Conditions: Nonalcoholic Steatohepatitis
Keywords: Non-alcoholic fatty liver disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 183
Healthy volunteers: no

Brief summary:
This study will evaluate the effect of each dose of MK-3655 versus placebo on the percentage of individuals with NASH resolution without worsening of fibrosis after 52 weeks. The primary hypothesis of the study is that at least 1 dose of MK-3655 is superior to placebo with respect to the percentage of individuals with NASH resolution without worsening of fibrosis after 52 weeks.

Detailed description:

Arms:
arm 1: Following a 2-week placebo run-in, participants will receive MK-3655 50 mg by subcutaneous (SC) injection once every 4 weeks (Q4W) for 52 weeks. arm 2: Following a 2-week placebo run-in, participants will receive MK-3655 100 mg by SC injection Q4W for 52 weeks. arm 3: Following a 2-week placebo run-in, participants will receive MK-3655 300 mg by SC injection Q4W for 52 weeks. arm 4: Following a 2-week placebo run-in, participants will receive Placebo by SC injection Q4W for 52 weeks.

Interventions: intervention 1: MK-3655 intervention 2: Placebo
Intervention descriptions: intervention 1: MK-3655 50, 100 or 300 dose for injection intervention 2: Matching placebo to MK-3655

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT04583423
Document Date:           24-Aug-2022           
A Phase 2b Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of MK-3655 in Individuals 
With Pre-cirrhotic Nonalcoholic Steatohepatitis


