasma glucose level (after 10 hours of fasting) 
that is  180 mg/dL (10.0 mmol/L), verified by a standard laboratory analysis (ie, YSI glucose analyzer 
at the site). Subjects who have confirmed FPG values that have reached the threshold limits will be 
counseled first. They will then have their FPG re-assessed, per PI discretion. If the FPG is still above the 
threshold they will be dropped from the study and may be replaced. 
2) If the subject who has type 2 DM in Part 2 has an FPG exceeding 15 mmol/L (270 mg/dL). Subjects FPG 
should be re-tested and confirmed by a morning fasting plasma glucose level (after 10 hours of fasting) 
ƚŚĂƚŝƐш270 mg/dL (15.0 mmol/L), verified by a standard laboratory analysis (ie, YSI glucose analyzer at 
the site). Subjects who have confirmed FPG values that have reached the threshold limits will be 
counseled first. They will then have their FPG re-assessed, per PI discretion. If the FPG is still above the 
threshold they will be dropped from the study and may be replaced. 
3) Difficult to keep taking part in the clinical trial due to any adverse events (AE). 
4) Violation of protocol 
5) Impossible to follow up on a subject. 
6) Withdrawal of consent by subject or legally acceptable representative. 
7) In case of discontinuation by the sponsor 
8) If the investigator judged that it is difficult to continue this study. 
9) If the subject is pregnant. 
10) Participation of subject who is not acceptable per inclusion and exclusion criteria. 
11) Administration of prohibited medications, or necessary to administer it. 
12) Treatment of prohibited therapies, or necessary to treat with them. 
13) Poor medication compliance.  
14) Others 
15) If missing dosing and/or visits occurs for many times (due to COVID-19 or any other inevitable reasons), 
The study investigator may withdraw or discontinue a subject from participation in the study, if the 
subject missed a specific numbers of dosing/dosing visits. Missed doses <70% may lead to 
discontinuation of subject, based on decision of investigator and sponsor. If a subject must miss dosing 
due to COVID-19 or any other unavoidable reasons, the willingness and safety of the subject will be 
taken into consideration. 
 
If for any reason during the study period the subject is withdrawn from participation or dropped the study prior 
to completion, the investigator should make every effort to conduct the planned evaluation in the follow-up visit. 
If possible, early termination visit is planned within 1 - 3 days after discontinuation of IP. Last IP administration 
date, withdrawal reason and all of information until the termination point should be recorded in source 
documents (SD) and Case Report Form. In order to prevent omissions of any adverse events, the investigator 
should contact the withdrawn subject via phone calls, letters (or e-mail), direct visits, etc., and leave relevant 
records. Also, even if tracking is not possible, try to contact as much as possible to minimize follow up failure and 
leave relevant record. In case of withdrawal caused by AE, should be followed until recovered (or the investigator 
judges normalization) or until the subject’s last visit completion, or until further follow up is judged to be 
meaningless. Particularly, in case of withdrawal caused by elevation of FPG corresponding to the reason 1) and 
2), IP should be stopped and follow up occur until FPG recovered or judged to be normal with the subject’s 
consent. If the investigator made the subject withdraw participation, that subjects cannot re-participate in this 
study. 
 
If the subject is withdrawn from the study prior to administration of IP, the subject may be replaced by a 
candidate subject. The subject who is withdrawn for reasons not related to safety, may be considered for 
replacement with the judgement of the investigator and sponsor. The results of study obtained from the subject 
until the withdrawal point may be reviewed for final evaluation if assessible.


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6. Study Design 
6.1. Duration of Clinical Trial 
The planned period of each cohort is 22 weeks including subject screening, treatments for 12 weeks, and follow-
up period. 
 
6.2. Study Design 
This is a double-blind, randomized, placebo controlled, multiple ascending dose (MAD) study to investigate the 
safety, tolerability, PD, and PK of the subcutaneous (SC) administration of HM15136 in obese subjects or 
overweight subjects with comorbidities. 
 
This study will be conducted in Part 1 and 2. In part 1, 12 subjects per cohort (HM15136 group 9 subjects, placebo 
group 3 subjects) will participate, and 3 cohorts will proceed sequentially, but may overlap during the execution. 
In part 2, enrolling 30 subjects in cohort 4 (HM15136 group 15 subjects, placebo group 15 subjects) will 
participate, and up to 12 subjects each in cohorts 5-7 (HM15136 group 9 subjects, placebo group 3 subjects). 12 
subjects per cohorts assigned to Part 1 and Part 2 will be randomized to HM15136 and placebo in a ratio of 9:3, 
and 30 subjects per cohort 4 assigned to Part 2 will be randomized to HM15136 and placebo in a ratio of 15:15. 
 
After Cohort 1 randomization is completed, the DMC will assess the safety and will make dosing and cohort 
escalation assessments and recommendations to decide whether subjects can be randomized into Cohort 2. 
 
Dose escalation from cohort 2 to next dose level for the subsequent Cohort 3 will be based on the safety, 
tolerability, available PD, and available PK data obtained from cohort 1 and through the 9th subject’s visit on Day 
29 in cohort 2. An independent DMC will assess the safety and will make dosing and cohort escalation 
assessments and recommendations. 
 
Dose escalation from cohort 3 to next dose level for the subsequent cohort (Cohort 4 in Part 2) will be based on 
the safety, tolerability, available PD, and available PK data obtained from cohort 1, 2 and through the 9th subject’s 
visit on Day 29 in cohort 3. An independent Data Monitoring Committee (DMC) will assess the safety and will 
make dosing and cohort escalation assessments and recommendations.  
 
If dose escalation is stopped, dose de-escalation may occur in subsequent cohorts, to further refine clinically 
relevant dose levels. 
 
The dose of cohorts 3 and 4 can be adjusted, but may not be over the planned dose of 0.08 mg/kg. The escalated 
dose should not be more than 2 times over the dose of the previous cohort.  
In part 2, after the review of the safety data, obtained by the 9th subject’s visit on Day 29 of Cohort 3 (in Part 1), 
Cohort 4 can be processed, if within the 0.08 mg/kg of dose, which is the planned maximum dose.  
The DMC will assess the safety and will make dosing and cohort escalation assessments and recommendations 
for the progress of Part 2. After the review of the safety data in Part 1, Part 2 may or may not proceed. 
 
Cohort 4 may be conducted with a lower number of subjects to adopt escalation design as previously performed 
in Part 1 for the safety assessment of the T2DM subjects. 
The maximum dose level for Part 2 will not exceed 0.06 mg/kg (tentative dose for Cohort 5 may be 0.02 mg/kg, 
tentative dose may be 0.04 mg/kg for Cohort 6). This dose level has been previously approved for subjects with 
T2DM by the independent DMC. Therefore, the decision to proceed to the next cohort/dose level from cohorts 
5-7 will be made per review of safety data by Sponsor, Investigator and Medical Monitor during a Data Review 
Meeting (DRM), which will take place after the 9th subject has comleted Visit Day 43 (which is after 6 weeks of 
dosing).  
Per DRM of Cohort 5 (after the 9th subject’s visit on day 43 of Cohorts 5), a dose escalation to Cohort 6 will not 
proceed at this timepoint and another DRM will be held after all 12 subjects in Cohort 5 have completed the final 
study visit on Day 113 (=F/U Visit), to assess the safety data and to make a decision to escalate to Cohort 6 or not. 


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Dose escalation from cohort 6 to the subsequent cohort 7 will follow the same dose escalation scheme and 
DRM(s) of the previous cohort. 
Cohorts 6 and Cohort 7 may be conducted at doses of 0.04 mg/kg and at 0.06 mg/kg respectively upon approval 
by the Investigator, Medical Monitor, and the Sponsor, if the safety is demonstrated in Cohort 5. 
If sufficient safety data are collected after cohort 5 or cohort 6 have been completed, no additional cohorts will 
be conducted, and sponsor may choose to complete study. 
The conduct of cohorts 6 and 7 is optional.  
 
 
6.3. Rationale of Trial Design 
6.3.1. 
Selection of subjects in test group 
Part 1 in this study is to administer HM15136 once a week for a total of 12 weeks to subjects who are obese or 
overweight with comorbidities. All cohorts in Part 2 will receive HM15136 once a week for a total 12 weeks for 
subjects who have type 2 DM among the obese or overweight with comorbidities. 
 
6.3.2. 
Selection of controlled Group 
The control group of each group of this study recruits the subjects on the same criteria as the test group. 
 
6.3.3. 
Rationale of initiation and maximum dosage adjustments 
A dose of 0.01, 0.02, 0.03, 0.05, 0.08, 0.10, or 0.12 mg/kg was given to HM-GCG-101, a single-dose study of 
HM15136 in healthy volunteers. In general, assuming that the clearance rate is the same for each dose, the AUC 
(AUC168ss) value for 1 week in the steady state after repeated administration is equal to the AUCinf value when 
the same dose is administered once. 
The planned maximum dose for this study is 0.08 mg/kg. The maximum AUCinf observed in the single dose study 
(HM-GCG-101) administered at this dose was 60,772 ng·h/mL. In addition, when the NOAEL of 0.5 mg/kg (human 
equivalent dose 0.08 mg/kg) in the rat 13-week toxicity evaluation (2018-0265) was repeatedly administered, 
the most conservative AUC0-168h value was 98,300 ng·h/mL at the 13th week. The safety margin of the 
maximum therapeutic dose of 0.08 mg / kg is approximately 1.6 times the most conservative value of the 13-
week AUC0-168h (98,300 / 60,772) in the NOAEL of the rat toxicity assessment at the 13th week. 
The planned starting dose for this study is 0.02 mg/kg. This was calculated in reverse order to achieve the 
maximum planned capacity (0.08 mg/kg) assuming a maximum two-fold of the three planned cohorts, and was 
also selected by considering the minimum effective capacity (ED10) value in the weight loss potency test (Dv-
8088, E2018242) conducted in rats and mice (In the weight loss efficacy test of rats and mice, ED10 was 0.012 
and 0.014 mg/kg respectively converted to equivalent human dose). 
6.3.4. 
Confirmation of dosage and escalation 
 
1) Part 1 
After Cohort 1 randomization is completed, the DMC will assess the safety and will make dosing and cohort 
escalation assessments and recommendations to decide whether subjects can be randomized into Cohort 2. 
Details will be defined in the DMC charter. Dose escalation from cohort 2 to next dose level for the subsequent 
Cohort 3 will be based on the safety, tolerability, available PD, and available PK data obtained from cohort 1 and 
from the 9th subject’s visit on Day 29 in cohort 2.  
The DMC will assess the safety and will make dosing and cohort escalation assessments and recommendations. 
Dose escalation from cohort 3 to next dose level for the subsequent cohort (Cohorts 4 in Part 2) will be based on 


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the safety, tolerability, available PD, and available PK data obtained from cohort 1, 2 and through the 9th subject’s 
visit on Day 29 in cohort 3. An independent Data Monitoring Committee (DMC) will assess the safety and will 
make dosing and cohort escalation assessments and recommendations.  
 
If dose escalation is stopped, dose de-escalation may occur in subsequent cohorts, to further refine clinically 
relevant dose levels. 
The dose of cohorts 3 and 4 can be adjusted, but may not be over the planned dose of 0.08 mg/kg. The escalated 
dose should not be more than 2 times over the dose of the previous cohort.  
In part 2, after the review of the safety data, obtained by the 9th subject’s visit on Day 29 of Cohort 3 (in Part 1), 
Cohort 4 can proceed if within the 0.08 mg/kg dose, which is the planned maximum dose.  
Based on the above, the dose per cohort of this study was planned as the below table. 
Cohorts 
Number of Subjects 
Treatment 
Cohort 1 
N=9 
HM15136 0.02 mg/kg 
N=3 
Placebo 
Cohort 2 
N=9 
HM15136 0.04 mg/kg 
N=3 
Placebo 
Cohort 3* 
N=9 
HM15136 ч0.08 mg/kg 
N=3 
Placebo 
* Dosage of Cohort 3 can be adjusted, but not be over the dosage presented in the table. 
The escalated dose should not be twice over the dose of the previous cohort. 
 
2) Part 2 
If necessary, after the review of the safety data obtained by the 9th subject’s visit on Day29 of Cohort 3 in Part 
1, the cohort can proceed within the 0.08 mg/kg dose, which is the planned maximum dose. 
 
The DMC will assess the safety and will make dosing and cohort escalation assessments and recommendations 
for the study progress of Part 2. 
The maximum dose level for Part 2, Cohorts 5-7 will not exceed 0.06 mg/kg (tentative dose for Cohort 5 may be 
0.02 mg/kg, tentative dose may be 0.04 mg/kg for Cohort 6). This dose level has been previously approved for 
subjects with T2DM. Therefore, the decision to proceed to the next cohort/dose level will be made per review 
of Sponsor, Investigator and Medical Monitor during a Data Review Meeting (DRM) after the 9th subject has 
completed the Day 43 visit.  
Per DRM for Cohort 5 (after the 9th subject’s visit on day 43 of Cohorts 5), a dose escalation to Cohort 6 will not 
proceed at this timepoint and another DRM will be held after all 12 subjects in Cohort 5 have completed the final 
study visit on Day 113 (=F/U Visit), to assess the safety data and to make a decision to escalate to Cohort 6 or not. 
Dose escalation from cohort 6 to the subsequent cohort 7 will follow the same dose escalation scheme and 
DRM(s) of the previous cohort. 
Cohorts 6 and Cohort 7 may be conducted at doses of 0.04 mg/kg and at 0.06 mg/kg respectively upon approval 
by the Investigator, Medical Monitor, and the Sponsor, if the safety is demonstrated in Cohort 5. 
If sufficient safety data are collected after cohort 5 or cohort 6 have been completed, no additional cohorts will 
be conducted, and sponsor may choose to complete study. 
 
 


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Cohorts 
Number of Subjects 
Treatment 
Cohort 4 
(DM) 
N=15 
HM15136 0.06 mg/kg 
N=15 
Placebo 
Cohort 5 
(DM) 
N=9 
,DϭϱϭϯϲчϬ͘ϬϮ-mg/kg 
N=3 
Placebo 
Cohort 6** 
(DM) 
N=9 
HM15136 чϬ͘Ϭϰ-mg/kg 
N=3 
Placebo 
Cohort 7** 
(DM) 
N=9 
,DϭϱϭϯϲчϬ͘Ϭϲ-mg/kg 
N=3 
Placebo 
 
* In part 2, if necessary, after the review of the safety data obtained by the 9th subject’s visit on Day29 of 
Cohort 3 in Part 1, the cohort- can proceed with 0.06 mg/kg dose. 
The dose and study progress of Part 2 should be guided by the recommendations of the DMC. After the 
review of the safety data in Part 1, Part 2 may not proceed. 
** Cohorts 6 and 7 are optional. 
 
6.4. Subjects Identification and Randomization 
6.4.1. 
Screening No. 
The unique subject identification (SID) number will be assigned to all screened subjects. The SID number consists 
of 4 digits and is numbered sequentially from X001 (X is institution‘s number.). The SID number is given in the 
order of subject screening (according to order consent of participation when the screening conducts in the same 
day.). The SID number would be managed from screening to randomization. The subject who has been withdrawn 
from this study prior to randomization and after screening will retain their SID number. 
 
6.4.2. 
Randomization No. 
The subjects enrolled in this study would be assigned randomly to each treatment group. The randomization 
code will be generated by biostatistics staff who are not related to this study, (independent to this study), using 
statistic software (SAS®, latest version) and block randomization method considering the predefined block size.  
Subjects in Part 1 will be assigned to HM15136 and placebo in a 3:1 ratio, in the case of Part 2, up to 66 subjects 
will be assigned to HM15136 and placebo. Thirty (30) subjects in Cohort 4 will be assigned in a ratio of 1:1 and 
12 subjects in each Cohort 5-7 will be in a 3:1 ratio according to rules below in Table 1.  
 
After the signing of informed consent, the investigator assigns the randomization number in the order of subjects 
who meet the in/exclusion criteria and are selected for participation. According to the protocol, the 
randomization number is given on Day -1 or Day -2, prior to administration of IP. The randomization number is 
kept in a limited place accessible only by pharmacy staff and can only be accessed by other personnel if the blind 
is broken. The randomization number includes the 3 digits of subject‘s number as presented in the below table. 


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Table 1. Randomization No. and Treatment Assignment 
 
Part 
Cohort 
Randomization No. 
Treatment Assignment* 
Part 1 
1 
101 - 112 
HM15136 0.02 mg/kg (N=9) 
Placebo (N=3) 
2 
201 - 212 
HM15136 0.04 mg/kg (N=9) 
Placebo (N=3) 
3 
301 - 312 
HM15136 ч0.08 mg/kg (N=9) 
Placebo (N=3) 
Part 2 
4 
401 - 430 
HM15136 0.06 mg/kg (N=15) 
Placebo (N=15) 
5 
501 – 512 
,DϭϱϭϯϲчϬ͘Ϭ2 mg/kg (N=9) 
Placebo (N=3) 
6 
601 – 612 
,DϭϱϭϯϲчϬ͘Ϭ4 mg/kg (N=9) 
Placebo (N=3) 
7 
701 – 712 
,DϭϱϭϯϲчϬ͘Ϭ6 mg/kg (N=9) 
Placebo (N=3) 
 
* In Part 1, dosage of Cohort 3 can be adjusted, but not be over the dosage presented in the table. The escalated dose should not be over 
twice the dose of the previous cohort. 
* In part 2, if necessary, after the review of the safety data obtained by the 9th subject’s visit on Day29 of Cohort 3 in Part 1, the cohort 
can be processed within the 0.06mg/kg dose. 
The dose and study progress of Part 2 should be guided by the recommendations of the DMC. After the review of the safety data in 
Part 1, Part 2 may not proceed. 
 
Once a randomization number has been assigned to one subject, the number cannot be assigned to another 
subject. If subject participation is withdrawn early and the subject is replaced under the direction of the sponsor, 
an alternate randomization number is assigned when the replacement subject successfully completes the 
screening. The randomization number of the replaced subject is generated so that it can be assigned to the same 
treatment group as the discontinued subject. The randomization number is divided into a total 3 digits with a 
‘Cohort No. (1 digit) + Enrollment order (2 digits).’ Iterated randomization numbers are made up of a total 4 digits, 
with ‘1‘ added to the beginning of the randomization number of the subject whose participation is to be 
withdrawn. For example, if replaced the subject 202, the randomization number of the alternative subject would 
be 1202. 
6.5. Blinding and Unblinding 
Although this study is conducted in a double blind, those who are responsible for preparation of IP are excluded. 
These staff are not involved in any other activity in this study. 
 
On a subject level, during the conduct of the study, unblinding may be conducted only for the subject who have 
medical emergencies that can be a problem for the subject’s safety (in the case of knowing the information of IP 
administered to the subject may affect the treatment of the emergency situation), or DLT (Dose limiting toxicity) 
occurred, or for determining whether to increase or decrease dosage as specified in the protocol and/or needed 
for the assessment of the DMC. Except for these reasons, unblinding should not occur on a subject level. The 
investigator must contact the principal investigator and Hanmi Pharm. Co., Ltd. to discuss this issue before the 
unblinding takes place. Emergency unblinding can be performed by the principal investigator using the IWRS. 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. The investigator should record 
the date and reason why unblinding occurred in the CRF 
 
If the investigator, or the staff performing evaluations, or a subject that is not kept in blind, this subject should 
be withdrawn from this study. And if unblinding occurred prior to completion of this study accidently or caused 
by SAE, the investigator should record this issue and provide prompt notice to Hanmi Pharm. Co., Ltd. However, 
if it is judged that the ethical reason or the unblinding effect on the safety of the subject is small, the subject can 
continue to participate in the study in judgement of investigator with Hanmi Pharma. Co., Ltd. 


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Due to COVID-19 outbreak, an interim analysis based on partially validated data for Part 1 will be performed for 
administrative purpose prior to database lock of Part 1. For this planned interim analysis, unblinding will occur 
after partially validated data transfer for Part 1.  
Designated personnel not involved in the study conduct will perform the interim analysis. Only authorized 
members who are listed in the Interim Analysis Unblinding and Information Dissemination Plan will have access 
to review the summary tables or figures of the interim analysis results, in which the information is presented in 
a grouped fashion with the actual treatment, e.g., mean treatment effect. 
 
Unblinding for final analysis of each part will also occur after the corresponding database locks for each Part 1 
and Part 2. The final analysis for each part will be performed separately, once each part is completed. 
For details please see section 11.3.1. Interim Analysis. 
 
 


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7. Completion and Early Discontinuation of the Clinical Trial 
7.1. Study Completion 
The end of entire study termination defines as the last subject’s study completion or the withdrawal of consent, 
follow-up failure, or termination caused by death. If it is judged that each subject completed the procedure of 
administration/visit schedule totally 22 weeks included treatment period for 12 weeks and the follow-up period, 
and evaluation of clinical laboratory test at the last visit, and resolve the AE occurred or proceeding at the last 
visit, or no further follow up is meaningful, that subject is considered to complete the study. 
7.2. Study Discontinuation 
If the investigator or sponsor or medical monitor got to know any situation or events that there is a potential risk 
to the subject if the study was continued, they may be terminated the study after appropriate discussion. Even 
if the above conditions are not met, the study may be terminated according to the sponsor's judgement. If the 
subject’s safety is threatened, the study must be stopped/terminated. The sponsor has the right to terminate 
this study at any time for failure to enroll a targeted number of subjects or for safety or other administrative 
reasons. 
7.3. Dose Escalation and Study Stopping Criteria 
<Dose Escalation Stopping Criteria> 
The procedure for determining the dose is as follows 
 
The main criterion for determining tolerability is emesis/vomiting (=gastrointestinal tolerability). 
 
