Clinical trial NCT04944992
Conditions: Nonalcoholic Fatty Liver Disease Nonalcoholic Steatohepatitis
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-08-04; Completion date: 2022-10-19
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The principal goal of this study is to determine the efficacy of efinopegdutide in liver fat reduction in participants with NAFLD. The primary hypotheses are that efinopegdutide is superior to semaglutide, or that efinopegdutide is superior to semaglutide by at least 10% with respect to mean relative reduction from baseline in liver fat content (LFC) after 24 weeks.

Detailed description:

Arms: arm 1: Efinopegdutide 20 mg/mL administered by injection once weekly for 24 weeks in a dose-escalation regimen: 2.4 mg from day 1 to week 3, 5.0 mg from week 4 to 7, and 10.0 mg from week 8 to 24. arm 2: Semaglutide 1.34 mg/mL administered by injection once weekly for 24 weeks in a dose-escalation regimen: 0.25 mg from day 1 to week 3, 0.5 mg from week 4 to 7, and 1.0 mg from week 8 to 24.
Interventions: intervention 1: Efinopegdutide 20 mg/mL intervention 2: Semaglutide 1.34 mg/mL
Intervention descriptions: intervention 1: Subcutaneous injection in a dose-escalation administration of 2.4 mg, 5.0 mg, and 10.0 mg intervention 2: Subcutaneous injection in a dose-escalation administration of 0.25 mg, 0.5 mg, and 1.0 mg

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04944992 
Document Date: 
26-Aug-2021
A Phase 2a, Randomized, Active-Comparator-Controlled, 
Open-Label Study to Evaluate the Efficacy and Safety of 
Efinopegdutide (MK-6024) in Individuals With Nonalcoholic Fatty 
Liver Disease.


PRODUCT: MK 6024  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, USA 
(MSD).
Protocol Title: A Phase 2a, Randomized, Active-Comparator-Controlled, Open-Label Study 
to Evaluate the Efficacy and Safety of Efinopegdutide (MK-6024) in Individuals With 
Nonalcoholic Fatty Liver Disease.
Protocol Number: 001-02
Compound Number: MK-6024
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter called the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
PO Box 100
Whitehouse Station, New Jersey, 08889-0100, USA
Regulatory Agency Identifying Number(s):
IND
153067
EudraCT
2020-005136-30
Approval Date: 26 August 2021
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
26-AUG-2021
This amendment was created primarily to add an IA.
Amendment 01
17-FEB-2021
This amendment was created primarily to add the Sponsor’s siDMC to supplement the 
safety data monitoring conducted in this study. Additional changes included 
corrections and clarifications to the protocol language.
Original Protocol
07-DEC-2020
Not applicable.
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PRODUCT: MK 6024  
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
This amendment was created primarily to add an IA.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Primary Change
4.1 Overall Design
4.2 Scientific Rationale for Study 
Design
4.4.1 Clinical Criteria for Early 
Study Termination
9.1 Statistical Analysis Plan 
Summary
9.7 Interim Analyses
Incorporation of an IA.
To inform on administrative decisions regarding other 
aspects of the efinopegdutide program.
In addition, to support potential termination of the 
study for futility based on poor LFC (MRI-PDFF) 
response and/or safety and tolerability issues.
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PRODUCT: MK 6024  
7
PROTOCOL/AMENDMENT NO.: 001 02 
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Section # and Name
Description of Change 
Brief Rationale 
2 Introduction
2.2.3 Information on Other 
Study-related Therapy
2.3 Benefit/Risk Assessment
4.2.2 Rationale for the Use of 
Active Comparator
4.3.3 Rationale for Dose Interval 
and Study Design
Added available semaglutide development 
program information as well as updated 
reference documents.
Revised to align with newly available information.
4.3.1 Starting Dose for This 
Study
6.1 Study Interventions
Administered
Revised the dosage levels of semaglutide 
per injection from 0.1875 mL to 0.19 mL, 
from 0.375 mL to 0.37 mL, and from 
0.75 mL to 0.74 mL.
Revised to match the information in the semaglutide 
Summary of Product Characteristics.
4.4.1 Clinical Criteria for Early 
Study Termination
9.7 Interim Analyses
10.1.4.2 Executive Oversight 
Committee
10.1.4.3 Internal Data 
Monitoring Committee
Clarified that the EOC is comprised of 
senior management in the TA (Diabetes, 
Endocrinology, and Metabolism) with 
programmatic oversight, who are not 
directly associated with study conduct.
Clarification
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Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
Updated Inclusion Criterion #1 to allow 
for historical MRI-PDFF imaging of the 
liver if performed ≤2 months before
V1/Screening and if obtained from the 
same study-qualified imaging center(s) 
and imaged per the Site Imaging Manual
for this study to be considered as 
potentially acceptable to determine LFC 
% as part of eligibility after consultation 
with the Sponsor.
To potentially reduce participant burden.
5.2 Exclusion Criteria
6.5 Concomitant Therapy
Updated Exclusion Criterion #36 to 
remove restrictions on vitamin E dose, 
and to only exclude participants on 
vitamin E if their dose is >100 IU/day and 
has not been stable for at least 3 months 
before V1/Screening.
Removed high dose vitamin E 
(>400 IU/day) from the list of prohibited 
medications.
Since use of high dose vitamin E (>400 IU/day) is 
common in the target study population, these changes
will allow participants on high dose vitamin E to 
participate in the study while the dose stability 
requirement will mitigate the potential confounding 
factor caused by high dose vitamin E.
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PRODUCT: MK 6024  
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PROTOCOL/AMENDMENT NO.: 001 02 
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Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
Clarified Exclusion Criterion #41:
Participation in an interventional 
clinical study is defined as having 
received an investigational compound 
or used an investigational device.
Participants enrolled in COVID-19 
vaccine trials may be included in this 
study and will be reviewed on a case-
by-case basis for approval by the 
Sponsor.
Clarification
5.2 Exclusion Criteria
Revised the platelet count study limit for 
exclusion in Table 1 Laboratory Exclusion 
Criteria from <150 × 109/L to 
<140 × 109/L.
To align with the central laboratory lower limit of 
normal.
5.2 Exclusion Criteria
Removed the reference to the 
operations/laboratory manual from 
footnote b in Table 1 Laboratory 
Exclusion Criteria.
Clarification
7.1 Discontinuation of Study 
Intervention
Corrected Note (1) under the tachycardia 
bullet to state that participants with a 
minimally symptomatic event that is not 
sustained or recurrent, and who do not
meet other discontinuation criteria may 
continue in the study.
Typographical error
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PRODUCT: MK 6024  
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PROTOCOL/AMENDMENT NO.: 001 02 
MK 6024 001 02 FINAL PROTOCOL
26 AUG 2021
Section # and Name
Description of Change 
Brief Rationale 
10.11 Appendix 11: 
Abbreviations
Corrected the expanded term for 
MRI-PDFF from Magnetic Resonance 
Imaging-Estimated Proton Density Fat 
Fracture to Magnetic Resonance Imaging-
Estimated Proton Density Fat Fraction.
Typographical error
Throughout the document
Editorial and formatting changes
Completed for emphasis, clarity, or consistency
Note: Minor edits such as the renumbering of tables or relettering of footnotes are not listed.
089F7K


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PRODUCT: MK 6024  
15
PROTOCOL/AMENDMENT NO.: 001 02 
MK 6024 001 02 FINAL PROTOCOL
26 AUG 2021
5
STUDY POPULATION ................................................................................................50
5.1
Inclusion Criteria.................................................................................................51
5.2
Exclusion Criteria................................................................................................52
5.3
Lifestyle Considerations......................................................................................59
5.3.1
Diet and Activity Counseling.......................................................................59
5.3.2
Alcohol, Caffeine, and Tobacco Restrictions ..............................................59
5.4
Screen Failures.....................................................................................................59
5.5
Participant Replacement Strategy......................................................................59
6
STUDY INTERVENTION............................................................................................60
6.1
Study Intervention(s) Administered...................................................................60
6.2
Preparation/Handling/Storage/Accountability .................................................62
6.2.1
Dose Preparation..........................................................................................62
6.2.2
Handling, Storage, and Accountability........................................................62
6.3
Measures to Minimize Bias: Randomization and Blinding..............................63
6.3.1
Intervention Assignment..............................................................................63
6.3.2
Stratification.................................................................................................63
6.3.3
Blinding........................................................................................................63
6.4
Study Intervention Compliance..........................................................................63
6.5
Concomitant Therapy..........................................................................................64
6.5.1
Rescue Medications and Supportive Care ...................................................65
6.6
Dose Modification (Escalation/Titration) ..........................................................65
6.6.1
Dose-Escalation (Up-Titration) ...................................................................65
6.6.2
Down-Titration ............................................................................................66
6.7
Intervention After the End of the Study............................................................66
6.8
Clinical Supplies Disclosure................................................................................66
6.9
Standard Policies..................................................................................................67
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................67
7.1
Discontinuation of Study Intervention...............................................................67
7.2
Participant Withdrawal From the Study...........................................................69
7.3
Lost to Follow-up .................................................................................................69
8
STUDY ASSESSMENTS AND PROCEDURES........................................................69
8.1
Administrative and General Procedures ...........................................................70
8.1.1
Informed Consent.........................................................................................70
8.1.1.1
General Informed Consent.................................................................71
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................71
8.1.1.3
Consent and Collection of Specimens for the PK Substudy..............71
089F7K


PRODUCT: MK 6024  
16
PROTOCOL/AMENDMENT NO.: 001 02 
MK 6024 001 02 FINAL PROTOCOL
26 AUG 2021
8.1.2
Inclusion/Exclusion Criteria ........................................................................71
8.1.3
Participant Identification Card.....................................................................72
8.1.4
Medical History ...........................................................................................72
8.1.5
Prior and Concomitant Medications Review...............................................72
8.1.5.1
Prior Medications...............................................................................72
8.1.5.2
Concomitant Medications..................................................................72
8.1.6
Assignment of Screening Number...............................................................72
8.1.7
Assignment of Treatment/Randomization Number.....................................72
8.1.8
Study Compliance........................................................................................73
8.1.8.1
Diet and Activity Counseling/Monitoring .........................................73
8.1.8.2
Assessment of Alcohol Consumption................................................73
8.1.8.3
Hypoglycemia and Hyperglycemia Counseling ................................73
8.1.8.4
Dehydration and Postural Hypotension Counseling..........................73
8.1.8.5
Injection Training (Participant and/or Caregiver)..............................73
8.1.8.6
Dispense Open-Label Study Intervention..........................................74
8.1.8.7
Witnessed Dosing ..............................................................................74
8.1.8.8
Dispense/Review Participant Diary ...................................................75
8.1.8.9
Study Intervention Accountability.....................................................75
8.1.9
Study Intervention Administration ..............................................................75
8.1.9.1
Timing of Dose Administration.........................................................75
8.1.10
Discontinuation and Withdrawal .................................................................76
8.1.10.1
Withdrawal From Future Biomedical Research ................................76
8.1.11
Participant Blinding/Unblinding..................................................................76
8.1.12
Calibration of Equipment.............................................................................77
8.2
Efficacy Assessments ...........................................................................................77
8.2.1
Liver Fat Content by Magnetic Resonance Imaging-Estimated Proton 
Density Fat Fraction.....................................................................................77
8.2.2
Body Weight Assessment and Monitoring ..................................................77
8.2.3
Lipid Metabolism.........................................................................................78
8.3
Safety Assessments...............................................................................................78
8.3.1
Physical Examinations.................................................................................78
8.3.2
Height...........................................................................................................78
8.3.3
Body Mass Index .........................................................................................79
8.3.4
12-Lead Electrocardiogram .........................................................................79
8.3.5
Vital Signs....................................................................................................79
8.3.6
Clinical Safety Laboratory Assessments .....................................................80
8.3.7
Pregnancy Testing........................................................................................80
8.3.8
Adverse Event Monitoring...........................................................................81
089F7K