PRODUCT: MK-3655  
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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 LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-3655 in Individuals With Pre-cirrhotic Nonalcoholic 
Steatohepatitis
Protocol Number: 001-05
Compound Number: MK-3655
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
134888
EudraCT
2019-003048-63
Approval Date: 24 August 2022
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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 05
24-AUG-2022
This amendment was created to harmonize follow-up safety monitoring of all 
study participants through Week 64 (previously only WOCBP were followed 
through Week 64).
Amendment 04
01-JUN-2022
This amendment was created primarily to modify the IA futility criterion based 
on an updated assessment of the minimum LFC response supportive of study 
continuation.
Amendment 03
22-SEP-2021
This amendment was created primarily to expand the participant population to 
include premenopausal women.
Amendment 02
05-MAY-2021
This amendment was created primarily to enhance operational efficiency of this 
study.
Amendment 01
19-FEB-2021
This amendment was created primarily to transition the committee used to 
supplement the routine study monitoring conducted in this study from the 
Sponsor’s siDMC to an eDMC. Additional changes included corrections and 
clarifications to the protocol language.
Original Protocol
30-JUL-2020
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
To harmonize follow-up safety monitoring of all study participants through Week 64 (previously only WOCBP were followed through 
Week 64).
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Primary Change
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities 
(SoA)
4.1 Overall Design
4.3.3 Rationale for Dose 
Interval and Study Design
8.1.8.8 Telephone Contact
8.3.10 Pregnancy Testing
8.4.1 Time Period and 
Frequency for Collecting 
AE, SAE, and Other 
Reportable Safety Event 
Information
Revised the approximate duration of 
participation of all participants in the study 
from 64 weeks to 72 weeks.
To harmonize follow-up safety monitoring of all 
study participants through Week 64 (previously 
only WOCBP were followed through Week 64).
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Section # and Name
Description of Change 
Brief Rationale 
8.11.6 Participants 
Discontinued From Study 
Intervention but Continuing 
to Be Monitored in the Study
8.11.7 Post-Treatment Visit 
and Telephone Contacts
9.6.2 Analysis Methods for 
Safety Analyses
Additional Changes
5.2 Exclusion Criteria
Added GLP-1 agonists under weight loss 
medication in Table 1 Stability Definitions for 
Medications and Other Substances.
To indicate approval of GLP-1 agonists for the 
treatment of obesity.
8.3.10 Pregnancy Testing
Clarified pregnancy testing.
Clarification
8.4 Adverse Events (AEs), 
Serious Adverse Events 
(SAEs), and Other 
Reportable Safety Events
Removed “AE and/or” from the sentence
discussing medication error, misuse, or abuse.
To align with the EU CTR.
Throughout document
Minor editorial changes.
To provide clarity.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA)................................................................................20
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................30
2.2.1
Pharmaceutical and Therapeutic Background .............................................30
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.2.1
MK-3655 Preclinical Overview.........................................................32
2.2.2.2
MK-3655 Clinical Overview .............................................................33
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................36
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................42
4.2.1.1
Efficacy Endpoints.............................................................................42
4.2.1.2
Patient-Reported Outcomes ...............................................................43
4.2.1.3
Safety Endpoints................................................................................44
4.2.1.4
Pharmacokinetic Endpoint.................................................................44
4.2.1.5
Immunogenicity Endpoints................................................................44
4.2.1.6
Pharmacodynamic Endpoints.............................................................44
4.2.1.7
Planned Exploratory Biomarker Research.........................................45
4.2.1.7.1
Planned Genetic Analysis ........................................................45
4.2.1.8
Future Biomedical Research..............................................................46
4.2.2
Rationale for the Use of Placebo .................................................................46
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................46
4.3
Justification for Dose...........................................................................................47
4.3.1
Starting Dose for This Study........................................................................47
4.3.2
Maximum Dose/Exposure for This Study ...................................................47
4.3.3
Rationale for Dose Interval and Study Design ............................................47
4.4
Beginning and End of Study Definition .............................................................49
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4.4.1
Clinical Criteria for Early Study Termination .............................................50
5
STUDY POPULATION ................................................................................................50
5.1
Inclusion Criteria.................................................................................................50
5.2
Exclusion Criteria................................................................................................53
5.3
Lifestyle Considerations......................................................................................61
5.3.1
Diet and Activity Counseling.......................................................................61
5.3.2
Alcohol Restrictions.....................................................................................61
5.4
Screen Failures.....................................................................................................61
5.5
Participant Replacement Strategy......................................................................61
6
STUDY INTERVENTION............................................................................................62
6.1
Study Intervention(s) Administered...................................................................62
6.2
Preparation/Handling/Storage/Accountability .................................................64
6.2.1
Dose Preparation..........................................................................................64
6.2.2
Handling, Storage, and Accountability........................................................64
6.3
Measures to Minimize Bias: Randomization and Blinding..............................65
6.3.1
Intervention Assignment..............................................................................65
6.3.2
Stratification.................................................................................................65
6.3.3
Blinding........................................................................................................65
6.4
Study Intervention Compliance..........................................................................65
6.5
Concomitant Therapy..........................................................................................66
6.5.1
Rescue Medications and Supportive Care ...................................................67
6.6
Dose Modification ................................................................................................67
6.7
Intervention After the End of the Study............................................................67
6.8
Clinical Supplies Disclosure................................................................................67
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...........................................................71
7.3
Lost to Follow-up .................................................................................................71
8
STUDY ASSESSMENTS AND PROCEDURES........................................................72
8.1
Administrative and General Procedures ...........................................................72
8.1.1
Informed Consent.........................................................................................72
8.1.1.1
General Informed Consent.................................................................73
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................73
8.1.2
Inclusion/Exclusion Criteria ........................................................................73
8.1.3
Participant Identification Card.....................................................................73
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8.1.4
Medical History ...........................................................................................74
8.1.5
Prior and Concomitant Medications Review...............................................74
8.1.5.1
Prior Medications...............................................................................74
8.1.5.2
Concomitant Medications..................................................................74
8.1.6
Assignment of Screening Number...............................................................74
8.1.7
Assignment of Treatment/Randomization Number.....................................74
8.1.8
Study Compliance (Intervention/Diet/Activity/Other) ................................75
8.1.8.1
Diet and Activity Counseling/Monitoring .........................................75
8.1.8.2
Assessment of Alcohol Consumption................................................75
8.1.8.3
Self-injection Training (Participant and/or Caregiver)......................75
8.1.8.4
Witnessed Dosing ..............................................................................75
8.1.8.5
Dispense Single-Blind and Double-Blind Study Intervention...........76
8.1.8.6
Dispense/Review Participant Dosing Diary.......................................76
8.1.8.7
Investigational Product Accountability..............................................77
8.1.8.8
Telephone Contact .............................................................................77
8.1.9
Study Intervention Administration ..............................................................78
8.1.9.1
Timing of Dose Administration.........................................................78
8.1.10
Discontinuation and Withdrawal .................................................................79
8.1.10.1
Withdrawal From Future Biomedical Research ................................79
8.1.11
Participant Blinding/Unblinding..................................................................79
8.1.12
Calibration of Equipment.............................................................................80
8.2
Efficacy Assessments ...........................................................................................80
8.2.1
Liver Fat Content by MRI-Estimated Proton Density Fat Fraction.............80
8.2.2
Liver Biopsy (Histology) and Assessment of Disease.................................81
8.2.3
Glycemic and Lipid Metabolism .................................................................81
8.2.4
Patient-Reported Outcomes .........................................................................82
8.3
Safety Assessments...............................................................................................82
8.3.1
Physical Examinations.................................................................................82
8.3.2
Height...........................................................................................................83
8.3.3
Body Weight Assessment and Monitoring ..................................................83
8.3.4
Body Mass Index .........................................................................................84
8.3.5
Model for End-Stage Liver Disease-Sodium Score.....................................84
8.3.6
12-Lead Electrocardiogram .........................................................................84
8.3.7
Vital Signs....................................................................................................84
8.3.8
Dual-Energy X-ray Absorptiometry ............................................................85
8.3.9
Clinical Laboratory Assessments (Hematology, Chemistry, Urinalysis, 
and Other) ....................................................................................................86
8.3.9.1
Bedtime Salivary Cortisol..................................................................87
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8.3.9.2
TSH and FT4......................................................................................87
8.3.9.3
IGF-1..................................................................................................88
8.3.10
Pregnancy Testing........................................................................................88
8.3.11
Suicidal Ideation and Behavior Monitoring.................................................89
8.3.11.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................89
8.3.11.1.1
Columbia-Suicide Severity Rating Scale.................................89
8.3.11.1.2
Patient Health Questionnaire – 9 .............................................90
8.3.12
Adverse Event Monitoring...........................................................................91
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................91
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................92
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......93
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...94
8.4.4
Regulatory Reporting Requirements for SAE .............................................94
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................94
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................95
8.4.7
Events of Clinical Interest (ECIs)................................................................95
8.5
Treatment of Overdose........................................................................................96
8.6
Pharmacokinetics.................................................................................................96
8.6.1
Blood Collection for Serum MK-3655 ........................................................96
8.7
Immunogenicity....................................................................................................97
8.8
Pharmacodynamics..............................................................................................98
8.8.1
Plasma and Serum Pharmacodynamic Samples ..........................................98
8.8.2
Biomarkers/Panels Reflecting Liver Inflammation and Fibrosis.................98
8.9
Biomarkers ...........................................................................................................99
8.9.1
Planned Genetic Analysis Sample Collection..............................................99
8.10
Future Biomedical Research Sample Collection...............................................99
8.11
Visit Requirements.............................................................................................100
8.11.1
Fasting Before Scheduled Visits................................................................100
8.11.2
Scheduling Visits .......................................................................................100
8.11.2.1
Visit Reminders ...............................................................................101
8.11.3
Screening....................................................................................................101
8.11.3.1
Visit 1/Screening..............................................................................101
8.11.3.2
Visit 2/MRI-PDFF ...........................................................................102
8.11.3.3
Visit 3/Liver Biopsy.........................................................................102
8.11.3.3.1
Participants With Historical Liver Biopsies ..........................102
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8.11.3.3.2
Participants Who Require an In-Study Liver Biopsy ............102
8.11.4
Placebo Run-in Period ...............................................................................103
8.11.5
Double-Blind Treatment Period.................................................................103
8.11.6
Participants Discontinued From Study Intervention but Continuing to 
Be Monitored in the Study.........................................................................104
8.11.7
Post-Treatment Visit and Telephone Contacts ..........................................105
9
STATISTICAL ANALYSIS PLAN ...........................................................................105
9.1
Statistical Analysis Plan Summary...................................................................105
9.2
Responsibility for Analyses/In-house Blinding ...............................................107
9.3
Hypotheses/Estimation ......................................................................................107
9.4
Analysis Endpoints.............................................................................................108
9.4.1
Efficacy Endpoints.....................................................................................108
9.4.2
Patient-Reported Outcome Endpoints........................................................108
9.4.3
Safety Endpoints........................................................................................108
9.4.4
Pharmacokinetic Endpoint.........................................................................108
9.4.5
Immunogenicity Endpoints........................................................................109
9.4.6
Pharmacodynamic Endpoints.....................................................................109
9.5
Analysis Populations..........................................................................................109
9.5.1
Efficacy Analysis Population.....................................................................109
9.5.2
Patient-Reported Outcome Analysis Population .......................................109
9.5.3
Safety Analysis Population........................................................................109
9.5.4
Pharmacokinetic Analysis Population .......................................................110
9.5.5
Immunogenicity Analysis Population........................................................110
9.5.6
Pharmacodynamic Analysis Population ....................................................110
9.6
Statistical Methods.............................................................................................110
9.6.1
Statistical Methods for Efficacy Analyses.................................................110
9.6.1.1
Primary Efficacy Endpoint ..............................................................111
9.6.1.2
Secondary Efficacy Endpoints.........................................................111
9.6.2
Analysis Methods for Safety Analyses......................................................113
9.6.3
Summaries of Demographic and Baseline Characteristics ........................115
9.7
Interim Analyses ................................................................................................115
9.8
Multiplicity .........................................................................................................117
9.9
Sample Size and Power Calculations ...............................................................117
9.9.1
Efficacy......................................................................................................117
9.9.2
Safety .........................................................................................................118
9.10
Subgroup Analyses.............................................................................................118
9.11
Compliance (Medication Adherence)...............................................................118
9.12
Extent of Exposure.............................................................................................119
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................120
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......120
10.1.1
Code of Conduct for Clinical Trials...........................................................120
10.1.2
Financial Disclosure...................................................................................122
10.1.3
Data Protection...........................................................................................122
10.1.3.1
Confidentiality of Data ....................................................................123
10.1.3.2
Confidentiality of Participant Records.............................................123
10.1.3.3
Confidentiality of IRB/IEC Information..........................................123
10.1.4
Committees Structure.................................................................................123
10.1.4.1
Executive Oversight Committee......................................................123
10.1.4.2
External Data Monitoring Committee .............................................124