Vomiting is associated with the pharmacologic administration of GLP-1 agonists and glucagon, and the 
severity of vomiting in this study is defined as.:  
o 
Moderate: 3-5 times vomiting within 24 hours (when the vomiting interval is at a minimum 
of 5 minutes or more, each vomiting event is counted.) 
o 
Severe: 6 times or more within 24 hours or requiring fluid injection via IV (intravenous) 
(when the vomiting interval is at a minimum of 5 minutes or more, each vomiting event is 
counted.) 
 
If one of the following criteria is met, an independent DMC will meet to assess safety in real-time and make 
dosing and cohort escalation assessments and recommendations, such as: IP administration and dose elevation 
should be stopped, or the dose level should be discontinued, suspended, or a dose modification or repetition 
should occur prior to proceeding to subsequent dosing, or dosing can continue. All decisions to increase the dose 
or discontinue dosing will be decided by the DMC. The DMC will determine when the safety and/or tolerance 
limits have been reached.  
1) Moderate or severe emesis occurred in 50% or more subjects in one cohort. 
2) Severe emesis occurred in 25% or more subjects in one cohort. 
3) At any time, if one subject dies (CTCAE grade 5 toxicity may be used as a grading scale) in one cohort. 
4) If severe AEs ;dŐƌĂĚĞш3 may be used as a grading scale) occurred in 2 subjects within one cohort. 
5) If moderate AEs ;dŐƌĂĚĞшϮŵĂǇďĞƵƐĞĚĂƐĂŐƌĂĚŝŶŐƐĐĂůĞͿoccurred in 2 subjects within one 
cohort and persisted for 7 days or more. 
6) If a SAE occurred in 1 subject or more within one cohort. 
7) If clinically significant similar laboratory abnormalities, clinically significant ECG or V/S abnormalities, or 
severe AEs in the same SOC (System organ class) occurred in 2 subjects or more receiving IP 
representing dose limiting toxicity (DLT).  
As the DMC is unblinded, any potential stopping rule event occurring in subjects receiving placebo would not be 
considered to be meet the stopping rule. Additionally, AEs considered to be unrelated to HM15136 would not 
be considered to meet the stopping rules. 


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< Data Monitoring Committee (DMC) > 
The DMC is a specific committee for the study and will function for safety review and dose escalation decisions 
as described above. The operations of the DMC will be defined in the DMC charter. 
The DMC will review safety data (adverse events, clinical laboratory, vital signs and electrocardiograms, and other 
unblinded relevant data). There will be 3 dose decisions. In addition the DMC will have unplanned meetings 
should stopping criteria appear to have been met. 
After Cohort 1 randomization is completed, the DMC will assess the safety and will make dosing and cohort 
escalation assessments and recommendations to decide whether subjects can be randomized into Cohort 2. 
Dose escalation from cohort 2 to next dose level for the subsequent Cohort 3 will be based on the safety, 
tolerability, available PD, and available PK data obtained from cohort 1 and through the 9th subject’s visit on Day 
29 in cohort 2. The DMC will make recommendations for the decision whether subjects can be randomized into 
Cohorts 3. 
The next dose level for the subsequent cohort (Cohorts 4 in Part 2) will be based on the safety, tolerability, 
available PD, and available PK data obtained from cohort 1, 2 and through the 9th subject’s visit on Day 29 in 
cohort 3. An independent Data Monitoring Committee (DMC) will assess the safety and will make dosing and 
cohort escalation assessments and recommendations.  
 
<Data Review Meeting> 
A data review meeting will be held by sponsor, investigator and medical monitor to review safety data after the 
9th subject of cohort 5 and 6 in Part 2 has completed their Day 43 visit. This time point is situated 6 weeks after 
the first dosing. safety data review will guide the decision for dosing and cohort escalation recommendations.. 
Additionally, a second DRM will be held and safety data from the 12th subject’s final visit on Day 113 _(=F/U Visit) 
will be reviewed to dose escalate. 
Dose escalation from cohort 6 to the subsequent cohort 7 will follow the same dose escalation scheme and 
DRM(s) of the previous cohort. 
Cohorts 6 and Cohort 7 may be conducted at doses of 0.04 mg/kg and at 0.06 mg/kg respectively upon approval 
by the Investigator, Medical Monitor, and the Sponsor, if the safety is demonstrated in Cohort 5. 
If sufficient safety data are collected after cohort 5 or cohort 6 have been completed, no additional cohorts will 
be conducted, and sponsor may choose to complete study. 
 
 
< Study Stopping Criteria> 
In addition to the DMC, during the study the investigator and the sponsor may suspend the study after 
appropriate discussion, due to but not limited to, the following situations or events, and submit to the IRB a 
sufficient written statement of reasons for the termination of the study. 
 
1) 
When any obvious or unacceptable risks to the subjects enrolled in this trial are found. 
2) 
If the sponsor decides to suspend or hold the development of IP. 
 
 


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8. Information and Control of Investigational Product 
8.1. Test Product 
Product or Code Name: 
HM15136 
Manufacturer:  
Hanmi Pharmaceutical Co., Ltd. 
Formulation/Properties:  
pre-filled syringe with a clear or almost colorless transparent sterile 
solution 
Raw material/Quantity:  
A synthetic conjugate of a glucagon analogue (GC15136) and a G4 Fc 
portion of human immunoglobulin (HMC001). The concentration is 10 
mg/mL as a protein and the total amount is 0.52 mL. 
Storage:  
Shade storage at 2 - 8 Ȕ refrigerated condition (Stable at room 
temperature for up to 12 hours) 
Expiration date: 
Up to 24 months from date of manufacture 
 
8.2. Comparator 
Product or Code Name: 
Placebo 
Manufacturer:  
Hanmi Pharmaceutical Co., Ltd. 
Formulation/Properties:  
pre-filled syringe with a clear or almost colorless transparent sterile 
solution 
Raw material/Quantity:  
Including excipients excluding the main components of the test product 
Storage:  
Shade storage at 2 - 8 Ȕ refrigerated condition 
Expiration date: 
Up to 24 months from date of manufacture 
 
8.3. Dosage and Administration 
Each administration group will receive either HM15136 or placebo by subcutaneous injection in the abdomen 
after at least 10 hours night fasting state via SC once a week for a total of 12 weeks. Injection sites will be rotated 
within the abdominal area at subsequent visits. 
8.4. Drug Supply, Package, Labelling and Storage 
The IP should be packaged in accordance with local legal requirement, and in accordance with FDA requirements 
and specific country regulatory requirements. 
 
The sponsor should pack the IP so that it is not contaminated or deteriorated during transportation or storage, 
and that packages of the test product and comparator can be easily distinguished according to each batch. The 
packing unit should consider the number of days of each visit and visit window, and provide an extra IP in order 
to prevent discontinuation of IP. 
 
All supplied IP should be stored in shade storage (ie, kept in a box until use) at 2 - 8 Ȕ refrigerated condition in 
accordance with the manufacturer’s guidance. HM15136 is stable at room temperature for up to 12 hours. Until 
delivery to the subject, the IP should be kept in a secure location with locks and accessible only to authorized 
personnel. 
8.5. Manufacture, Prescription, Inventory Management and Disposal/Destruction 
8.5.1. 
Manufacture 
The IP is provided in pre-filled syringes. The dosage of the drug is based on the weight measured on the day 
before the administration (up to two decimal places). The volume to be injected is also determined by the dose 


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CONFIDENTIAL 
 
level. The concentration of HM15136 is 10 mg/mL. The determined injection volume is prepared into the 
administration syringe according to the instructions contained in the pharmacy manual. 
Per COVID-19 modification, weight may be measured on day -2 intead of day -1, and this weight may be used for 
the calculation of the IP dose for the indiviudal subject.  
 
8.5.2. 
Release of IP 
Releasing of IP used for this study should be done on a subject-by-subject basis by the investigator or staff in 
charge of this study, after confirmation of subject eligibility 
 
8.5.3. 
Inventory Management and Record 
The management pharmacist should keep and manage a record of the randomization number, the date of the 
prescription, the number being released, etc., and check the inventory and keep a record of the receipt, storage, 
release, and returning of IP.  
Each IP administered is also recorded. 
Clinical research associate (hereinafter, CRA) for monitoring would regularly review administrative records to 
verify the use of all IP. The investigator is responsible for maintaining an accurate record of the IP management 
during the full period of study. And IP and related products should not be used for purposes other than those 
specified in the protocol.  
The CRU will destroy all used syringes of IP and placebo at the CRU by the end of the study.  
 
At the end of the study, all remaining IP, including unused and partially used IP will be destroyed in a documented 
process after confirmation by the responsible CRA.  


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9. Clinical Trial Methods and Administration Plan 
9.1. Overall Clinical Trial Method 
 
 
An additional data review meeting will be held after all of the 12 subjects in Cohort 5 have completed 
the final study visit (F/U Visit) on Day 113. Cohorts 6 and 7 are optional. 
 
 
Dosage, Method, Period of Investigational product 
The IP will be injected to the subject via SC administration in 3 dose cohorts in Part 1, and in up to 4 cohorts in 
part 2.  
Planned cohorts are below. 
 
Part 
Cohorts 
Number of Subjects 
Treatment 
Part 1 
Cohort 1 
N=9 
HM15136 0.02 mg/kg 
N=3 
Placebo 
Cohort 2 
N=9 
HM15136 0.04 mg/kg 
N=3 
Placebo 
Cohort 3* 
N=9 
HM15136 0.08 mg/kg 
N=3 
Placebo 
Part 2** 
Cohort 4 
N=15 
HM15136 0.06 mg/kg 
N=15 
Placebo 
Cohort 5 
N=9 
HM15136 0.02 mg/kg 
N=3 
Placebo 
Cohort 6 
N=9 
HM15136 0.04 mg/kg 
N=3 
Placebo 
N=9 
HM15136 0.06 mg/kg 


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Cohort 7 
N=3 
Placebo 
* Dosage of Cohort 3 can be adjusted, but not be over the dosage presented in the table. The escalated dose should not be over twice 
than the dose of the previous cohort. 
** In part 2, if necessary, after the review of the safety data obtained by the 9th subject’s visit on Day29 of Cohort 3 in Part 1, cohort can 
proceed within the 0.06 mg/kg dose, which is the planned maximum dose. 
A DMC will assess the safety and will make dosing and cohort escalation assessments and recommendations for the study progress of 
Part 2.  
For cohorts 5-7, after the safety data obtained by the 9th subject on day 43 are reviewed by Sponsor, investigator and medical monitor, 
dose escalation may proceed. An additional DRM will be held after all subjects have completed the dosing for Cohort 5. 
 
Each subject will receive either HM15136 or placebo in the morning of Day 1 in the abdomen, after at least 10 
hours night fasting state, via SC injection. The subject should maintain fasting state for 4 hours after the injection. 
After 4 hours, a post-administration assessment is performed, and a standardized lunch is provided to the subject. 
Per COVID-19 modification, if standardized lunch is not available, subjects may be provided with a snack bag. 
The administration period of IP is a total of 12 weeks at once a week. Dosing windows for in-house and outpatient 
visits will be provided in the Operations Manual. 
9.2. Past medication and Concomitant Medication 
During the period from within 2 weeks before the screening visit to the follow-up visit, antacids, anticoagulants, 
drugs that directly modify gastrointestinal (GI) motility (Anticholinergics, anticonvulsants, serotonin type 3 (5HT3) 
antagonists, dopamine antagonists or opiates) are prohibited unless approved by the sponsor. The use of 
acetylsalicyclic acid (e.g., Bayer® Aspirin) 81 mg/day taken prophylactically is not considered anticoagulation 
therapy for the purposes of this protocol.  During the period from within 3 months before the screening visit to 
the follow-up visit, drugs known to interfere with glucose or insulin metabolism (Use of any drugs regardless of 
oral or parenteral corticosteroids or topiramate, monoamine oxidase (MAO) inhibitors, growth hormone etc.) are 
prohibited unless approved by the sponsor. Any weight control treatments are prohibited, including prescription 
drugs, over the counter drugs, and herbal medications and supplements. 
Acetaminophen/Tylenol® is prohibited 14 days before the in-house stay until a follow-up visit. 
Per COVID-19 modification, Acetaminophen/Tylenol® is prohibited 14 days before the outpatient visit on Day -2 
until a follow-up visit. 
 
Concomitant medications are allowed if the investigator determines that drugs are necessary for the treatment 
of adverse events. 
 
9.3. Treatment Compliance 
IP administration is performed by trained and qualified person designated by the investigator. If any deviations 
occur from the planned dosing procedure, the description is recorded.  
 


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10. Procedure and Assessment of Clinical Trial 
10.1. Visit Schedule 
 
Each subject should have a Screening visit up to 35 days the initial dosage. 
 
Each subject will be in-house 2 times and have 16 outpatient visits, including follow-up visit. Per COVID-
19 modification, visit schedule may be modified to only outpatient visits and phone visits. 
 
10.1.1. Scheduled Visit 
1) Screening  
Provide the subjects with sufficient information (In terms of life limitations including trial visits and diet) 
about their responsibilities and all the procedures anticipated in the study, the risks and benefits of 
HM15136 administration, and their rights during participation in the study. The subject has an opportunity 
to ask questions and has enough time for reflection on their study participation. If the subject wishes to 
participate in the study, the subject is asked to sign the informed consent form (ICF) and the date and time 
will be documented. Site staff must first receive written informed consent from the test subject before 
initiating the procedure. 
 
Subjects who are likely to be selected for this study are required to eat and drink routinely until the 
screening visit. /ĨƐƵďũĞĐƚƐĂƌĞĨĂƐƚŝŶŐ;ŽŶůǇǁĂƚĞƌĨŽƌшϭϬŚŽƵƌƐͿ͕ĂůůƐĐƌĞĞŶŝŶŐĂƐƐĞƐƐŵĞŶƚƐŵĂǇďĞĚŽŶĞŽŶ
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 (eg, laboratory assessments). 
 
The subjects who screen fail can be re-screened once; if the lab results are out of range during the screening, 
they can be retested as needed at the discretion of the investigator. The investigator may also consult with 
the medical monitor about abnormal lab results and retesting.  
 
2) In-house Periods 
At In-house Period 1, after successful completion of the screening visit, only those subjects who meet all 
the inclusion criteria and none of the exclusion criteria should return to the institution on Day -2 and admit 
to the clinical ward. When the first admitted, the following variables are checked. 
1. Alcohol exhalation test 
- 
Check for positive reaction 
2. Drug abuse urine screening 
- 
Check for positive reaction  
3. Pregnancy test for female of child-bearing age (Urine)   
- 
Check for positive reaction 
4. Confirmation of the use of restricted concomitant medication/therapy within 24 hours before the 
admission to the unit (Day -2)  
5. Any medical condition that the investigator judges may interfere with the interpretation of the study 
results or results. The investigator may also consult with the medical monitor.  
 
At check-in for the in-house period, subjects will not be allowed to check in if they meet any of the criteria 
stated above. The in-house period may be rescheduled per Investigator discretion. Variables will be checked 
again. 
Only subjects with T2DM, that will be eligible to participate in Part 2 of the study, will be provided with a 
glucometer for blood glucose control. For details please see the Operations Manual. 
 
Per COVID-19 modification, In-house Period 1 may be performed as outpatient visits. After successful 


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completion of the screening visit, only those subjects who meet all the inclusion criteria and none of the 
exclusion criteria should return to the institution on Day -2 for the outpatient visit, where the following 
variables are checked. 
 
1. Alcohol exhalation test 
- 
Check for positive reaction 
2. Drug abuse urine screening 
- 
Check for positive reaction  
3. Pregnancy test for female of child-bearing age (Urine)   
- 
Check for positive reaction 
4. Confirmation of the use of restricted concomitant medication/therapy within 24 hours before the  
Day -2 Visit.  
5. Any medical condition that the investigator judges may interfere with the interpretation of the study 
results or results. The investigator may also consult with the medical monitor.  
Subjects will not be allowed to continue with the visit if they meet any of the criteria stated above. The visit 
may be rescheduled per Investigator discretion. Variables will be checked again. 
 
 
3) Baseline 
At baseline test (Day -2) after the admission to the unit, review the variables/criteria (only items applicable 
for the in-house stay and prior medication, stated as #1-5 in section above) to confirm the eligibility of the 
subject. The baseline evaluation is conducted from the Day -2 to Day 1, prior to the first dosing. ABP 
monitoring period starts on Day -2 to familiarize the subjects with the device. Measurements from Day -1 
to Day 1 will be taken as baseline assessments. 
Per COVID-19 modification, at baseline test (Day -2) review the variables/criteria stated as #1-5 in section 
above to confirm the eligibility of the subject. The baseline evaluation is conducted from the Day -2 to Day 
1, prior to the first dosing. ABP monitoring period starts on Day -2 to familiarize the subjects with the device. 
Measurements from Day -1 to Day 1 will be taken as baseline assessments. Additionally, Holter monitoring 
will be initiated on Day -2 as well. Measurements from Day -1 to Day 1 will be taken as baseline assessments. 
 
4) Treatment period 
The treatment period is performed over 12 weeks, including the baseline and 2 in-house stays. 
£ In-house 1: The IP will be administered on Day 1, and blood sample collection will be conducted during 
the hospitalization assessment period (until Day 8) for the safety monitoring and PK and PD assessment. 
¤ In-house 2: The subject will return on Day 77 and after admission, the IP will be administered on Day 
78, and blood sample collection will be conducted during the hospitalization assessment period (until 
the Day 82) for the safety monitoring and PK and PD assessment  
Per COVID-19 modification, the treatment period is performed over 12 weeks, including baseline and 
outpatient visits.  
 
5) OPD visits 
The OPD visits will be conducted on Day 10, 11, 15, 17, 18, 22, 29, 36, 43, 50, 57, 64, 71 with safety and 
PK/PD assessments. 
Per COVID-19 modification, all visits may be performed as outpatient visits.  
 
6) Follow up 
The follow up visit will be conducted on Day 85, 99, 113 with safety and PK/PD assessments. 
 


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CONFIDENTIAL 
 
7) End of treatment (EOT) visit 
Subjects who withdraw their consent or withdraw from participation in the study may have an EOT visit as 
soon as possible. The EOT may be performed after withdrawal of the subject’s consent or withdraw from 
participation in the study as soon as possible. The planned evaluation and procedures for the follow-up visit 
on Day 113 may be conducted at the EOT. Specific assessments form the other follow-up visits may be added 
per request, if needed. 
 
 
10.1.2. Unscheduled Visit 
During the study, the subject may be required to attend additional visits separate from the planned visits in the 
study plan, if necessary. For example, if an AE is suspected, or follow up is needed after AE occurrence, conduct 
the necessary tests according to the investigator's judgment. These relevant visits should be recorded in both 
the CRF and source document, and the schedule of the study plan should not be changed due to unscheduled 
visits. 
 
  
10.2. Enrollment and Clinical Evaluation 
10.2.1. Assessment items per visit 
1) Screening (Week -5 to -1) 
(1) Informed consent 
(2) In/Exclusion criteria 
(3) Demographics 
(4) Prior medication and medical history taking 
(5) 12-lead ECG 
(6) Vital signs  
(7) Clinical laboratory test 
༃ Hematology 
༄ Blood chemistry 
༅ Blood coagulation 
༆ Urine analysis 
(8) Infection of HBV, HCV and Anti-body, infection of HIV 
(9) Pregnancy test (Urine) 
(10) Serum FSH (Only Postmenopausal female) 
(11) eGFR 
(12) TSH 
(13) Amylase, Lipase 
(14) Calcitonin 
(15) HbA1c 
(16) Fasting plasma glucose (FPG) 
(17) Fasting insulin, Fasting C-peptide 
(18) Serum lipid profiles 
(19) Physical examination (PE) 
(20) Concomitant medication 
(21) Adverse events 
(22) Drug abuse urine screening and alcohol exhalation test 
(23) Body weight 
(24) Height, BMI 
(25) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 


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CONFIDENTIAL 
 
 
2) Day -2 
(1) In/Exclusion criteria 
(2) PD assessment 
£ FPG 
¤ HbA1c 
(3) 12-lead ECG 
(4) ABP monitoring 
(5) Vital sign 
(6) Clinical laboratory test (not performed in Part 2) 
༇ Hematology 
༈ Blood chemistry 
༉ Blood coagulation 
༊ Urine analysis 
(7) Pregnancy test (Urine) 
(8) Abbreviated PE 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12)  Dietary education and counseling 
(13) Body weight 
(14)  BMI 
(15) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
 
Per COVID-19 modification, Day -2 may include the following assessments: 
(1) In/Exclusion criteria 
(2) Randomization 
(3) PD assessment 
£ MRI/MRI-PDFF, only if available and MRI center can perform assessment 
¤ FPG 
¥ HbA1c 
(4) 12-lead ECG 
(5) Instructions onABP monitoring 
(6) ABP monitoring 
(7) Instructions onHolter monitoring 
(8) Holter monitoring 
(9) Vital sign 
(10) Clinical laboratory test (not performed in Part 2) 
༃ Hematology 
༄ Blood chemistry 
༅ Blood coagulation 
༆ Urine analysis 
(11) Pregnancy test (Urine) 
(12) Abbreviated PE 
(13) Concomitant medication 
(14) Adverse events 
(15) Drug abuse urine screening and alcohol exhalation test 
(16) Dietary education and counseling 
(17) Diet Diary Distribution 


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CONFIDENTIAL 
 
(18) Body weight 
(19) BMI 
(20) Tympanic temperature 
(21) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
(22) Instructions on 7-point SMBG at home 
(23) SMBG Diary Distribution 
(24) Instructions on FBG measurements at home via glucometer 
Per COVID-19 modification, Day -2 has a visit window of ±1 day. 
 