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PRODUCT: MK 6024  
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MK 6024 001 02 FINAL PROTOCOL
26 AUG 2021
LIST OF FIGURES
Figure 1
Study Design....................................................................................................26
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a, Randomized, Active-Comparator-Controlled, Open-Label Study 
to Evaluate the Efficacy and Safety of Efinopegdutide (MK-6024) in Individuals With 
Nonalcoholic Fatty Liver Disease.
Short Title: Phase 2a Study of Efinopegdutide (MK-6024) in Individuals With NAFLD
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
In males and females aged 18 to 70 years (in Taiwan, aged 20 to 70 years; in South Korea, 
aged 19 to 70 years [Appendix 7]) with NAFLD:
Objectives
Endpoints
Primary
•
To evaluate the effect of efinopegdutide 
versus semaglutide on mean relative 
reduction from baseline in LFC after 
24 weeks.
•
Hypothesis (H1): Efinopegdutide is 
superior to semaglutide with respect to 
mean relative reduction from baseline in 
LFC after 24 weeks.
•
Hypothesis (H2): Efinopegdutide is 
superior to semaglutide by 10% or more 
with respect to mean relative reduction 
from baseline in LFC after 24 weeks.
•
LFC (%) measured by MRI-PDFF 
(evaluated by BICR)
•
To evaluate the safety and tolerability of 
efinopegdutide compared with 
semaglutide.
•
AEs
•
Discontinuation of study intervention 
due to AEs
Secondary
•
To evaluate the effect of efinopegdutide
versus semaglutide on mean absolute
reduction from baseline in LFC after 
24 weeks.
•
LFC (%) measured by MRI-PDFF 
(evaluated by BICR)
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Objectives
Endpoints
•
To evaluate the effect of efinopegdutide 
versus semaglutide on mean percent 
change from baseline in body weight at 
24 weeks.
•
Weight (kg)
•
To evaluate the effect of efinopegdutide 
versus semaglutide on change from 
baseline in fasting lipid levels over 
24 weeks.
•
Lipid profile: cholesterol (total, non-
HDL-C, HDL-C, LDL-C), TG, and 
apoB
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of individuals with NAFLD
Population
Males and females aged 18 to 70 years (in Taiwan, aged 
20 to 70 years; in South Korea, aged 19 to 70 years
[Appendix 7]) with NAFLD and LFC ≥10% by MRI-
PDFF
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active-comparator-control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 72 weeks from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
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Number of Participants:
Approximately 130 participants will be randomized.
Intervention Groups and Duration:
Intervention 
Groups
Participants will be randomized in a 1:1 ratio and dosed Q1W.
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin
Treatment
Period
(24 Weeks)
Use
Group 1
Efinopegdutide
2.4 mg
Q1W
SC
V3 up to V7
Experimental
Efinopegdutide
5.0 mg
Q1W
SC
V7 up to V8
Experimental
Efinopegdutide
10.0 mg
Q1W
SC
V8 up to V12
Experimental
Group 2
Semaglutide
0.25 mg
Q1W
SC
V3 up to V7
Experimental
Semaglutide
0.5 mg
Q1W
SC
V7 up to V8
Experimental
Semaglutide
1.0 mg
Q1W
SC
V8 up to V12
Experimental
Admin administration; Q1W once every week; SC subcutaneous; V visit.
Current or former names or aliases for the study intervention are as follows: 
HM12525A, JNJ-64565111, MK-6024, and efinopegdutide.
Total 
Number of 
Intervention 
Groups/
Arms
2
Duration of 
Participation
Each participant will participate in the study for approximately 32 weeks from 
the time the participant provides documented informed consent through the 
final contact.
After a staged screening period (V1 up to V3) of approximately 4 weeks, each 
eligible participant will be randomized to receive open-label efinopegdutide
or semaglutide for approximately 24 weeks (V3 up to V12). A follow-up visit 
(V13) will occur approximately 5 weeks after the last dose of study 
intervention.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
The Data Monitoring Committee for this study is the MRL siDMC.
Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 11.
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PRODUCT: MK 6024  
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
089F7K