10.1.4.3
Clinical Adjudication Committee (CAC) ........................................124
10.1.5
Publication Policy......................................................................................125
10.1.6
Compliance with Study Registration and Results Posting Requirements .125
10.1.7
Compliance with Law, Audit, and Debarment ..........................................125
10.1.8
Data Quality Assurance .............................................................................126
10.1.9
Source Documents .....................................................................................127
10.1.10
Study and Site Closure...............................................................................127
10.2
Appendix 2: Clinical Laboratory Tests............................................................128
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................130
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................130
10.3.2
Definition of AE ........................................................................................130
10.3.3
Definition of SAE ......................................................................................131
10.3.4
Additional Events Reported.......................................................................133
10.3.5
Recording AE and SAE .............................................................................133
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................136
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................138
10.5
Appendix 5: Contraceptive Guidance..............................................................139
10.5.1
Definitions..................................................................................................139
10.5.2
Contraception Requirements......................................................................140
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................141
10.7
Appendix 7: Country-specific Requirements..................................................146
10.7.1
China-specific Requirements.....................................................................146
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10.7.2
Argentina-specific Requirements...............................................................147
10.7.3
Taiwan-specific Requirements...................................................................147
10.7.4
Japan-specific Requirements .....................................................................147
10.7.5
Korea-specific Requirements.....................................................................148
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 149
10.9
Appendix 9: Approximate Blood Volume Table.............................................150
10.10 Appendix 10: Management of Participants With Elevated Liver Enzymes.151
10.11 Appendix 11: Patient Health Questionnaire - 9 ..............................................153
10.12 Appendix 12: NASH Clinical Research Network (CRN) Scoring System 
for Determining Eligibility and Assessing Secondary Histological 
Endpoints............................................................................................................154
10.13 Appendix 13: eGFR Equations.........................................................................155
10.14 Appendix 14: Common Terminology Criteria for Adverse Events Version 
5.0.........................................................................................................................156
10.15 Appendix 15: Abbreviations .............................................................................157
11
REFERENCES.............................................................................................................161
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LIST OF TABLES
Table 1
Stability Definitions for Medications and Other Substances...........................59
Table 2
Laboratory Exclusion Criteria..........................................................................60
Table 3
Study Interventions..........................................................................................63
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................93
Table 5
Pharmacokinetic Sampling Time Points..........................................................97
Table 6
Analysis Strategy for Key Efficacy Endpoints..............................................113
Table 7
Analysis Strategy for Safety Parameters........................................................115
Table 8
Posterior Probabilities for Observed Differences in % Relative Reduction 
in LFC............................................................................................................116
Table 9
Examples of AE Incidences for Which the 95% CI for the Difference 
Would Exclude Zero......................................................................................118
Table 10
Protocol-Required Laboratory Assessments..................................................129
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LIST OF FIGURES
Figure 1
Study Design....................................................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-3655 in Individuals With Pre-cirrhotic Nonalcoholic 
Steatohepatitis
Short Title: Phase 2b Study of MK-3655 in Individuals with Pre-cirrhotic NASH
Hypotheses, Objectives, and Endpoints:
In males and females aged 18 to 80 years (in Japan and Taiwan, aged 20 to 80 years
[Appendix 7]) with pre-cirrhotic NASH:
Primary Objectives
Primary Endpoints
To evaluate the effect of each dose of 
MK-3655 versus placebo on the proportion 
of individuals with NASH resolution without 
worsening of fibrosis after 52 weeks.
Hypothesis (H1): At least 1 dose of 
MK-3655 is superior to placebo with respect 
to the proportion of individuals with NASH 
resolution without worsening of fibrosis after 
52 weeks.
- NASH resolution (defined as a score of 
0-1 for inflammation, 0 for ballooning, and 
any grade of steatosis) without worsening 
of fibrosis assessed with the NASH CRN 
scoring system (evaluated by BICR)
To evaluate the safety and tolerability of 
MK-3655 compared with placebo.
- AEs
- Discontinuation of study intervention due 
to AEs
Secondary Objectives
Secondary Endpoints
To evaluate the effect of each dose of 
MK-3655 versus placebo on mean percent 
relative reduction from baseline in LFC after 
24 weeks.
- LFC (%) measured by MRI-PDFF 
(evaluated by BICR)
To evaluate the effect of each dose of 
MK-3655 versus placebo on the proportion 
of individuals with ≥1 stage improvement in 
fibrosis without worsening of steatohepatitis 
after 52 weeks.
- ≥1 stage improvement in fibrosis without 
worsening of steatohepatitis (defined as no 
increase in the ballooning, inflammation, 
or steatosis scores) assessed with the 
NASH CRN scoring system (evaluated by 
BICR)
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To evaluate the effect of each dose of 
MK-3655 versus placebo on the proportion 
of individuals with ≥2 point improvement in 
the NAS without worsening of fibrosis after 
52 weeks.
- ≥2 point improvement in the NAS with 
≥1 point improvement in inflammation or 
ballooning without worsening of fibrosis 
assessed with the NASH CRN scoring 
system (evaluated by BICR)
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of individuals with pre-cirrhotic NASH.
Population
Males and females aged 18 to 80 years (in Japan and 
Taiwan, aged 20 to 80 years [Appendix 7]) with pre-
cirrhotic NASH, Stage 2 or 3 liver fibrosis, and a NAS ≥4
with a score ≥1 point in each component (ie, lobular 
inflammation, ballooning, and steatosis).
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participant or Subject
Investigator
Sponsor
Care Provider
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 45.5 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 328 participants will be randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Participants will be randomized in a 1:1:1:1 ratio and dosed Q4W.
Intervention 
Group Name
Drug
(Conc)
Dose 
Strength
Dose 
Frequency
Route of 
Admin
Treatment Period
(V5 to V15)
Use
Group 1
MK-3655 
(33.3 mg/mL)
50 mg
1 × 1.5 mL 
injection 
Q4W
SC
Double-Blind 
Treatment Period 
Test 
Product
MK-3655 
Matching 
Placebo
0 mg
1 × 1.5 mL 
injection 
Q4W
SC
Double-Blind 
Treatment Period 
Placebo
Group 2
MK-3655 
(33.3 mg/mL)
100 mg
2 × 1.5 mL 
injections 
Q4W
SC
Double-Blind 
Treatment Period 
Test 
Product
Group 3
MK-3655 
(100 mg/mL)
300 mg
2 × 1.5 mL 
injections 
Q4W
SC
Double-Blind 
Treatment Period 
Test 
Product
Group 4
MK-3655 
Matching 
Placebo
0 mg
2 × 1.5 mL 
injections 
Q4W
SC
Double-Blind 
Treatment Period 
Placebo
admin=administration; conc=concentration; Q4W=once every 4 weeks; SC=subcutaneous; V=visit.
Other current or former name or alias for the study intervention is
NGM313.
Total 
Number of 
Intervention 
Groups/Arms
4
Duration of 
Participation
Each participant will participate in the study for approximately 72 weeks, 
from the time the participant provides documented informed consent
through the final contact.
After a staged screening period (Visit 1 through Visit 3) of approximately
6 weeks (±28 days), each eligible participant will enter a 2-week, single-
blind placebo run-in period (Visit 4 up to Visit 5/Randomization). On 
completion of the placebo run-in, eligible participants will be randomized 
to receive assigned double-blind intervention and participate through 
Visit 15/Week 52. A post-treatment follow-up visit (Visit 16) will occur
4 weeks after Visit 15. Post-treatment follow-up telephone contacts will be 
performed at Weeks 60 and 64.
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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 an eDMC.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 15.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Administrative and General Procedures
Informed Consent
X
Informed consent must 
be documented before 
any study procedures are 
performed and may be 
completed before V1.
Informed Consent 
for FBR
X
Participation in FBR is 
not required for 
participation in the main 
study.
Inclusion/Exclusion 
Criteria
X
X
X
Alcohol consumption 
assessed as part of 
exclusion criterion #11 
(see Section 5.2).
Participant 
Identification Card
X
X
At the time of 
randomization (V5), the 
site will add the 
treatment/randomization 
number to the participant 
identification card.
Medical History
X
Prior and 
Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assignment of 
Screening Number
X
Contact IVRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Treatment 
Randomization
X
Participants will be 
randomized after 
confirmation of 
eligibility and before D1 
procedures/assessments.
Diet and Activity 
Counseling/ 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
alcohol consumption
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment will be 
performed before 
administration of study 
intervention.
Self-Injection 
Training -
Participant and/or 
Caregiver
X
X
Retraining will be 
performed by site 
personnel at subsequent 
visits, as needed.
In Japan, administration 
of study intervention is 
not allowed by a 
caregiver (see 
Appendix 7).
Witness Dose of 
Study Interventions
X
X
X
X
X
X
X
X
X
X
X
Performed after all 
procedures/assessments 
are complete.
Placebo Dispensing 
(For Run-in Period)
X
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
MK-3655/Matching 
Placebo Dispensing
(For Double-Blind 
Treatment Period)
X
X
X
X
X
X
X
X
X
X
Dispense Participant 
Diary 
X
Review Participant 
Diary (Date and 
location of injection 
and experience)
X
X
X
X
X
X
X
X
X
X
X
X
X
Participants will be 
directed to bring diaries 
back at ALL visits for 
review by site personnel.
Investigational 
Product 
Accountability
X
X
X
X
X
Participants will be 
directed to return all vials 
(used and unused) for 
visual inspection by site 
personnel.
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Telephone Contact
X---------X
(Within 
3 days 
before V2 
and V3)
X-----X
(Wk 2)
X--------------X
(Wks 28, 36, & 
44)
X
X
Telephone contact by the 
investigator/qualified 
designee or site staff will 
be made:
(1) within the 3 days 
before V2 and V3 to 
assess for concomitant 
medications and AEs as 
well as remind 
participants about their 
upcoming appointments,
(2) at Wk 2 to perform a 
C-SSRS assessment,
(3) at Wks 28, 36, and 44
to assess for AEs and 
concomitant medications, 
record body weight, 
assess pregnancy status
(if applicable), and to 
assess compliance with 
study intervention 
administration, and
(4) at Wks 60 and 64 to 
assess for AEs and 
pregnancy status (if 
applicable).
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PRODUCT: MK-3655  
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Efficacy Procedures
MRI-PDFF
X
X
Xa
Assessed by BICR.
Liver Biopsy
X
X
Xb
For management of 
participants with 
historical liver biopsies, 
see Section 8.11.3.3.1.
Assessed by BICR. 
A1C
X
X
X
X
X
X
X
Fasting Plasma 
Glucose
X
X
X
X
X
X
X
X
X
Fasting Lipid 
Profile, apoB, and 
apoA1
X
X
X
X
X
X
Lipid profile includes 
total cholesterol, non-
HDL-C, HDL-C, LDL-C, 
and TG. apoB and apoA1 
will not be collected at 
V1.
Patient-Reported Outcomes
CLDQ NAFLD-
NASH
X
X
X
Perform PROs in the 
order listed in Column 1 
of the SoA.
PGI-S
X
X
X
EQ-5D-5L
X
X
X
Safety Assessments/Procedures
Complete Physical 
Examination 
X
X
X
Directed Physical 
Examination
X
X
X
X
Height
X
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PRODUCT: MK-3655  
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Body Weight
Assessment and 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
At V11 participants will 
be provided digital scales 
to assess body weight at 
home at Wks 28, 36, 
and 44.
BMI
X
MELD-Na score
X
12-lead ECG
X
X
X
Performed after 10 
minutes in a supine 
position and before BP 
and HR assessments.
Vital Signs (HR, BP, 
and Temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HR and BP will be 
collected at all scheduled 
visits. Temperature will 
be collected at V5.
HR and BP performed
after a 10-minute resting 
period.
DXA
X
X
Xc
BMD and body 
composition.
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PRODUCT: MK-3655  
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Urine Pregnancy 
Test (if applicable)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect predose (except 
at DC and V16).
At V11, V12, and V13 
WOCBP will be provided 
pregnancy test kits to 
assess pregnancy status at 
home at Wks 28, 36, 
and 44 (see 
Section 8.3.10).
At V16 WOCBP will be 
provided pregnancy test 
kits to assess pregnancy 
status at home at Wks 60 
and 64 (see 
Section 8.3.10).
Serum hCG will be 
performed when a 
pregnancy is suspected.
FSH
X
If applicable.
PT and INR
X
Hepatitis B (HBsAg) 
and Hepatitis C 
(anti-HCV)
X
For Argentina-specific 
requirements see 
Appendix 7.
ACTH
X
X
X
X
X
X
X
X
X
Samples should be 
collected between 7 AM 
and 10 AM.
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Bedtime Salivary 
Cortisol
X
X
X
X
X
X
X
X
X
X
Salivary cortisol test kits 
will be provided to 
participants at the visit 
prior to the required 
sample collection 
timepoint (except V1). 
Participants are to collect 
bedtime salivary cortisol 
at home between 9 PM 
and midnight the evening 
before the study visit. 
The sample should be 
returned to the site the 
following day (no later 
than 72 hours from the 
time of collection).
TSH
X
X
X
X
X
X
X
FT4
X
X
X
X
X
X
X
IGF-1
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
X
Serum Ketones
X
X
X
X
X
X
X
Includes acetoacetate 
acid and beta-
hydroxybutyrate.
Urinalysis
X
X
X
Bone Biomarkers 
(Serum P1NP and 
CTX)
X
X
X
X
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
C-SSRS: Screening 
Version
X
C-SSRS: Since Last 
Visit Version
X
X
X
X
X
X
X
X
X
X
X
X
X
X
An additional C-SSRS 
assessment will be 
performed at 2 wks after 
randomization by 
telephone contact.
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE Monitoring
X-----------------------------------------------------------------------------------------------------X
X
X
Immunogenicity/PK/PD/Biomarkers
Immunogenicity 
Assay (ADA)
X
X
X
X
X
X
X
Collect predose (except 
at DC and V16).
MK-3655 PK Blood 
Sample
X
X
X
X
X
X
X
X
Collect predose (except 
at DC and V16).
Adiponectin
X
X
X
X
Collect predose (except 
at DC).
Fasting Insulin
X
X
X
X
Collect predose (except 
at DC).
HOMA-IR
X
X
X
X
Fasting FFA
X
X
X
X
Collect predose (except 
at DC).
FIB-4
X
X
X
X
NFS
X
X
X
X
APRI
X
X
X
X
Pro-C3
X
X
X
X
Collect predose (except 
at DC).
Blood for Serum 
Biomarkers
X
X
X
X
X
X
X
Collect predose (except 
at DC).
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Study Period
Screening
Placebo 
Run-in
Double-Blind Treatment
Post-Treatment Follow-up
Notes
Visit Number/Title
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
DC
16
TC
TC
For participants who 
DC study intervention 
early, see Section 8.11.6.
Scheduled Week
-8 to -2
-2
0
D1
4
8
12
16 20 24 32 40 48 52
N/A
56
60
64
Visit Window 
Guideline (Days):
±28
±3
±5
-
+7
Blood for Plasma 
Biomarkers
X
X
X
X
X
X
X
Collect predose (except 
at DC).
Blood for Genetic 
Analysis 
X
Collected from 
randomized participants 
only. See Section 8.9.1.
A1C=glycated hemoglobin; ACTH=adrenocorticotropic hormone; ADA=anti-drug antibodies; AE=adverse event; apoA1=apolipoprotein A1; apoB=apolipoprotein B; 
APRI=AST/platelet ratio index; BICR=blinded independent central review; BMD=bone mineral density; BMI=body mass index; BP=blood pressure; CLDQ NAFLD-
NASH=chronic liver disease questionnaire for nonalcoholic fatty liver disease – nonalcoholic steatohepatitis; C-SSRS=Columbia-Suicide Severity Rating Scale; CTX=collagen 
type 1 cross-linked telopeptide; D=Day; DC=discontinuation; DXA=dual-energy x-ray absorptiometry; ECG=electrocardiogram; FBR=future biomedical research; FFA=free fatty 
acid; FIB-4=fibrosis-4; FSH=follicle stimulating hormone; FT4=free thyroxine; HBsAg=Hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=Hepatitis C 
virus; HDL-C=high density lipoprotein-cholesterol; HOMA-IR=homeostatic model assessment-insulin resistance; HR=heart rate; ICF=Informed Consent Form; IGF-1=insulin-
like growth factor-1; INR=international normalized ratio; IVRS=interactive voice response system; LDL-C=low density lipoprotein-cholesterol; MELD-Na=model for end-stage 
liver disease-sodium score; MRI-PDFF=magnetic resonance imaging-estimated proton density fat fraction; NFS=NAFLD fibrosis score; P1NP=procollagen type 1 N-terminal 
propeptide; PD=pharmacodynamics; PGI-S=Patient Global Impression of Severity; PHQ-9=Patient Health Questionnaire – 9; PK=pharmacokinetic; PRO=patient-reported 
outcomes; Pro-C3=propeptide of type III collagen; PT=prothrombin time; TC=telephone contact; TG=triglycerides; TSH=thyroid-stimulating hormone; V=visit; Wk=week; 
WOCBP=woman/women of childbearing potential.
a For participants who discontinue study intervention AND where at least 4 wks have passed since the first dose of study intervention, the end of study MRI-PDFF should be 
performed as part of the DC visit procedures. See Section 8.11.6.
b For participants who discontinue study intervention AND where at least 12 wks have passed since the first dose of study intervention, the end of study liver biopsy should be 
performed as part of the DC visit procedures. See Section 8.11.6.
c For participants who discontinue study intervention AND where at least 24 wks have passed since the first dose of study intervention, the end of study DXA procedure should be 
performed as part of the DC visit procedures. See Section 8.11.6.
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2
INTRODUCTION
2.1
Study Rationale
MK-3655 is a humanized mAb that selectively activates the FGFR1c/KLB receptor complex. 
MK-3655, formerly NGM313, was initially discovered by NGM Biopharmaceuticals, Inc 
(NGM). In Phase 1 single and multiple ascending dose testing, MK-3655 demonstrated good 
safety and tolerability, a PK profile potentially supporting monthly dosing by subcutaneous 
administration, and biomarker confirmation of robust on-target pharmacology. In a Phase 1b 
study (MK-3655 P005 [NGM 17-0202]; N=25) in obese, insulin-resistant, nondiabetic male 
and female participants, a single dose of MK-3655 resulted in a significant reduction in LFC 
assessed by MRI-PDFF and improved insulin sensitivity assessed by hyper-insulinemic, 
euglycemic clamp. These data support the further development of MK-3655 as a NASH 
therapeutic agent.
The principal goals of this Phase 2b study are to assess whether the pharmacological effects 
observed in earlier studies are seen in the target population of NASH patients with Stage 2 
and 3 fibrosis, to assess whether MK-3655 treatment can achieve histologic improvement of 
NASH activity and fibrosis, to expand the safety and tolerability characterization of 
MK-3655, and to identify optimal doses for further development.
2.2
Background
Refer to the IB for detailed background information on MK-3655.
2.2.1
Pharmaceutical and Therapeutic Background
NAFLD is a condition of increased accumulation of fat (triglycerides) in hepatocytes. 
NAFLD is primarily 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 encompasses a spectrum of disease, ranging from simple 
steatosis to gradual development of chronic inflammation (steatohepatitis or NASH), fibrosis, 
and ultimately cirrhosis. Approximately 3% of the NAFLD population will transition to 