3) Day -1 
(1) Randomization 
(2) PD assessment 
£ MRI/MRI-PDFF 
¤ FPG 
(3) 7-point Self-monitoring of blood glucose (SMBG) 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital sign 
(7) Clinical laboratory test (not performed in Part 2) 
༃ Hematology 
༄ Blood chemistry 
༅ Blood coagulation 
༆ Urine analysis 
(8) Concomitant medication 
(9) Adverse events 
(10) Body weight 
Per COVID-19 modofication, Day -1 may be performed as a phone visit and only the following variables 
may be assessed/will be recorded: 
(1) PD assessment 
£ MRI/MRI-PDFF, only if available and MRI center can perform assessment 
(2) Reminder to perform and record 7-point self-monitoring of blood glucose (SMBG) and bring 
diary to next visit 
(3) Concomitant medication 
(4) Adverse events 
Per COVID-19 modification, Day -1 has a visit window of ±2 day. 
 
 
4) Day 1 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ Fructosamine, Glycated albumin 
¤ FPG 
¥ Fasting insulin, Fasting C-peptide 
¦ HOMA-IR, HOMA-ɴ 
§ Incretins / metabolic hormones 
¨ Amino-acid profile 


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CONFIDENTIAL 
 
© Serum lipid profiles 
ª Inflammatory markers 
« ɴ-hydroxybutyrate 
(4) 7-point SMBG 
(5) ABP monitoring 
(6) Holter monitoring 
(7) Vital signs 
(8) Clinical laboratory test 
༃ Hematology 
༄ Blood chemistry 
༅ Blood coagulation 
༆ Urine analysis 
(9) TSH 
(10) Amylase, lipase 
(11) Calcitonin 
(12) LH, FSH (Only female subject) 
(13) Injection site reactions 
(14) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(15) Concomitant medication 
(16) Adverse events 
(17) Body weight 
(18) BMI 
(19) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
Per COVID-19 modification, Day 1 may have additional assessments: 
(20) Drug abuse urine screening and alcohol exhalation test 
(21) SMBG diary review 
(22) SMBG Diary Distribution 
(23) ABP monitoring data may be downloaded 
(24) Holter monitoring data may be downloaded 
(25) Diet diary distribution 
(26) Diet diary review 
(27) Dietary education 
Per COVID-19 modification, Day 1 has a visit window of ±1 day. 
 
5) Day 2 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 7-point SMBG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test (not performed in Part 2) 
༃ Hematology 
༄ Blood chemistry 
༅ Blood coagulation 
༆ Urine analysis 


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CONFIDENTIAL 
 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
Per COVID-19 modification, Day 2 may be performed as a phone visit and only the following variables may 
be assessed/will be recorded: 
(1) Reminder to perform and record 7-point self-monitoring of blood glucose (SMBG) and bring 
diary to next visit 
(2) Injection site reactions 
(3) Concomitant medication 
(4) Adverse events 
 
 
6) Day 3 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
¥ Incretins / metabolic hormones 
¦ Amino-acid profile 
§ Serum lipid profiles 
¨ Inflammatory markers 
© ɴ-hydroxybutyrate 
(3) 7-point SMBG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
Per COVID-19 modification, Day 3 (±1) may have additional assessments: 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Dietary education 
(15) Glucometer download and/or SMBG Diary Review 
(16) SMBG Diary Distribution 
(17) ABP monitoring data may be downloaded 
(18) Holter monitoring data may be downloaded 
If visit is not feasible on Day 3 (e.g., due to Day 1 being on a Friday), the visit can be moved to the next day 
or previous day and will therefore be combined with the phone visit on the that day (e.g., combined visit 
for Day 3 and Day 4) to keep the schedule for the following visits. If this visit is moved/combined, all other 


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CONFIDENTIAL 
 
visits between the first and second dosing will be performed as scheduled to ensure that weekly dosing 
can be performed as scheduled. 
 
7) Day 4 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 7-point SMBG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test (not performed in Part 2) 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
Per COVID-19 modification, Day 4 may be performed as a phone visit and only the following variables may 
be assessed/will be recorded: 
(1) Reminder to perform and record 7-point self-monitoring of blood glucose (SMBG) and bring 
diary to next visit 
(2) Injection site reactions 
(3) Concomitant medication 
(4) Adverse events 
Per COVID-19 modification, Day 4 has a visit window of ±1 day. 
 
 
8) Day 5 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 7-point SMBG 
(4) 12-lead ECG 
(5) ABP monitoring 
(6) Holter monitoring 
(7) Vital signs 
(8) Clinical laboratory test (not performed in Part 2) 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(9) Injection site reactions 
(10) Concomitant medication 


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CONFIDENTIAL 
 
(11) Adverse events 
Per COVID-19 modification, Day 5 (±1) may have additional assessments: 
(12) Drug abuse urine screening and alcohol exhalation test 
(13) Diet diary distribution 
(14) Diet diary review 
(15) Dietary education 
(16) Glucometer download and/or SMBG Diary Review 
(17) SMBG Diary Distribution 
(18) ABP monitoring data may be downloaded 
(19) Holter monitoring data may be downloaded 
If visit is not feasible on Day 5 (e.g., due to Day 1 being on a Wednesday), visit can be moved to the next 
day or previous day and will be combined with the phone visit on the next day (e.g., Day 6) to keep the 
schedule for the following visits. If this visit is moved/combined, all other visits between the first and 
second dosing will be performed as scheduled to ensure that weekly dosing can be performed as 
scheduled 
 
9) Day 6~7 
(1) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(2) 12-lead ECG 
(3) Vital signs 
(4) Clinical laboratory test (not performed in Part 2) 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(5) Injection site reactions 
(6) Concomitant medication 
(7) Adverse events 
Per COVID-19 modification, Days 6 and 7 may be performed as a phone visit and only the following 
variables may be assessed/will be recorded: 
(1) PD assessment 
£ FBG at home via glucometer 
(2) Reminder to perform and record 7-point self-monitoring of blood glucose (SMBG) and bring 
diary to next visit 
(3) Injection site reactions 
(4) Concomitant medication 
(5) Adverse events 
Per COVID-19 modification, Days 6 and 7 have a visit window of ±1 day. 
 
 
10) Day 8 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 


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CONFIDENTIAL 
 
¥ Incretins / metabolic hormones 
¦ Amino-acid profile 
§ Serum lipid profiles 
¨ Inflammatory markers 
© ɴ-hydroxybutyrate 
(4) 12-lead ECG 
(5) Vital signs 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) Injection site reactions 
(8) Concomitant medication 
(9) Adverse events 
(10) Diet diary distribution 
(11) Body weight 
(12) BMI 
(13) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
(14) Diet Diary Distribution 
(15) Dietary education 
Per COVID-19 modification, Day 8 may have additional assessments: 
(16) Drug abuse urine screening and alcohol exhalation test 
(17) Diet diary review 
(18) Dietary education 
(19) Glucometer download and/or SMBG Diary Review for FPG review that was performed on 
Day 6 
 
 
11) Day 10 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) Vital signs 
(5) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(6) FPG via YSI 
(7) Injection site reactions 
(8) Concomitant medication 
(9) Adverse events 
(10) Drug abuse urine screening and alcohol exhalation test 


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CONFIDENTIAL 
 
(11) Diet diary distribution 
(12) Diet diary review 
(13) Dietary education 
Per COVID-19 modification, Day 10 has a visit window of ±1 day. 
 
12) Day 11 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) Vital signs 
(5) FPG via YSI 
(6) Injection site reactions 
(7) Concomitant medication 
(8) Adverse events 
(9) Drug abuse urine screening and alcohol exhalation test 
(10) Diet diary distribution 
(11) Diet diary review 
(12) Dietary education 
Per COVID-19 modification, Day 11 has a visit window of ±2 days. 
 
13) Day 15(±1) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
¥ Incretins / metabolic hormones 
¦ Amino-acid profile 
§ Serum lipid profiles 
¨ Inflammatory markers 
© ɴ-hydroxybutyrate 
(4) 12-lead ECG 
(5) Vital signs 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) TSH 
(8) Amylase, Lipase 
(9) Calcitonin 
(10) LH, FSH (Only female subject) 
(11) FPG via YSI 
(12) Injection site reactions 


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(13) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(14) Abbreviated PE 
(15) Concomitant medication 
(16) Adverse events 
(17) Drug abuse urine screening and alcohol exhalation test 
(18) Diet diary distribution 
(19) Diet diary review 
(20) Body weight 
(21) BMI 
(22) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
(23) Dietary education 
 
14) Day 17 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) Vital signs 
(5) FPG via YSI 
(6) Injection site reactions 
(7) Concomitant medication 
(8) Adverse events 
(9) Drug abuse urine screening and alcohol exhalation test 
(10) Diet diary distribution 
(11) Diet diary review 
(12) Dietary education 
Per COVID-19 modification, Day 17 has a visit window of ±1 day. 
 
15) Day 18 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) Vital sign 
(5) FPG via YSI 
(6) Injection site reactions 
(7) Concomitant medication 
(8) Adverse events 
(9) Drug abuse urine screening and alcohol exhalation test 
(10) Diet diary distribution 
(11) Diet diary review 
(12) Dietary education 
Per COVID-19 modification, Day 18 has a visit window of ±2 days. 
 
16) Day 22(±2) 
(1) Administration IP 


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CONFIDENTIAL 
 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(4) 12-lead ECG 
(5) Vital sign 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) FPG via YSI 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Body weight 
(15) Dietary education 
 
17) Day 29(±2) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ Fructosamine, Glycated albumin 
¤ FPG 
¥ Fasting insulin, Fasting C-peptide 
¦ Incretins / metabolic hormones 
§ Amino-acid profile 
¨ Serum lipid profiles 
© Inflammatory markers 
ª ɴ-hydroxybutyrate 
(4) 12-lead ECG 
(5) Vital sign 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) TSH 
(8) Amylase, Lipase 
(9) Calcitonin 
(10) LH, FSH (Only female) 
(11) FPG via YSI 


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CONFIDENTIAL 
 
(12) Injection site reactions 
(13) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(14) Abbreviated PE 
(15) Concomitant medication 
(16) Adverse events 
(17) Drug abuse urine screening and alcohol exhalation test 
(18) Diet diary distribution 
(19) Diet diary review 
(20) Body weight 
(21) BMI 
(22) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
(23) Dietary education 
 
18) Day 36(±2) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(4) 12-lead ECG 
(5) Vital sign 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) FPG via YSI 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Body weight 
(15) Dietary education 
 
19) Day 43(±2) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(4) 12-lead ECG 
(5) Vital sign 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 


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Page 88 / 127 
CONFIDENTIAL 
 
¥ Blood coagulation 
¦ Urine analysis 
(7) FPG via YSI 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Body weight 
(15) Dietary education 
 
20) Day 50 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(4) 12-lead ECG 
(5) Vital signs 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) FPG via YSI 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Body weight 
(15) Dietary education 
 
21) Day 57(±2) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ HbA1c 
¤ Fructosamine, Glycated albumin 
¥ FPG 
¦ Fasting insulin, Fasting C-peptide 
§ HOMA-IR, HOMA-ɴ 
¨ Incretins / metabolic hormones 
© Amino-acid profile 


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ª Serum lipid profiles 
« Inflammatory markers 
¬ ɴ-hydroxybutyrate 
(4) 12-lead ECG 
(5) Vital signs 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) TSH 
(8) Amylase, Lipase 
(9) Calcitonin 
(10) LH, FSH (Only female) 
(11) FPG via YSI 
(12) Injection site reactions 
(13) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(14) Abbreviated PE 
(15) Concomitant medication 
(16) Adverse events 
(17) Drug abuse urine screening and alcohol exhalation test 
(18) Diet diary distribution 
(19) Diet diary review 
(20) Body weight 
(21) BMI 
(22) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
(23) Dietary education 
 
22) Day 64(±2) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(4) 12-lead ECG 
(5) Vital signs 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) Injection site reactions 
(8) Concomitant medication 
(9) Adverse events 
(10) Drug abuse urine screening and alcohol exhalation test 
(11) Diet diary distribution 


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CONFIDENTIAL 
 
(12) Diet diary review 
(13) Body weight 
(14) Dietary education 
 
23) Day 71(±2) 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(4) 12-lead ECG 
(5) Vital signs 
(6) Clinical laboratory test 
£ Hematology 
¤ Blood Chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(7) FPG via YSI 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Body weight 
(15) Dietary education 
 
24) Day 77 
(1) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(2) 12-lead ECG 
(3) ABP monitoring 
(4) Vital sign 
(5) Clinical laboratory test (not performed in Part 2) 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(6) Pregnancy test (Urine) 
(7) Injection site reactions 
(8) Abbreviated PE 
(9) Concomitant medication 
(10) Adverse events 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Body weight 


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(13) BMI 
(14) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
(15) Diet diary review 
Per COVID-19 modification, Day 77 may be performed as a phone visit and only the following variables 
may be assessed/will be recorded: 
(1) PD assessment 
£ FBG at home via glucometer 
(2) Injection site reactions 
(3) Concomitant medication 
(4) Adverse events 
Per COVID-19 modification, Day 77 has a visit window of ±1 day. 
 
 
 
25) Day 78 
(1) Administration IP 
(2) PK assessment 
(3) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
¥ Incretins / metabolic hormones 
¦ Amino-acid profile 
§ Serum lipid profiles 
¨ Inflammatory markers 
© ɴ-hydroxybutyrate 
(4) 7-Point SMBG 
(5) ABP monitoring 
(6) Holter monitoring 
(7) Vital sign 
(8) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(9) Injection site reactions 
(10) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(11) Concomitant medication 
(12) Adverse events 
(13) Body weight 
(14) BMI 
(15) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
Per COVID-19 modification, Day 78 may have additional assessments: 
(16) 12-lead ECG 
(17) Pregnancy test (Urine) 
(18) Abbreviated PE 
(19) 7-point SMBG may be partly performed at home 


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(20) Drug abuse urine screening and alcohol exhalation test 
(21) SMBG Diary Distribution 
(22) Diet Diary Distribution 
(23) Diet Diary review 
(24) Dietary education 
(25) 12-lead ECG 
(26) Glucometer download and/or SMBG Diary Review for FPG review that was performed on 
Day 77 
 
 
26) Day 79 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 7-Point SMBG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test (not performed in Part 2) 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
Per COVID-19 modification, Day 79 may be performed as a phone visit and only the following variables 
may be assessed/will be recorded: 
(1) Reminder to perform and record 7-point self-monitoring of blood glucose (SMBG) and bring 
diary to next visit 
(2) Injection site reactions 
(3) Concomitant medication 
(4) Adverse events 
Per COVID-19 modification, Day 79 has a visit window of ±1 day. 
 
 
 
27) Day 80 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
¥ Incretins / metabolic hormones 
¦ Amino-acid profile 
§ Serum lipid profiles 
¨ Inflammatory markers 


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© ɴ-hydroxybutyrate 
(3) 7-Point SMBG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
Per COVID-19 modification, Day 80 (±1) may have additional assessments: 
(11) Drug abuse urine screening and alcohol exhalation test 
(12) Diet diary distribution 
(13) Diet diary review 
(14) Dietary education 
(15) Glucometer download and/or SMBG Diary Reviewfor 7-point profile and FPG review 
(16) SMBG Diary Distribution 
(17) ABP monitoring data may be downloaded 
(18) Holter monitoring data may be downloaded 
If visit is not feasible on Day 80 (e.g., due to Day 1 being on a Wednesday), visit can be moved to the next 
day or previous day and will be combined with the phone visit on the next day (Day 81) to keep the 
schedule for the following visits. If this visit is moved/combined, all other visits after the last dosing will be 
performed as scheduled. 
 
 
28) Day 81 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 7-Point SMBG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test (not performed in Part 2) 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
Per COVID-19 modification, Day 81 may be performed as a phone visit and only the following variables 
may be assessed/will be recorded: 


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(1) Injection site reactions 
(2) Concomitant medication 
(3) Adverse events 
Per COVID-19 modification, Day 81 has a visit window of ±1 day. 
 
 
 
29) Day 82 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) ABP monitoring 
(5) Holter monitoring 
(6) Vital signs 
(7) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(8) Injection site reactions 
(9) Concomitant medication 
(10) Adverse events 
(11) Diet diary distribution 
(12) Dietary education 
Per COVID-19 modification, Day 82 (±1) may have additional assessments: 
(13) Drug abuse urine screening and alcohol exhalation test 
(14) Diet diary distribution 
(15) Diet diary review 
(16) Dietary education 
(17) Glucometer download and/or SMBG Diary Reviewfor 7-point profile and FPG review 
(18) SMBG Diary Distribution 
(19) ABP monitoring data may be downloaded 
(20) Holter monitoring data may be downloaded 
 
 
30) Day 85(±2) 
(1) PK assessment 
(2) PD assessment 
£ MRI/MRI-PDFF (MRI-PDFF only if the liver fat’s MRI-PDFF prior to the first dosing 
showed equal to or more than 10% ΀шϭϬй΁) 
¤ HbA1c 
¥ Fructosamine, Glycated albumin 
¦ FPG 
§ Fasting insulin, Fasting C-peptide 


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¨ HOMA-IR, HOMA-ɴ 
© Incretins / metabolic hormones 
ª Amino-acid profile 
« Serum lipid profiles 
¬ Inflammatory markers 
­ ɴ-hydroxybutyrate 
(3) 12-lead ECG 
(4) Vital signs 
(5) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(6) TSH 
(7) Amylase, Lipase 
(8) Calcitonin 
(9) LH, FSH (Only female) 
(10) Injection site reactions 
(11) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(12) Abbreviated PE 
(13) Concomitant medication 
(14) Adverse events 
(15) Drug abuse urine screening and alcohol exhalation test 
(16) Diet diary review 
(17) Body weight 
(18) BMI 
(19) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
Per COVID-19 modification, MRI/MRI-PDFF, only to be performed if available and MRI center can perform 
assessment. If MRI/MRI-PDFF assessment is not possible during the stated time period, due to COVID- 
restrictions, MRI/MRI-PDFF may be performed at a later timepoint, but prior to the last visit on Day 113. 
 
31) Day 99(±2) 
(1) PK assessment 
(2) PD assessment 
£ FPG 
¤ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) Vital signs 
(5) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(6) Abbreviated PE 
(7) Concomitant medication 
(8) Adverse events 


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(9) Drug abuse urine screening and alcohol exhalation test 
(10) Body weight 
(11) BMI 
(12) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
 
32) Day 113(±2) 
(1) PK assessment 
(2) PD assessment 
£ HbA1c 
¤ Frutosamine, glycated albumin 
¥ FPG 
¦ Fasting insulin, Fasting C-peptide 
(3) 12-lead ECG 
(4) Vital signs 
(5) Clinical laboratory test 
£ Hematology 
¤ Blood chemistry 
¥ Blood coagulation 
¦ Urine analysis 
(6) Pregnancy test (Urine) 
(7) TSH 
(8) Amylase, Lipase 
(9) Calcitonin 
(10) LH, FSH (Only female) 
(11) Immunogenicity (ADAbs, nAbs, anti-PEG) 
(12) Abbreviated PE 
(13) Concomitant medication 
(14) Adverse events 
(15) Drug abuse urine screening and alcohol exhalation test 
(16) Body weight 
(17) BMI 
(18) Waist circumference, Hip circumference, Waist-to-hip ratio (WHR) 
 
10.2.2. Assessment variable 
1) Demographics 
• 
Birth Date 
• 
Gender 
• 
Childbearing 
• 
Ethnicity (Hispanic / Latin American or non-Hispanic / non-Latin American) 
• 
Race (Caucasian, American Indian / Alaska Native, Asian, Hawaiian Aboriginal or other Pacific 
Islander, Black / African American) 
• 
Smoking history 
• 
Caffeine use History (or other beverages with an arousal effect) 
• 
Special meals (vegetarians) 
• 
History of blood donation or plasma donation 
 


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2) Prior medication and medical history taking 
 
Medical history 
 
Medication history 
 
3) Drug abuse urine screening and alcohol exhalation test 
 
Drug abuse history 
 
Alcohol abuse history 
 
4) Physical examination (PE) 
(Complete or Abbreviated) physical examination is performed at the time specified in the assessment 
schedule. 
 
Complete PE (physical examination) includes that assessment of overall appearance and systemic review 
(i.e., skin, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph node, respiratory, cardiovascular, 
gastrointestinal, limb, musculoskeletal, nervous, psychological). 
 