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PRODUCT: MK 6024  
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2
INTRODUCTION
NAFLD is characterized by steatosis within the liver. It is increasingly recognized as the 
hepatic manifestation of overall metabolic dysfunction and is closely associated with obesity, 
insulin resistance, and T2DM [Younossi, Z. M., et al 2016]. In a meta-analysis conducted by 
Younossi et al, the global prevalence of NAFLD among T2DM patients was 55.5% and the 
global prevalence of NASH among patients with T2DM was 37.3% [Younossi, Z. M., et al 
2019].
GLP-1 agonism is associated with reductions in serum glucose and weight loss. There are 
several GLP-1 agonists approved for the treatment of T2DM and approved or in development 
for obesity. GLP-1 receptor agonists enhance glucose-stimulated insulin secretion and have 
become useful treatments for T2DM. At the doses that have been developed for diabetes
indications (eg, liraglutide 1.8 mg daily, semaglutide 1.0 mg weekly), GLP-1 receptor 
agonists are associated with weight loss of approximately 3% to 5%, generally attributed to 
reductions in food intake. More recently, higher dose administration of GLP-1 receptor 
agonists has been pursued for weight loss indications. Liraglutide 3.0 mg daily and 
semaglutide 2.4 mg once weekly are approved for weight loss in the United States and 
European Union and in the United States, respectively.
The weight loss associated with GLP-1 agonists is also associated with decreased 
inflammation within the liver of patients with NASH. The Liraglutide Efficacy and Action in 
NASH (LEAN) Phase 2 study showed 39% (9/23) of participants who received liraglutide 
1.8 mg daily and underwent an end of treatment liver biopsy after 48 weeks had resolution of 
definite NASH compared with 9% (2/22) in the placebo group [Armstrong, M. J., et al 2016].
Semaglutide is currently being evaluated for NASH in late stage studies. A Phase 2b study
with semaglutide at 0.1 mg, 0.2 mg, or 0.4 mg SC once daily (0.7 mg to 2.8 mg weekly)
showed histologic resolution of NASH without worsening of fibrosis in 40.4% to 58.9% of 
participants relative to placebo (17.2%) after 72 weeks of dosing [Newsome, P. N., et al 
2020].
Glucagon receptor activation has direct effects on lipolysis, basal energy expenditure, and 
liver lipid metabolism, and may complement the effects of GLP-1 receptor agonism for the 
treatment of NASH [Seghieri, M., et al 2018]. Glucagon has been shown to cause reductions 
in food intake and increases in energy expenditure. However, the metabolic effects of 
glucagon, particularly the hyperglycemic effects, limit the utility of glucagon as a weight loss 
agent. The combination of GLP-1 receptor agonism with glucagon receptor agonism thus 
offers the potential for complementary effects on weight loss, while attenuating the 
hyperglycemia that would be associated with pure glucagon activity.
Efinopegdutide (MK-6024) is a synthetic modified oxyntomodulin peptide. It is the site-
specific form of HMGLP/GCG25 (a GLP-1/glucagon dual agonist peptide) that is linked via 
a polyethylene glycol linker to a human IgG fragment with agonist activity at both the GLP-1 
and the glucagon receptors. Oxyntomodulin is a 37 amino acid peptide product of the 
proglucagon gene released from the L-cells of the small intestine in response to food 
ingestion [Wynne, K., et al 2006]. Oxyntomodulin activates both the GLP-1 and glucagon 
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receptors. Oxyntomodulin, administered 3 times daily before a meal, decreased appetite and 
reduced body weight by 2.3 kg during a 4-week period in healthy overweight and obese 
participants [Wynne, K., et al 2005]. In addition to the beneficial effects of weight loss on 
NAFLD, glucagon agonism may provide additional reduction in hepatic fat by stimulating 
fatty acid oxidation and reducing lipogenesis in the liver relative to GLP-1 agonism alone
[Boland, M. L., et al 2020].
Efinopegdutide was originally developed by Hanmi Pharmaceuticals. Phase 1 and 2 studies 
supported administration of a Q1W SC injection. A 26-week Phase 2b study in obese 
participants and a 12-week Phase 2b study in obese participants with T2DM, evaluated the 
weight loss and glycemic efficacy, and safety/tolerability of efinopegdutide at doses up to 
10 mg Q1W. Dose-dependent reductions in body weight with Q1W administration of 
efinopegdutide were observed in these Phase 2b studies in obese participants with and 
without T2DM. Weight loss was greater or similar to liraglutide 3 mg daily, which is the 
dose approved for obesity. The absence of glucose-lowering in the face of weight loss in 
these studies is attributable to glucagon receptor target engagement, but without deleterious 
effects on glycemia in nondiabetic or in T2DM participants. The increase in serum ketones 
(beta-hydroxybutyrate) and reduction in bicarbonate observed in these Phase 2b studies are 
consistent with enhancement of fatty acid oxidation and glucagon activation in the liver 
(MSD; data on file).
In 2 mouse models of NASH, the GLP-1R/GCGR co-agonist cotadutide reduced fibrosis to a 
greater extent than the GLP-1 receptor agonist liraglutide with similar degrees of weight loss
[Boland, M. L., et al 2020]. In another mouse model of NASH, the co-agonist ALT-801 
suppressed hepatic stellate cell pathway pro-fibrosis genes more than the GLP-1 receptor 
agonist semaglutide [Nestor, J. J., et al 2020]. In a 54-week Phase 2 study with cotadutide, 
reductions in Pro-C3 levels, a marker of hepatic fibrogenic activity, were greater compared 
with liraglutide, albeit in conjunction with greater weight loss (5% versus 3.3%) [Nahra, R.,
et al 2020] [Dela Cruz, J. 2020].
As neither the GLP-1 receptor nor the glucagon receptor are expressed in human Kupffer or 
stellate cells, these findings suggest that anti-fibrotic effects may be mediated by upstream 
reductions in steatosis and inflammation. In summary, glucagon receptor agonism may 
provide additional reductions in hepatic fat and potentially on hepatic fibrosis than the 
reductions mediated by weight loss observed with GLP-1 agonism.
2.1
Study Rationale
The principal goals of this Phase 2a study are to assess the effects on hepatic fat reduction 
and fibrosis biomarkers of GLP-1 and glucagon receptor co-agonism with efinopegdutide
relative to GLP-1 agonism alone with the use of semaglutide, and inform on the role of 
efinopegdutide as a potential novel therapy for NASH.
The study will also expand the safety and tolerability characterization of efinopegdutide.
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2.2
Background
Refer to the IB for detailed background information on efinopegdutide.
2.2.1
Pharmaceutical and Therapeutic Background
NAFLD affects approximately 25% of the global adult population and is a condition
associated with an increased accumulation of TG in the liver. NAFLD encompasses a 
spectrum of disease, ranging from simple steatosis to NASH that is associated with chronic 
inflammation within the liver described histologically as steatohepatitis with or without 
fibrosis[Kechagias. S., et al 2020]. An increasing proportion of NAFLD cases will progress 
to NASH, rising from 20% to 27% between the years 2015 and 2030 [Friedman, S. L., et al 
2018].
In general, patients with NASH are diagnosed between the ages of 40 and 60 years, and have 
associated metabolic comorbidities that include obesity, dyslipidemia, T2DM, and MetS
[Younossi, Z. M., et al 2016] [Younossi, Z., et al 2018] [Chalasani, N., et al 2018].
Approximately 20% of the NASH population will progress to cirrhosis with increases in all 
cause and liver-related mortality including increased rates of hepatocellular carcinoma 
[Sheka, A. C., et al 2020]. Additionally, some patients develop hepatocellular carcinoma 
without cirrhosis [Stine, J. G., et al 2018] [Perumpail, R. B., et al 2015]. NASH remains an 
area of unmet need with no approved therapies and a growing global prevalence.
NAFLD has been recognized as the hepatic manifestation of overarching metabolic 
dysregulation and is considered a consequence of obesity-related insulin resistance resulting 
in increased trafficking of fatty acids from adipose to liver and de novo hepatic lipogenesis 
[Fabbrini, E., et al 2010].
NAFLD patients are typically asymptomatic; therefore, more likely to initially be identified 
based on risk factors (obesity, MetS, T2DM) and/or abnormal liver tests without alternate 
explanation. The presence of steatosis may be assessed through imaging (ultrasound, 
magnetic resonance imaging). In patients with confirmed steatosis, the risk for NASH and 
advanced fibrosis can be further assessed through laboratory panels and imaging-based 
assessments of liver stiffness. These diagnostics cannot definitively diagnose NASH or 
fibrosis stage but are useful in assessing risk of advanced fibrosis. 
Lifestyle modification directed at weight loss and exercise remain the most recommended 
treatment for NAFLD; however, even in well-organized settings, only a minority of patients 
achieve and sustain weight loss. Presently, there are no agency-approved medications for the 
treatment of NASH. According to evidence-based practice guidelines, pioglitazone and high 
dose vitamin E (800 IU/day) are now recommended as pharmacotherapies for biopsy-proven 
NASH patients with and without diabetes, respectively [Sumida, Y. 2018]. However, neither 
pioglitazone nor vitamin E have demonstrated in the NASH population a robust histological 
efficacy, been studied long-term to assess impact on liver-related outcomes or have fully 
characterized safety. The absence of well-characterized, safe, and highly effective NASH 
treatments is a significant unmet medical need recognized by both medical societies and 
regulatory agencies [Friedman, S. L., et al 2018] [Chalasani, N., et al 2018].
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2.2.2
Preclinical and Clinical Studies
Toxicology and clinical data are briefly summarized below. Refer to the efinopegdutide IB 
for a more extensive summary of the preclinical and clinical data available for 
efinopegdutide.
2.2.2.1
Efinopegdutide Preclinical Overview
The preclinical safety profile of efinopegdutide has been assessed in safety pharmacology 
studies, single-dose toxicity studies, 2 repeat-dose toxicology studies in rats for 4- and 
26-weeks duration, and 2 repeat-dose toxicology studies in monkeys for 4- and 16-weeks 
duration.
In GLP safety pharmacology studies in male rats, single-dose injections of efinopegdutide
caused no notable effects on respiratory parameters but caused neurobehavioral changes that 
were secondary to the expected pharmacological effect of large body weight loss. In GLP 
cardiovascular safety studies in cynomolgus monkeys, efinopegdutide caused non-dose-
dependent relatively higher nocturnal HR as well as dose-dependent increased body 
temperature and slight QTcR interval prolongation; however, parameters were not considered 
adverse. No other notable effects on cardiovascular parameters were observed.
The predominant treatment-related effects of efinopegdutide in 4-week repeat-dose toxicity 
studies in rats and monkeys are attributable to exaggerated pharmacological actions of 
efinopegdutide on GLP-1R and GCGR receptors that caused pronounced dose-related 
decreases in body weight, body weight gain, and food consumption compared with controls. 
In turn, these effects led to several dose-related secondary findings on hematology, clinical 
chemistry, urinalysis, and gross and microscopic pathology parameters that were considered 
to result from the pronounced adverse effects on body weight and food consumption and 
associated metabolic stress. These effects are consistent with findings associated with feed 
restriction and stress responses. In the monkey, there was an additional effect of increased 
cellularity of endocrine islet cells in the pancreas. Similar effects of increased cellularity of 
the pancreas with no increase in cell proliferation have been observed in monkeys during 
development of other GLP-1 agonists (eg, albiglutide, exenatide) and were considered to be 
pharmacologically mediated.
Findings in the 26-week rat study were consistent with those in the shorter term 4-week rat 
study. The chronic monkey study was initiated as a 26-week study, but the study duration 
was shortened to 16 weeks because it was not possible to maintain systemic exposure due to 
ADA formation. The ADAs were neutralizing against GLP-1R activity and to a lesser extent 
against GCGR activity. 
2.2.2.2
Efinopegdutide Clinical Overview
Based on completed clinical studies, at least 1 dose of efinopegdutide has been administered 
to a total of 783 participants across 7 Phase 1 studies and 2 Phase 2b studies. Key safety data 
are summarized below.
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multiplicity). Corresponding placebo-subtracted percent changes were -4.56%, -5.85%, 
and -7.23% for the 5.0 mg, 7.4 mg, and 10.0 mg efinopegdutide dose groups, respectively 
(p<0.001), thereby meeting the primary efficacy objective. Clinically meaningful weight 
reduction was observed in all 3 doses of efinopegdutide as early as Week 2 and generally 
increased through Week 12. Treatment with efinopegdutide was associated with non-dose-
dependent reductions in SBP and DBP along with elevations in pulse rate. The rate pressure 
product at Week 12 was not meaningfully increased compared with baseline (MSD; data on 
file).
At Week 12, there was a nominal 0.13% increase in the level of HbA1c (A1C) from baseline 
in the efinopegdutide 5.0 mg dose group compared with small reductions of -0.03% 
and -0.07% in the 7.4 mg and 10.0 mg efinopegdutide dose groups along with a -0.19% 
reduction in the placebo group. Consistent with the A1C data, there was little change in FPG; 
an increase of 2.5 mg/dL and 1.1 mg/dL was observed in the 5.0 mg and 7.4 mg 
efinopegdutide dose groups compared with reductions of -11.7 mg/dL and -5.8 mg/dL in the 
efinopegdutide 10.0 mg and placebo dose groups, respectively. Fasting plasma insulin levels 
increased from baseline by 22%, 25%, and 6% in the 5.0 mg, 7.4 mg, and 10.0 mg 
efinopegdutide dose groups, respectively, compared with a 5% increase in the placebo group
(MSD; data on file).
Study 64565111OBE2001 was a randomized, double-blind placebo-controlled and open-
label active-controlled, parallel-group, 5-arm, multicenter Phase 2b study. Nondiabetic, obese 
(BMI: ≥35 kg/m2 to ≤50 kg/m2) participants 18 to 70 years of age (inclusive) were assessed.
A total of 474 participants were randomized to placebo (n 60), efinopegdutide at 5.0 mg
(n 59), 7.4 mg (n 118), and 10.0 mg (n 118); or open-label liraglutide 3.0 mg (n 119). At 
Week 26, all 3 doses of efinopegdutide significantly reduced body weight from baseline 
compared with placebo (after adjustment for multiplicity) with corresponding placebo-
subtracted percent changes of -6.8%, -8.1%, and -10.0% for the efinopegdutide 5.0 mg, 
7.4 mg, and 10.0 mg dose groups, respectively, thereby successfully meeting the primary 
objective. At Week 26, the liraglutide group showed a placebo-subtracted reduction in body 
weight of -5.8% (MSD; data on file).
At Week 26, there was no change in the levels of A1C in the efinopegdutide and placebo
groups compared with a -0.2% reduction in the liraglutide group. Consistent with the A1C
data, there was little change in FPG in the efinopegdutide and placebo groups compared with
an approximate -6 mg/dL reduction in the liraglutide group. Fasting plasma insulin levels 
compared with baseline were unchanged in the liraglutide group, increased by 30% across 
the efinopegdutide dose groups, and decreased by 17% in the placebo group (MSD; data on 
file).
The 24-hour assessments of vital signs measured in a substudy showed treatment and non-
dose-dependent related effects. There was a decrease in 24-hour mean SBP from baseline to 
the last measurement in the efinopegdutide dose groups relative to placebo. The placebo-
subtracted mean reduction in SBP was -4.6 mm Hg, -4.4 mm Hg, and -9.8 mm Hg for the 
5.0 mg, 7.4 mg, and 10.0 mg dose groups, respectively. Similarly, there efinopegdutide was a 
decrease in 24-hour mean DBP from baseline to the last measurement in the efinopegdutide
dose groups relative to placebo. The placebo-subtracted mean reduction in DBP 
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Semaglutide 1.0 mg SC Q1W is an approved dose for T2DM and is associated with weight 
loss that is expected to reduce LFC. Notably, higher doses of semaglutide are approved for 
obesity and in late stage development for NASH. Although semaglutide is not currently 
indicated in the broad NAFLD population, there is experience from ongoing clinical studies
and no unanticipated safety issues have been reported. This was the rationale to consider 
semaglutide as an active comparator at the dose of 1.0 mg Q1W. Furthermore, the study 
population will contain a large proportion of participants with T2DM for which semaglutide 
is indicated; based on a recent large meta-analysis the global prevalence of NAFLD among 
T2DM patients was 55.5% [Younossi, Z. M., et al 2019].
Based on available data to date from preclinical and clinical findings, efinopegdutide was 
found to be generally well tolerated. Potential adverse effects that have developed in clinical 
testing to date include gastrointestinal intolerance and increases in HR. Both appear to be 
generally consistent with effects reported for other agents in the GLP-1 receptor agonist 
class.
The majority of TEAEs were related to the gastrointestinal system, with nausea, vomiting, 
events concerning abdominal discomfort/distension/pain, eructation, and dyspepsia being the 
most frequently reported. To improve gastrointestinal tolerability, this study will use a 
8-week dose-escalation regimen as gradual dose-escalation of GLP-1 agonists have been
shown to successfully reduce the proportion of participants experiencing dose-limiting 
nausea and vomiting.
The increases in HR associated with administration of efinopegdutide have generally 
increased with dose. Therefore, in addition to routine monitoring of HR at each study visit, 
participants that experience an increase in HR >100 bpm (tachycardia) of any duration 
associated with symptoms the study investigator considers potentially related to cardiac 
ischemia, congestive heart failure and/or hemodynamic compromise will be discontinued 
from study intervention (see Section 7.1).
Also observed, and specific to participants with T2DM treated with efinopegdutide, were 
isolated increases in FPG. While glucagon and GLP-1 agonism have counteracting effects on 
glucose control, dual agonism of GLP-1 and GCGR generally leads to improved glucose 
control in participants with T2DM as the effects of GLP-1 to increase insulin secretion 
appear to overcome the effects of glucagon agonism to increase endogenous glucose 
production. However, it is possible that some participants may be more sensitive to the 
glucagon agonism induced by efinopegdutide than to the GLP-1 agonism, and these 
participants may have plasma glucose concentrations increased by treatment with 
efinopegdutide. As participants with severe obesity, such as those enrolled in this study, are 
at risk to develop prediabetes and diabetes over time, the glycemic status of all participants 
enrolled will be monitored throughout the duration of study.
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Given the partial similarities in the mode of action with other approved GLP-1 receptor 
agonists, other potential adverse human effects include pancreatitis and elevations in 
calcitonin. Therefore, in addition to the routine assessment of AEs, the following safety 
measures are included to monitor and address these potential effects: participants with 
personal or family histories of medullary thyroid carcinoma or multiple endocrine neoplasm 
type-2 syndrome as well as personal history of pancreatitis will be excluded from 
participating in the study, and those enrolled will undergo periodic monitoring of calcitonin, 
and amylase/lipase.
Given the lack of available treatment options for patients with NASH, the serious potential 
health risks of progressive fibrosis and cirrhosis, and the available preclinical and clinical 
data summarized above and in the IB that indicate efinopegdutide may be an effective 
treatment for NASH, the benefit-to-risk assessment for conducting this study is considered to 
be favorable.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In males and females aged 18 to 70 years (in Taiwan, aged 20 to 70 years; in South Korea, 
aged 19 to 70 years [Appendix 7]) with NAFLD:
Objectives
Endpoints
Primary
•
To evaluate the effect of efinopegdutide 
versus semaglutide on mean relative 
reduction from baseline in LFC after 
24 weeks.
•
Hypothesis (H1): Efinopegdutide is 
superior to semaglutide with respect to 
mean relative reduction from baseline in 
LFC after 24 weeks.
•
Hypothesis (H2): Efinopegdutide is 
superior to semaglutide by 10% or more 
with respect to mean relative reduction 
from baseline in LFC after 24 weeks.
•
LFC (%) measured by MRI-PDFF 
(evaluated by BICR)
•
To evaluate the safety and tolerability of 
efinopegdutide compared with 
semaglutide.
•
AEs
•
Discontinuation of study intervention due 
to AEs
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CCI
).