cirrhosis with a mean follow-up of 7.6 ± 4.0 years (range, 0.1 to 23.5 years) [Adams, L. A., 
et al 2005]. Additionally, some patients develop hepatocellular carcinoma without cirrhosis 
[Stine, J. G., et al 2018] [Perumpail, R. B., et al 2015]. 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] [Tholey, D. 2020]. Globally, the 
estimated prevalence of NAFLD is approximately 25% of the adult population and an 
increasing proportion of these cases will be NASH; rising from 20% to 27% between the 
years 2015 and 2030 [Friedman, S. L., et al 2018]. Additionally, NASH has been recognized 
as one of the leading causes of cirrhosis in adults in the US, and NASH-related cirrhosis is 
currently considered the second most common indication for liver transplants in the US
[Younossi, Z. M., et al 2016].
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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, MRI). 
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. The liver biopsy remains the gold standard against which 
noninvasive methods are judged for definitive diagnosis and/or intervention [Rockey, D. C., 
et al 2009] [Chalasani, N., et al 2018].
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] [Food and Drug Administration 2018] 
[Chalasani, N., et al 2018].
The focus of this study is to evaluate MK-3655, a humanized mAb that selectively activates 
the FGFR1c/KLB receptor complex that mediates most or all the metabolic benefits of 
FGF21 and its pharmacologic analogs including insulin sensitization, lipid profile 
improvements, and liver fat reduction [Owen, B. M., et al 2015] [Sanyal, A., et al 2018]. 
FGFR1c/KLB is also considered the principal target mediating the robust anti-steatotic effect 
reported for a FGF19 analog [Owen, B. M., et al 2015] [Harrison, S. A., et al 2018]. Unlike 
FGF21 and FGF19 analogs, MK-3655 selectively activates only FGFR1c/KLB, which may 
confer an optimal therapeutic profile through avoidance of unfavorable effects potentially 
mediated by activation of other FGFR/KLB complexes. FGF21-mediated activation of 
FGFR2/KLB and FGFR3/KLB may potentially contribute to unfavorable effects which have 
been associated with FGF21s including effects on the hypothalamic-pituitary axis, bone, 
heart rate, blood pressure, glucocorticoids, and female reproductive function [Wei, W., et al
2012] [Talukdar, S., et al 2016] [Kim, A. M., et al 2017] [Owen, B. M., et al 2015] [Owen, 
B. M., et al 2013] [Singhal, G., et al 2016]. FGFR4/KLB-mediated modulation of bile acid 
metabolism is presumed to be responsible for the substantial LDL-C elevation seen with 
administration of an FGF19 analog [Harrison, S. A., et al 2018].
Given the central role of insulin resistance in the pathogenesis of NAFLD/NASH, a well-
tolerated insulin-sensitizing agent with beneficial effects on steatosis and other aspects of 
MetS would be a potentially compelling therapeutic option for the dysmetabolic NASH 
population.
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2.2.2
Preclinical and Clinical Studies
Toxicology and clinical data are briefly summarized below. Refer to the MK-3655 IB for a 
more extensive summary of the preclinical and clinical data available for MK-3655.
2.2.2.1
MK-3655 Preclinical Overview
The preclinical safety profile of MK-3655 has been assessed in 3 GLP-toxicology studies in
NHP of up to 28-weeks in duration. MK-3655 does not bind to FGFR1c/KLB in lower 
species; therefore, no toxicology studies have been conducted in other species.
In nonclinical studies, there were no notable effects of MK-3655 on CV, respiratory, or 
neurobehavioral parameters in NHPs. In a 9-week repeat-dose study, MK-3655 was 
generally well tolerated in NHPs with no remarkable treatment-related changes in clinical 
observations or clinical pathology parameters up to the highest dose tested (15 mg/kg; Q2W). 
Body weight loss with associated microscopic changes in adipose tissue (reduced adipocyte 
size and fat content) were observed at all MK-3655 doses.
In a 28-week repeat-dose study, there were no effects noted in electrocardiography, 
ophthalmology, testicular volume, semen analysis, clinical pathology, or T-cell dependent 
antibody responses. Noteworthy findings related to MK-3655 treatment were generalized or 
widespread alopecia without corresponding microscopic changes in most animals, decreased 
food consumption, remarkable body weight loss, decreased fat mass (DXA), decreased bone 
mineral content, amenorrhea (1 animal) with microscopic alterations in female reproductive 
organs, prolonged menstrual cycles, and microscopic changes in adipose tissue (reduced 
adipocyte size and fat content). Alopecia, bone mineral content decreases, and menstrual 
cycle changes were considered likely secondary to body weight loss and adipose tissue 
changes. The amenorrhea and reproductive tract atrophy, both observed in a single female 
NHP, may be due entirely to weight loss and therefore not likely to be relevant to humans.
A subsequent 4-month menstrual cyclicity study in NHP with a 6-month recovery (control 
and 5 mg/kg Q4W groups; n=12 normally cycling females/group) was conducted to provide 
a definitive assessment of menstrual cycle changes in MK-3655 treated animals. In this 
study, NHP (n=12 with a total of 108 menstrual cycles) with demonstrated continuous 
MK-3655 exposure for up to 4 months and pharmacologically-mediated body weight loss 
(-10% to -34% of their prestudy weight) did not have test article-related menstrual cycle 
changes. The NOEL for menstrual cycle changes was 5 mg/kg Q4W (18,000 μg/mL*hour; 
2 times the clinical exposure at 300 mg Q4W). Based on these data, the menstrual cycle 
changes observed in the 28-week repeat-dose toxicity study are attributed to normal 
variability in length of menstrual cycles in NHP, changes in social housing conditions, and/or 
stress/poor body condition resulting from body weight loss (see IB).
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2.2.2.2
MK-3655 Clinical Overview
In clinical data available as of 06-DEC-2020, at least one dose of MK-3655 has been 
administered to 208 participants and at least one dose of placebo or comparator drug has 
been administered to 68 participants across 5 Phase 1 studies (4 completed and 1 ongoing)
(MSD data on file). Safety data are summarized below.
In the MK-3655 P004 study (completed), healthy overweight and obese adult participants 
received single doses of MK-3655 3 mg to 360 mg (n=63) or placebo (n=20) and 53 healthy 
overweight and obese adult participants were randomized to receive MK-3655 10 mg to 
240 mg or placebo (n=15) dosed Q4W for 3 months.
In the MK-3655 P005 study (completed), nondiabetic participants with increased LFC were 
randomized to receive either a single dose of MK-3655 240 mg (n=17) or pioglitazone 45 mg 
(n=8) orally daily for 35 days.
In the MK-3655 P002 study (completed), overweight and obese participants with increased 
LFC received 8 weekly doses of MK-3655 (n=15; 300 mg on Week 1 and 150 mg on 
Weeks 2 through 8) or placebo (n=5).
In the MK-3655 P003 study (completed), healthy Japanese male participants received single 
doses of MK-3655 60 mg to 360 mg (n=18) or placebo (n=6) and healthy Japanese male 
participants received 8 weekly doses of MK-3655 (n=6, 300 mg on Week 1 and 150 mg on 
Weeks 2 through 8) or placebo (n=2).
In the MK-3655 P006 study (ongoing), healthy Chinese male participants received single 
doses of MK-3655 60 mg to 360 mg (n=27) or placebo (n=9) and healthy Chinese male 
participants received 8 weekly doses of MK-3655 (n=9, 300 mg on Week 1 and 150 mg on 
Weeks 2 through 8) or placebo (n=3). Study P006 remains ongoing and blinded to treatment 
at the participant-level.
MK-3655 exposure versus time profiles and PK data suggest MK-3655 displays nonlinear 
kinetics at lower doses, which is anticipated for a mAb that displays target-mediated 
clearance. Based on the 120 mg, 240 mg, and 360 mg SAD dose cohorts in P004, the mean 
half-life (t1/2) increased from approximately 9 days to 14 days with increasing dose level.
PK data from the P002 study indicate that the geometric mean AUCD29-57 (989 day*µg/mL), 
representative of the highest exposures anticipated to be achieved over any 28-day interval in 
that study, was approximately 2.5-fold greater than the 28-day AUC reported following a 
single dose of 360 mg in Study P004 and approximately 3.3-fold greater than the 28-day 
AUC following 240 mg Q4W for 3 months. In the multiple-dose panel of Study P003, the 
28-day AUC following the eighth weekly dose was 1065.80 day*µg/mL.
The ADA results from the completed clinical studies (P002, P003, P004, P005) suggest that 
the incidence of treatment-boosted and treatment-emergent positive participants was <10%. 
The ADA titer values in these studies were near the limit of detection. In addition, the 
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presence of ADA did not appear to affect the PK profiles in these subjects relative to other 
subjects in the same dose group who were negative for ADA.
PD data from the Phase 1 studies demonstrated that MK-3655 appears to be 
pharmacologically active for at least 4 weeks as evidenced by increased adiponectin, 
increased insulin sensitivity, and improved fasting lipid profiles including marked reductions 
in TG, more modest increases in HDL-C, and decreases in LDL-C. Effects on adiponectin 
and fasting lipids are sustained during multiple dosing with MK-3655 in overweight/obese 
participants. Improvement in insulin sensitivity has been most clearly demonstrated in 
Study P005 using hyper-insulinemic-euglycemic clamp following a single dose of MK-3655
in overweight/obese, insulin-resistant participants with elevated LFC. In other Phase 1 
studies, among overweight/obese individuals who were not specifically selected for baseline 
insulin resistance, insulin sensitivity as estimated by HOMA-IR remained similar to baseline 
or trended toward greater insulin sensitivity following multiple doses of MK-3655. 
Furthermore, data from Study P005 showed that over 3 to 5 weeks after a single 240 mg dose 
of MK-3655, LFC measured by MRI-PDFF was substantially reduced.
Single and multiple doses of MK-3655 were generally well tolerated in the clinical program. 
No deaths have occurred. No drug-related SAEs have been reported. No anaphylactic or 
immune-mediated AEs have been reported. The majority of AEs have been mild or 
moderate.
The AE of increased appetite has occurred only in participants randomized to MK-3655 and 
has appeared to be more common at higher doses. Of participants randomized to MK-3655;
9.5% who received a single dose in the SAD portion and 37.7% who received multiple doses 
in the MAD portion in Study P004, 11.8% who received a single dose in Study P005, and 
66.7% who received multiple doses in Study P002 reported AEs of increased appetite. None 
of the participants randomized to placebo or comparator drug in the Phase 1 studies have 
reported increased appetite. Notably, no participants in Study P003 reported increased 
appetite even though this study assessed single doses of MK-3655 tested in Study P004 and 
the multiple-dose regimen of MK-3655 tested in Study P002. No other AEs appeared to be 
potentially dose-related. The reason for the difference in occurrence of increased appetite 
AEs in Study P003 and other Phase 1 studies is unknown.
In contrast to the weight loss observed in NHPs, weight gain has been observed with 
MK-3655 treatment in humans. Body weight increased following single and multiple doses 
of MK-3655. Weight gain generally continued beyond the final dose, likely due to the long 
t1/2 and biological activity of MK-3655. Throughout dosing and follow-up periods, body 
weight gain occurred in the context of unchanged or improved metabolic parameters relative 
to baseline including reduced hepatic fat, greater insulin sensitivity, reduced TG, and 
increased HDL-C.
In the MAD portion of Study P004, weight continued to increase over time in the MK-3655 
groups. Following 3 monthly doses of MK-3655 in healthy overweight participants, 
statistically significant mean weight gain was observed at Day 85 in the 120 mg (3.90 kg ± 
3.84 kg, p=0.007) and 240 mg (3.30 kg ± 2.90 kg, p<0.001) dosing groups. Weight gain in 
the placebo group was not significant (1.03 kg ± 3.36 kg, p=0.313). At the end of the follow-
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up period on Day 141, nominal mean weight gain from baseline was observed in the 60 mg 
(3.78 kg ± 8.09 kg), 120 mg (4.67 kg ± 3.61 kg), and 240 mg (5.27 kg ± 3.48 kg) dosing 
groups. Lesser nominal weight gain from baseline was observed in the placebo group at 
Day 141 (0.63 kg ± 5.57 kg). No statistics were performed for weight change at Day 141.
Weight gain was also observed among participants randomized to multiple doses of 
MK-3655 in Study P002 and Study P003. In these studies, the final dose of MK-3655 was 
administered on Day 50 and weight gain continued for several weeks after the final dose up 
to a maximum placebo adjusted increase of 5% to 6% from baseline. The trajectory and 
magnitude following 150 mg Q1W dosing was similar to that following 120 mg Q4W or 
240 mg Q4W dosing, suggesting that dosing regimens ≥120 mg Q4W do not result in greater 
weight gain. Clinical assessments, including physical examination and laboratory values, do 
not support fluid retention as a major contributor to weight gain. Exploratory analyses in the 
MAD module of Study P004, in Study P002 and in Study P003 using DXA measurements 
suggest the observed increase in body weight is due to increased accumulation of adipose 
tissue.
In both the P002 study and P003 study, greater increases in mean pulse and ventricular rate 
change from baseline were seen in the MK-3655 group than in the placebo group, but the 
between-group differences were typically small in magnitude and of uncertain clinical 
significance. Additionally, no meaningful differences in systolic or diastolic blood pressure 
were observed between the MK-3655 group and the placebo in either study.
Based on the clinical program to date, which has explored exposures above those planned for 
this study, no signals have been identified that would preclude further clinical development.
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.
In clinical studies to date, MK-3655 was found to be well tolerated with a favorable safety 
profile. Importantly, MK-3655 demonstrates a robust and clinically meaningful reduction in 
LFC as well as other beneficial metabolic effects including insulin sensitization, increased 
HDL-C, and decreased TG and LDL-C.
Each participant will have up to 2 liver biopsies. A liver biopsy is the gold standard for the 
assessment of fibrosis stage and disease progression in NASH patients and will be performed 
in this study. Although pain and bruising at the biopsy or incision site are the most common 
complications after a liver biopsy, infection and injury to another organ or prolonged
bleeding from the biopsy or incision site may also occur.
Given the lack of available treatment options for patients with pre-cirrhotic 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 MK-3655 may be 
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an effective and treatment for NASH, the benefit-to-risk assessment for conducting this study 
well tolerated 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 80 years (in Japan and Taiwan, aged 20 to 80 years
[Appendix 7]) with pre-cirrhotic NASH:
Objectives
Endpoints
Primary
To evaluate the effect of each dose of 
MK-3655 versus placebo on the proportion 
of individuals with NASH resolution 
without worsening of fibrosis after
52 weeks.
Hypothesis (H1): At least 1 dose of 
MK-3655 is superior to placebo with 
respect to the proportion of individuals with 
NASH resolution without worsening of 
fibrosis after 52 weeks.
•
NASH resolution (defined as a score of 
0-1 for inflammation, 0 for ballooning, 
and any grade of steatosis) without 
worsening of fibrosis assessed with the 
NASH CRN scoring system (evaluated 
by BICR)
To evaluate the safety and tolerability of 
MK-3655 compared with placebo.
•
AEs
•
Discontinuation of study intervention
due to AEs
Secondary
To evaluate the effect of each dose of 
MK-3655 versus placebo on mean percent 
relative reduction from baseline in LFC 
after 24 weeks.
•
LFC (%) measured by MRI-PDFF 
(evaluated by BICR)
To evaluate the effect of each dose of 
MK-3655 versus placebo on the proportion 
of individuals with ≥1 stage improvement 
in fibrosis without worsening of 
steatohepatitis after 52 weeks.
•
≥1 stage improvement in fibrosis
without worsening of steatohepatitis
(defined as no increase in the 
ballooning, inflammation, or steatosis 
scores) assessed with the NASH CRN 
scoring system (evaluated by BICR)
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Objectives
Endpoints
To evaluate the effect of each dose of 
MK-3655 versus placebo on the proportion 
of individuals with ≥2 point improvement 
in the NAS without worsening of fibrosis 
after 52 weeks.
•
≥2 point improvement in the NAS with 
≥1 point improvement in inflammation 
or ballooning without worsening of 
fibrosis assessed with the NASH CRN
scoring system (evaluated by BICR)
Tertiary/Exploratory
To evaluate the effect of each dose of 
MK-3655 versus placebo on change from 
baseline in glycemic responses after
52 weeks.
•
A1C (glycated hemoglobin)
•
FPG
To evaluate the effect of each dose of 
MK-3655 versus placebo on change from 
baseline in lipid levels after 52 weeks.
•
Lipid profile: cholesterol (total, 
non-HDL-C, HDL-C, LDL-C) and TG
•
apoA1 and apoB
To evaluate the effect of each dose of 
MK-3655 versus placebo on change from 
baseline in NASH-specific quality of life,
health state, and global severity of 
symptoms after 52 weeks.
•
Total score and domain scores as 
measured by CLDQ NAFLD-NASH
•
Rating of global severity of symptoms 
measured by PGI-S
•
Health state description and evaluation
by EQ-5D-5L
To evaluate the PK of each dose of 
MK-3655 at Weeks 0, 4, 8, 12, 24, 52, 
and 56.
•
MK-3655 (serum PK): Trough
concentration
To evaluate ADA to each dose of MK-3655
at Weeks 0, 4, 12, 24, 52, and 56.
•
ADA to MK-3655: Incidence and 
magnitude (titer)
To evaluate the effect of each dose of 
MK-3655 versus placebo on change from 
baseline on PD parameters through
Week 52.
•
Adiponectin
•
Fasting insulin
•
HOMA-IR
•
FFA
•
Body composition assessed by DXA
•
Biomarkers/panels reflecting liver 
inflammation and fibrosis including 
routine liver tests (ALT, AST), FIB-4, 
NFS, APRI, and Pro-C3
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Objectives
Endpoints
To identify molecular (genomic, metabolic, 
and/or proteomic) biomarkers that may be 
indicative of clinical response/resistance, 
safety, PD activity, and/or the mechanism 
of action of MK-3655.
•
Molecular (genomic, metabolic, and/or 
proteomic) determinants using blood 
and/or tissue and association to response
To explore the relationship between genetic 
variation, including but not limited to
PNPLA3, TM6SF2, MBOAT7, GCKR, 
HSD17B13, PPP1R3B, and LYPLAL1 and 
response to the intervention(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in this study.
•
Germline genetic variation and 
association to response
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2b, multi-site, randomized, placebo-controlled, parallel-group, double-blind, 
study of MK-3655 in participants with pre-cirrhotic NASH. This study will be conducted in 
conformance with GCP.
The duration of the study will be approximately 72 weeks (with up to 16 clinic visits) for 
each participant. This will include a 6-week (±28 days) screening period (Visit 1 through
Visit 3); a 2-week single-blind placebo run-in period (Visit 4 up to Visit 5); a 52-week 
double-blind, placebo-controlled treatment period (Visit 5 through Visit 15/Week 52); a post-
treatment follow-up visit (Visit 16) at 4 weeks after Visit 15; and post-treatment follow-up
telephone contacts at Weeks 60 and 64.
Approximately 328 males and females aged 18 to 80 years (in Japan and Taiwan, aged 20 to
80 years [Appendix 7]) with histological confirmation of NASH, NAS ≥4 with a score 
≥1 point in each component (steatosis, ballooning, and lobular inflammation) and a fibrosis 
score of Stage 2 or 3, will be randomized in this study to evaluate the efficacy and safety of 
MK-3655 compared with placebo.
Management of Participants Before Randomization
During the 6-week (±28 days) screening period (Visit 1 through Visit 3), participants will be 
evaluated for study eligibility using the staged process detailed below; Visit 1/Screening, 
Visit 2/MRI-PDFF, and Visit 3/Liver Biopsy. Eligibility for continued study participation 
will be assessed at Visits 1, 4, and 5 based on the criteria detailed in Section 5.
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At Visit 1/Screening, consented participants will complete all Visit 1 procedures as detailed 
in the SoA, as well as be assessed for the availability of historical liver biopsy samples. Liver 
biopsies conducted within 6 months of Visit 1/Screening, for which slides can be obtained 
and submitted to the central laboratory vendor for BICR, are considered adequate for study 
entry as long as the tissue sample is considered adequate for evaluation by the central 
reader(s) and all criteria specified in Sections 5.1 and 5.2 are met.
Screening management after Visit 1/Screening and before Visit 4/Placebo Run-in will occur 
as follows:

Participants with a historical liver biopsy performed within 6 months before 
Visit 1/Screening:
o
Safety laboratory tests (ie, liver function, renal function, and hematological 
parameters) must meet study eligibility criteria assessed at Visit 1/Screening before 
proceeding to Visit 2/MRI-PDFF. Other pending Visit 1/Screening laboratory 
assessment results are not required to proceed to Visit 2/MRI-PDFF.

Note: Participants will be screen failed for any exclusion criteria identified during 
Screening.
o
Biopsy samples will be submitted to the central laboratory vendor for processing and 
BICR if safety laboratory tests (ie, liver function, renal function, and hematological 
parameters) meet study eligibility criteria assessed at Visit 1/Screening.
o
Visit 2/MRI-PDFF may be scheduled/performed before receipt of the liver biopsy 
report from the central laboratory vendor.
o
If LFC by MRI-PDFF is ≥8% as determined by BICR at the iCRO, histology from the 
liver biopsy meets study entry criteria, and all other eligibility criteria are met, the 
participant will proceed to Visit 4/Placebo Run-in.

If LFC by MRI-PDFF or liver histology does not meet study eligibility criteria, 
the participant will be screen failed.
Note: If the historical liver biopsy cannot be assessed for any reason (including 
sample quality), the participant, if agreeable, will proceed through screening 
procedures consistent with the process below for participants who do not have a 
historical liver biopsy within 6 months of Visit 1/Screening.
Participants without a liver biopsy performed within 6 months before Visit 1/Screening:
o
Safety laboratory tests (ie, liver function, renal function, and hematological 
parameters) must meet study eligibility criteria assessed at Visit 1/Screening before 
proceeding to Visit 2/MRI-PDFF.