Abbreviated PE (Abbreviated physical examination) includes that assessment of overall appearance and 
skin, cardiovascular, respiratory system and abdomen. Abbreviated PE may lead to a complete PE if it is 
deemed necessary by the investigator. Other assessments may be conducted as the investigator deems 
necessary. 
 
 
Measurement of height taking off the shoes (cm) 
 
Measurement of weight taking off the shoes (kg) (Two decimal places to calculate IP dose for 
study) 
 
Waist circumference (cm) 
 
Hip circumference (cm) 
 
Waist-to-hip ratio (WHR) 
 
Body mass index (kg/m2, BMI, To the first decimal place) 
 
5) Vital Sign 
In the case of visits including a sampling procedure for the assessment of pharmacokinetic parameters, the 
vital sign should be performed before PK Sampling. 
Vital sign is evaluated at the specified schedule, and measures the following: 
 
• 
Supine position BP: Systolic blood pressure (mmHg) and Diastolic blood pressure (mmHg) 
• 
Heart rate (HR) (bpm) 
• 
Respiratory rate (Breath per minute) 
• 
Tympanic temperature (Ȕ) 
 
Supine position BP and HR are should be recorded after taking a rest for at least 5 minutes in supine position. 
 
6) 12-lead ECG 
The 12-lead ECG is performed at the specified schedule (In screening, single evaluation, all other evaluations 
are repeated 3 times.). 


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At the screening visit, a 12-lead ECG is conducted 1 time. All other 12-lead ECGs should be repeated 3 times. 
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. 
 
The 12-lead ECG should be conducted after the subject has rested for at least 5 minutes in a supine position. 
3 times repeated ECGs are each spaced at least 30 seconds apart, but all three ECG measurement times 
should not exceed 2 minutes. The ECG includes all 12 standard derivations and a lead ǥ rhythm strip at the 
bottom of traces. The ECG is recorded on paper at a speed of 25 mm/sec. 
 
The following ECG parameters are collected: 
Ventricular Rate, PR interval, QRS interval, RR interval, QT interval and QT interval corrected for heart rate 
(QTc) (The corrected QTc [QTcF] and QTcF using Fridericia‘s correction formula) 
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. 
 
All ECG must be assessed by a qualified investigator to determine if there is an abnormality. 
 
7) ABP monitoring (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 the overnight period, measurements 
will be taken 1x per hour 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 
2 x per hour during the day and then 1 x per hour during the night. 
The post-dose assessment period will start in the morning of Day 1. Measurements will be taken 2 x per 
hour during the day and then 1 x per hour 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 1 x per hour until the morning of Day 78.  
The post-dose assessment period will start in the morning of Day 78. Measurements will be taken 2 x per 
hour during the day and then 1 x per hour every day (for every 24-hour period), until the morning of Day 82. 
Time points stated in the Study Flow. 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, as well as detailed 
instructions of disconnection of subjects for personal hygiene (shower), blood pressure frequency, data 
management and medical review. 
Per COVID-19 modification, ABPM will be provided for the safety of the subjects but will be moved to 
outpatient setting. Subjects will therefore be provided with personal instructions on site and instructions to 
take home for use and care. 
 
 
8) 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 


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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/ Holter Procedure 
Manual, as well as detailed instructions of data management and medical review. 
Time points stated in the Study Flow. 
Per COVID-19 modification, Holter monitoring will be provided for the safety of the subjects but will be 
moved to outpatient setting. Subjects will therefore be provided with personal instructions on site and 
instructions to take home for use and care. 
 
 
9) Clinical laboratory test 
Clinical laboratory evaluations are performed per specified evaluation schedule, and clinical laboratory tests 
are conducted in the laboratories in accordance with the appropriate laboratory manual. Samples are 
collected in appropriate tubes and processed according to standard laboratory procedures. 
 
< Clinical laboratory assessment> 
 
Hematology 
White blood cell (WBC) count 
Neutrophil: Percent and absolute count 
Red blood cell (RBC) count 
Lymphocyte: Percent and absolute count 
Reticulocyte count 
Monocyte: Percent and absolute count 
Hemoglobin (Hb) 
Eosinophil: Percent and absolute count 
Hematocrit (HCT) 
Basophil: Percent and absolute count 
Mean corpuscular volume (MCV) 
Platelet count 
Mean corpuscular hemoglobin (MCH) 
Red blood cell distribution width (RDW) 
Mean corpuscular hemoglobin concentration (MCHC) 
 
Blood chemistry 
Alanine aminotransferase (ALT) 
Lactate dehydrogenase (LDH) 
Aspartate aminotransferase (AST) 
Phosphorus (P) 
Albumin 
Potassium (K) 
Alkaline phosphatase (ALP) 
Sodium (Na) 
Blood urea nitrogen (BUN) 
Total bilirubin 
Creatinine 
Total protein 
BUN/Creatinine Ratio 
Triglyceride (TG) 
Calcium (Ca) 
Uric acid 
Blood carbon dioxide (CO2) concentration 
Hemoglobin A1c (HbA1c)***** 
Ferritin*  
Fructosamine***** 
Chloride (Cl) 
Glycated albumin***** 
Cholesterol 
Thyroid stimulating hormone (TSH) ***** 
Gamma glutamyltransferase (GGT) 
Estimated Glomerular filtration rate, eGFR)** 
Follicle stimulating hormone (FSH)***  
Amylase***** 
Luteinizing hormone (LH)**** 
Lipase***** 
 
Calcitonin***** 
Blood coagulation 
activated Partial thromboplastin time (PTT) 
International normalized ratio (INR) 
Prothrombin time (PT) 
 
Urine analysis 
pH and urine specific gravity 
Urobilinogen 
White blood cell (WBC) 
Bilirubin 
Albumin (protein) 
Nitrite 


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Glucose  
Color 
Ketones 
Microscopy 
Virus serology 
Hepatitis B core antibody (anti-HBc) 
Hepatitis C antibody (HCVab) 
Hepatitis B surface antigen (HBsAg) 
Human immunodeficiency virus (HIV)  
Urine drug screening 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine 
Cannabinoids 
 
Pregnancy test (urine) 
Beta human chorionic gonadotropin (beta-hCG): All of female 
 
*     Measured on Day 1 prior to administration, Day 57, Day 85. 
**    Conducted only at screening visit 
***   Serum FSH conducted at screening is evaluated only for postmenopausal female subjects. The FSH conducted at the 
specified evaluation schedule after the screening visit is evaluated only for the female subjects for safety evaluation.  
****  The LH conducted at the specified evaluation schedule after the screening visit is evaluated only for the female 
subjects for safety evaluation. 
***** Measured on indicated timepoints of the [STUDY FLOW] table. 
 
All values outside the normal range are flagged for the attention of the investigator or subinvestigator. The 
investigator or subinvestigator indicates whether the value is of clinical significance.  
If the results of any of the tests (or repeat tests if performed) on a sample taken during screening are found 
to be clinically significant, the subject will not be able to participate in the study without permission from 
the medical monitor. If medically necessary, additional tests may be carried out during the test. If a clinically 
significant abnormality is found in the sample collected from the date of signing the consent form to the 
follow-up visit, it should be recorded as an adverse event, and according to the judgement of the 
investigator or subinvestigator, the subjects should receive follow up until the test results are normalized 
or stabilized. Prior to recording an event as AE, it needs to be confirmed/determined that it is not a 
concomitant condition. Concomitant conditions that exists prior to signing the informed consent form (ICF) 
are not considered adverse events unless they worsen during the study. The pre-existing conditions are 
recorded as part of the subject's medical history 
 
10) Fasting Plasma Glucose  
FPG will be measured via YSI in addition to the FPG measure that is included in clinical laboratory 
assessments. The measurement of glucose via YSI should be performed for all subjects and for all 
outpatient visits. Values will be entered in the CRF. 
Per COVID-19 modification, FBG measurements may be performed at home via glucometer by subjects. 
Data will be downloaded from glucometer at the next visit and/or data may be recorded in the SMBG 
diary. Timepoints will follow the SOE for COVID-19. 
 
11) Concomitant medication 
Concomitant medications are collected at each visit. Medications that have been initiated and terminated 
prior to the first dose of IP (Day 1) are collected as the prior medications. 
 
12) Injection site reaction 
Injection site reaction assessments for IP administration are assessed within 30 minutes before dosing and 
at 4 and 12 hours after dosing on Day 1 (time window is 30 min), by a person not involved in the dosing. It 
might be assessed more frequently, eg, after each new dosing, if deemed necessary by the Investigator.  


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Injection site reaction assessments on the day of administration of IP (other than Day 1) are conducted 
within at least 30 minutes after administration. During in-house periods, Injection Site Reactions should be 
evaluated every morning, at the time of last administration of the IP, within a window of ± 30 minutes of 
that administration. At OPD visits without administration of the IP, Injection Site Reactions should be 
evaluated in the morning, at the time of last IP administration within a window of ± 30 minutes of dosing 
time 
The final injection site reaction assessment is conducted on Day 85. 
Per COVID-19 modification, Injection Site Reactions may be evaluated by the subjects on days where a 
phone visit occurs. 
 
 
erythema is evaluated as follows. 
 
0 – None 
 
1 – Very mild erythema (hardly noticeable) 
 
2 – Marked erythema 
 
3 – Moderate to severe erythema 
 
4 – Severe erythema (red like red radish) or some necrotic scabs (deeply damaged)  
 
edema is evaluated as follows. 
 
0 – None 
 
1 – Very mild edema (hardly noticeable) 
 
2 – Mild edema (The edge of the area is clearly raised and the outline is distinct) 
 
3 – Moderate edema (About 1mm raised) 
 
4 – Severe edema (Over 1mm raised and extended beyond exposed area) 
For injection site reaction assessment, all positive reactions are documented as adverse events. Measure 
the diameter of the affected area in centimeters (cm) using a measuring tape and record the condition of 
the injection site. All of the sites where injection site reaction has occurred should be recorded using digital 
photographs. For clinically significant injection site reactions, the subject may be referred to a dermatologist 
or a skin biopsy may be performed for additional histological examination. The biopsy is performed using a 
4 mm punch biopsy around the injection site. Before biopsy is performed, the biopsy site is anesthetized 
with lidocaine. The wound is sealed with a Steristrip suture tape. If it is necessary the wound may be close 
with stitches, stitches will be removed after about 2 weeks. Record the time between injection and biopsy. 
Microscopic examination and histological examination for punch biopsy are performed in a qualified 
laboratory. 
 
13) Pharmacodynamics (PD) assessment 
Measure the MRI/MRI-PDFF test, blood sample collection, and tympanic temperature with 
pharmacodynamic variables. 
 
£ MRI-PDFF  
MRI-PDFF test is used to assess absolute and % changes of liver fat. This test is performed prior to Day -1 
for all eligible subjects (MRI may be performed while Screening calcitonin results are pending). This test 
should be conducted as close as possible to the Day 85 of the 12th week before the Day 85 PK sampling. 
However, on Day 85 of the MRI-PDFF measurement, the MRI-PDFF will only be conducted if the liver fat on 
Day -1 was equal to or greater than 10% ;шϭϬйͿ. 


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Per COVID-19 modification, If MRI/MRI-PDFF assessment is not possible during the stated time period, due 
to COVID- restrictions, MRI/MRI-PDFF may be performed at a later timepoint, but prior to the last visit 
possible, on Day 113. If MRI/MRI-PDFF assessment is not possible due to restricted access of MRI center 
under COVID-19 restrictions, the missing assessment will be documented in the CRFs (specific information 
will be captured that explains the basis of the missing data due to COVID-19). The missing assessment will 
be documented as a protocol deviation (with reason due to COVID-19 stated). 
 
¤ MRI imaging 
The MRI imaging will be used to assess changes in visceral fat volume, determined by absolute and 
relative percent changes. This test is performed prior to Day -1 for all eligible subjects (MRI may be 
performed while Screening calcitonin results are pending). This test should be conducted as close as 
possible to the Day 85 of the 12th week before the Day 85 PK sampling. 
Per COVID-19 modification, If MRI/MRI-PDFF assessment is not possible during the stated time period, due 
to COVID- restrictions, MRI/MRI-PDFF may be performed at a later timepoint, but prior to the last possible 
visit, which is on Day 113. If MRI/MRI-PDFF assessment is not possible due to restricted access of MRI 
center under COVID-19 restrictions, the missing assessment will be documented in the CRFs (specific 
information will be captured that explains the basis of the missing data due to COVID-19). The missing 
assessment will be documented as a protocol deviation (with reason due to COVID-19 stated). 
 
¥ Blood sample collection 
• Incretins/metabolic hormones: Glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), 
glucagon, fibroblast growth factor 21 (FGF 21), leptin. 
 Serum lipid profiles: Total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very 
low-density lipoprotein (VLDL), triglycerides, free fatty acids (FFAs). 
 Amino-acid profile 
 Glucose metabolism parameter: Fasting plasma glucose (FPG), fasting insulin, fasting C-peptide, HbA1c, 
fructosamine, glycated albumin. 
 To confirm insulin resistance: HOMA-IR. 
 To confirm insulin secretion function: HOMA- ɴ. 
 To confirm inflammatory markers: high-sensitive C-reactive protein (hs-CRP), adiponectin. 
 To test the keton bodies: ɴ-hydroxybutyrate.  
 
Blood samples for analysis of the above items are collected at the specified schedule in the evaluation 
schedule and the PD sample collection schedule. When the PK sample collection time is changed, the time 
point of collecting the fasting blood glucose samples can be adjusted between the cohorts. 
Details on the collection, handling and transport of blood samples are separately summarized in the 
laboratory manual. The blood for the sample is processed and the plasma and serum are analyzed using a 
verified assay method. 
 
¦ Temperature tympanic 
The tympanic body temperature for PD assessment is measured along with the vital signs at the specified 
evaluation schedule. Additionally, during the in-house periods, tympanic temperature will be measured  
2 x /24 hours. Exact measuring timepoints and windows will be stated in the Operations Manual. 
Per COVID-19 modification, tympanic temperature will be measured only as stated under the section vital 
signs during the study. 
 
 
§ 7-point profile, Self-monitoring of blood glucose (SMBG) 


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To be measured 15 minutes before the meal (± 10 minutes), 2 hours after the meal starts (± 15 minutes), 
and 15 minutes before the evening snack (± 10 minutes). For the Day 1 and Day 78 SMBG, 5 -point testing 
can be done (exclude tests before and after breakfast), as subjects need to be fasting for 4 hours after 
administration if IP. Details around the assessment of 7-point profiles will be provided in the Operations 
Manual.  
Per COVID-19 modification, subjects will be instructed on how to perform a 7-point profile SMBG at home. 
They will receive instrcutions to take home. A SMBG diary will be distributed to record values. 
 
¨ Fasting condition 
Fasting condition should be maintained about 10 hours when applicable. 
 
© Incretins / metabolic hormones, Inflammatory markers 
All incretins, metabolic hormones, and inflammatory markers are collected at the same time as the PK 
Sampling collection. 
 
14) Immunogenicity (ADAbs, nAbs, anti-PEG) 
The sample blood for assessment of ADAbs, nAbs, anti-PEG should be collected at the specified schedule 
in the evaluation schedule. 
 
15) Pharmacokinetic (PK) assessment 
Blood samples for analysis of HM15136 should be collected at the specified schedule in the evaluation 
schedule and PK sample collection schedule. If PK data are available indicating that other time points would 
be more advantageous, the timing of sample collection for PK analysis may be adjusted between cohorts. 
Details of the collection, handling and transport of blood samples are separately summarized in the 
laboratory manual. The blood for the sample is processed and the serum are analyzed using a verified assay 
method. 
Per COVID-19 modification, PK sampling scheduled may follow the modified PK sampling schedule. 
 
16) Diet diary (distribution, review) 
During the OPD visits (Day 10 through Day 71, Day 77 and 85), check the diet diary of the subject against 
protocol section 10.2.3. (Restrictions), subsection 1, regarding whether or not the eating habits are well 
maintained according to the restrictions on food and beverages. 
The subject will receive diet diary during the outpatient period and will record the diet diary. The prepared 
diet diary will be reviewed and directed at the next outpatient visit. 
Per COVID-19 modification, diet diary distribution will start earlier as study visit schedule was modified to 
OPV days.  
 
17) Dietary education 
Subjects will receive dietary education/nutrition counseling on Day -2, the first day of the in-house period, 
and standardized meals throughout the in-house periods. Weight maintaining diet instructions will be 
repeated after the completion of all examinations to ensure that the subject complies with food and 
beverage restrictions during the OPD visits. Repeat counseling will be performed as stated in Study Flow. 
Per COVID-19 modification, diet education will start earlier, as  study visit schedule was modified to OPV 
days.  
 


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10.2.3. Restrictions 
1) Restriction on food and beverages 
The subjects should fast without taking any food or drink (except water) for at least 10 hours before in-
house periods, OPD visits, or follow-up visits. 
During the in-house periods, a standardized weight maintaining diet will be served to the subjects. 
Subjects should maintain their normal diet after discharge and until the end of the study.  
Therefore, the investigator or the staffs involved in the study should educate the subjects in relation to 
the above items during in-house and OPD visits and check whether the subject complied by checking 
the diet diaries. 
 
Food intake is not allowed within 10 hours before the IP administration and 4 hours after IP 
administration on Day 1 and 78. This question should be recorded by asking the subjects before the IP 
administration. 
 
During In-house periods 1 and 2, meals are served. For details please see the Operations Manual. On 
Day 1 and 78 (the days of IP administration), breakfast is not served to subject and lunch is served after 
4 hours of evaluation/collection. 
Breakfast is served after collecting fasting state samples. 
Foods with grapefruit, pomelo, or seville Orange (including marmalade) or beverages are not allowed 
within 48 hours before, or during the in-house periods. 
Products containing quinine (e.g., carbonated water) are not allowed within 7 days before, or during 
the in-house periods. 
Per COVID-19 modification, standardized meals might not be available and subjects may therefore be 
provided with a snack bag. 
 
 
2) Contraception 
To ensure that female partners of male subjects exposed to clinical trial medications will not get 
pregnant, or to prevent any partner from being exposed to the semen of the male subject, a male 
subject who is not surgically sterile, (defined as at least 1 year after vasectomy), must use an acceptable 
method of contraception from screening visit until 60 days after IP administration. If the subject would 
prefer abstinence, Sexual abstinence must be consistent with a routine lifestyle of sexual inactivity. 
Periodic abstinence [e.g., calendar day, ovulation, symptom-related method or post ovulation method] 
and coitus interruptus is not an acceptable method of contraception). Condoms should be used with 
spermicidal foam/gel/film/cream/ suppository. Contraceptive methods for female partners should also 
be encouraged and are the same as those stated in the section below for female subjects of child-
bearing potential. The contraceptive method must be used for a period of 60 days after administration 
of the IP. The adequacy of other contraceptive methods is assessed by the investigator on a case-by-
case basis. Male subjects with a pregnant female partner at signing of informed consent, may be 
included in the study, as semen of male subject that will be exposed to trial medication cannot lead to 
conception. 
 
Females must be non-pregnant and non-lactating, and either surgically sterile (eg, bilateral tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral ovariectomy) or postmenopausal 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 


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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 childbearing potential do not need to have a serum hCG test at Screening, as urine 
hCG test will be assessed at Screening. 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 with perfect use, including hormonal 
intrauterine devices (coil), oral hormonal contraceptives, sexual abstinence, or a surgically sterilized 
partner. If the subject would prefer abstinence, sexual abstinence must be consistent with a routine 
lifestyle of sexual inactivity. Periodic abstinence [e.g., calendar day, ovulation, symptom-related method 
or post ovulation method] and coitus interruptus is not an acceptable method of contraception). Oral 
hormonal contraceptives have to be taken at least 2 months prior to Screening until 30 days after the 
last Follow-up Visit. The adequacy of other contraceptive methods is assessed by the investigator on a 
case-by-case basis. 
 
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. 
 

3) Alcohol and Caffeine 
Alcohol consumption should be avoided within 48 hours prior to any visit and during the subject's stay 
in the institution. The subjects should not consume more than 3 units of alcohol per days during the 
study period (1 unit is same as about a cup of beer [284 mL], a small cup of wine [125 mL], one standard 
volume of spirits [25 mL], a cup of raw rice wine (Makgeolli)[250 mL]). 
 
Caffeinated food or beverages (e.g., chocolate, coffee, tea, cola, Red Bull) are not allowed within 24 
hours prior to each visit and during the subject's stay in the institution. 
 
4) Smoking and cigarettes 
The heavy smoker (the subject who has daily use of more than 10 cigarettes/day, or 2 cigars/day, or 
equivalent use of any tobacco product) is excluded. The subject must not smoke during the in-house 
periods. 
 
5) Activities and exercises 
The subjects should not do the hard physical training (e.g., long-distance running, weight training, or 
any physical activity outside their usual activities) within 48 hours prior to all test visits and during their 
stay at the hospital. The subjects should not start any new physical training and not raise the training 
intensity beyond their usual amount during the period of participation in this study. However, the 
subject can participate light leisure activity (e.g., watching television, computer game, reading books). 
 


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6) Others 
The subjects should not have donated whole blood (400 mL) within 60 days, or have donated blood 
components (500 mL) within 14 days prior to screening. And after the completion of this study, the 
subjects should not donate blood or plasma (500 mL or more) for at least 3 months. 
The male subjects should not donate sperm throughout the entire study period, and at least 60 days 
after the administration of IP. 
 