PRODUCT: MK 6024  
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The currently approved dose of semaglutide is 1.0 mg SC Q1W for T2DM. Based on 
multiple epidemiologic studies, the NAFLD population contains a large proportion of 
individuals with T2DM, thus we anticipate the T2DM population will be well represented in 
this study with an enrollment cap of approximately 60% in each of the arms. As a higher 
dose of semaglutide is in late stage development for the treatment of NAFLD/NASH, the 
results from this study of semaglutide 1.0 mg Q1W will be used to model anticipated changes 
in LFC with higher doses to inform on the relative efficacy of efinopegdutide 10.0 mg Q1W.
The approximate 4-week screening period will allow time before randomization to obtain 
laboratory results that are needed to determine the participant’s eligibility for the study. 
Participants enrolled in this study will likely have no prior experience with injection of 
medication; therefore, injection training of participants/caregivers by the study staff on the 
use of the prefilled syringes/pens for injection will be performed on Day 1 and V7/Week 4. 
Injection training will be provided at other visits as needed. The duration of the treatment 
period in this study is 24 weeks, which should be sufficient to capture the maximal or near-
maximal relative reductions of LFC in the active doses. The 5-week post-treatment follow-up 
visit is designed to assess safety by collecting data on SAEs or resolution of ongoing SAEs 
that occurred since the last dose of study intervention.
The incorporation of an IA will inform on administrative decisions regarding other aspects of 
the efinopegdutide program. In addition, the IA may be used to support potential termination 
of the study for futility based on poor LFC (MRI-PDFF) response and/or safety and 
tolerability issues.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
One of the key goals of this study is to demonstrate the efficacy of efinopegdutide in the 
treatment of individuals with NAFLD. Participants will have images of the liver obtained by 
MRI-PDFF which will be centrally analyzed by BICR. The primary efficacy endpoint is the 
effect of efinopegdutide versus semaglutide on mean relative reduction (%) from baseline in 
LFC measured by MRI-PDFF after 24 weeks of treatment with the image analysis performed 
by BICR. MRI-PDFF is a highly accurate noninvasive measure of the proportion of fat 
content of a tissue. This technique separates the water and fat signals in the image using the 
difference in magnetic resonance frequencies of protons in water and fat. It represents the 
percentage ratio of fat signal over the sum of fat and water signal. MRI-PDFF can be used for 
measuring LFC over the entire liver and is usually reported as a single value averaged over 
the whole liver. MRI-PDFF is an established methodology for quantitative assessment of 
LFC that has been assessed as a primary or secondary endpoint in Phase 2 clinical 
development programs for NASH [Madrigal Pharmaceuticals, Inc. 2017] [Bautz, D. 2018] 
[Harrison, S. A., et al 2018].
The secondary efficacy endpoints that will be assessed include the effect of efinopegdutide
versus semaglutide on mean absolute reduction from baseline in LFC measured by 
MRI-PDFF (evaluated by BICR) after 24 weeks of treatment, and the changes from baseline 
after 24 weeks in body weight and lipid metabolism. Body weight reduction is an anticipated 
089F7K


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CCI
).


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expected at higher doses of semaglutide that may be approved in the future for NASH and 
will inform on the relative efficacy of efinopegdutide.
The basis for the 24-week duration of study intervention in this study was informed first, by
the 12 week period to reach steady-state exposures using a dose-titration approach, and 
second, by the need to allow sufficient time for GLP-1 and glucagon receptor agonism 
mediated weight loss to occur to obtain a robust assessment of the reduction in LFC in both 
active treatment arms. The rationale for a 24-week study duration is supported by the lack of 
significant reductions in LFC observed in 12-week studies with other GLP-1 agonists in 
individuals with T2DM and overweight patients with T2DM [Tang, A., et al 2015] [Smits, 
M. M., et al 2016] while significant reductions observed with longer durations of treatment.
In a study where participants were treated with exenatide (n 19) and liraglutide (n 6) for 
24 weeks, a significant relative reduction of 42% in LFC was observed, with parallel 
reductions in body weight (5.0 kg) and in A1C (1.6%) [Cuthbertson, D. J., et al 2012]. More 
recently, the results of the Lira-NAFLD study (N 68) showed participants with inadequately 
controlled T2DM treated with liraglutide for 24 weeks experience a significant 31% 
reduction in LFC (MRI-PDFF) compared with participants with intensification of their 
antidiabetic treatment with insulin. This study also showed that the effect of liraglutide 
treatment on liver fat was mainly driven by body weight loss [Petit, J. M., et al 2017].
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
This study may be terminated early for safety concerns or futility by the TA-EOC (see 
Section 9.7).
5
STUDY POPULATION
Male and female participants with NAFLD between the ages of 18 and 70 years (inclusive) 
(in Taiwan, between the ages of 20 and 70 years; in South Korea, aged 19 to 70 years
[inclusive] [Appendix 7]) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has an LFC ≥10% as assessed by MRI-PDFF at V2/MRI-PDFF.
Note: Prior MRI-PDFF imaging of the liver performed ≤2 months of V1/Screening,
obtained from the same study qualified imaging center(s), and imaged per the Site 
Imaging Manual for this study may be acceptable to determine LFC % as part of 
eligibility.
2. Has a BMI ≥25 kg/m2 and ≤50 kg/m2 at the time of V1/Screening.
3. Has stable weight (based on self-reporting) defined as ≤5% gain or loss of body weight 
for at least 3 months before V1/Screening.
4. Meets 1 of the following criteria:

Has no history of T2DM
OR

Has a history of T2DM with an A1C ≤8.5% at V1/Screening AND controlled by diet 
or a stable dose of metformin for the 3 months before V1/Screening.
Note: Antihyperglycemic agents, other than metformin, are not permitted.
Demographics
5. Is male or female, from 18 years to 70 years of age (inclusive) (in Taiwan, from 20 years 
to 70 years of age [inclusive]; in South Korea, from 19 years to 70 years [inclusive]
[Appendix 7]), at the time of signing the informed consent.
Female Participants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 5 weeks
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after the last dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the 
first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are in 
Section 8.3.7.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR and/or the PK 
substudy. However, the participant may participate in the main study without 
participating in FBR and/or the PK substudy.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
Metabolic/Endocrine
1. Has a history of T1DM, diabetic ketoacidosis, or diabetes secondary to pancreatitis or 
pancreatectomy.
2. Has a history of obesity with a known secondary cause (eg, Cushing’s disease/syndrome).
3. Has an ongoing, inadequately controlled hypothyroidism or hyperthyroidism.
Note: Participants taking thyroid hormone replacement therapy must be on stable doses 
for at least 6 weeks before V1/Screening.
4. Has a history of glucagonoma.
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5. Has a personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasm type-2 syndrome.
6. Has a calcitonin value of ≥50 pg/mL (≥50 ng/L) at V1/Screening.
7. Has symptomatic hyperglycemia that, in the investigator’s opinion, requires immediate 
initiation, adjustment, or addition of antihyperglycemic therapy.
Cardiovascular
8. Has significant systemic or major illnesses including recent events (≤6 months before 
V1/Screening) of congestive heart failure (NYHA functional class III to IV of the 
American Heart Association), unstable angina, myocardial infarction, arterial 
revascularization, stroke, or transient ischemic attack.
9. Has a history of pathologic, symptomatic, or sustained tachyarrhythmia (eg, atrial 
fibrillation, sustained supraventricular tachycardia, symptomatic non-sustained 
supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation).
10. Has a history of Wolff-Parkinson-White syndrome or congenital long QT syndrome.
11. Has an average triplicate seated BP reading of SBP ≥160 mm Hg and/or DBP ≥100 mm 
Hg at V1/Screening.
Note: If the participant meets this exclusion criterion AND the investigator believes that 
the value can be explained by reversible cause (eg, anxiety, recent exertion, etc.), the BP
measurements can be repeated (ie, in triplicate with at least 2 minutes between 
measurements) after the participant has rested for at least 10 minutes OR BPs can be 
retested at an unscheduled screening visit. If repeat measurements still meet this 
exclusion criterion, the participant must be excluded.
12. Has an average triplicate seated HR reading of <50 bpm or >100 bpm.
Note: If the participant meets this exclusion criterion AND the investigator believes that 
the value can be explained by reversible cause (eg, anxiety, recent exertion, etc.), the HR
measurements should be repeated (ie, in triplicate with 2 minutes between measurements) 
after the participant has rested for at least 10 minutes. If the participant has a resting 
sitting HR <50 bpm or >100 bpm on repeat (ie, average of 3 consecutive measurements), 
the participant must be excluded.
Gastrointestinal and Hepatic
13. Has a history or evidence of chronic liver disease other than NAFLD or NASH, including 
but not limited to, hepatitis B as defined by the presence of HBsAg, hepatitis C as defined 
by the presence of HCV RNA or positive hepatitis C antibody (anti-HCV), drug-induced 
liver disease, autoimmune liver disease, primary biliary cholangitis, primary sclerosing 
cholangitis, Reye Syndrome, Wilson’s disease, alpha-1-antitrypsin deficiency, 
hemochromatosis, or known bile duct obstruction.
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14. Has a known history of cirrhosis:

Fibrosis score >3 based on a historical liver biopsy or a liver stiffness score >14 kPa 
based on a historical FibroScan®.
Note: Participants with a historical diagnosis of NASH (F0 to F3) by liver biopsy 
(local reading) within 6 months of V1/Screening could be eligible to enroll in the 
study.