Note: Other pending Visit 1/Screening laboratory assessment results are not 
required to proceed to Visit 2/MRI-PDFF. Participants will be screen failed for 
any exclusion criteria identified during Screening.
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o
If LFC by MRI-PDFF is ≥8% as determined by BICR at the iCRO and all other 
Visit 1/Screening eligibility criteria are met, the participant will progress to 
Visit 3/Liver Biopsy.
o
If liver histology meets study eligibility criteria at Visit 3 and all other eligibility 
criteria are met, the participant will proceed to Visit 4/Placebo Run-in.
o
If a participant does not meet study eligibility criteria for LFC (Visit 2) or liver 
histology (Visit 3), they will be screen failed following that visit.
Placebo Run-in
Eligible participants will enter the 2-week, single-blind, placebo run-in period at 
Visit 4/Week -2 and will:

Receive training/instructions on the preparation and self-administration of the 
investigational product and be witnessed in the administration of two 1.5 mL 
subcutaneous injections of single-blind investigational product.
Note: Participants will be re-instructed on appropriate injection technique as needed 
based on observed injection experience.

Receive a diary that will be used throughout the study to record experience with self-
injection and immediate/delayed injection reactions.

Receive dietary and activity counseling. Note, at subsequent study visits as specified in 
the SoA, the participant will review the diet and activity guidance sheets. Counseling will
be provided.

Be assessed for suicidal ideation and behavior using the C-SSRS and depression severity 
using the PHQ-9.