10.2.4. Handling of hypersensitivity 
1) Anaphylaxis 
Anaphylaxis is a rapidly progressing systemic severe allergy reaction that is a life-threatening acute immune 
response.  
If symptoms suggesting anaphylactic shock (exacerbation of respiratory symptoms, oligopnea or peripheral 
organ dysfunction due to hypotension, allergic symptoms of skin-mucosal tissues, etc.) are detected within 
a few minutes of the administration of the IP, the IP administration should be stopped immediately, and the 
subject should be rested in supine position and with leg elevation, and avoid the issues caused by dyspnea 
or vomiting. 
The IP administration must be stopped immediately. 
If anaphylactic symptoms are evident, epinephrine IM (intramuscular) injection should be given to the 
median anterolateral side of the thigh. And the laboratory test required to diagnose to anaphylaxis like 
Tryptase etc. can be conducted according to the judgement of the investigator.   
If necessary, treatment for dyspnea such as oxygen supply etc. and treatment for hypotension/shock such 
as intravenous infusion of fluid can be performed, and BP, pulse rate, respiration, and oxygen saturation 
can be monitored. 
 
10.3. Endpoints 
10.3.1. Primary endpoints 
To assess safety and tolerability of HM15136 after repeated subcutaneous (SC) doses for 12 weeks. 
 
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 
of HM15136 [Appendix]. 
 
Incidence of clinical lab abnormalities: 
including serum amylase, serum lipase, coagulation, thyroid stimulating hormone (TSH), serum calcitonin. 
Only for female, LH (Luteinizing hormone) and FSH (follicle stimulating hormone) are additionally included. 
 
Immunogenicity: 
Anti-drug antibodies (ADAbs), neutralizing antibodies (nAbs), anti-polyethylene glycol antibodies (anti-PEG) 
 
Incidence and severity of clinical findings on physical examination 
 
Change from baseline in vital signs: 
Supine position blood pressure (BP), heart rate (HR), respiratory rate, and tympanic temperature 
 
Changes of blood pressure (BP) and heart rate:  
BP assessed by 24-hour ambulatory blood pressure monitoring (ABPM); 
HR assessed by 24-hour ambulatory electrocardiography monitoring (Holter ECG; central reader) 
 
Change from baseline in 12-lead ECG parameters: 
the primary ECG endpoint will be QTcF 
 
Injection site reactions  


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To assess the pharmacokinetic (PK) profile of HM15136 after administration of repeated subcutaneous (SC) doses 
in obese subjects by, but not limited to: 
 
Cmax: Maximum concentration 
 
Tmax: Time to reach Cmax 
 
Ctrough: Trough serum concentration 
 
AUC: Area under the concentration-time curve 
Ex.) AUC0-t: AUC at steady state during the period of injection (AUC0-t at steady state) 
 
Kel: Terminal elimination rate constant 
 
t1/2: Terminal half-life 
 
CL/F: Apparent clearance 
 
Vz/F: Apparent volume of distribution 
 
10.3.2. Exploratory endpoints 
To assess pharmacodynamics (PD) properties of HM15136 after repeated SC doses 
 
Incretins / metabolic hormones 
1) Glucagon-like peptide-1 (GLP-1) 
2) Gastric inhibitory polypeptide (GIP) 
3) Glucagon 
4) Fibroblast growth factor 21 (FGF 21) 
5) Leptin 
 
Serum lipid profiles 
1) Total cholesterol 
2) Low-density lipoprotein (LDL) 
3) High-density lipoprotein (HDL) 
4) Very low-density lipoprotein (VLDL) 
5) Triglycerides 
6) Free fatty acids (FFAs) 
 
Amino-acid profile 
 
Glucose metabolism parameter 
1) Fasting plasma glucose (FPG) 
2) Fasting insulin, Fasting C-peptide 
3) 7-point Self-monitoring of blood glucose (SMBG) 
4) HbA1c 
5) Fructosamine 
6) Glycated albumin 
 
Insulin resistance 
- 
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) 
 
Insulin secretion function 
- 
Homeostatic Model Assessment for ɴ Cell Function (HOMA-ɴͿ 
 
Assessment of absolute and % changes of liver fat via MRI-PDFF (Magnetic resonance imaging-estimated 
proton density fat fraction) 
(However, assessment of liver fat via MRI-PDFF will only be performed on day 85, if the liver fat prior to the 
first dosing  10%) 
 
Changes in visceral fat volume, determined by absolute and relative percent change assessed by MRI 


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 
Body weight 
 
Body mass index (BMI) 
 
Waist circumference 
 
Hip circumference 
 
Waist-to-hip ratio (WHR) 
 
Temperature (tympanic) 
 
Inflammatory markers 
1) High-sensitive C-reactive protein (hs-CRP) 
2) Adiponectin 
 
Keton body 
- 
ɴ-hydroxybutyrate 
 
10.4. Safety assessment 
10.4.1. Adverse Event (AE) 
Reporting of AEs will begin from the date each subject signs an informed consent form (ICF) and will continue 
until the follow-up visit. 
 
10.4.2. Definition of AE 
An ‘Adverse Event (AE)’ is any untoward medical occurrence and unintentional sign, symptom or disease in a 
clinical study, and which does not necessarily have a causality with the IP. Concomitant conditions that existed 
prior to signing the ICF are not considered adverse events unless they worsen during the study. The pre-existing 
conditions are recorded as part of the subject's medical history. 
 
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. 
 
A ‘Suspected adverse reaction’ is defined as 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. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
 
A ‘Serious AE (SAE) refers to any of the following cases.  
1) 
Results in death, Is Life-threatening: This means that the subject was at risk of dying at the time of the 
event and does not mean an event based on the assumption that death could have resulted if the 
symptoms were more severe. 
2) 
Requires inpatient hospitalization or prolongation of existing hospitalization 
3) 
Results in persistent or significant disability/incapacity 
4) 
Is a Congenital anomaly/birth defect 
5) 
Is other important medical event that may require intervention to prevent items # 1 through #4, or 
may expose the subjects to danger, even though the event is not immediately life-threatening or fatal 
or does not result in hospitalization. 
 
Although, important medical events that do not result in death, are not life-threatening, or do not require 
hospitalization, may be considered as SAEs when, based on appropriate medical judgement, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the above listed results. 


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Examples of such medical events include allergic bronchoconstriction requiring intensive treatment in an 
emergency room or clinic room, blood diseases or seizures not causing hospitalization, and the occurrence of 
drug dependence or drug abuse. 
 
Serious AEs and severe AEs should be distinguished. Severity is a measure of intensity, while seriousness is 
defined by the above criteria. For example, if the subject has mild gastrointestinal bleeding and needs overnight 
hospitalization for monitoring, it may consider as a serious AE, but it is not necessarily severe. Likewise, severe 
AEs in terms of intensity are not necessarily serious AEs. For example, alopecia can be assessed as severe by 
intensity, but it is not considered a serious AE. Medical decisions and scientific judgments must be made when 
determining whether the AEs are serious and whether the AEs should be reported rapidly. 
 
Adverse Event of Special Interest (AESI) are selected, non-serious adverse events. They will be reported to the 
sponsor within the same timeline of SAE, using a SAE report form. 
 
The AESI in this study are as follows.  
x 
Necrolytic migratory erythema 
x 
Cholelithiasis 
 
'Unexpected AE‘ refers to an AE pattern or risk outside of the investigator brochure (IB) or product information 
insert etc., that contains available relevant drug information. 
 
‘Treatment emergent adverse event (TEAE)‘ refers to any clinically significant event not present before exposure 
to study drug administration, or any event already present prior to study drug administration, that worsens in 
either intensity or frequency after exposure to the study drug. 
 
The collection of AEs should continue through to the end of follow-up. 
 
10.4.3. Recording of AE 
AEs of each subject should be collected and recorded from the date of signing the ICF until the end of study 
participation (it refers to when the subject either discontinues or completes the study). AEs can be reported 
spontaneously by subject, as well as study staff can discover them from open and non-leading questions (like 
‘How did you feel about your health conditions since I last asked you these questions?’) in the physical 
examination. All AEs and rescue actions should be recorded. The AE characteristics, start date (together with the 
time known), end date (together with time known), severity and action taken should be recorded with the 
seriousness of AE and causality with IP together with assessment of investigator or subinvestigator. 
 
All AEs should be recorded using the language presented to the investigator (verbatim) individually. But this is 
not the case if the AE is already known as part of conditions, disease, or syndrome according to the opinion of 
the investigator. In the latter case, the name of condition or disease or syndrome should be specified rather than 
each individual symptom. The AE would be coded using MedDRA (Medical Dictionary for Regulatory Activities). 
 
10.4.4. Severity of AE 
The investigator assesses the intensity of all AEs in terms of severity in accordance with the following standard 
grade assessment criteria. 
 
1) Mild: It is usually a temporary symptom, not affect the performance of routine daily activities of the 
subject. Usually, no treatment is required. 
2) Moderate: Due to noticeable symptom, the subject feels uncomfortable. It might somewhat affect the 


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performance of the routine daily activities of the subject. Treatment may be required. 
3) Severe: The symptoms induce considerable discomfort. It much affects the performance of the routine 
daily activities of the subject. It may be impossible to continue participating in the study and treatment 
may be required. 
 
10.4.5. Causality with IP 
The investigator will judge the causality between the AE and IP according to reviewing in many ways (e.g., past 
medical history, health conditions, administration time, administration status etc.) following below.  
1) Related 
(1) There is an evidence that the drug has been administered.  
(2) Event or laboratory test abnormality, with plausible time relationship to drug intake.  
(3) The AE is most likely explained by the administration of this drug than any other reason. 
(4) The AE disappears with dechallenge of IP.  
(5) Rechallenge (if available) results are positive. 
(6) The AE is consistent with information already known for this drug or for the same class of drug. 
(7) The administration of this drug is judged to be due to an AE at the same level as other possible causes. 
(8) If more data are needed or an additional material is being reviewed for proper assessment of the 
relevance of this drug to AEs. 
(9) If the information on the causality between the administration of this drug and the AE is insufficient or 
cannot be determined as a conflict, and cannot be supplemented or confirmed. 
 
 
2) Not related 
(1) The subject has not been administered the drug 
(2) Event or laboratory test abnormality, with unreasonable time relationship to drug intake 
(3) There is another obvious cause for AE (e.g., other drug use, latent disease and etc.) and a reasonable 
explanation for the AE is available. 
 
10.4.6. Seriousness 
Severity is a measure of intensity, while seriousness is defined by specified in section 10.4.2. 
 
10.4.7. SAEs and AESI Reporting 
Details of reporting SAEs and AESIs should be referenced in the Safety Management Plan (SMP).  The 
investigator should report to the sponsor or qualified vendor writing a SAE report via fax or e-mail within 24 
hours of recognizing all SAEs and AESIs regardless of their causality with the IP that occurred during the study 
period (the period from the subject’s hospitalization to follow up visit). 
SAEs and AESIs occurring after a follow-up visit (end of the study) should be reported to the sponsor by the 
investigator if the investigator determines that there is a reasonable causality with the IP. 
 
The minimum information required for the initial report as follows. 
 
Report sender (name and contactable No. of investigator) 
 
Subject’s identification (the screening/randomization No., not name of the subject) 
 
Protocol No. 
 
Information of SAE (start/end date, seriousness)  
 
Details of IP (IP dose, frequency, the first administration date, the last administration date) 
 
Assessment of causality 


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However, if available, the initial SAE report should include all of the available information about the SAE, and the 
written SAE report should be sent to sponsor via fax or e-mail.  
Upon receipt of the initial SAE report, the sponsor’s PV department reviews the information and if necessary, 
contacts to the investigator to obtain additional information for the assessment of the events. Details around 
SAE report preparation by Sponsor’s PV department and timeline for submission to ProSciento for review and 
handling will be described in the SMP. 
 
The investigator should report to the sponsor or qualified vendor a follow up report written within 24 hours of 
when conditions of the SAE or AESI have changed (i.e., discharge of post hospitalization, exacerbation of 
conditions) or additional information obtained. Details around SAE report preparation by Sponsor’s PV 
department and timelines for submission to Medical Monitor and sponsor will be described in the SMP. 
 
The investigator is responsible for notifying the IRB about the SAE, and the sponsor or qualified vendor is 
responsible for reporting the SAE to regulatory authorities in accordance with local requirements. 
All serious and unexpected suspected 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. 
 
10.4.8. Follow-up of AE 
AEs experienced by the subject will be monitored regardless of their causality with the IP until the resolution of 
the AE, or all abnormal laboratory results are returned to baseline level, or stabilization to the level allowed by 
the investigator and responsible medical professional, or a satisfactory description of the observed change is 
made, or until follow up of the subject fails 
 
10.4.9. SUSAR (Suspected unexpected serious adverse reaction) 
The sponsor should report any SUSAR to the investigator and FDA until the deadline, according to the following 
categories. The investigator should report to the IRB until the deadline, according to the regulation of the IRB.  
 
Results in death or Life-threatening: The sponsor must notify FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days 
after the sponsor's initial receipt of the information. Other SUSARs: The sponsor must notify FDA of any 
other SUSAR as soon as possible but in no case later than 15 calendar days after the sponsor's initial 
receipt of the information. 
 
10.5. Pregnancy 
The investigator is responsible for reporting all pregnancy events occurring during the study period (from the 
signing the ICF until the follow up visits) to the sponsor and following up. 
Pregnancy only is not considered to be an AE, unless it is suspected that the IP may have interfered with the 
effectiveness of the contraceptives. The choice of abortion should not be considered an AE unless it is purposed 
as treatment. The hospitalization for normal delivery of healthy newborn infants should not be considered a SAE. 
If a female subject receiving the IP becomes pregnant, the investigator should submit to sponsor the Clinical Trial 
Pregnancy Report within 24 hours after recognizing subject’s pregnancy. Even if the subject’s study participation 
is withdrawn or the study is terminated, the investigator should follow up the pregnancy process and results, 
and record. 
The investigator should submit to sponsor the Clinical Trial Pregnancy Report within 24 hours after recognizing 
the pregnancy results (i.e., normal delivery or choice of abortion etc.).  
If a female partner of a male subject receiving the IP becomes pregnant, the investigator will notify the sponsor 
of that pregnancy event within 24 hours of recognizing via fax or e-mail. 


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The investigator should acquire the ICF to share the pregnancy information, and submit to sponsor a ‘clinical trial 
pregnancy report’ within 24 hours, and follow up and notify to sponsor about the process and results of 
pregnancy.  
 
All related SAEs (e.g., serious complication of maternity, abortion purposed to treatment, ectopic pregnancy, 
stillbirth, congenital deformation, birth defect) occurred during the pregnancy should be recorded in template 
of SAE report, and should be reported to sponsor or qualified vendor within 24 hours following the SAE reporting 
process. 
 
10.6. Safety Reporting to Institutional Review Boards (IRBs) or Independent Ethic Committees 
(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. Statistical analysis and statistical consideration 
11.1. General Considerations 
The statistical analysis plan will be provided separately before the first database lock takes place and it will 
describe the details of statistical methods. Violations in the planned analysis will be described in the clinical study 
report (CSR) and will be reviewed for justification. 
 
11.1.1. Population 
The blind meeting will be held to define populations before the random code release. 
 
1) Safety population: Includes all random allocated subjects in the study who received at least one dose 
of study medication (HM15136 or placebo). The subject is included in the analysis depending on the 
cohort of IP in the study. 
 
2) PK (Pharmacokinetic) population: Includes all random allocated subjects who have at least one 
quantifiable HM15136 concentration measurement (without major protocol deviation or violation that 
would have an impact on the absorption, distribution, metabolism or excretion of HM15136). The 
subject is included in the analysis depending on the cohort of IP in the study. 
 
3) PD (Pharmacodynamics) population: Includes all random allocated subjects in the study who received 
at least one dose of study medication (HM15136 or placebo) with sufficient evaluable PD data 
appropriate for the evaluation of interest (without major protocol deviation or violation that would 
have an impact on the PD of HM15136). The subject is included in the analysis depending on the cohort 
of IP in the study. 
 
11.1.2. Handling of Missing Data  
For a missing value occurred due to withdrawal or other reasons before the end of the study after the 
administration of the IP, the imputation method will be defined in the SAP. The missing data pattern of data 
related to COVID-19 will be explored and if needed, an exploratory data analysis (EDA) will be conducted. 
 
11.2. Statistical Analysis 
11.2.1. General Principles of Statistical Analysis 
Continuous data will be summarized using descriptive statistics (number, mean, standard deviation (SD), 
minimum, median, and maximum) for each cohort (but placebo in each cohort/dose level will be combined as 
one group). If applicable, there will be summarized the changes to the baseline. Categorical data will be 
summarized using a frequency table (number, percentage) for each cohort/dose level (but placebo in each 
cohort/dose level will be combined as one group). 
 
11.2.2. Protocol Deviation/Violation 
Protocol violations will be listed by subjects. 
 
11.2.3. Subject participation status 
The subjects to be excluded from the safety population, PK population, and PD population and the excluded data 
will be listed together with the reason for exclusion. Summarize the subject’s participant status by cohort/dose 


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level (but placebo in each cohort/dose level will be combined as one group) but including as below: The number 
of group, percentage, number of subjects who received the IP after randomization, number and percentage of 
subjects who completed a study, number and percentage of subjects who are excluded in a study (describe 
reasons for exclusion). A data of all subjects who random allocated will be presented. 
 
Discontinuation of subject’s participation will be listed by the end date of participation, the period of treatment, 
reasons for discontinuation and the answer to prior consent. 
Provide a list of randomization and include follows: Randomization number, screening number, cohort, Dose 
level that the subject is assigned. 
 
11.2.4. Demographics, Physical examination and Baseline characteristics 
Demographics (age, gender, ethnicity, race) and physical examination (height, weight, BMI) will be listed by each 
subject and summarized about safety population, using each dose level (but, placebo in each cohort/dose level 
will be combined as one group). The denominator of the percentage will be the number of subjects in the safety 
population or the number of all subjects in each cohort/dose level. 
Medical history will be listed by subjects, explanation of disease (or surgery), AE classification using a MedDRA 
(System Organ Class (SOC), preferred term (PT), an onset date and an end date (or in progress). 
 
11.2.5. Prior medication and concomitant medication and Administration of medication  
Prior medications refer to medications that were started and terminated before administration of the IP. 
Concomitant medication refers to medications that were administered after administration of the IP (includes 
the medication that start before the IP and continue to be used together). 
Prior medications and concomitant medications will be listed by each subject. 
Prior medications and concomitant medications will be classified by the latest version of WHO (World Health 
Organization) drug dictionary. 
 
11.2.6. IP administration status 
A list of IP administration including dosing date and time will be generated. 
 
11.2.7. Endpoints 
All demographics, safety data, PK / PD data will be summarized and tabulated with descriptive statistics and/or 
testing statistics. PK data will be presented as graph. PK/PD relationship about IP exposure and exploratory 
evaluation variables will be presented as graph. 
 
1) Adverse events (AEs) 
All of AEs will be listed. The number of subjects and their percentages who meet AEs are tabulated using 
SOC and PT by each cohort/dose level (but, placebo is combined one dose separately). The number of 
subjects and their percentages who meet AEs at least one or more are listed. AEs will be classified by severity 
and related status with IP and will be tabulated. SAEs will be listed separately. 
 
2) Physical examination (PE) 
Abnormalities of physical examination will be listed. 
 
3) Vital signs 


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Changed values of vital signs which are measured from baseline to each visit will be listed by subject. 
Clinically significant abnormalities of vital sign that the investigator assesses as AEs will be presented in the 
AE list. Changed values from baseline to each visit will be tabulated. 
 
4) 12-lead ECG 
The mean and individual values of the 3-time repeated ECG intervals will be listed in each subject and each 
visit, and the mean changes versus the baseline as well as the observed measurement will be presented. 
The observed measurement will be summarized descriptively by table form. The changes versus baseline by 
all of 12-lead ECG data will be summarized descriptively. Categorical QTc analysis will be also performed. 
The primary ECG endpoint will be QTcF. 
 
5) ABPM and Holter ECG 
The 24-hour blood pressure (day and nighttime systolic/diastolic BP) collected from ABPM, and 24-hour 
Holter ECG (endpoints will be defined in the SAP) will be summarized descriptively by cohort/dose level. 
 
6) Laboratory test 
A listing of laboratory values will be provided by subject. Notable values among laboratory values will be 
flagged and will be assessed by the investigator. Clinically significant abnormalities of laboratory values that 
the investigator assesses as AEs will be presented in the AE list. Changed values from baseline to each visit 
will be tabulated. Amino acid labs will not undergo a medical review as these are not needed for safety 
evaluation of the subjects. 
 
7) Assessment of Injection site reaction 
All injection site reactions will be considered as AEs and will be analyzed in the AE analysis. 
 
8) Pharmacodynamics (PD) assessment 
A descriptive summary of the PD assessment will be presented each time point by cohort/dose level (But 
placebo in each cohort/dose level will be combined as one group.). The PD parameters will be summarized 
by cohort/dose level. The association between IP exposure and PD assessment valuables will be analyzed 
by showing pharmacodynamic (PD) graphs or by modeling PK/PD as appropriate. 
 