Evidence of decompensated liver disease including but not limited to ascites, 
esophageal or gastric variceal bleeding, hepatocellular carcinoma, hepatic 
encephalopathy, splenomegaly, or spontaneous bacterial peritonitis.
15. Has a history of acute or chronic pancreatitis.
16. Has a history of a bariatric surgical procedure or a known clinically significant gastric 
emptying abnormality (eg, severe gastroparesis or gastric outlet obstruction).
Psychiatric-Related
17. Has a previous or current history of a clinically significant eating disorder (eg, anorexia 
nervosa, bulimia, or binge-eating).
18. Has a history of severe psychiatric disorders (eg, schizophrenia, bipolar disorder, etc.), 
major depressive disorder, or any lifetime history of suicide attempt.
Other Medical Conditions
19. Has a history of malignancy ≤5 years before providing documented informed consent for 
the study except for squamous or basal cell carcinomas of the skin and carcinomas in situ
of the cervix.
20. Has a clinically active hematologic disorder (eg, aplastic anemia, symptomatic anemia, 
myeloproliferative or myelodysplastic syndromes, proliferative bone marrow disorder, 
thrombocytopenia) and/or hemostasis disorder (eg, Von Willebrand disease, hemophilia, 
Factor V Leiden thrombophilia, sickle-cell disease, polycythemia, leukemia).
21. Has HIV as assessed by medical history or current use of antiretroviral therapy.
22. Has undergone a major surgery (eg, requiring general anesthesia) within 3 months before 
providing documented informed consent for the study, or has not fully recovered from 
surgery, or has major surgery planned during the participation of the current study.
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
23. Has a history of organ transplantation, except for corneal transplant.
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24. Has received blood products ≤2 months before V1/Screening, and/or donated blood 
products ≤1 month before V1/Screening, and/or plans to donate blood products 
throughout the duration of the study.
25. Has active diabetic proliferative retinopathy or a history of maculopathy.
Note: Participants with non-proliferative diabetic retinopathy may participate in the 
study.
26. Has untreated obstructive sleep apnea.
Prior/Concomitant Therapy
27. Has known allergies, hypersensitivity, contraindication, or intolerance to the active 
ingredients and/or excipients of efinopegdutide or semaglutide.
28. Has been treated with any GLP-1 receptor agonist or investigational GLP-1/GCGR
co-agonist within the 6 months before V1/Screening.
29. Has been treated with thiazolidinediones (ie, pioglitazone, rosiglitazone) within the 
6 months before V1/Screening.
30. Has previous or current use of prescription weight-management medications (including 
but not limited to orlistat, topiramate and/or phentermine, lorcaserin, naltrexone and/or 
bupropion), or over-the-counter weight-loss medications or therapies within the 3 months
before V1/Screening.
31. Has been treated with systemic corticosteroid medication within the 3 months before 
V1/Screening or is likely to require treatment with systemic corticosteroid medication 
during the study treatment period (for longer than 2 consecutive weeks in duration).
Note: Participants using inhaled, intranasal, intra-articular, or topical corticosteroids or 
corticosteroids in therapeutic replacement doses may participate.
32. Has been treated with any of the following medications within the 3 months before 
V1/Screening or is likely to require treatment with the following medications during the 
study treatment period:

Antipsychotic drugs

Anticonvulsants (eg, barbiturates, gamma-aminobutyric acid analogs, hydantoins, 
phenyltriazines, succinimides, valproic acid and its derivatives, carbamazepine, 
zonisamide, and felbamate)

Tricyclic antidepressants, lithium, levodopa, and dopamine receptor agonists
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33. Is currently on treatment with selective serotonin reuptake inhibitors (eg, fluoxetine, 
sertraline, paroxetine, escitalopram, citalopram, dapoxetine, seproxetine, zimelidine, 
mesembrine, reboxetine) and/or serotonin-norepinephrine reuptake inhibitors 
(eg, venlafaxine, duloxetine, desvenlafaxine, milnacipran, fluvoxamine) that is not a 
stable dose for at least 3 months before V1/Screening.
34. Is currently on treatment with an antihypertensive therapy that is not a stable dose for at 
least 3 months before V1/Screening.
Note: Beta blockers (systemic and ophthalmic) or medications with sympathomimetic 
activity (eg, pseudoephedrine, phenylpropanolamine, inhaled albuterol, methylphenidate) 
are prohibited.
35. Is currently on treatment with an antihyperlipidemic therapy that is not a stable dose for 
at least 1 month before V1/Screening.
36. Is currently on treatment with >100 IU/day of vitamin E AND the dose has not been 
stable for at least 3 months before V1/Screening.
37. Is on treatment with anticoagulants (eg, warfarin, heparin).
38. Is on treatment with or has used drugs associated with NAFLD (eg, amiodarone, anabolic 
steroids, chemotherapeutic agents [ie, 5-fluorouracil, tamoxifen, irinotecan, cisplatin, and 
asparaginase], cocaine, dronedarone, estrogens at doses greater than those used for 
hormone replacement or contraception, methotrexate, tetracycline [intravenous 
administration at high doses], valproic acid, and other known hepatotoxins [ie, drugs with 
a warning of hepatotoxicity in the package insert]) ≤6 months before V1/Screening.
39. Has a recent history of drug abuse (defined as within 3 years of V1/Screening) or is a 
current user of recreational or illicit drugs at the time of V1/Screening.
40. Is currently on treatment with or is likely to require treatment with a prohibited 
medication listed in Section 6.5.
Prior/Concurrent Clinical Study Experience
41. Is currently participating in or has participated in an interventional clinical study and 
received an investigational compound or used an investigational device ≤3 months 
(≤6 months for a NAFLD or NASH interventional clinical study with an investigational 
compound or device) before participating in this current study. Participants enrolled in 
observational studies or COVID-19 vaccine trials may be included and will be reviewed 
on a case-by-case basis for approval by the Sponsor.
Diagnostic Assessments
42. Has a clinically significant ECG abnormality that requires further diagnostic evaluation 
or intervention (eg, new arrhythmia, conduction disturbance) at V1/Screening.
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43. Has an inability to have an MRI-PDFF performed due to:

Claustrophobia to a degree that prevents tolerance of an MRI-PDFF scanning 
procedure.
Note: Sedation is permitted at the discretion of the investigator.

Metallic implant of any sort that prevents MRI-PDFF examination including, but not 
limited to, aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, 
neural stimulator, metallic contraceptive device, metallic tattoo, body piercing that 
cannot be removed, cochlear implant, or any other contraindication to MRI-PDFF
examination.
44. Has poor venous access that precludes the routine peripheral blood sampling required for 
this study.
45. Has exclusionary laboratory values as listed in Table 1.
Note: If any of the laboratory exclusion criteria in Table 1 are met at the V1/Screening, 
the site may have the abnormal value retested 1 time.
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Table 1
Laboratory Exclusion Criteria
Parametera
Population
(if applicable)
Study Limit for Exclusion
eGFRb
-
<45 mL/min/1.73 m2
ALT
-
>5 × ULN
AST
-
>5 × ULN
ALP
-
>2 × ULN
Albumin
-
<3.5 g/dL
Total bilirubinc
-
≥1.3 mg/dL
INR
-
>ULN
Lipase
-
>ULN
Triglycerides
-
≥600 mg/dL (≥6.77 mmol/L)
Hemoglobin
Male
Female
<12.0 g/dL (120 g/L)
<11.0 g/dL (110 g/L)
Platelet count
-
<140 × 109/L
Bicarbonate
-
<20 mEq/L
Thyroid-stimulating hormone
-
Outside the central laboratory normal range
ALP alkaline phosphatase; ALT alanine aminotransferase; AST aspartate aminotransferase; CKD Epi Chronic Kidney 
Disease Epidemiology Collaboration; eGFR estimated glomerular filtration rate; INR international normalized ratio; 
ULN upper limit of normal; V visit.
a Participants with an exclusionary laboratory value may have 1 repeat determination performed if the investigator 
considers the V1/Screening result to be inconsistent with prior determinations. Only the laboratory test not meeting entry 
criterion should be repeated (not the entire panel). The last laboratory draw/result should be used to assess the exclusion 
criterion.
b Calculated by the central laboratory using the CKD Epi formula.
c Participants with an elevated total bilirubin but with a direct bilirubin within normal limits are eligible.
Other Exclusions
46. Routinely consumes ≥480 mg of caffeine in caffeinated beverages per day.
Note: One cup of coffee contains approximately 120 mg of caffeine. Refer to the label of 
the caffeinated product for individual caffeine content.
47. Has a previous or current history of significant alcohol consumption for a period of more 
than 3 consecutive months within the 24 months before V1/Screening.
Note: Significant alcohol consumption is defined as approximately 7 standard drinks per 
week in females and approximately 14 standard drinks per week in males, on average. 
One standard drink is defined as any beverage containing 14 g of pure alcohol or as 
defined by local guidelines.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strengths Dosage Levels
Route 
of 
Admin
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Group 1
Experi-
mental
Efinopegdutide 
20 mg/mL
Drug
Sterile 
Solution
2.4 mg
1 x 0.12 mL 
Injection Q1W
SC
V3 up to V7
Experi-
mental
IMP
Provided 
Centrally by 
the Sponsor
Group 1
Experi-
mental
Efinopegdutide 
20 mg/mL
Drug
Sterile 
Solution
5.0 mg
1 x 0.25 mL 
Injection Q1W
SC
V7 up to V8
Experi-
mental
IMP
Provided 
Centrally by 
the Sponsor
Group 1
Experi-
mental
Efinopegdutide 
20 mg/mL
Drug
Sterile 
Solution
10.0 mg
1 x 0.5 mL 
Injection Q1W
SC
V8 up to V12
Experi-
mental
IMP
Provided 
Centrally by 
the Sponsor
Group 2
Active 
Compa-
rator
Semaglutide
1.34 mg/mL
Drug
Sterile 
Solution
0.25 mg
1 x 0.19 mL 
Injection Q1W
SC
V3 up to V7
Experi-
mental
IMP
Provided 
Centrally by 
the Sponsor
Group 2
Active 
Compa-
rator
Semaglutide
1.34 mg/mL
Drug
Sterile 
Solution
0.5 mg
1 x 0.37 mL 
Injection Q1W
SC
V7 up to V8
Experi-
mental
IMP
Provided 
Centrally by 
the Sponsor
Group 2
Active 
Compa-
rator
Semaglutide
1.34 mg/mL
Drug
Sterile 
Solution
1.0 mg
1 x 0.74 mL 
Injection Q1W
SC
V8 up to V12
Experi-
mental
IMP
Provided 
Centrally by 
the Sponsor
Admin administration; EEA European Economic Area; IMP investigational medicinal product; NIMP noninvestigational medicinal product; Q1W once every week; 
SC subcutaneous; V visit.
Notes:
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
For the efinopegdutide 2.4 mg dose, site personnel must expel the contents of the efinopegdutide 10.0 mg prefilled syringe into a sterile empty vial. Only the equivalent 
efinopegdutide 2.4 mg dose will be drawn up into a sterile syringe and administered at the site.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. The rationale 
for selection of doses to be used in this study is in Section 4.3.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to open-label 
efinopegdutide 10.0 mg Q1W SC or semaglutide 1.0 mg Q1W SC.
6.3.2
Stratification
Intervention randomization will be stratified according to concurrent diagnosis of T2DM at 
the time of randomization (Yes or No). If either proportion of participants, those with T2DM 
or those without T2DM, exceeds approximately 60% of the total targeted sample size, the 
remaining participants enrolled will be restricted to the other stratum within this stratification 
factor.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the interventions administered.
6.4
Study Intervention Compliance
When participants/caregivers administer study intervention at the site, compliance with study 
intervention will be assessed by site personnel observation. The date and time of each dose 
administered in the clinic will be recorded in the source documents, the CRF, and the 
participant diary. At all protocol-specified site visits, the investigator or qualified designee is 
to record whether treatment is taken per protocol. If not, the date(s) and reason for each 
dosing noncompliance must be recorded.
When participants/caregivers administer study intervention at home, compliance with study 
intervention will be assessed at the next site visit. Compliance will be assessed using 
participant diaries. Also, a visual inspection of the prefilled syringes/pens returned (used and 
unused) will be performed (when available). Deviation(s) from the prescribed dosage 
regimen will be recorded in the CRF.
If a discrepancy is noted when comparing entries in the participant’s diary with the amounts 
of returned study intervention, the investigator or qualified designee must discuss the 
discrepancy with the participant and the explanation must be documented. Only the 
participant shall make any changes to the diary entries. The investigator or qualified designee
will be responsible for transferring the appropriate information from the diary onto the 
appropriate CRF.
A record of the number of prefilled syringes/pens dispensed to and returned by each 
participant must be maintained and reconciled with study intervention and compliance 
records at the sites, by qualified site staff. Intervention start and stop dates, including dates 
for intervention delays and/or dose reductions will also be recorded in the CRF.
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medications or vaccinations
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Sponsor Clinical Director or appropriate designee should be contacted if there are any 
questions regarding concomitant or prior therapy.
Both efinopegdutide and semaglutide have the potential to delay gastric emptying based on 
GLP-1 receptor agonism. A delay in gastric emptying can potentially impact the absorption 
of concomitantly administered oral medications. Therefore, caution should be exercised 
when oral medications are concomitantly administered with efinopegdutide or semaglutide.
Prohibited Medications
Medications listed below are prohibited during the treatment and post-treatment follow-up 
periods:

Antihyperglycemic agents: Except metformin or open-label study intervention 
(efinopegdutide or semaglutide)
Note: Sulfonylureas are prohibited unless needed for additional therapy for T2DM
management.