9) Immunogenicity (ADAbs, nAbs, anti-PEG) 
The result of Immunogenicity (ADA, nAbs, anti-PEG) will be listed by each subject and will be presented and 
will be summarized by cohort/dose level (But placebo in each cohort/dose level will be combined as one 
group.).  
 
10) Pharmacokinetic (PK) assessment 
The concentration-time data of a subject will be listed and will be displayed as a graph from a linear and a 
log scale. Concentration-time data will be summarized as a table and a graph (a linear and a log scale) by 
cohort/dose level. Noncompartmental PK parameters will be analyzed using R, SAS or Phoenix® WinNonlin®. 
The PK parameter data will be listed and will be summarized by cohort/dose level. 
 
Dose proportionality will be assessed using log-transformed PK parameters AUC0-t, AUCinf, Cmax values and a 
linear regression approach to log-transformed dose levels. Dose proportionality will be presented by graph. 
Based on the results of the data review, additional analysis will be conducted if deemed necessary. 
 
11.3. Statistical Analysis Timing and Decision for Sample Sizes 


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11.3.1. Interim analysis 
An interim analysis will be performed for administrative purposes, to aid in the planning of future studies in the 
development program after all healthy subjects in Part 1 have been finalized. Part 1 includes all subjects in cohorts 
1-3. As COVID-19 may lead to challenges in the collection of data, only partially validated data might be available 
for the planned interim analysis. This interim analysis will be performed for administrative purpose prior to 
database lock of Part 1. Unblinding will occur prior to the database lock for Part 1. Designated personnel not 
involved in the study conduct will perform the above stated interim analysis. Only authorized members who are 
listed in the Interim Analysis Unblinding and Information Dissemination Plan will have access to review the 
summary tables or figures of the interim analysis results, in which the information is presented in a grouped 
fashion with the actual treatment, e.g., mean treatment effect. The interim analysis will include an assessment 
of all efficacy, safety, and PK variables of Part 1. 
An additional interim analysis will be performed after database lock for Part 1, which is the final analysis of Part 
1. The final analysis results of part 1 will be included in the final clinical study report (CSR) along with the final 
analysis of Part 2. 
Both analyses for Part 1 may occur, while Part 2 will continue in a blinded fashion. The study will be conducted as 
outlined in this protocol. Part 2 will be performed independently from the conduct/results of the Part 1 and will 
not lead to changes to the conduct of the protocol. After Part 2 (T2DM cohorts) has been completed, a final 
analysis, that only includes the results of Part 2, will be conducted after data base lock of Part 2. 
For details on the interim analysis based on semi-clean data, please refer to the Interim Analysis Unblinding and 
Information Dissemination Plan. 
11.3.2. Confirmation of sample sizes 
This study determined the number of subjects without consideration of statistical validity. The number of 
subjects for the Part 1 will be 12 (HM15136: placebo = 3:1) for each cohort, and for the Part 2 will be 30 for the 
cohort 4 (HM15136: placebo = 1:1), and 12 for cohorts 5-7 (HM15136: placebo = 3:1). This is consistent with the 
typical sample size used in the similar study to evaluate safety and PK. Therefore, 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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12. Data Management 
12.1. Data Recording 
Use the electronic case report form (eCRF), an electronic data collection system, to manage data collection during 
the clinical trials. The eCRF is a software tool designed to ensure quality assurance and facilitate data collection 
during clinical trials. This system complies with the Code of Federal Regulations (CRF) 21 part 11. The investigator 
should record all data that is collected from this study on the e-CRF which Hanmi Pharm. Co., Ltd provides. The 
electronic data capture (EDC) system may only use the person who is authorized and all traces of entry, 
modification, saving and deletion of an e-CRF through the EDC system will be recorded. The investigator 
guarantees that the data of the eCRF entered through electronic signature is accurate, complete, decodable and 
timely. The eCRF created through the EDC system will be delivered to institutions via storing on electronic storage 
media as the copy and stored on the same basis as the other basic documents, after the end of study. 
 
12.2. Data Collection 
All data that are required in a protocol should be collected from an e-CRF and all information are recorded on an 
e-CRF should be matched the Source Document (SD). The collection of data on the CRF must follow the 
instructions described in an e-CRF completion guideline. The investigator is ultimately responsible for collecting 
and reporting all clinical data entered in an e-CRF. After writing an e- CRF, the investigator signs each CRF to 
ensure that the information recorded in the CRF is true. The investigator is finally responsible for the accuracy 
and reliability of all recorded data in the CRF in all cases. 
 
12.3. Data Access 
Hanmi Pharm. Co., Ltd. should establish a security system to prevent all unauthorized access to the database. In 
addition, a list of authorized users needs to be prepared. The completed original CRF is the exclusive property of 
Hanmi Pharm. Co., Ltd., and it cannot be disclosed to a third party without written permission from the Hanmi 
Pharm. Co., Ltd. 
 
12.4. Data Protection and Storage 
Both the Hanmi Pharm. Co., Ltd. and the investigator have responsibilities to archive the study data, including all 
documents for at least 3 years even if the study completed or terminated mandatory. However, the archiving 
period may be extended if it is deemed necessary. 
Hanmi Pharm. Co., Ltd. should notify the investigator and principal of institution as the document about the 
necessity and storage period of the data. If it is judged that there is no need to keep the data, Hanmi Pharma. 
Co., Ltd. should notify the investigator and principal of institution as the document. 


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13. Ethical considerations and administrative procedures 
13.1. Ethical Considerations 
This study will be conducted in accordance with the Protocol , the International Conference on Harmonization - 
Good Clinical Practice (ICH-GCP)10: Consolidated Guidance (E6), the Declaration of Helsinki11 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, in conducting and evaluating the study and recording the results of the study. 
This clinical trial will also be implemented in accordance with national applicable regulatory requirements. 
 
13.2. Informed Consent  
The investigator should give the subject a sufficient opportunity to explain all the details related to the clinical 
trial and to know all the predictable results. The contents of the subject’s consent must be documented. The 
investigator must sign and confirm the subject’s informed consent form. The investigator should not carry out 
any specific examination for the purpose of clinical trial only, until the consent of the subject is obtained. 
 
13.3. IND (Investigational New Drug) Approval 
Protocol and related documents must be reviewed and approved by a properly constituted IRB and the FD. 
 
13.4. Case Report Form (CRF) 
Relevant Documents (RDs) means physician’s records of subjects held by the institutions. Most of RDs is a chart 
of the hospital or physician and all recorded information in the CRF should be matched with the RDs. The case 
record used in this study is eCRF, the development, maintenance and data management of the eCRF is performed 
by the CRO entrusted by Hanmi Pharm. Co., Ltd. The input and modification of the data would be made by the 
authorized subinvestigator by the principal investigator (PI) and final review and signature of the data should be 
done by the PI. The PI signs and ensures that the information recorded in the CRF is true, and the PI is finally 
responsible for the accuracy and reliability of all recorded data in the CRF in all cases. If the input data is modified, 
the revision history is automatically saved, and it is not possible to delete the input data. The eCRF should be 
submitted as a copy if necessary, and Hanmi Pharm. Co., Ltd. should keep it for 3 years from the end of the study. 
 
13.5. Confidentiality 
The names of all subjects should be kept confidential and recorded and evaluated by the number given in the 
clinical trial to identify the subjects. Informs the subject that all clinical trial data will be stored on the computer 
and treated as strictly confidential. The signed subject’s ICF is kept by the PI. The PI should keep the relevant 
records of the subject’s number and name list. The subject’s ICF and the subject’s list should be kept by the 
institution for 3 years from the end of the study. After that consult and determine with Hanmi Pharm. Co., Ltd. 
about storage and management. To prevent errors that may appear, the investigator will contact Hanmi Pharm. 
Co., Ltd. before the discarding the records. 
 
13.6. Knowledge of Protocol 
The Principal Investigator and study staffs have to understand the protocol and then conduct. 
 
 
13.7. Monitoring and Auditing 


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Hanmi Pharm. Co., Ltd. or delegated CRO may perform a Pre-Study Visit (PSV). In order to ensure that clinical 
trials are conducted in accordance with the ICH-GCP, Declaration of Helsinki and other applicable regulatory 
requirements, and the clinical trial may be registered domestic/oversea. Hanmi Pharm. Co., Ltd. or qualified 
designee can conduct monitoring and audit. The principal investigator has agreed to permit the audit by signing 
this protocol. When monitoring this clinical trial, it is necessary to confirm that the case record is complete and 
clear, and can be compared with the original records (source data), and the investigator should cooperate with 
the Hanmi Pharm. Co., Ltd. or qualified designee at any time. 
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. 
Copies of any subject source documents that are provided to the Sponsor must have certain personally 
identifiable information removed. 
Per COVID-19 modification, in case on-site monitoring visits might not be possible, the use of central and remote 
monitoring programs to maintain oversight of clinical sites may be considered.  
 
 
13.8. Recording and Dissemination of Results 
13.8.1. Recording 
1) 
All data collected during this study should be recorded by the investigator in the eCRF provided by Hanmi 
Pharm. Co., Ltd. or designee. 
2) 
Ife data are missing, the investigator should give a reasonable explanation. 
3) 
The final, recorded CRF is signed by the principal investigator. 
4) 
When the modification of the CRF data, original data should be remained, and the information of staff who 
modified the data should be remain too.  
 
13.8.2. Dissemination 
As the signing this protocol, the investigator agrees to use the results of this study for registration, publishment 
and offering this information for medical/pharmaceutical experts, etc. Hanmi Pharm. Co., Ltd. reserves the right 
to review the contents about this study results, before the publishment of this study result in academic magazine 
or journals. 
 
13.9. Protocol Amendment 
Neither the investigator nor Hanmi Pharm. Co., Ltd. can change the protocol during the study without the 
consent of the other party. Once the study has begun, it should be modified only in exceptional cases. When the 
protocol is needed to any modification, all parties involved must be signed and agreed in written. Depending on 
what has been modified, approval from the FDA and/or the IRB may be required. 
 


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14. Other considerations to conduct the clinical trial 
14.1. Institution 
The principal of the institution should prepare perfectly necessary laboratories, facilities, and experts in order to 
conduct the study properly. 
 
14.2. Investigator 
The principal investigator should be fully understood the AEs and precautions specified in this protocol, during 
the study or after the study, the subject should be provided with appropriate medical treatment for any AEs 
(including any clinical significant laboratory abnormal results) occurring in the study. If the subject's 
comorbidities discovered by the investigator are in need of medical treatment, it should be notified to subject. 
In the event of any SAE occurred during clinical trials, it should be reported to the IRB and Hanmi Pharm. Co., 
Ltd. immediately. 
 
14.3. Subinvestigator 
The expected AEs and precautions specified in this protocol should be fully understood in advance, if any SAE 
occurred during the clinical trial, it should be reported to the principal investigator and Hanmi Pharm. Co., Ltd. 
immediately. 
 


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15. References 
 
1. Kim, W. J., & Lee, C. B. (2016). New drugs for obesity treatment. The Korean Journal of Medicine, 90(2), 
121-126. 
2. Lee, Ji Soo, et al. "Effect of weight reduction on obesity-specific quality of life (QOL) in obese subjects." 
The Korean Journal of Obesity 15.2 (2006): 106-113. 
3. Kyoung Kon Kim. (2011). Pharmacotherapy for Obesity. J Korean Med Assoc, 54(4): 409-418. 
4. Young Sil Eom and Byung-Joon Kim. " Glucagon-Like Peptide-1 (GLP-1) Agonist." Korean Journal of 
Medicine 87.1 (2014): 9-13. 
5. Oh, Seungjoon. "Glucagon-like Peptide-1 Analogue and Dipeptidyl Peptidase-IV Inhibitors." Journal of 
Korean Endocrine Society 21.6 (2006): 437-447. 
6. Chun, Hyun-Ji, and Hyuk-Sang Kwon. "Clinical Efficacy of Glucagon Like Peptide-1 (GLP-1) Analogues." 
Journal of Korean Diabetes 14.3 (2013). 
7. Nuffer, W. A., & Trujillo, J. M. (2015). Liraglutide: a new option for the treatment of obesity. 
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 35(10), 926-934. 
8. Korean society for the study of obesity (http://www.kosso.or.kr) 
9. HM15136(LAPSGCG36: Long-Acting Glucagon Analog-HMC001 conjugate) investigator brochure (IB) 
10. International Conference on Harmonization. ICH Harmonized Tripartite Guideline. Good Clinical 
Practice. 01-May-1990. 
11. World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research Involving 
Human Subjects, 64th WMA General Assembly, Fortaleza, Brazil, October 2013. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 [Appendix] Adverse Event Guidance of HM15136 
 
<General Statement> 
As any new investigational product may have unexpected adverse events, the following guidance is offered for 
potential, but unexpected, toxicities for HM15136. 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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Grading* 
Management 
G1: Asymptomatic abnormal cardiac biomarker 
testing, including abnormal ECG 
All grades (G1-G4) 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 
 
 
 


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2. Rash/Inflammatory Dermatitis and Other Skin Disorders  
Definitions:  
 
Erythema multiforme major and minor (a targetoid reaction in the skin and mucous membranes usually 
triggered by infections, such as Herpes Simplex 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)  
 
Lichenoid (resembling the flat-topped, polygonal and sometimes scaly or hypertrophic lesions of lichen 
planus)  
 
Eczematous (Inflammatory dermatitis characterized by pruritic, erythematous, scaly or crusted papules 
or plaques on the skin, which is vulnerable to superinfection) 
 
 Psoriasiform (resembling the well-demarcated, erythematous and scaly papules and plaques of 
psoriasis)  
 
Morbilliform (a 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  
 
Palmoplantar erythrodysaesthesia (PPE) (hand-foot syndrome) (redness, numbness/burning/itching 
and superficial desquamation of the palms and soles)  
 
Neutrophilic dermatoses (e.g. sweet’s syndrome)  
 
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: 
T 
a screening antinuclear antibody test, SSA/Anti-Ro, SS-B/Anti-La 
T 
if predominantly photodistributed/photosensitivity, anti-histone, ds-DNA and other relevant 
serologies. 
T 
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 
 
Review full list of patient medications to rule out other drug-induced cause for photosensitivity 
 
 


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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 
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 
 
 
 
 
 
 


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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: 
T 
bile duct is dilated and/or 
T 
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. 
 
 
 


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CONFIDENTIAL 
 
 
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: 
Statistical Analysis Plan 
Protocol HM-GCG-102 
 
A Phase 1, study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple doses of HM15136 in obese or overweight subjects with comorbidities 
 
Phase 1 
Original Protocol:  
Version 1.0:  23 JULY 2019 
Version 2.0: 28 AUGUST 2019 
Version 3.0: 17 DECEMBER 2019 
Version 4.0: 20 FEBRUARY 2020 
Version 5.0: 20 MAY 2020 
Version 6.0: 29 OCTOBER 2020 
 
Current CRF Version: Version 5.0 (11 JUNE 2020) for Part 2 Study    
Version 6.0 (6 JULY 2020) for Part 1 Study 
 
 
 
Prepared by: ________________________ 
Tim Lin, MS 
Senior Statistician, Statistics 
Pharmapace, Inc. 
 
 
 
Version: Amendment 1 
Date: 8 FEBRUARY 2021 
 
 
Tim Lin, MS
Pharmapace, Inc.
Senior Statistician, Statistics


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
2 
 
Statistical Analysis Plan 
Protocol HM-GCG-102 
A Phase 1, study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple doses of HM15136 in obese or overweight subjects with comorbidities 
 
Phase 1 
Original Protocol: 
 
Version 1.0: 23 JULY 2019 
Version 2.0: 28 AUGUST 2019 
Version 3.0: 17 DECEMBER 2019 
Version 4.0: 20 FEBRUARY 2020 
Version 5.0: 20 MAY 2020 
Version 6.0: 29 OCTOBER 2020 
 
Current CRF Version: Version 5.0 (11 JUNE 2020) for Part 2 Study 
Version 6.0 (6 JULY 2020) for Part 1 Study 
 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
 
 
 
 
 
Date:  
 
OakPil Han 
Director of BioMetrics 
Hanmi Pharmaceutical Co., Ltd. 
 
 
 
Version: Amendment 1  
Date: 8 FEBRUARY 2021 
 
 
OakPil Han
Director of BioMetrics
Hanmi Pharmaceutical Co., Ltd.


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
3 
 
Table of Contents 
List of Abbreviations .................................................................................................................... 6 
1. 
Introduction ...................................................................................................................... 10 
2. 
Study Overview ................................................................................................................ 10 
2.1. 
Study Design ..................................................................................................................... 10 
2.2. 
Randomization and Blinding Procedures ...................................................................... 11 
2.3. 
Sample Size and Power .................................................................................................... 13 
2.4. 
Dose Escalation Stopping Criteria ................................................................................. 13 
2.5. 
Study Stopping Criteria .................................................................................................. 14 
2.6. 
Study Procedures and Visit Structure ........................................................................... 14 
3. 
Study Objectives and Endpoints..................................................................................... 15 
3.1. 
Primary Objectives and Endpoints ................................................................................ 15 
3.1.1. Safety and Tolerability Objectives and Endpoints ....................................................... 15 
3.1.2. Pharmacokinetic Objectives and Endpoints ................................................................. 15 
3.2. 
Exploratory Objectives and Endpoints .......................................................................... 16 
3.2.1. Pharmacodynamic Objectives and Endpoints .............................................................. 16 
4. 
Analysis Populations ........................................................................................................ 17 
4.1. 
Randomized Population .................................................................................................. 17 
4.2. 
Safety Population ............................................................................................................. 17 
4.3. 
Pharmacokinetic Population ........................................................................................... 17 
4.4. 
Pharmacodynamic Population ........................................................................................ 17 
5. 
Study Subjects .................................................................................................................. 18 
5.1. 
Subject Disposition........................................................................................................... 18 
5.2. 
Subject Eligibility ............................................................................................................. 18 
5.3. 
Demographic and Baseline Characteristics ................................................................... 18 
5.4. 
Medical History ................................................................................................................ 18 
5.5. 
Study Drug Administration ............................................................................................ 18 
5.6. 
Extent of Exposure ........................................................................................................... 18 
5.7. 
Prior Medications and Concomitant Medications ........................................................ 19 
5.8. 
Protocol Deviations .......................................................................................................... 19 
6. 
Statistical Methods of Analysis ....................................................................................... 19 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
4 
 
6.1. 
General Considerations ................................................................................................... 19 
6.1.1. Statistical Notation and Presentation ............................................................................. 19 
6.1.2. Study Baseline .................................................................................................................. 20 
6.1.3. Handling of Multiple Observations or Out of Window Observations ........................ 20 
6.1.4. Handling of Missing or Partial Dates ............................................................................. 20 
6.1.5. Handling Outliers and Unquantifiable Measurements ................................................ 21 
6.2. 
Safety Analysis ................................................................................................................. 21 
6.2.1. Adverse Events ................................................................................................................. 21 
6.2.2. Local Tolerability ............................................................................................................. 22 
6.2.3. Clinical Laboratory Assessments ................................................................................... 22 
6.2.4. Vital Signs ......................................................................................................................... 23 
6.2.5. Electrocardiograms.......................................................................................................... 23 
6.2.6. Physical Examination ...................................................................................................... 23 
6.2.7. 24 Hour Ambulatory Blood Pressure Monitoring ........................................................ 23 
6.2.8. 24 Hour Holter ECG Monitoring ................................................................................... 23 
6.2.9. Immunogenicity................................................................................................................ 24 
6.3. 
Pharmacokinetic Analysis ............................................................................................... 24 
6.3.1. HM15136 Pharmacokinetic Concentration Analysis ................................................... 24 
6.3.2. HM15136 Pharmacokinetic Parameter Analysis .......................................................... 24 
6.3.3. Dose Proportionality Analysis ........................................................................................ 24 
6.4. 
Pharmacodynamic Analysis ............................................................................................ 25 
6.4.1. Analysis of Exploratory Incretins/Metabolic Hormone Endpoints ............................ 25 
6.4.2. Analysis of Exploratory Serum Lipid Profiles Endpoints............................................ 26 
6.4.3. Analysis of Exploratory Amino-Acid Profile Endpoint ............................................... 26 
6.4.4. Analysis of Exploratory Glucose Metabolism Parameter Endpoints ......................... 26 
6.4.5. Analysis of Exploratory Homeostatic Model Assessment Endpoints ......................... 26 
6.4.6. Analysis of Exploratory MRI Endpoints ....................................................................... 26 
6.4.7. Analysis of Exploratory Anthropomorphic Measure Endpoints ................................ 27 
6.4.8. Analysis of Tympanic Temperature ............................................................................... 27 
6.4.9. Analysis of Exploratory Inflammatory Markers and Ketone Body Endpoints ......... 27 
7. 
Interim Analysis ............................................................................................................... 27 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
5 
 
8. 
Statistical Software .......................................................................................................... 28 
9. 
References ......................................................................................................................... 28 
10. 
Appendix ........................................................................................................................... 29 
 
 
 
Table 1. Treatment Assignment................................................................................................. 12 
Table 2: Schedule of Events ....................................................................................................... 29 
Table 3: PK Sampling Schedule ................................................................................................ 42 
 
 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
6 
 
Summary of Amendment 1 
Revision/Rationale 
Original Text 
Amended Text 
Change of time point for 
dose escalation from Cohort 
5 to Cohort 6 and 
additional Data Review 
Meeting (DRM) 
Section 2.1 Study Design, 
the last paragraph: 
 
Dose escalation will proceed 
in the same manner for all 
subsequent cohorts. 
 
Original text has been 
replaced with the following 
paragraphs: 
 
Per DRM of Cohort 5 (after 
the 9th subject’s visit on day 
43 of Cohorts 5), a dose 
escalation to Cohort 6 will 
not proceed and another 
DRM will be held after all 12 
subjects in Cohort 5 have 
completed the final study 
visit on Day 113 (=F/U 
Visit), in order to assess the 
safety data. 
Dose escalation from Cohort 
6 to the subsequent Cohort 7 
will follow the same dose 
escalation scheme and 
DRM(s) of the previous 
cohort.  
Cohorts 6 and Cohort 7 may 
be conducted at doses of 0.04 
mg/kg and at 0.06 mg/kg 
respectively upon approval by 
the Investigator, Medical 
Monitor, and the Sponsor, if 
the safety is demonstrated in 
Cohort 5. If sufficient safety 
data are collected after cohort 
5 or cohort 6 have been 
completed, no additional 
cohorts will be conducted, 
and sponsor may choose to 
complete study. 
 
 
 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
7 
 
Revision/Rationale 
Original Text 
Amended Text 
 
Section 2.2 Randomization 
and Blinding Procedure, 
Table 1 footnote: 
 
Cohort 7 will be optional. 
 
Original sentence has been 
revised: 
 
The conduct of Cohorts 6 and 
7 will be optional. 
Section 2.3 Sample Size and 
Power 
 
None 
A new sentence has been 
added: 
 
Note that the conduct of 
Cohorts 6 and 7 will be 
optional. 
 
Section 2.4 Dose Escalation 
Stopping Criteria, the last 
paragraph 
 
None 
A new paragraph has been 
added: 
 
Per DRM of Cohort 5 (after 
the 9th subject’s visit on day 
43 of Cohorts 5), a dose 
escalation to Cohort 6 will 
not proceed and another 
DRM will be held after all 12 
subjects in Cohort 5 have 
completed the final study 
visit on Day 113 (=F/U Visit) 
to assess the safety data. 
As the investigators entered 
repeated vital signs 
measurements differently, a 
decision was made to allow 
unscheduled visits data to 
be included in analysis. 
Section 6.1.3 Handling of 
Multiple Observations or 
Out of Window 
Observations 
 
None 
A new paragraph has been 
added: 
 
For vital signs data, if 
measurements are duplicated 
within the visit window, the 
data from the unscheduled 
visit will be used and the 
average of the scheduled and 
unscheduled visits will be 
taken for summary table. A 
footnote will be added to 
table to highlight the 
exception. 
 
 
 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
8 
 
List of Abbreviations 
ADAbs 
Anti-drug antibodies 
AE 
Adverse event 
ANOVA 
Analysis of Variance 
anti-PEG 
Anti-polyethylene glycol 
ATC 
Anatomic therapeutic chemistry 
AUC 
Area under the curve 
BLQ 
Below limit of quantitation  
BMI 
Body mass index 
CIs 
Confidence Intervals 
CL/F 
Apparent clearance 
Cmax 
Max concentration 
CRF 
Case Report Form 
CSR 
Clinical study report 
Ctrough 
Trough concentration 
CV 
Coefficient of variation 
DLT 
Dose limiting toxicity 
DMC 
Data monitoring committee 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FFAs 
Free fatty acids 
FGF 21 
Fibroblast growth factor 21 
FPG 
Fasting plasma glucose 
GIP 
Gastric inhibitory polypeptide 
GLP-1 
Glucagon-like peptide - 1 
HbA1c 
Hemoglobin A1c 
HDL 
High density lipid 
HOMA-B 
Homeostatic Model Assessment for β Cell 
Function  
HOMA-IR 
Homeostatic Model Assessment for Insulin 
Resistance  
hs-CRP 
High sensitivity c-reactive protein 
IP 
Investigational product 
IRB 
Investigational Review Board 
IV 
Intravenous 
Kel 
Terminal elimination rate constant 
LDL 
Low density lipid 
LS 
Least Squares 
MAD 
Multiple ascending dose 
max 
Maximum 
MedDRA 
Medical dictionary for regulatory affairs 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
9 
 
min 
Minimum 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging – proton density 
fat fraction 
n 
Sample size 
nAbs 
Neutralizing antibodies 
PD 
Pharmacodynamics, pharmacodynamic 
PK 
Pharmacokinetics, pharmacokinetic 
PT 
Preferred Term 
QTcF 
Frederica’s QT corrected interval 
Rdnm 
Ratio of dose normalized geometric means 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard Error 
SMBG 
Self-monitoring of blood glucose 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to max concentration 
TSH 
Thyroid stimulating hormone 
T2DM 
Type 2 diabetes mellitus 
VLDL 
Very low density lipid 
VS 
Vital signs 
Vz/F 
Apparent volume of distribution 
WHO DDE 
World health organization drug dictionary 
WHR 
Waist hip ratio 
 
 
 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
10 
 
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 
HM15136 in obese or overweight subjects with comorbidities. The original statistical analysis 
plan (SAP) was developed based on Hanmi Pharmaceutical Protocol HM-GCG-102 (version 5.0 
dated 20 MAY 2020) and case report form version 5.0 dated 11 JUNE 2020 for Part 2 Study and 
6.0 dated 6 JULY 2020 for Part 1 Study.  
The original SAP was finalized prior to data analyses and before database lock of Part 1 Study. 
The current SAP amendment is created to incorporate contents from protocol version 6.0 (dated 
29 OCTOBER 2020, post Part 1 database lock) regarding the change of time point for dose 
escalation from Cohort 5 to Cohort 6 and additional Data Review Meeting (DRM). The conduct 
of Cohorts 6 and 7 is determined to be optional for Part 2 Study. 
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 double-blind, randomized, placebo controlled, multiple ascending dose (MAD) study to 
investigate the safety, tolerability, PD, and PK of the subcutaneous (SC) administration of 
HM15136 in obese subjects or overweight subjects with co-morbidities. This study will be 
conducted in Part 1 and 2. In Part 1, enrolling 12 subjects per cohort (HM15136 group 9 
subjects, placebo group 3 subjects) will participate, and 3 cohorts will proceed sequentially, but 
may overlap during the conduct. In Part 2, enrolling 30 subjects in Cohort 4 (HM15136 group 15 
subjects, placebo group 15 subjects) will participate, and up to 3 additional cohorts may proceed 
with 12 subjects per Cohorts 5-7 (HM15136 group 9 subjects, placebo group 3 subjects). 12 
subjects per cohort assigned to Part 1 and Part 2 will be randomized to HM15136 and placebo in 
a ratio of 3:1, and 30 subjects per Cohort 4 assigned to Part 2 will be randomized to HM15136 
and placebo in a ratio of 1:1. The final analysis for each part will be performed separately once 
each part is complete. Due to COVID-19 outbreak, an interim analysis based on partially 
validated data for Part 1 will be performed for administrative purpose prior to database lock of 
Part 1.  
After Cohort 1 randomization is completed, the Data Monitoring Committee (DMC) will assess 
the safety and will make dosing and cohort escalation assessments and recommendations to 
decide whether subjects can be randomized into Cohort 2. Details will be defined in the DMC 
charter.  


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
11 
 
Dose escalation from Cohort 2 to next dose level for the subsequent Cohort 3 will be based on 
the safety, tolerability, available PD, and available PK data obtained from Cohort 1 and through 
the 9th subject’s visit on Day 29 in Cohort 2. An independent DMC will assess the safety and 
will make dosing and cohort escalation assessments and recommendations.  
The next dose level for the subsequent cohort (Cohort 4 in Part 2) will be based on the safety, 
tolerability, available PD, and available PK data obtained from Cohort 1, 2 and through the 9th 
subject’s visit on Day 29 in Cohort 3. An independent DMC will assess the safety and will make 
dosing and cohort escalation assessments and recommendations. If dose escalation is stopped, 
dose de-escalation may occur in subsequent cohorts, to further refine clinically relevant dose 
levels.  
The dose of Cohorts 3 and 4 can be adjusted, but may not be over the planned dose of 0.08 
mg/kg. The escalated dose should not be more than 2 times over the dose of the previous cohort. 
In Part 2, after the review of the safety data, obtained by the 9th subject’s visit on Day 29 of 
Cohort 3 (in Part 1), Cohort 4 can proceed with a dose of ≤ 0.08 mg/kg dose, which is the 
planned maximum dose.  
A DMC will assess the safety and will make dosing and cohort escalation assessments and 
recommendations for the study progress of Part 2. After the review of the safety data in Part 1, 
Part 2 may or may not proceed. Cohort 4 may be conducted with a lower number of subjects. 
Cohort 5 may start immediately and may overlap with the conduct of subjects in Cohort 4. 
In Part 2, dose escalation from Cohort 5 to the subsequent Cohort 6 will be made after a DRM, 
held by Sponsor, Investigator and Medical Monitor, and the safety data obtained from the 9th 
subject’s visit on Day 43 (=after 6 weeks of dosing) will be reviewed.  Per DRM of Cohort 5 
(after the 9th subject’s visit on day 43 of Cohorts 5), a dose escalation to Cohort 6 will not 
proceed and another DRM will be held after all 12 subjects in Cohort 5 have completed the final 
study visit on Day 113 (=F/U Visit), in order to assess the safety data. 
Dose escalation from Cohort 6 to the subsequent Cohort 7 will follow the same dose escalation 
scheme and DRM(s) of the previous cohort.  
Cohorts 6 and Cohort 7 may be conducted at doses of 0.04 mg/kg and at 0.06 mg/kg respectively 
upon approval by the Investigator, Medical Monitor, and the Sponsor, if the safety is 
demonstrated in Cohort 5. If sufficient safety data are collected after cohort 5 or cohort 6 have 
been completed, no additional cohorts will be conducted, and sponsor may choose to complete 
study. 
2.2. Randomization and Blinding Procedures 
The subjects enrolled in this study would be assigned randomly to each treatment group. 
Subjects in Part 1 will be assigned to HM15136 and placebo in a 3:1 ratio, in the case of Part 2, 
up to 66 subjects will be assigned to HM15136 and placebo. Thirty subjects in Cohort 4 will be 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
12 
 
assigned to HM15136 and placebo in a ratio of 1:1, and 12 subjects in Cohorts 5 to 7 will be 
assigned to HM15136 and placebo in a 3:1 ratio according to rules below in Table 1. 
Table 1. Treatment Assignment 
Part 
Cohort 
Treatment Assignment* 
Part 1 
1 
HM15136 0.02 mg/kg (N=9) 
Placebo (N=3) 
2 
HM15136 0.04 mg/kg (N=9) 
Placebo (N=3) 
3 
HM15136 ≤0.08 mg/kg (N=9) 
Placebo (N=3) 
Part 2 
4 (DM) 
HM15136 0.06 mg/kg (N=15) 
Placebo (N=15) 
5 (DM) 
HM15136 ≤0.02 mg/kg (N=9) 
Placebo (N=3) 
6 (DM) 
HM15136 ≤0.04 mg/kg (N=9) 
Placebo (N=3) 
7 (DM) 
HM15136 ≤0.06 mg/kg (N=9) 
Placebo (N=3) 
* In Part 1, dosage of Cohort 3 can be adjusted, but not be over the dosage presented in the table. 
The escalated dose should not be over twice the dose of the previous cohort. 
* In Part 2, if necessary, after the review of the safety data obtained by the 9th subject’s visit on 
Day 29 of Cohort 3 in Part 1, the Cohorts 4 to 7 can proceed within the doses in Table 1. The 
dose and study progress of Part 2 should be guided by the recommendations of the DMC. After 
the review of the safety data in Part 1, Part 2 may or may not proceed. The conduct of Cohorts 6 
and 7 will be optional. 
Due to COVID-19 outbreak, an interim analysis based on partially validated data for Part 1 will 
be performed for administrative purpose prior to database lock of Part 1. For this planned interim 
analysis, unblinding will occur after partially validated data transfer for Part 1. Designated 
personnel not involved in the study conduct will perform the interim analysis. Only authorized 
members who are listed in the Interim Analysis Unblinding and Information Dissemination Plan 
will have access to review the summary tables or figures of the interim analysis results, in which 
the information is presented in a grouped fashion with the actual treatment, e.g., mean treatment 
effect. 
Unblinding for final analysis of each part will also occur after the corresponding database locks 
for each Part 1 and Part 2. The final analysis for each part will be performed separately, once 
each part is completed. For the second planned interim analysis described in Section 7, 
unblinding will occur after database lock for Part 1, to analyze the data from all healthy subjects 
(i.e. data from completed Cohorts 1-3). The study will proceed as planned with Part 2 in a 
blinded fashion. Otherwise, unblinding may be conducted only for the subject who have medical 
emergencies that can be a problem for the subject’s safety (in the case of knowing the 
information of IP administered to the subject may affect the treatment of the emergency 
situation), or DLT (Dose limiting toxicity) occurred, or for determining whether to increase or 
decrease dosage as specified in the protocol. Except for these reasons, unblinding should not 
occur. The investigator must contact the principal investigator and Hanmi Pharm. Co., Ltd. to 
discuss this issue before unblinding takes place. Emergency unblinding can be performed by the 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
13 
 
principal investigator using the IWRS. It should be ensured that no study personnel are 
unblinded to other subjects. Study site personnel directly associated with the conduct of the study 
will not be unblinded. The investigator should record the date and reason why unblinding 
occurred in the CRF. 
If the investigator, or the staff performing evaluations, or a subject that is not kept in blind, this 
subject should be withdrawn from this study. And if unblinding occurred prior to completion of 
this study accidently or caused by SAE, the investigator should record this issue and provide 
prompt notice to Hanmi Pharm. Co., Ltd. However, if it is judged that the ethical reason or the 
unblinding effect on the safety of the subject is small, the subject can continue to participate in 
the study in judgement of investigator with Hanmi Pharma. Co., Ltd. 
2.3. Sample Size and Power 
This study determined the number of subjects without consideration of statistical validity. The 
number of subjects for the Part 1 will be 12 (HM15136: placebo = 9:3) for each cohort, and for 
the Part 2 will be up to 66, 30 for Cohort 4 (HM15136: placebo = 15:15) and 12 for Cohorts 5-7 
(HM15136: placebo = 9:3). This is consistent with the typical sample size used in the similar 
study to evaluate safety and PK. Therefore, no formal sample size calculation will be performed. 
Note that the conduct of Cohorts 6 and 7 will be optional. 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. 
2.4. Dose Escalation Stopping Criteria 
The procedure for determining the dose is as follows 
• 
The main criteria for determining tolerability is emesis/vomiting (=gastrointestinal 
tolerability). 
• 
Vomiting is associated with the pharmacologic administration of GLP-1 agonists and 
glucagon, and the severity of vomiting in this study is defined as: 
o Moderate: 3 -5 times vomiting within 24 hours (when vomiting interval is at a 
minimum 5 minutes or more, each vomiting event is counted.) 
o Severe: 6 times or more within 24 hours or requiring fluid injection via IV 
(intravenous) (when the vomiting interval is at a minimum 5 minutes or more, 
each vomiting event is counted.) 
If one of the following criteria is met, an independent DMC will meet to assess safety in real-
time and make dosing and cohort escalation assessments and recommendations, such as: IP 
administration and dose elevation should be stopped, or the dose level should be discontinued, 
suspended, or a dose modification or repetition should occur prior to proceeding to subsequent 
dosing, or dosing can continue. All decisions to increase the dose or discontinue dosing will be 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
14 
 
decided by the DMC. The DMC will determine when the safety and/or tolerance limits have 
been reached. 
1) Moderate or severe emesis occurred in 50% or more subjects in one cohort. 
2) Severe emesis occurred in 25% or more subjects in one cohort. 
3) At any time, if the subject dies (CTCAE grade 5 toxicity may be used as a grading scale) 
in one cohort. 
4) If severe AEs (CTCAE grade ≥3 may be used as a grading scale) occurred in 2 subjects 
within one cohort. 
5) If moderate AEs (CTCAE grade ≥2 may be used as a grading scale) occurred in 2 
subjects within the one cohort for 7 days or more. 
6) If a SAE occurred in 1 subject or more within the one cohort. 
7) If clinically significant similar laboratory abnormalities, clinically significant ECGs or 
V/S abnormalities, or severe AEs in the same SOC (System organ class) occurred in 2 
subjects or more receiving IP representing dose limiting toxicity (DLT). 
As the DMC is unblinded, any potential stopping rule event occurring in subjects receiving 
placebo would not be considered as meeting the stopping rule. Additionally, AEs considered to 
be unrelated to HM15136 would not be considered as meeting the stopping rules. 
A data review meeting will be held by sponsor, investigator and medical monitor to review 
safety data after the 9th subject of Cohorts 5 and 6 in Part 2 has completed their Day 43 visit. 
This time point is situated 6 weeks after the first dosing. Safety data review will guide the 
decision for dosing and cohort escalation recommendations.  
Per DRM of Cohort 5 (after the 9th subject’s visit on day 43 of Cohorts 5), a dose escalation to 
Cohort 6 will not proceed and another DRM will be held after all 12 subjects in Cohort 5 have 
completed the final study visit on Day 113 (=F/U Visit) to assess the safety data.  
2.5. Study Stopping Criteria 
In addition to the DMC, during the study the investigator and the sponsor may suspend the study 
after appropriate discussion, due to but not limited to, the following situations or events, and 
submit to the IRB a sufficient written statement of reasons for the termination of the study. 
1) When any obvious or unacceptable risks to the subjects enrolled in this trial are found. 
2) If the sponsor decides to suspend or hold the development of IP. 
2.6. Study Procedures and Visit Structure 
In the appendix, Table 2 describes the procedures and visit structure for this study. The PK 
sample schedule is also in the appendix as Table 3 and Table 4. 


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
15 
 
3. Study Objectives and Endpoints 
3.1. Primary Objectives and Endpoints 
3.1.1. Safety and Tolerability Objectives and Endpoints 
To assess safety and tolerability of HM15136 after multiple subcutaneous doses for 12 weeks by 
assessing: 
x Incidence of adverse events: 
o Potential unexpected adverse events include: cardiovascular events, 
rash/inflammatory dermatitis and other skin disorders, gastrointestinal events, and 
gallstone formation. 
x Incidence of clinical lab abnormalities: 
o Including serum amylase, serum lipase, coagulation, thyroid stimulating hormone 
(TSH), serum calcitonin. Only for female, LH (Luteinizing hormone) and FSH 
(follicle stimulating hormone) are additionally included. 
x Immunogenicity: Anti-drug antibodies (ADAbs), neutralizing antibodies (nAbs), and 
anti-polyethylene glycol antibodies (anti-PEG) 
x Incidence of clinically significant physical examination findings 
x Change from baseline in vital signs: 
o Supine position blood pressure 
o Heart Rate 
o Respiratory rate 
o Tympanic temperature 
x Change from baseline in blood pressure assessed by 24-hour ambulatory blood pressure 
monitoring 
x Change from baseline in heart rate assessed by 24-hour ambulatory electrocardiography 
monitoring (Holter ECG) 
x Change from baseline in 12-lead electrocardiogram parameters: 
o Primary electrocardiogram endpoint: QT corrected QTcF 
x Presence of injection site reactions 
3.1.2. Pharmacokinetic Objectives and Endpoints 
To assess the PK profile of HM15136 after administration of multiple subcutaneous doses in 
obese subjects by, but not limited to: 
x Cmax: maximum concentration 
x Tmax: time to reach Cmax 
x Ctrough: trough serum concentration 
x AUC: area under the concentration-time curve 
o AUC0-t  
o AUCinf  


                        
 
 
HM-GCG-102 Statistical Analysis Plan 
 
 
16 
 
x Kel: terminal elimination rate constant 
x t1/2: terminal half-life 
x CL/F: apparent clearance 
x Vz/F: apparent volume of distribution 
x AR: accumulation ratio 
3.2. Exploratory Objectives and Endpoints 
3.2.1. Pharmacodynamic Objectives and Endpoints 
To evaluate the PD properties of HM15136 after multiple subcutaneous doses by assessing: 
x Change from baseline in incretins/metabolic hormones: 
o Glucagon-like peptide-1 (GLP-1) 
o Gastric inhibitory polypeptide (GIP) 
o Glucagon 
o Fibroblast growth factor 21 (FGF 21) 
o Leptin 
x Change from baseline and percent change from baseline in serum lipid profiles: 
o Total cholesterol 
o Low-density lipoprotein (LDL) 
o High-density lipoprotein (HDL) 
o Very low-density lipoprotein (VLDL) 
o Triglycerides 
o Free fatty acids (FFAs) 
x Change from baseline in amino-acid profile 
x Change from baseline in glucose metabolism parameters: 
o Fasting plasma glucose (FPG) 
o Fasting insulin, Fasting C-peptide 
o 7-point Self-monitoring of blood glucose (SMBG) 
o HbA1c 
o Fructosamine 
o Glycated albumin 
x Change from baseline in insulin resistance: 
o Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) 
x Change from baseline in insulin secretion function: 
o Homeostatic Model Assessment for β Cell Function (HOMA-β) 
x Change from baseline (absolute) and percent change from baseline (relative) of liver fat 
via magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) 
(However, assessment of liver fat via MRI-PDFF will only be performed on day 85, if the 
liver fat prior to the first dose is ≥ 10%) 
x Change from baseline and percent change from baseline in visceral fat volume, 
determined by absolute and relative percent change assessed by MRI 


                        
 
 
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x Change from baseline and percent change from baseline in anthropomorphic measures: 
o Body weight 
o Body mass index (BMI) 
o Waist circumference 
o Hip circumference 
o Waist-to-hip ratio (WHR) 
x Change from baseline in tympanic temperature 
x Change from baseline in Inflammatory markers: 
o High-sensitive C-reactive protein (hs-CRP) 
o Adiponectin 
x Change from baseline in ketone bodies: 
o β-hydroxybutyrate 
4. Analysis Populations 
4.1. Randomized Population 
The randomized population will include all randomized subjects in the study. The randomized 
population will be used for disposition and analysis population summaries and listings.  
4.2. Safety Population 
The safety population will include all randomized subjects in the study who received at least one 
dose of study medication, HM15136 or placebo. Subjects will be analyzed based on the actual 
treatment they received during the study. The safety population will be used for demographic, 
baseline characteristics, subject eligibility and safety summaries. 
4.3. Pharmacokinetic Population 
The PK population will include all randomized subjects who have at least one quantifiable 
HM15136 concentration measurement without important protocol deviations or violations that 
would have impact on the absorption, distribution, metabolism or excretion of HM15136. The 
PK population will be used for PK concentration and PK parameter summaries. As the study is 
double-blinded, a memo will be prepared to select the PK population based on dummy subject 
ID prior to treatment unblinding of Part 1 and Part 2. 
4.4. Pharmacodynamic Population 
The PD population will include all randomized subjects who have received at least one dose of 
study medication, HM15136 or placebo with sufficient evaluable PD data appropriate for the 
evaluation of interest without important protocol deviation or violation that would have an 
impact on the PD of HM15136. The PD population will be used for PD assessment and PD 
parameter summaries. Determination of the PD population will be documented in a memo prior 
to treatment unblinding of Part 1 and Part 2. 