Prescription weight-management medications or over-the-counter weight-loss 
medications or therapies

Corticosteroids: Treatment with oral, intravenous, or intramuscular corticosteroids for 
longer than 2 consecutive weeks in duration or repeated courses of pharmacologic 
doses of corticosteroids are prohibited. Inhaled, intranasal, intra-articular, or topical 
corticosteroids, or corticosteroids in therapeutic replacement doses are allowed
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
Antipsychotic drugs

Anticonvulsants

Tricycle antidepressants, lithium, levodopa, and dopamine receptor agonists

Beta blockers (systemic and ophthalmic) or medications with sympathomimetic 
activity

Anticoagulants (eg, warfarin, heparin)

Drugs associated with NAFLD (eg, amiodarone, anabolic steroids, chemotherapeutic 
agents [ie, 5-fluorouracil, tamoxifen, irinotecan, cisplatin, and asparaginase], cocaine, 
dronedarone, estrogens at doses greater than those used for hormone replacement or 
contraception, methotrexate, tetracycline [intravenous administration at high doses], 
valproic acid, and other known hepatotoxins [ie, drugs with a warning of 
hepatotoxicity in the package insert])
Note: Investigators are encouraged to review each medication for potential 
hepatotoxicity by searching https://ncbi.nlm.nih.gov/books/n/livertox

Antiretroviral therapies

Any other investigational agent
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
6.6
Dose Modification (Escalation/Titration)
6.6.1
Dose-Escalation (Up-Titration)
Efinopegdutide
Efinopegdutide will be supplied as a sterile solution for injection at a concentration of 
20.0 mg/mL. Efinopegdutide will be provided in syringes with an attached 29-gauge needle 
and prefilled with nominal volumes of 0.25 mL or 0.5 mL of efinopegdutide (5.0 mg or 
10.0 mg, respectively). For the efinopegdutide 2.4 mg Q1W dose, the contents of a
efinopegdutide 10 mg (0.5 mL) prefilled syringe will be dispensed into a sterile empty vial 
and 0.12 mL (2.4 mg) will be drawn into a new empty 0.3 mL syringe with 0.01 mL 
gradations.
Participants randomized to efinopegdutide will start the study (V3/Day 1) on a dose of 
2.4 mg Q1W (0.12 mL/injection). The efinopegdutide 2.4 mg Q1W dose will be prepared as 
described above and will be repeated at V4, V5, and V6. Note: These doses will be 
administered at the study site.
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At V7/Week 4 dose-escalation of efinopegdutide will proceed to 5.0 mg (0.25 mL) Q1W.
From V8/Week 8 dose-escalation of efinopegdutide will proceed to 10.0 mg (0.5 mL) Q1W.
For participants who in the opinion of the investigator cannot tolerate the efinopegdutide
10.0 mg Q1W dose, see Section 6.6.2.
Semaglutide
Semaglutide will be supplied as a sterile solution in a prefilled, disposable, single-patient-use 
pen that contains either 2 mg of semaglutide in 1.5 mL (1.34 mg/mL) or 4 mg of semaglutide
in 3 mL (1.34 mg/mL) in the following package configurations: (1) delivers 0.25 mg per 
injection, (2) delivers 0.5 mg per injection, or (3) delivers 1 mg per injection.
Participants randomized to semaglutide will start the study (V3/Day 1) on a 0.25 mg Q1W 
dose. Dose-escalation of semaglutide will proceed to 0.5 mg Q1W after 4 weeks of dosing 
(V7/Week 4) followed by a dose-escalation to 1.0 mg Q1W after another 4 weeks of dosing 
(V8/Week 8). Note: Study intervention will be administered at the study site at V3/Day1
through V7/Week 4.
For participants who in the opinion of the investigator cannot tolerate the semaglutide 1.0 mg
Q1W dose, see Section 6.6.2.
The rationale for the dose-escalation regimens can be found in Section 4.3.
6.6.2
Down-Titration
The intention of the protocol is to maintain participants on the target dose of study 
intervention for as long as possible after randomization.
If a participant experiences intolerance AND has reached the target dose of efinopegdutide
10 mg Q1W or semaglutide 1.0 mg Q1W, the participant’s efinopegdutide or semaglutide
can be down-titrated to 5.0 mg Q1W or 0.5 mg Q1W, respectively, as considered appropriate 
by the investigator. Down-titration below 5.0 mg Q1W for efinopegdutide or 0.5 mg Q1W 
for semaglutide will not be permitted.
If a participant has had efinopegdutide/semaglutide down-titrated from the target dose, then 
up-titration should be considered when clinical tolerance of the study intervention has been 
achieved.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists will not be provided.
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The emergency unblinding call center will be available so that a health care provider can 
obtain information about study intervention in emergency situations where the investigator is 
not available (see Section 8.1.11).
6.9
Standard Policies
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled 
follow-up, even if the participant has discontinued study intervention. Therefore, all 
participants who discontinue study intervention before completion of the protocol-specified 
treatment period will still continue to be monitored in the study and participate in the study 
visits and procedures as specified in Section 1.3 and Section 8.12.5 unless the participant has 
withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
1. The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
2. The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
3. For participants randomized to efinopegdutide, the participant is unable to tolerate at least 
the 5.0 mg Q1W dose. For participants randomized to semaglutide, the participant is 
unable to tolerate at least the 0.5 mg Q1W dose.
4. After a prolonged study intervention interruption (defined as 2 consecutive missed doses) 
and after consultation with the Sponsor.
5. The participant has a confirmed positive serum pregnancy test.
6. The participant/caregiver is unable to administer study intervention by V6.
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Clinical Events
7. The participant has a CTCAE Grade 3 clinical AE that is considered drug-related by the 
investigator.
8. The participant has any CTCAE Grade 4 clinical AE, unless the investigator and Sponsor 
concur that the AE is clearly not causally related to study intervention and that 
continuation/resumption of study intervention does not place the participant at 
unnecessary risk.
The following AE is an exception to #7 and #8. For this event, CTCAE severity grading will 
not be used as a basis for a participant to be discontinued from study intervention. The 
requirement for a participant to be discontinued from study intervention is listed for the AE.

Tachycardia: A participant with tachycardia (mean sitting HR >100 bpm) of any 
duration associated with symptoms that the study investigator considers potentially 
related to cardiac ischemia, congestive heart failure, and/or hemodynamic 
compromise will be discontinued from study intervention. Concerning symptoms 
might potentially include chest discomfort, chest pain, shortness of breath, and/or 
lightheadedness.
Note (1): Participants with a minimally symptomatic event that is not sustained or 
recurrent, and who do not meet other discontinuation criteria may continue in the 
study.
Note (2): HR assessments are based on the mean of 3 consecutive values. HR
monitoring and assessment instructions are detailed in Section 8.3.5.
Laboratory Test Abnormalities
9. The participant has a CTCAE Grade 3 laboratory abnormality considered drug-related by
the investigator, if clinically significant medical intervention is required to treat the event
and/or the abnormality leads to hospitalization.
10. The participant has any CTCAE Grade 4 laboratory abnormality that requires clinically
significant medical intervention to treat the event and/or the abnormality leads to
hospitalization. Continuation/resumption of study medication may be considered if the
investigator and Sponsor concur that the abnormality is clearly not causally related to
study medication and that this does not place the participant at unnecessary risk.
The following laboratory abnormalities are exceptions to #9 and #10. For these events,
CTCAE severity grading will not be used as a basis for a participant to be discontinued from
study intervention. The requirements for a participant to be discontinued from study
intervention are listed for each laboratory abnormality.

Abnormalities of ALT and/or AST: If the participant has abnormal ALT and/or 
AST meeting criteria specified in Appendix 9 and no other cause for the combination 
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant 
(or their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.1.3
Consent and Collection of Specimens for the PK Substudy
The investigator or medically qualified designee will explain the PK substudy consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to the PK substudy. A copy of the informed consent will be given to the participant before 
performing any procedure related to the PK substudy.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician (or a qualified designee), to ensure that the participant qualifies for the study.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization (V3/Week 0), site personnel will add the treatment/randomization number to 
the participant identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified requirements (see Sections 5.1 and 5.2), and record prior medication taken 
by the participant within 3 months before V1/Screening. The site may rely on participant 
report for this information.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study on the appropriate eCRF.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
After all required screening procedures have been completed and a participant’s eligibility 
has been confirmed, the study randomization visit will be registered in IVRS.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
089F7K


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PRODUCT:  MK 6024  
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will take home the written instructions (V3 only) and will be instructed to review these 
materials at home.
2. Participants/caregivers will be expected to administer the study intervention 
(efinopegdutide or semaglutide) under the guidance of the site staff.

Administration of study intervention should occur after completion of all study 
procedures including the collection of all fasting blood samples.
8.1.8.6
Dispense Open-Label Study Intervention
Participants will be dispensed open-label study intervention (efinopegdutide or semaglutide) 
at scheduled study visits from V3/Week 0 (Day 1) through V7/Week 4.
At study visits V7/Week 4 through V11/Week 20, study intervention kits will be dispensed to 
participants to self-administer study intervention at home.
Refer to Section 8.1.9 for further details.
8.1.8.7
Witnessed Dosing
Administration of study intervention will be witnessed by the investigator and/or qualified 
study staff at V3/Week 0 through V7/Week 4. Dosing should occur after completion of all 
study procedures including the collection of all fasting blood samples.
During the treatment period:
1. Retraining on the administration of study intervention will be provided as needed during 
the study and documented by site staff as appropriate.
2. Participants/caregivers should be instructed to refer to the written instructions when 
administering injections of the study intervention at home.
Notes:

No coaching by site staff will be provided to the participant/caregiver during study 
intervention administration unless deemed necessary.

If a participant/caregiver is unable to administer study intervention, the site staff may 
administer the dose of study intervention to the participant through V5/Week 2.

If a participant/caregiver is unable to administer study intervention by V6/Week 3, 
they will be discontinued from study intervention.
089F7K


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(',&'.' ).'$'C+$)!/'#!%),$*&'9!((#$!+$)+
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CCI
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CCI
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CCI
).


PRODUCT:  MK 6024  
82
PROTOCOL/AMENDMENT NO.:  001 02  
MK 6024 001 02 FINAL PROTOCOL
26 AUG 2021
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the event causes the participant to be excluded from the study or is the 
result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure.
From the time of intervention randomization through 5 weeks after the last dose of study 
intervention, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.  
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
089F7K


PRODUCT:  MK 6024  
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment including 
placebo run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event.
Report all
Previously reported –
Follow to 
completion/termination
; report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 calendar 
days of learning 
of event
DILI drug induced liver injury; ECI event of clinical interest; NSAE nonserious adverse event; SAE serious adverse 
event.
089F7K


PRODUCT:  MK 6024  
84
PROTOCOL/AMENDMENT NO.:  001 02  
MK 6024 001 02 FINAL PROTOCOL
26 AUG 2021
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
089F7K


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).


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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If after the 
study has begun changes are made to primary and/or key secondary hypotheses or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but before database lock, will be documented in a sSAP 
and referenced in the CSR for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR.
Other planned analyses (ie, those specific to the analysis of PK data and FBR) will be 
documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized here. The comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
A Phase 2a, Randomized, Active-Comparator-Controlled, Open-Label
Study to Evaluate the Efficacy and Safety of Efinopegdutide (MK-6024) 
in Individuals With Nonalcoholic Fatty Liver Disease
Treatment Assignment
Participants (approximately 130) will be randomized in a 1:1 ratio 
between 2 treatment groups: (1) efinopegdutide 10.0 mg Q1W or
(2) semaglutide 1.0 mg Q1W. Randomization will be stratified by T2DM 
status (Yes or No).
Analysis Populations
Efficacy: FAS
Safety: APaT
Primary Endpoint
Relative reduction (%) from baseline in LFC at Week 24.
Key Secondary Endpoint
Not applicable.
Statistical Methods for 
Key Efficacy Analyses
The primary efficacy analysis will compare the efficacy of efinopegdutide 
to semaglutide in relative reduction (%) from baseline in LFC at Week 24. 
The difference (efinopegdutide minus semaglutide) in means and the 
associated 90% CI and p-value will be provided based on a cLDA model.
For the primary hypotheses, efinopegdutide will be considered superior to 
semaglutide if the 1-sided p-value is <0.05 (ie, lower bound of the 2-sided 
90% CI excludes zero). If the test of superiority is successful, and if the 
lower bound of the 2-sided 90% CI is at least 10%, efinopegdutide will be 
considered superior to semaglutide by 10% or more.
Statistical Methods for 
Key Safety Analyses
For analyses in which 95% CIs will be provided for the between-treatment 
difference (efinopegdutide minus semaglutide) in the percentage of 
participants with events, these analyses will be performed using the M&N 
method [Miettinen, O. and Nurminen, M. 1985].
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Interim Analyses
An IA is planned for administrative purposes. In addition, the IA may be 
used to assess futility. The IA is planned to be performed once ≥25 
participants in the efinopegdutide group have had LFC measured by MRI-
PDFF at the Week 24 assessment.
The study may stop for futility if the posterior probability is <5% that the 
true mean relative reduction from baseline in LFC is ≥30% for the 
efinopegdutide group.
Multiplicity
The Type-I error rate will be controlled at 1-sided =0.05 using an 
ordered testing procedure. H1 (superiority) will be tested first. H2 
(superiority by 10% or more) will be tested only if the success criterion of 
H1 is met.
Sample Size and Power
The planned sample size is approximately 130 participants.
The sample size was chosen based on the primary endpoint, relative 
reduction (%) from baseline in LFC at Week 24, assuming a true treatment 
difference of approximately 19.4%, a common SD of 20%, and 10% 
dropouts.
(H1) A sample size of 65 participants per arm provides approximately 
99% power to establish that efinopegdutide is superior to semaglutide, 
with a 1-sided =0.05.
(H2) A sample size of 65 participants per arm provides approximately 
80% power to establish that efinopegdutide is superior to semaglutide by
at least 10%, with a 1-sided =0.05.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a randomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented by the IRT vendor.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
For analysis purposes, the baseline assessment is considered the one closest to but before or 
on the day of randomization (Day 1).
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9.4.1
Efficacy Endpoints
Primary Efficacy Endpoint

Mean relative reduction (%) from baseline in LFC measured by MRI-PDFF 
(evaluated by BICR) after 24 weeks.
Secondary Efficacy Endpoints

Mean absolute reduction (%) from baseline in LFC measured by MRI-PDFF 
(evaluated by BICR) after 24 weeks.

Mean percent change from baseline in body weight after 24 weeks.

Mean change from baseline in fasting lipid levels over 24 weeks.
Efficacy endpoints are further described in Section 4.2.1.1.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory safety tests, and vital signs.
Safety parameters are described in Section 4.2.1.2.
9.4.3
Pharmacokinetic Endpoint
The key PK endpoint for efinopegdutide is Ctrough.
Additional details are in Section 4.2.1.3.
9.4.4
Pharmacodynamic Endpoints
PD endpoints are biomarkers and/or composite scores reflecting liver inflammation and 
fibrosis including ELF, CK-18 M30, and Pro-C3.
Additional details are in Section 4.2.1.4.
9.4.5
Immunogenicity Endpoints
Immunogenicity endpoints are the incidence and magnitude (titer) of ADA to efinopegdutide.
Additional details are in Section 4.2.1.5.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The FAS population will serve as the primary population for all efficacy analyses. All 
randomized participants who have at least 1 injection (including only partial) of study 
intervention and have at least 1 assessment will be included in this population. Participants 
will be included in the treatment group to which they are randomized.
For analyses that require a baseline value, participants with a missing baseline value will be 
excluded.
9.5.2
Safety Analysis Population
Analyses of safety will be performed in the APaT population, consisting of all randomized 
participants who received at least 1 injection (including only partial) of study intervention. 
Participants will be included in the treatment group corresponding to the study treatment they 
received for the analysis of safety data. This will be the randomized treatment group for all 
participants except for those who take incorrect study intervention for the entire treatment 
period. Such participants will be included in the treatment group corresponding to the study 
intervention actually received. Any participant who receives both correct and incorrect study 
intervention injections will be analyzed according to the randomized treatment group and a 
narrative will be provided for any events that occur during the injection period for which the 
participant was incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Safety analysis will be based on observed data only. No imputation will be performed for 
missing data.
9.5.3
Pharmacokinetic Analysis Population
The population for PK data analysis will include all participants with at least 1 measurable 
PK sample after treatment with efinopegdutide.
9.5.4
Pharmacodynamic Analysis Population
The population for the PD endpoints will be the FAS population. All randomized participants 
who have at least 1 injection (including only partial) of study intervention and have at least 
1 assessment for those analyses for which this is required will be included in this population.
9.5.5
Immunogenicity Analysis Population
The population for immunogenicity analysis will include all participants with at least 1 ADA 
assay result after treatment with efinopegdutide.
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9.6
Statistical Methods
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type-I error control strategy are described in Section 9.8. Nominal p-values (ie, unadjusted 
for multiplicity) may be computed for other efficacy analyses for descriptive purposes rather
than for assessing statistical significance. All statistical tests will be conducted at the 0.05
(1-sided) level.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the exploratory objectives will be described in the sSAP.
The primary efficacy estimand (treatment policy) used for this study, following the guidance 
in ICH E9 (R1) [European Medicines Agency 2020], has the following 5 attributes:
1. The treatment condition of interest and, as appropriate, the alternative treatment 
condition to which the comparison will be made: intervention with efinopegdutide or 
semaglutide.
2. The population of patients targeted by the clinical question: individuals with NAFLD.
3. The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question: relative reduction (%) from baseline in LFC.
4. The specification of how to account for other intercurrent events to reflect the 
scientific question of interest: Discontinuation of study treatment, down-titration of 
study treatment, and taking additional medication are intercurrent events of interest. A 
treatment policy approach will be taken for intercurrent events. Thus, responses 
following intercurrent events are of interest for the estimand.
5. The population-level summary for the endpoint which provides the basis for a 
comparison between-treatment conditions: difference in the mean relative reduction 
(%) from baseline at Week 24.
9.6.1.1 Primary Efficacy Endpoint
The primary approach for addressing the primary hypotheses will use a cLDA method 
proposed by Liang and Zeger [Liang, K-Y. and Zeger, S. L. 2000]. This model assumes a 
common baseline mean across treatment groups within strata and a different mean for each 
treatment group at the Week 24 post-baseline time point. In this model, the response vector 
consists of the baseline value and the calculated relative reduction (%) from baseline at the 
Week 24 post-baseline time point. Time is treated as a categorical variable so that no 
restriction is imposed on the trajectory of the means over time. The analysis model will also 
adjust for treatment, time, stratum (Section 6.3.2), treatment by stratum interaction, time by 
treatment, and time by stratum interaction. The treatment difference (efinopegdutide versus 
semaglutide) in terms of mean relative reduction (%) from baseline in LFC after 24 weeks
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will be estimated and tested from this model. An unstructured covariance matrix will be used 
to model the correlation among repeated measurements.
A p-value for the comparison of efinopegdutide versus semaglutide <0.05 (1-sided) will be 
considered statistically significant. If this is significant, and if the lower bound of the 2-sided 
90% CI is at least 10%, efinopegdutide will be considered superior to semaglutide by 10% or 
more.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups within each stratum. Of note, if there are no missing data, the estimated 
treatment difference from the above cLDA model will be identical to that from a traditional 
longitudinal ANCOVA model which uses the baseline value as a covariate. However, unlike 
longitudinal ANCOVA, the cLDA model accounts for variability in the baseline values, thus 
providing more accurate standard errors and CIs for individual treatment effects. Moreover, 
this model allows the inclusion of participants who are missing either the baseline or the 
Week 24 post-baseline measurement, thereby increasing efficiency.
The model-based least squares mean change from baseline for each treatment group and 
difference (with CI) between-treatment groups at the Week 24 post-baseline time point will 
be summarized.
Some participants who discontinue from the study before their Week 24 assessment may
have a post-randomization LFC measurement before discontinuation. For the primary 
analysis at the Week 24 timepoint, the Week 24 assessment used in the analysis will be the 
assessment that is closest to the Week 24 nominal visit (Day 168) that is on or after relative 
Day 28.
The primary analysis approach is based on an assumption that the mechanism for missing 
data is ‘missing at random’. If significance is achieved in the first hypothesis test (H1), 
sensitivity analyses of relative reduction (%) from baseline in LFC will be performed to 
assess the robustness of the primary analysis results to violations of the ‘missing at random’ 
assumption. The sensitivity analyses will be described in the sSAP.
9.6.1.2 Secondary Efficacy Endpoints 
All secondary efficacy endpoints will be analyzed using the same cLDA model as described 
for the primary endpoint in Section 9.6.1.1. For analysis of absolute reduction from baseline 
in LFC, the response vector will consist of observed baseline and post-baseline values. For 
other endpoints except TG, the response vector will consist of the baseline value and the 
calculated percent changes from baseline. For analyses of TG, the response vector will 
consist of log-transformed baseline and post-baseline values. The treatment difference in
terms of mean percent changes from baseline to a given time point will be estimated from 
this model through back-transformations.
Table 6 summarizes the analysis strategies for the primary and secondary efficacy endpoints.
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Table 6
Analysis Strategy for Key Efficacy Variables
Endpoint
Approach
Statistical Method
Missing Data Approach
Primary Endpoint
Mean relative reduction (%) from 
baseline in LFC
Primary
cLDA
Model-based
Secondary Endpoints
Mean absolute reduction from baseline 
in LFC 
Primary
cLDA
Model-based
Mean percent change from baseline in 
body weight 
Primary
cLDA
Model-based
Mean percent change from baseline in 
lipid profile (Total cholesterol, HDL-C, 
LDL-C, Non-HDL-C, TG, and apoB)
Primary
cLDA
Model-based
apoB apolipoprotein B; cLDA constrained longitudinal data analysis method; HDL C high density lipoprotein
cholesterol; LDL C low density lipoprotein cholesterol; LFC liver fat content; TG triglycerides.
9.6.2
Analysis Methods for Safety Analyses
Safety and tolerability will be assessed, comparing efinopegdutide to semaglutide, by clinical 
review of all relevant parameters including AEs, laboratory tests, and vital signs. The 
primary approach to analysis of safety will include all data through 24 weeks on treatment 
including the 5-week follow-up assessment (data out to the follow-up assessment will be 
considered as on treatment based on a 35-day relative day cutoff post last dose).
Adverse Events
AEs will be coded using the standard MedDRA and grouped according to SOC.
The analysis of safety results will follow a tiered approach (Table 7). The tiers differ with 
respect to the analyses that will be performed. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. No AEs 
have been designated as Tier 1 for this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for between-
treatment differences in the proportion of participants with events.
Membership in Tier 2 requires that at least 4 participants in any treatment group exhibit the 
event. All other AEs and PDLCs will belong to Tier 3. The threshold of at least 4 events was
chosen because the 95% CI for the between-group difference in percent incidence will
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always include zero when the treatment groups each have fewer than 4 events and thus would
add little to the interpretation of potentially meaningful differences.
In addition, adjudication-confirmed AEs (ie, pancreatitis), summary measures of AEs 
consisting of the percentage of participants with any AE, with a drug-related AE, with a 
SAE, with an AE which is both drug-related and serious, who discontinued due to an AE, 
and who died will be considered Tier 2 endpoints.
The 95% CIs will be performed using the M&N method [Miettinen, O. and Nurminen, M. 
1985].
Because many 95% CIs may be provided without adjustment for multiplicity, the CIs should 
be regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in AEs and PDLCs.
Tier 3 Events
Safety endpoints that are not Tier 2 events will be considered Tier 3 events. Only point 
estimates by treatment group will be provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory and vital signs 
parameters, summary statistics for baseline, on treatment, and change from baseline values 
will be provided by treatment group.
Adjudicated Adverse Experiences
For AEs prespecified for adjudication (see Section 10.1.4.1), results of adjudication will also 
be provided as a listing in the CSR for this study. Further details may be provided in the 
sSAP.
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Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any serious AE 
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4 of participants in 
1 of the treatment groups)
X
X
Adjudicated AEs
X
X
Tier 3
Specific AEs, SOCs, or PDLCs (incidence <4 of participants in 
all the treatment groups)
X
Change from baseline results (laboratory tests, ECGs, vital signs)
X
AE adverse event; CI confidence interval; ECG electrocardiogram; PDLC predefined limit of change; SOC system 
organ class; X results will be provided.
9.6.3
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed using tables and/or graphs. No statistical hypothesis tests will 
be performed on these characteristics. The number and percentage of participants screened 
and randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables, baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
9.6.4
Analysis Methods for Pharmacokinetic Analyses
The details of PK analyses will be provided in a pharmacometric analysis plan. 
9.7
Interim Analyses
An IA is planned for administrative purposes. In addition, the IA may be used to assess 
futility. The IA is planned to be performed once ≥25 participants in the efinopegdutide
treatment group have had LFC measured at the V12/Week 24 assessment. Key endpoints to 
be evaluated include LFC, body weight, AEs, and laboratory PDLC.
The IA will be performed by an internal independent statistician and scientific programmer 
who will have no other responsibilities associated with the study, and results will be 
reviewed by the TA-EOC.
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
One participant develops a CTCAE Grade 5 AE that is considered drug-related by the 
investigator
Note: As described in Section 7.1, discontinuation for tachycardia does not use CTCAE 
grading. If 3 participants in the same treatment group meet the tachycardia 
discontinuation criterion AND the events are considered drug-related by the investigator, 
the siDMC will be triggered.
The results of the IA and the safety data review (if conducted) will not be shared with the 
investigators before the completion of the study. The processes by which recommendations 
and decisions are reached and communicated for the safety data review will be documented 
in a protocol-specific siDMC charter.
9.8
Multiplicity
The Type-I error rate will be controlled at 1-sided 0.05 using an ordered testing procedure. 
H1 (superiority) will be tested first. H2 (superiority by 10% or more) will be tested only if 
the success criterion for H1 is met.
9.9
Sample Size and Power Calculations
9.9.1
Efficacy
The planned sample size is approximately 130 participants (65 participants per arm). The 
sample size was chosen based on the mean relative reduction (%) from baseline in LFC 
measured by MRI-PDFF at Week 24, assuming a treatment difference of approximately 
19.4% and a dropout rate (without a Week 24 value) of 10% in each treatment group. The 
value of 19.4% is derived based on the following additional assumptions: 20% treatment 
difference among participants who complete 24 weeks of treatment (approximately 80% of 
the study population) and 10% to 15% treatment difference among participants who 
discontinue treatment prematurely but have a measurement in the range for Week 24 
(approximately 10% of the study population). The half-width of the 90% CI is expected to be 
6.1%.
Based on the above assumptions, the study has approximately 99% power to demonstrate that 
efinopegdutide is superior to semaglutide (H1) and approximately 80% power to demonstrate 
that efinopegdutide is superior to semaglutide by at least 10% (H2), at a 1-sided 0.05 for 
each hypothesis.
Table 10 displays the power for H1 and H2 under various assumptions for the difference and 
SD.
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Table 10
Power (%) for Hypothesis 1/Hypothesis 2 Under Various Assumptions
True SD of Relative Reduction (%)
From Baseline in LFC at Week 24
True Difference in Mean Relative Reduction (%) From Baseline
15
20
25
15
>99/55.9
>99/97.4
>99/>99
20
>99/38.3
>99/85.2
>99/>99
25
94.3/28.8
>99/69.4
>99/94.3
LFC liver fat content; SD standard deviation.
The power is calculated based on a sample size of 65 participants per arm, a dropout rate of 10% (ie, 10% missing values 
at Week 24), and a 1 sided 0.05.
9.9.2
Safety
Given the sample size of 65 participants per arm, Table 11 provides examples of differences 
in proportions in AEs between efinopegdutide and semaglutide that would have a 95% CI 
that excludes zero.
Table 11
Examples of Adverse Event Incidences for Which the 95% Confidence Interval
for the Difference Would Exclude Zero
Efinopegdutide
n/N (%)
Semaglutide
n/N (%)
Difference in % Versus Semaglutide
Estimate (95% CI)a
4/65 (6.2%)
7/65 (10.8%)
9/65 (13.8%)
0/65 (0.0%)
1/65 (1.5%)
2/65 (3.1%)
6.2 (0.4, 14.8)
9.2 (1.2, 19.3)
10.8 (1.4, 21.7)
AE adverse event; CI confidence interval; M&N Miettinen and Nurminen; n number of participants with an AE; 
N population size.
a Based on the M&N method [Miettinen, O. and Nurminen, M. 1985].
9.10
Subgroup Analyses
The primary efficacy endpoint will be summarized for each of the following baseline defined 
subgroups:

Concurrent diagnosis of T2DM at the time of randomization (Yes or No)

Age (≥65 years or <65 years)

BMI (>30 kg/m2 or ≤30 kg/m2)

LFC (>median or ≤median)

Sex (male or female)
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9.11
Compliance (Medication Adherence)
Compliance data for study intervention will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
For each participant, percent compliance (reflecting the percent of time on study intervention 
from the first dose until study intervention discontinuation) and percent adherence (reflecting 
the percent of time on study intervention from the first dose until study discontinuation) will 
be calculated using the following formulas:
Compliance (%) 
Number of Compliant Weeks
× 100%
Number of Weeks in the Treatment Period
Adherence (%) 
Number of Compliant Weeks
× 100%
Number of Weeks in the Study Period
As the study intervention is a weekly injection, the week that the participant received an 
injection of the study intervention following the time of dose administration (Section 8.1.9)
will be considered compliant weeks. However, participants will be considered noncompliant 
for those weeks that the study intervention CRF indicates general compliance problems.
The number of weeks in the treatment period is defined as the number of weeks from the 
week of the first dose of study intervention to the week of the last dose of study intervention. 
For percent adherence, the number of weeks in the study is the total number of weeks from 
the week of the first dose to the week of study completion (Week 24) or withdrawal from the 
study (up to Week 24), excluding the 5 weeks of follow-up post last dose.
Summary statistics will be provided on percent compliance and percent adherence by 
treatment group.
9.12
Extent of Exposure
The extent of exposure to study intervention will be evaluated by summary statistics and 
frequencies for the “Number of Weeks on Study Intervention” by treatment group.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:

Results in death

Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.

Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.

Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
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•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
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•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
089F7K


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10.8
Appendix 8: Other Medical Device: Complaints Including Product Quality 
Complaint, Malfunction, Serious Injury, Death, Fetal Distress/Fetal Death and 
Congenital Anomaly: Definitions and Reporting
Not applicable.
089F7K


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10.10 Appendix 10: Common Terminology Criteria for Adverse Events Version 5.0
The descriptions and grading scales found in the NCI CTCAE, Version 5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Qui
ck_Reference_5x7.pdf) will be used for AE reporting except as noted in Section 7.1.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
A1C
Glycated Hemoglobin
ABPM
Ambulatory Blood Pressure Monitoring
ADA
Anti-Drug Antibodies
ADL
Activities of Daily Living
ADME
Absorption, Distribution, Metabolism, and Excretion
AE
Adverse Event 
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
APaT
All Participants as Treated
apoB
Apolipoprotein B
AST
Aspartate Aminotransferase
BICR
Blinded Independent Central Review
BMI
Body Mass Index
BP
Blood Pressure
bpm
Beats Per Minute
CAC
Clinical Adjudication Committee
CI
Confidence Interval
CK-18 M30
Cytokeratin 18 Antibody M30
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
cLDA
constrained Longitudinal Data Analysis Method
Cmax
maximum Plasma Concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CSR
Clinical Study Report
Ctrough
trough Concentration
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
D
Day
DBP
Diastolic Blood Pressure
DC
Discontinuation
DILI
Drug-Induced Liver Injury
DNA
Deoxyribonucleic Acid 
DPP-4
Dipeptidyl Peptidase-4
ECG
Electrocardiogram 
ECI
Event of Clinical Interest
eCRF
electronic Case Report Form
EDC
Electronic Data Collection 
eGFR
estimated Glomerular Filtration Rate
ELF
Enhanced Liver Fibrosis
ELISA
Enzyme-Linked Immunosorbent Assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT
End of Treatment
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FPG
Fasting Plasma Glucose
FSH
Follicle Stimulating Hormone 
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Abbreviation
Expanded Term
GCGR
G-protein Coupled Glucagon Receptor
GCP
Good Clinical Practice 
GI
Gastrointestinal
GCKR
Glucokinase Regulatory Protein
GLP
Good Laboratory Practice
GLP-1
Glucagon-like Peptide-1
GLP-1R
Glucagon-like Peptide-1 Receptor
H1, H2
Hypothesis 1, Hypothesis 2
HA
Hyaluronic Acid
HbA1C
Glycated Hemoglobin
HBsAg
Hepatitis B Surface Antigen
hCG
human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HDL-C
High Density Lipoprotein-Cholesterol
HIV
Human Immunodeficiency Virus
HR
Heart Rate
HRT
Hormone Replacement Therapy
HSD17B13
Hydroxysteroid 17-Beta Dehydrogenase 13
IA
Interim Analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
IgG
Immunoglobulin G
ID
Identification
IEC
Independent Ethics Committee
IND
Investigational New Drug 
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IVRS
Interactive Voice Response System
LDL-C
Low Density Lipoprotein-Cholesterol
LFC
Liver Fat Content
LS
Least Squares
LYPLAL1
Lysophospholipase-like Protein 1
M&N
Miettinen and Nurminen
MBOAT7
Membrane Bound O-Acyltransferase Domain-Containing 7
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
Multiple Endocrine Neoplasia Syndrome Type 2
MetS
Metabolic Syndrome
MRI-PDFF
Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction
MRL
Merck Research Laboratories
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NAFLD
Nonalcoholic Fatty Liver Disease
NASH
Nonalcoholic Steatohepatitis
NCI
National Cancer Institute
NYHA
New York Heart Association
PD
Pharmacodynamic
089F7K


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11
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