                        
 
 
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5. Study Subjects 
5.1. Subject Disposition 
Subject disposition will be summarized/listed for the randomized population by: 
x Number and percentage of subjects who withdraw prior to receive randomized study 
medication 
x Number and percentage of subjects who completed the study 
x Number and percentage of subjects who withdrew from the study; further summarized by 
the reason for withdrawal from the study. 
5.2. Subject Eligibility 
Subject eligibility, such as inclusion and exclusion criteria will be presented in listings. 
5.3. Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized descriptively for all 
subjects by treatment group for the safety population. Demographic and baseline characteristics 
include, but are not limited to: age, gender, ethnicity, race, body weight, height, body mass index 
(BMI), Liver fat via MRI-PDFF, Visceral fat via MRI, HbA1c, C-peptide, insulin, fasting plasma 
glucose, total cholesterol, HDL, LDL, VLDL, and triglycerides. The denominator of the 
percentage of subjects will be the number of subjects in the safety population at each cohort/dose 
level (placebo subjects will be pooled into one treatment group). 
5.4. Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
version 22.0) and summarized/listed by system organ class (SOC) and preferred term (PT) by 
cohort/dose level (placebo subjects will be pooled into one treatment group) for the safety 
population. 
5.5. Study Drug Administration 
Study drug administration data will be listed. 
5.6. Extent of Exposure 
Exposure will be summarized for the safety population. The summary of exposure will include 
the number of doses received, total dose administered, and the duration of exposure by 
cohort/dose level. Duration of exposure will be defined as the last dose date of treatment minus 
the first dose date of treatment. 
Total duration of exposure to study drug (weeks) = (last dose date – first dose date +7)/7  


                        
 
 
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5.7. Prior Medications and Concomitant Medications 
Concomitant medication refers to medications that were administered after administration of the 
IP (includes the medication that start before IP and continue to be used together).  Prior 
medication is defined as any medication that start and end before administration of the IP.  
The WHO Drug Dictionary Enhanced (B3 WHO Drug Global version 2019 March) will be used 
to categorize the verbatim descriptions of medications into the 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 in the database. 
The number and percentage of subjects receiving concomitant medications will be summarized 
by cohort/dose level, and by anatomical therapeutic chemistry (ATC) classification, ATC level 2 
and level 4, for the safety population. Prior medications will only be listed. 
5.8. Protocol Deviations 
Protocol deviations will be listed. Category of the protocol deviations will be included in the 
listing. 
6. Statistical Methods of Analysis 
6.1. General Considerations 
Summary and analysis of Part 1 and Part 2 will be separate. Placebo subjects within each part of 
the study will be pooled in summaries and listings. Exploratory analysis for subgroup of subjects 
being impacted by COVID-19, versus those not being impacted, may be conducted to assess 
missing data due to COVID-19.  As the number of subjects in the subgroup analysis will be 
much smaller than the original planned population, caution should be taken when interpreting the 
inferential statistical results. Please refer to Sections 6.3 and 6.4 for COVID-19 subgroup 
analyses.  
All data collected in the EDC and external data sets will be listed using the safety population. 
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, 
frequency and percentage in each category will be provided. For log-normal distributed data, 
geometric mean, standard error (SE) of the geometric mean, and coefficient of variation (CV) 
will also be provided. The geometric mean is calculated as the exponential of the arithmetic 
mean calculated from data on a log scale. The geometric CV is calculated as CV% = 100% כ
ݏݍݎݐሺሺߪଶሻെͳሻ, where σ is the standard deviation of the data on the natural log scale. 
Means, least squares (LS) means, and medians will be rounded to 1 decimal place greater than 
the precision of the original value. SDs, SEs, and confidence intervals (CIs) will be rounded to 2 


                        
 
 
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decimal places greater than the precision of the original value. Minimum and maximum values 
will be rounded to the precision of the original value. Percentages for summarizing categorical 
data will be rounded to one decimal place. P-values will be presented with 4 decimal places and 
values less than 0.0001 will be presented as <.0001. 
All inferential statistical testing will be two-sided and conducted at the 0.05 significance level, 
unless specified otherwise. No multiplicity adjustment will be used for this study. 
6.1.2. Study Baseline 
%aseline will be defined as the last non-missing observation obtained prior to the administration 
of the first dose of study medication, unless otherwise specified. 
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. 
6.1.3. Handling of Multiple Observations or Out of Window Observations 
Per COVID-19, additional modifications were made to the visit schedule in protocol version 5.0; 
refer to Table 2 for schedule of events. It was noted that after the protocol amendment, the study 
might have 2 subjects from Cohort 4 and all subjects from Part 2 that follow the modified visit 
schedule.  
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. For PD data 
with multiple observations on the same day and time point, the last observation will be used. 
All values, scheduled or unscheduled, will be presented in data listings.  
On scheduled visits with missing assessments, unscheduled assessments within the visit window, 
if available, may be used for analysis. 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 vital signs data, if 
measurements are duplicated within the visit window, the data from the unscheduled visit will be 
used and the average of the scheduled and unscheduled visits will be taken for summary table. A 
footnote will be added to table to highlight the exception. 
6.1.4. Handling of Missing or Partial Dates 
In cases of incomplete dates for adverse events or non-study medications, the missing 
component(s) will be assumed as the most conservative value(s) possible. The imputation rules 
are designed to conservatively capture adverse events as treatment-emergent and medications as 
concomitant. For example, the following algorithm for missing start date of adverse events will 
be followed: 


                        
 
 
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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. 
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 on the same day as the dosing was administered.   
Adverse events and medications with missing or partial end dates will be imputed to 
conservatively capture treatment-emergent or concomitant status. 
Date imputation will only be used for computational purposes; e.g., identifying treatment-
emergent adverse events or identifying concomitant medications. Actual data values, as they 
appear in the clinical database, will be shown in the data listings. 
6.1.5. Handling Outliers and Unquantifiable Measurements 
The following rules will be applied when PK 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 individual PK concentration plots: BLQ values will not be displayed but will be 
flagged for reference in the by-subject listings. 
For the calculation of descriptive statistics of concentrations or derivation of PK parameters: 
values that are BLQ and values deemed implausible will be set to missing.  
For safety laboratory abnormality assessments, and potentially some PD variables: 
x Values that are recorded with “>” (greater than) or “<” (lower than) the normal ranges, 
except some categorical variables, the numeric values will be used for descriptive 
statistical summary. For example, a value of >900 mg/dL will be set to 900 mg/dL for 
descriptive summary, and will be printed as “>900 mg/dL” on by-subject listing. 
x Range result of “Low” will be assigned if the value is less than the lower limit of the 
normal range. 
x Range result of “High” will be assigned if the value is greater than the upper limit of 
normal. 
6.2. Safety Analysis 
6.2.1. Adverse Events 
Adverse events (AEs) will be coded using MedDRA, version 22.0.  


                        
 
 
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AEs will be summarized for the safety population. 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. All of AEs will be listed.  
AEs with onset date/time on or after receiving the dosing of study medication, or pre-existing 
AEs that increase either severity or frequency on or after receiving the dosing of study 
medication will be considered as TEAE.  
An overall summary of TEAEs will be generated.  
TEAEs will be summarized by: 
x SOC and PT 
x SOC, PT, and maximum severity by treatment group 
x TEAEs that are related to study medication per investigator’s decision 
x TEAEs leading to study discontinuation 
x TEAEs that are serious (treatment-emergent SAEs)  
x Adverse events of special interest:  
o Necrolytic migratory erythema 
o Cholelithiasis 
6.2.2. Local Tolerability 
The number and percentage of subjects with any injection site reactions will be summarized by 
treatment group over the entire study and by visit and time point. The number and percentage of 
subjects with specific site reactions such as pain on palpation, itching, erythema, edema, and 
induration 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.  
6.2.3. Clinical Laboratory Assessments 
All hematology, clinical chemistry, and urinalysis results (including serum amylase, serum 
lipase, coagulation, thyroid stimulating hormone (TSH), serum calcitonin, eGFR) will be 
summarized. eGFR will be calculated using the following formula: 
175 x (creatinine in mg/dL)-1.154 x (age)-0.203 x (0.742 if female) x (1.212 if black) 
175 x (creatinine in μmol/L divided by 88.42)-1.154 x (age)-0.203 x (0.742 if female) x (1.212 if 
black) 
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 (with 
clinical significance and without clinical significance) status changes from baseline. Percentages 


                        
 
 
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of abnormal readings without clinical significance and abnormal readings with clinical 
significance will also be summarized.  
6.2.4. Vital Signs 
Observed values and the change from baseline in vital sign parameters such as, supine position 
blood pressure, heart rate, respiratory rate, and tympanic temperature, will be listed and 
summarized descriptively by cohort/dose level and time point. 
6.2.5. Electrocardiograms 
Observed values and the change from baseline in ECG parameters will be listed and summarized 
descriptively by cohort/dose level and time point. Overall interpretation of 12-lead ECG profiles 
over time will be summarized by categorical levels of normal, abnormal not clinically 
significant, and abnormal clinically significant; shift tables will summarize the shifts from 
baseline to each post baseline visit. 
6.2.6. Physical Examination 
The clinical findings during physical examination will be listed. 
6.2.7. 24 Hour Ambulatory Blood Pressure Monitoring 
Mean day time (10:00 to 20:00) and night time (00:00-6:00) systolic and diastolic BP and heart 
rate will be summarized for each day from Day -2 to Day 5 and Day 77 to Day 82 (Fagard 2008).  
Baseline for 24 hour ABPM will be derived using the mean of the pre-dose measurements from 
Day -1 to Day 1. 
6.2.8. 24 Hour Holter ECG Monitoring 
Observed values from 24-Hour Holter ECG will be summarized by time point for each 
assessment day. 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. 


                        
 
 
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6.2.9. Immunogenicity 
Anti-drug antibodies (ADAbs, anti-HM15136 antibodies) will be summarized categorically, 
displaying the tier 1 (putative positive and negative) and tier 2 (positive and negative) tests by 
cohort/dose level 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. 
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. 
6.3. Pharmacokinetic Analysis 
PK analysis will be performed using the PK population. Additional COVID-19 subgroup 
analysis for those being impacted by COVID-19 versus those not being impacted may be 
provided for HM15136 concentrations over time and for HM15136 PK parameters using the 
descriptive statistical summary table and/or plots. However, unless necessary, the dose 
proportionality will not be explored for COVID-19 subgroups 
6.3.1. HM15136 Pharmacokinetic Concentration Analysis 
The concentration-time data of HM15136 will be summarized descriptively by cohort/dose level. 
Two line plots for mean concentration +/- standard deviation over time, one on original raw scale 
and the other on the logarithm scale, will be generated for the PK population with cohort/dose 
level overlaid. Graphical analysis using line plots of individual profiles will also be performed. 
6.3.2. HM15136 Pharmacokinetic Parameter Analysis 
The non-compartmental PK parameters of HM15136 will be summarized descriptively by 
cohort/dose level. AUC parameters, AUC0-t at steady state and Cmax, will be log-transformed and 
geometric statistics will be included. Graphical analysis using box plots for PK parameters of 
AUC0-t at steady state and Cmax will be performed. To calculate AUC, for the absorption phase, 
the linear rule will be used; and for the elimination phase, the logarithmic rule will be used. 
6.3.3. Dose Proportionality Analysis  
Dose proportionality will be assessed using log-transformed PK parameters, AUC0-t at steady 
state and Cmax, and a linear regression approach to log-transformed dose levels. The power model 
will be used to analyze the dose proportionality. The estimate of the ratio of the dose normalized 
geometric means, Rdnm, and the corresponding 90% CI will be derived. 
The power model is defined as follows:  
 
Where 
log(ܲܭ௜) = α + (β) * log(dosei) + Ɛi 


                        
 
 
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ܲܭ௜ is the PK parameter (Cmax or AUC0-t at steady state) observation for the subject i.  
α is the population intercept. 
β is the population slope. 
dosei is the dosage for the subject i. 
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. 
Log(PK parameter) and log(dose) will be plotted in a line plot for AUC0-t at steady state and 
Cmax. 
6.4. Pharmacodynamic Analysis 
PD analysis will be performed using the PD population. Additional COVID-19 subgroup 
analysis for those being impacted by COVID-19 versus those not being impacted may be 
provided for PD endpoints using the descriptive statistical summary table and/or inferential 
statistics, if deemed necessary. 
6.4.1. Analysis of Exploratory Incretins/Metabolic Hormone Endpoints 
The observed values and the change from baseline in incretins/metabolic hormone endpoints, 
such as GLP-1, GIP, glucagon, FGF21 and leptin, will be summarized descriptively by 
cohort/dose level and time point. 
A mixed model repeated measures analysis will be performed with the change from baseline in 
incretins/metabolic hormone endpoint as the dependent variable, treatment group, analysis visit 
and the interaction between treatment group and analysis visit as factors, and the baseline of the 
dependent variable as a covariate. Repeated measures on each subject, at each visit, 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 least squares (LS) mean, standard error of LS mean and 95% confidence interval will be 
presented by treatment group for each post baseline analysis visit. The LS mean difference 
between active treatment group minus pooled placebo, standard error of the LS mean difference 
from placebo, and the 95% confidence interval will be presented by analysis visit.  


                        
 
 
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6.4.2. Analysis of Exploratory Serum Lipid Profiles Endpoints 
The observed values and the change from baseline and percent change from baseline in serum 
lipid profile endpoints, total cholesterol, LDL, HDL, VLDL, triglycerides and FFA, will be 
summarized descriptively by cohort/dose level and time point. 
A similar mixed model repeated measures analysis as described previously will be performed for 
the change from baseline and percent change from baseline in serum lipid profile endpoints. 
6.4.3. Analysis of Exploratory Amino-Acid Profile Endpoint 
The observed values and the change from baseline in amino-acid profile will be summarized 
descriptively by cohort/dose level and time point. 
6.4.4. Analysis of Exploratory Glucose Metabolism Parameter Endpoints 
Fasting plasma glucose, glucose via YSI, insulin, c-peptide, HbA1c, fructosamine, and glycated 
albumin measurements and change from baseline will be summarized by dosage and visit. A 
similar mixed model repeated measures analysis as described previously will be performed for 
the change from baseline and percent change from baseline in each of these parameters. 
Individual SMBG measurements of each time point, as the daily/weekly mean, the daily/weekly 
pre-meal mean and daily/weekly post-meal mean measurements will be presented in a listing. 
Subject SMBG of each time point, the daily/weekly mean of pre-meal and post-meal SMBG will 
be summarized by part/cohort/dose level as well as change from baseline. Mean SMBG (+/- SD) 
at each time point of baseline, Week 1 and Week 12 will be plotted.  
6.4.5. Analysis of Exploratory Homeostatic Model Assessment Endpoints 
Observed values and the change from baseline in HOMA endpoints such as, HOMA-IR and 
HOMA-β, will be summarized descriptively by cohort/dose level and time point. 
A similar mixed model repeated measures analysis as described previously will be performed for 
the change from baseline in HOMA endpoints. 
6.4.6. Analysis of Exploratory MRI Endpoints 
Observed values and the change from baseline (absolute) and percent change from baseline 
(relative) in MRI endpoints such as of liver fat via MRI-PDFF and visceral fat volume, will be 
summarized descriptively by cohort/dose level and time point. Note: MRI-PDFF at Day 85 is 
only measured if the Day -1 or Baseline visit is ≥ 10% liver fat. 
A Wilcoxon Mann Whitney test will be performed to test the change from baseline and the 
percent change from baseline in MRI endpoints by treatment group. The p-value from the 
Wilcoxon Mann Whitney test will be presented. In addition, the estimate of the median and the 
exact 95% confidence limits estimated by the Hodges-Lehmann estimator will be presented. 


                        
 
 
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In addition, an analysis of variance (ANOVA) model will be performed; the difference between 
each HM15136 dose group and placebo and its associated 95% confidence interval and p-value 
will be presented. 
6.4.7. Analysis of Exploratory Anthropomorphic Measure Endpoints 
The observed values and the change from baseline and percent change from baseline in 
anthropomorphic measures such as, body weight, BMI, waist circumference, hip circumference, 
WHR, will be summarized descriptively by cohort/dose level and time point. 
A similar mixed model repeated measures analysis as described previously will be performed for 
the change from baseline and percent change from baseline in anthropomorphic measure 
endpoints. 
6.4.8. Analysis of Tympanic Temperature 
The observed values and the change from baseline and percent change from baseline in tympanic 
temperature will be summarized descriptively by cohort/dose level and time point for 4AM, 
6PM, and combined. 
A similar mixed model repeated measures analysis as described previously will be performed for 
the change from baseline and percent change from baseline in tympanic temperature for 4AM, 
6PM, and combined. 
6.4.9. Analysis of Exploratory Inflammatory Markers and Ketone Body Endpoints 
The observed values and the change from baseline in inflammatory markers, such as hs-CRP and 
adiponectin, and the observed values and the change from baseline in ketone bodies such as β-
hydroxybutyrate, will be summarized descriptively by cohort/dose level and time point. 
A similar mixed model repeated measures analysis as described previously will be performed for 
the change from baseline in inflammatory markers and ketone body endpoints. 
7. Interim Analysis 
An interim analysis will be performed for administrative purposes, to aid in the planning of 
future studies in the development program after all healthy subjects in Part 1 have been finalized. 
Part 1 includes all subjects in Cohorts 1-3. As COVID-19 may lead to challenges in the 
collection of data, only partially validated data might be available for the planned interim 
analysis. This interim analysis will be performed for administrative purpose prior to database 
lock of Part 1. Unblinding will occur prior to the database lock for Part 1. Designated personnel 
not involved in the study conduct will perform the above stated interim analysis. Only authorized 
members who are listed in the Interim Analysis Unblinding and Information Dissemination Plan 
will have access to review the summary tables or figures of the interim analysis results, in which 
the information is presented in a grouped fashion with the actual treatment, e.g., mean treatment 
effect. The interim analysis will include an assessment of all efficacy, safety, and PK variables of 
Part 1. 


                        
 
 
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An additional interim analysis will be performed after database lock for Part 1, which is the final 
analysis of Part 1. The final analysis results of part 1 will be included in the final CSR along with 
the final analysis of Part 2. 
Both analyses for Part 1 may occur, while Part 2 will continue in a blinded fashion. The study 
will be conducted as outlined in this protocol. Part 2 will be performed independently from the 
conduct/results of the Part 1 and will not lead to changes to the conduct of the protocol. After 
Part 2 (T2DM cohorts) has been completed, a final analysis, that only includes the results of Part 
2, will be conducted after data base lock of Part 2. For details on the interim analysis based on 
semi-clean data, please refer to the Interim Analysis Unblinding and Information Dissemination 
Plan. 
8. Statistical Software 
All statistical analyses will be performed using SAS® version 9.4. PD parameters will be derived 
with SAS® version 9.4. PK parameters will be derived with standard non-compartmental 
methods using WinNonlin v5.2 or higher. 
9. 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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10. Appendix 
Table 2: Schedule of Events  
Schedule of Events (Part 1) 
 


 
 
 
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Schedule of Events (Part 2) 
 
 


 
 
 
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Schedule of Events (Part 1 and Part 2 COVID-19 Modification) 
 
 


 
 
 
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Table 3: PK Sampling Schedule 
 
 
 


                        
 
 
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PK Sampling Schedule (Parts 1 and 2) – COVID-19 Modification