Have DXA imaging performed to assess baseline body composition and BMD. If the 
DXA image is unusable due to failing quality control requirements, it will not be 
repeated.
Participants meeting study entry eligibility criteria at Visit 4/Placebo Run-in as detailed in 
Sections 5.1 and 5.2, will proceed to Visit 5/Randomization.
Management of Randomized Participants
At Visit 5/Day 1, participants who meet eligibility criteria will enter the 52-week 
double-blind treatment period. Participants (82 per group) will be randomized in a 1:1:1:1 
ratio to 1 of 4 treatment groups: (1) MK-3655 50 mg Q4W, (2) MK-3655 100 mg Q4W, 
(3) MK-3655 300 mg Q4W, and (4) matching placebo. Participants will administer
2 subcutaneous injections at a volume of 1.5 mL each once every 4 weeks.
Randomization will be stratified according to: (1) concurrent diagnosis of T2DM at the time 
of randomization, (2) fibrosis score (Stage 2 or 3), and (3) region (Japan, East Asia excluding 
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Japan, or Other). 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. 
Note: In Japan, enrollment will not be restricted by this cap, and sites will be able to continue 
to enroll participants with or without T2DM (see Appendix 7).
After completing the 52-week double-blind, placebo-controlled treatment period, participants 
will enter the post-treatment period and complete a follow-up visit 4 weeks after 
Visit 15/Week 52. Post-treatment follow-up telephone contacts will be performed for all 
participants at Weeks 60 and 64.
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in the NCI CTCAE, Version 5.0 (see Section 10.14). Regular safety 
assessments will be performed during the study (see Section 8.3).
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
There will be a non-binding IA performed once ≥25 participants per group have been 
randomized and have completed an MRI-PDFF at the 24-week post-randomization 
assessment. The IA will include a review of MRI-PDFF and safety data. Results of the IA
will be reviewed by an eDMC, who will make a recommendation to continue, modify, or end 
the study according to the plan to be described in detail in the eDMC charter.
4.2
Scientific Rationale for Study Design
The goals of this Phase 2b study design are to provide evidence of efficacy on histological 
endpoints (including NASH resolution and improvement in fibrosis), to obtain adequate dose 
response information to support dose selection for the Phase 3 program, and to assess safety 
and tolerability over 52 weeks in the intended treatment population.
The MK-3655 dose range of 50 mg to 300 mg Q4W evaluated in this study is expected to
enable the identification of the optimal dose and treatment frequency for Phase 3 while 
balancing efficacy, safety, and convenience.
The study treatment period of 52 weeks is based on the timeframe in which a histological 
response with MK-3655 treatment is expected; informed by the experience of other NASH 
programs and for consistency with agency recommendations [European Medicines Agency 
2018] [Neuschwander-Tetri, B. A., et al 2015] [Food and Drug Administration 2018]
[Ratziu, V., et al 2016]. The study design will enable characterization of the treatment effect 
size and variability around the histological endpoints to support planning of statistical 
analyses and powering for Phase 3 studies.
The incorporation of an IA will allow for review of interim efficacy and safety data to inform 
administrative decisions regarding other aspects of the MK-3655 program, and to support 
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potential termination of the study for futility based on poor LFC (MRI-PDFF) response
and/or safety/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 MK-3655 in the treatment 
of individuals with pre-cirrhotic NASH. The primary efficacy endpoint is NASH resolution 
(defined as a score of 0-1 for lobular inflammation, 0 for ballooning, and any grade of 
steatosis) without worsening of fibrosis after 52 weeks of treatment. The primary efficacy 
endpoint is a histological assessment of paired liver biopsies (baseline and end of 52 weeks 
of treatment) performed centrally and blinded to time point, participant, and clinical 
information. The key features of NASH (ie, lobular inflammation, ballooning, and steatosis) 
and changes in fibrosis will be evaluated according to the NASH CRN scoring system (see 
Section 8.2.2 and Appendix 12), which is a validated, semi-quantitative tool used to assess 
treatment response and provides a reliable way to define and quantify the severity of ongoing 
liver injury as assessed by a liver biopsy. The NASH CRN scoring system assesses NASH 
activity and fibrosis stage based on the following scoring scales: lobular inflammation score 
(0-3); hepatocyte ballooning score (0-2); steatosis score (0-3); and fibrosis score (0-4). The 
NAS is calculated as the unweighted sum of the scores for inflammation, ballooning, and 
steatosis and ranges from 0-8 (highest activity).
The main secondary efficacy endpoint is the mean percent relative reduction from baseline in 
LFC measured by MRI-PDFF after 24 weeks of treatment with the data analysis performed 
by a central reading center. 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 some 
Phase 2 clinical development programs for NASH [Madrigal Pharmaceuticals, Inc. 2017]
[Bautz, D. 2018] [Harrison, S. A., et al 2018].
The other secondary efficacy endpoints are histological assessments to support the primary 
efficacy endpoint and include: (1) at least 1 stage improvement in fibrosis without worsening 
of steatohepatitis (defined as no increase in the NAS for ballooning, inflammation, or 
steatosis) after 52 weeks and (2) at least a 2 point improvement in the NAS including at least 
1 point improvement in inflammation or ballooning, without worsening of fibrosis after 
52 weeks.
Exploratory efficacy endpoints that will be assessed include glycemic and lipid metabolism. 
Glycemic efficacy endpoints will include the changes from baseline after 52 weeks of 
treatment in A1C and FPG. A1C reflects average glucose concentrations over the past 3 to 
4 months and, therefore, provides a useful index of the glycemic control of MK-3655 over 
that period. The measurement of FPG will provide insight into the effects of MK-3655 on 
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this endpoint and characterize the earlier time course of glucose control in this study. Lipid 
metabolism endpoints will include changes in baseline after 52 weeks of treatment in 
cholesterol (total, non-HDL-C, HDL-C, LDL-C), TG, apoA1, and apoB. These parameters 
provide insight into the effects of MK-3655 on this endpoint and characterize the time course 
of lipid metabolism in this study.
4.2.1.2
Patient-Reported Outcomes
An evaluation of PROs at Week 0 and Week 52 of treatment will be conducted using the 
CLDQ NAFLD-NASH, PGI-S, and EQ-5D-5L. An assessment of disease impact and 
treatment experience from the participant’s perspective can provide important information in 
evaluation of benefits and risks of a developing medical product. These questionnaires will 
be used to supplement information obtained from the primary and secondary endpoints.
CLDQ NAFLD-NASH
The CLDQ NAFLD-NASH, a NASH-specific version of the CLDQ, measures disease-
specific health-related quality of life. The CLDQ NAFLD-NASH consists of 36 questions 
divided into 6 domains: abdominal symptoms, activity, emotional, fatigue, systemic 
symptoms, and worry. The CLDQ NAFLD-NASH has a 7-point Likert-type response scale 
ranging from 1 (all the time) to 7 (none of the time) with “1” indicating most impairment and 
“7” indicating least impairment. The recall period is “during the last 2 weeks”. The CLDQ 
NAFLD-NASH was first validated in patients with NAFLD, and later validated in NASH 
populations, in 2 separate studies [Younossi, Z. M., et al 2017] [Younossi, Z. M., et al 2019].
PGI-S
To help interpret the data from the CLDQ NAFLD-NASH, a PGI-S question will be included 
in this study and responses will be used as an anchor for characterizing clinically meaningful 
changes. The PGI-S is a single-item question for assessing the severity of overall symptoms 
associated with fatty liver disease. The response options of the PGI-S include: no symptoms, 
mild, moderate, severe, and very severe. Consistent with CLDQ NAFLD-NASH, the recall 
period is “past 2 weeks”. Information from anchor-based analysis using data from this study 
will provide the basis for a CLDQ NAFLD-NASH total score characterization which will be 
useful to interpret PRO data collected within future confirmatory studies. The anchor-based 
approach is proposed in accordance with the 2009 FDA Guidance for Industry, Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
Claims [U.S. Food and Drug Administration 2009].
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The EQ-5D-5L descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
has 5 levels and the participant will be asked to indicate their health state using a 5-level 
rating scale. The EQ visual analog scale records the participant’s self-rated health on a 
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vertical visual analog scale where the endpoints are labeled “best imaginable health state”
and “worst imaginable health state”. This information can be used as a quantitative measure 
of health outcome as judged by the individual participant.
4.2.1.3
Safety Endpoints
The safety data for MK-3655 to date has been described in detail in Section 2.2.2 and in the 
IB.
In support of the safety objective to evaluate the safety and tolerability profile of MK-3655,
the safety and tolerability endpoints will be assessed by clinical evaluation of AEs (including 
adjudication of malignancies and CV events) and inspection of other study parameters 
including vital signs (ie, heart rate, blood pressure, temperature), body weight, physical 
examination, standard laboratory safety tests, 12-lead ECGs, ketone levels, BMD by DXA, 
and evaluation of biomarkers of bone formation (P1NP) and resorption (CTX) will be 
performed. Additional class-related hypothalamic-pituitary function safety endpoints will be 
assessed including bedtime salivary cortisol, ACTH, TSH, FT4, and IGF-1.
All procedures will be conducted at the time points specified in the SoA. AEs will be graded 
and recorded throughout the study and during the follow-up period according to NCI 
CTCAE, Version 5.0 (see Section 10.14). Note: For AEs that are an exception to the NCI 
CTCAE grading, see Section 7.1.
4.2.1.4
Pharmacokinetic Endpoint
The PK endpoint for MK-3655 is Ctrough taken before dose administration. PK samples will 
be collected from all participants on each visit as described in the SoA (Section 1.3) and in 
Table 5. These samples will be used to evaluate not only PK concentrations, but also PK/PD 
and PK/AE relationships of MK-3655 via modeling exercises, as appropriate.
4.2.1.5
Immunogenicity Endpoints
Immunogenicity to MK-3655 will be described as the results of the ADA assay from samples 
taken during the double-blind treatment period (Visits 5, 6, 8, 11, and 15) and during the 
post-treatment period (Visit 16). ADA samples will be collected before the administration of 
study intervention (if applicable) and from all participants. The incidence and magnitude 
(titer) of ADA positive participants and potential effects of ADA on PK, PD, and safety will 
be reported, as appropriate.
4.2.1.6
Pharmacodynamic Endpoints
PD endpoints that will be assessed include changes from baseline through Week 52 in
adiponectin, HOMA-IR, fasting insulin, fasting FFAs, body composition assessed by DXA, 
and biomarkers reflecting liver inflammation and fibrosis.
Adiponectin is a protein produced by adipocytes and an established marker for FGFR1c/KLB
target engagement at adipose tissue that may potentially mediate some of the beneficial 
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therapeutic effects of MK-3655 on the liver. Adiponectin has been demonstrated preclinically 
to have an anti-fibrotic action in the liver and epidemiological studies have shown that low 
adiponectin levels are associated with NASH independent of insulin resistance and BMI
[Fitzpatrick, E. 2014] [Targher, G., et al 2004].
HOMA-IR (fasting glucose [mmol/L] multiplied by fasting insulin [µU/L], then divided by 
the constant 22.5) has been widely used for the estimation of insulin resistance [Matthews, D. 
R., et al 1985]. The anti-steatotic effect of MK-3655 is expected to be due, in part, to 
improved adipose insulin sensitivity resulting in decreased trafficking of FFA from adipose 
to the liver. Therefore, fasting FFA will be assessed to inform on the therapeutic mechanism 
of MK-3655. Body composition will be assessed by DXA; a validated, fast, reproducible, 
noninvasive method of assessing body composition.
Since fibrosis stage is a major predictor of liver-related mortality, the evaluation of liver 
inflammation and fibrosis are critical in the management of patients with NAFLD. The 
following biomarkers or composite scores will be assessed as potential metrics for estimation 
of baseline severity of liver inflammation and fibrosis and/or response to treatment: routine 
liver tests (ALT, AST), FIB-4, NFS, APRI, and Pro-C3. These noninvasive biomarkers or 
composite scores will be used to supplement information obtained from the primary and 
secondary efficacy endpoints (see Section 8.8.2).
4.2.1.7
Planned Exploratory Biomarker Research
MK-3655 is intended to deliver therapeutic benefit through targeting a mechanism of action 
(FGFR1c/KLB agonism) that has demonstrated promising pharmacology regarding liver fat, 
insulin sensitivity, and lipid profiles in MK-3655 studies and in studies of FGF21 and FGF19
analogs. However, the mechanisms through which these effects are achieved are not 
completely understood. Therefore, much remains to be learned regarding how MK-3655 
works and how it may be best used to treat patients with NASH. To aid future patients, it is 
important to investigate, in our clinical studies, the determinants of therapeutic response to 
MK-3655 as well as any safety/tolerability issues associated with MK-3655. Additionally, 
there is a critical need in the NASH field for the development of noninvasive approaches to 
the diagnosis, risk stratification, and treatment response monitoring for patients with NASH. 
Therefore, it is also important to investigate potential strategies to address these gaps.
To aid in these efforts, exploratory assessments of known and/or unknown biomarkers may 
be performed. Specifically, blood samples will be collected to enable exploratory analyses of 
circulating molecules (eg, protein, DNA, RNA, metabolites). In addition, exploratory 
assessments of liver biopsy tissue (eg, alternative methods for quantifying fibrosis, 
immunohistochemical analyses to assess specific cell populations, gene expression analyses) 
maybe also performed. Such exploratory histologic analyses will not require collection of 
liver tissue beyond that collected to address the specified study objectives.
4.2.1.7.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
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that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome, genes previously associated with 
NASH will specifically be investigated to assess their relationship to treatment response 
including: PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13, PPP1R3B, and LYPLAL1.
4.2.1.8
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
A placebo group is included in this study to maintain the study blind; allowing for an 
unbiased assessment of efficacy and safety. Additionally, placebo-controlled studies are 
considered the most rigorous design to determine the risks and benefits of a new treatment.
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
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applications and studies that are intended for submission in a NDA or BLA to the Neurology 
or Psychiatry Divisions of the FDA, as well as assessment in studies that fall within the 
guidance for other reasons (eg, CNS active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
Published human gene expression profiling data indicate that KLB and FGFR1c may be
co-expressed in the CNS [Talukdar, S., et al 2016]. Though penetrance into the CNS for a 
mAb, such as MK-3655, is typically low, it is unknown whether CNS concentrations of MK-
3655 are high enough to exert a pharmacologic effect. Though there are no specific 
psychiatric concerns for the KLB/FGFR1c target, it has not been well-studied and there may 
be biological plausibility for psychiatric effects. Additionally, there is a high prevalence of 
obesity in the NASH population and there is an association of obesity with depression. 
Therefore, this study will use the C-SSRS for prospective assessment of suicidal ideation and 
behavior and the PHQ-9 for depression severity during the study.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
Participants will be on a fixed dose regimen of MK-3655 (50 mg Q4W, 100 mg Q4W, or 
300 mg Q4W) or matching placebo for the duration of the study.
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose for participants will be 300 mg Q4W. Participants will be exposed to 
MK-3655 for approximately 52 weeks. For more information, see Section 6.1 and 
Section 8.1.9.
4.3.3
Rationale for Dose Interval and Study Design
In Phase 1 single and multiple ascending dose testing, MK-3655 demonstrated good safety 
and tolerability, a PK profile potentially consistent with monthly dosing by subcutaneous 
administration, and biomarker confirmation of robust on-target pharmacology. To identify 
optimal doses and regimens for further development we will use three Q4W dose groups in 
this study design.
The dose range for this study was selected based on several different PK/PD analyses 
assessed from Phase 1 data, which reflect target engagement and/or presumed target-
mediated pharmacology including adiponectin, TG, HDL-C, HOMA-IR, and 
MRI-PDFF-assessed LFC. Currently, the relationship between changes in these biomarkers 
and the histologic efficacy is unknown. Based on these analyses, the low dose of 50 mg Q4W
is predicted to achieve discernable, but sub-maximal LFC reduction and improvements in 
other PD biomarkers assessed, while 300 mg Q4W is predicted to deliver near-maximal or 
maximal responses in those same measurements.
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Steady state exposures at the 300 mg Q4W dose level in Phase 2b is currently predicted to 
exceed those of the chronic toxicology NOAEL (AUCD0-28: 146 day*µg/mL) by 3.2-fold, 
though remain well below the highest exposures assessed in the chronic toxicology study 
(AUCD0-28: 5875 day*µg/mL). As noted in Section 2.2.2.2, single and multiple doses of 
MK-3655 were generally well tolerated in the clinical program, including the 150 mg Q1W
dose regimen of MK-3655 has been generally well tolerated in the multiple-dose Phase 1 
study P002 and the multiple-dose portion of the Phase 1 study in Japanese participants P003. 
Exposures in P002 and P003, over the last 4 weeks of dosing were approximately 6.8-fold 
and 8.2-fold, respectively, greater than those at the chronic toxicology NOAEL and 
approximately 2.1-fold and 2.6-fold, respectively, greater than those predicted for the 300 mg 
Q4W dose arm in this study.
Exceeding the NOAEL in this study is considered appropriate given the nature of the 
toxicities and the mitigations incorporated in the protocol. The dose-limiting weight loss 
observed in NHPs does not appear to translate to humans given the modest weight gain 
observed in Phase 1 and would be easily detected through the frequent body weight 
assessments in this study.
Published nonclinical data suggest potential for a weight-independent, mechanism-based 
effect of FGF21 on bone [Wei, W., et al 2012] [Owen, B. M., et al 2015]. Administration of 
one FGF21 analog in humans resulted in bone biomarker changes consistent with net bone 
loss, though there was potentially confounding concurrent weight loss [Talukdar, S., et al 
2016]. Notably, there was no evident impact of MK-3655 on biomarkers of bone formation 
(P1NP) or resorption (CTX) or on DXA-assessed BMD over 12 weeks of dosing in the MAD 
part of MK-3655 P004 study (NGM 15-0201). There was also no evident impact of MK-
3655 on P1NP or CTX over 8 weeks of dosing in MK-3655 P002 in which exposures over 
the last 4 weeks of dosing (AUCD29-57: 989 day*µg/mL) were approximately 2-fold greater 
than those predicted for the top (300 mg Q4W) dose arm in this study and approached the 
exposures at which decreased bone mineral content was observed in female NHPs (≥AUCD0-
28: 971 day*µg/mL). The observed trend to reversibility of the bone mineral content effect in 
chronic toxicology provides additional reassurance regarding safety for study participants.
Menstrual cycle prolongation, which was previously observed in the chronic toxicity study, 
was not recapitulated at comparable MK-3655 exposures in a 4-month repeat-dose study 
dedicated to assessing menstrual cyclicity in cynomolgus monkeys. MK-3655 treatment 
resulted in substantial body weight loss but did not cause menstrual cycle changes in a large 
cohort of regularly cycling NHP evaluated in this study. At the NOEL of the NHP menstrual 
cyclicity study, MK-3655 exposure was 2-fold higher than the projected clinical exposure at 
300 mg Q4W. Based on these data, menstrual cycle changes in the chronic toxicity study are 
attributed to normal variability in length of menstrual cycles in NHP, changes in social 
housing conditions, and/or stress/poor body condition resulting from body weight loss.
Therefore, the totality of the MK-3655 nonclinical data indicate that MK-3655 does not 
cause menstrual cycle changes in cynomolgus monkeys. Further, based on the totality of the 
nonclinical data, there is no evidence that MK-3655 will impact fertility in female or male 
participants (see IB).
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This study population will include premenopausal and postmenopausal women and will 
follow CTFG guidance for investigational products with demonstrated or suspected human 
teratogenicity/fetotoxicity in early pregnancy [Heads of Medicines Agencies 2020]. Concerns 
related to the potential for developmental toxicity are based on nonclinical FGF21 data that 
suggest that KLB/FGFR1c agonism may affect fetal growth, bone development/growth, and 
adipose tissue development. All WOCBP included in this study will be required to use a 
contraceptive method that is highly effective (with low user dependency) throughout the 
treatment period and through the post-treatment follow-up period. Additionally, WOCBP
must have a negative highly sensitive pregnancy test within 24 hours before the first dose of 
study intervention and a pregnancy test conducted at monthly intervals during the treatment 
and post-treatment follow-up periods (see Sections 5.1, 8.3.10, and 10.5.2). As preclinical 
developmental toxicity studies have not been conducted with MK-3655, no specific exposure 
threshold for developmental risk has been identified. Contraception and pregnancy testing for 
WOCBP will continue for 16 weeks after the last dose of MK-3655 (ie, Week 48), by which 
time complete or near-complete washout of MK-3655 will have been achieved and drug 
concentrations will have declined to sub-pharmacologic levels. The post-treatment follow-up 
for all participants will extend through Week 64.
The accrued bone biomarker and DXA data summarized above suggest low risk for 
MK-3655 to have deleterious bone effects. To expand this characterization, bone biomarkers 
(P1NP and CTX) and BMD (DXA) will be assessed in this study. To minimize the potential 
for confounding these assessments, participants will be excluded from study participation if 
at Visit 1/Screening they have a known history of osteoporosis or other indication for 
treatment with specified bone-active agents (see Section 5.2). Participants will not be 
excluded if an indication for treatment with the bone-active pharmacological classes of 
agents listed in Section 5.2 is identified after Visit 1/Screening. This includes any participant 
diagnosed with osteoporosis by DXA imaging performed during the placebo run-in. The 
number of such participants is expected to be small, and unlikely to undermine the study-
wide characterization of bone biomarker and bone density responses. Such participants will 
be referred to their personal physician for management of osteoporosis.
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).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area, the local start of the study in 
the European Economic Area is defined as First Site Ready in any Member State.
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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 by the eDMC for safety concerns or futility based on the 
results of the IA (see Section 9.7).
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age, race, ethnicity, and sex. The collection and use of these 
demographic data will follow all local laws and participant confidentiality guidelines while 
supporting the study of the disease, its related factors, and the IMP under investigation. 
Males and females with pre-cirrhotic NASH aged 18 to 80 years (in Japan and Taiwan, aged 
20 to 80 years [Appendix 7]) will be randomized in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. Has histological confirmation of NASH based on a liver biopsy obtained ≤6 months 
before Visit 1/Screening. If no acceptable biopsy performed ≤6 months before
Visit 1/Screening is available, a liver biopsy will be performed at Visit 3/Liver Biopsy.
Histological criteria for study entry include:

NAS ≥4 with a score ≥1 point in each component (steatosis, ballooning, and lobular 
inflammation),
AND

NASH CRN fibrosis score of Stage 2 or 3.
2. Has an MRI-PDFF ≥8% as assessed at Visit 2/MRI-PDFF.
Note: Prior MRI-PDFF imaging of the liver performed ≤2 months before
Visit 1/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.
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3. Has a baseline MELD-Na score ≤12 at Visit 1/Screening.
Demographics
4. Is a male or female aged 18 years to 80 years (in Japan and Taiwan, aged 20 to 80 years
[Appendix 7]), at the time of signing the ICF.
5. Has a BMI ≥25 kg/m2 and ≤50 kg/m2 at the time of Visit 1/Screening.
6. Has stable weight (based on self-reporting) defined as ≤5% gain or loss of body weight 
for at least 3 months before Visit 1/Screening.
Note: For participants whose baseline liver biopsy was obtained before Visit 1/Screening,
weight must have been stable for at least 3 months before the date of the historical liver 
biopsy and through Visit 1/Screening.
7. Meets one of the following criteria:

Has no history of T2DM.
OR

Has a history of T2DM with an A1C ≤9.5% at Visit 1/Screening and controlled by
diet or stable doses of AHAs.
Note: See Section 5.2 (Exclusion Criteria) and Table 1 for allowable AHAs and their 
associated stability definitions.
8. Has a systolic blood pressure of ≤160 mm Hg and a diastolic blood pressure ≤90 mm Hg 
(after at least a 10-minute seated rest) based on the mean of 3 measurements at 
Visit 1/Screening OR blood pressure is considered likely to be below these limits by 
Visit 5/Randomization (Day 1) with initiation or adjustment of antihypertensive 
medication.
Note: Investigators are encouraged to maximize blood pressure control according to
current guidelines before Visit 5/Randomization.
-
The participant may have blood pressure medication initiated or adjusted and be 
enrolled if repeat blood pressure measurements meet the inclusion criterion at 
Visit 5/Randomization.
-
Randomization may be rescheduled once by 1 week in an attempt to meet the 
Visit 5/Randomization blood pressure requirement. If at the rescheduled visit a 
participant still does not meet the Visit 5/Randomization blood pressure inclusion 
requirement, they will be screen failed.
-
All participants must meet the blood pressure inclusion requirement at 
Visit 5/Randomization.
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9. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
and/or other study procedures.
Male Participants
10. Contraceptive use by male participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Female Participants
11. 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:
-
Uses 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 16 weeks 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. Contraceptive use by women should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies.
-
Has 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 8.3.10.
-
Abstains from breastfeeding during the study intervention period and for at least 
16 weeks after the last dose of study intervention.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
12. The participant (or legally acceptable representative, if applicable) has provided
documented informed consent for the study. The participant may also provide consent for 
FBR. However, the participant may participate in the main study without participating in 
FBR.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has presence of cirrhosis on liver biopsy.
2. Has Type 1 diabetes.
3. Has a history of malignancy, unless cancer free ≥5 years, or is under evaluation for active 
or suspected malignancy before signing the ICF except for adequately treated basal cell 
or squamous cell skin cancer or in situ cervical cancer.
4. Has a history of bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy, gastric 
band) ≤5 years before Visit 1/Screening.
Note: For participants whose baseline liver biopsy was obtained before Visit 1/Screening, 
there must be no history of bariatric surgery ≤5 years before the liver biopsy and through 
Visit 1/Screening.
5. Has undergone a major surgical procedure ≤3 months before signing the ICF or has major 
surgery planned during the study.
Note: A participant who has undergone minor surgery ≤3 months before
Visit 1/Screening and is fully recovered or a participant who has planned minor surgery 
may participate. Minor surgery is defined as a surgical procedure involving local 
anesthesia.
6. Has a history or evidence of:

Chronic liver disease other than NASH

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); participants with a history of HCV infection may be included if HCV 
PCR is negative ≥3 years
Note: For participants whose baseline liver biopsy was obtained before
Visit 1/Screening, HCV PCR must be negative ≥3 years before the liver biopsy and 
through Visit 1/Screening.

Drug-induced liver disease

Ongoing autoimmune liver disease

Decompensated liver disease (ascites, esophageal or gastric variceal bleeding, hepatic 
encephalopathy, or other signs or symptoms of advanced liver disease)
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
HIV

Primary biliary cirrhosis (cholangitis)

Primary sclerosing cholangitis

Reye Syndrome

Splenomegaly

Wilson’s disease

Documented Cushing disease, Cushing syndrome, or any condition associated with 
hypercortisolism (ie, high amounts of circulating cortisol that may be a pathological 
or non-pathological condition [eg, functional adrenal adenoma, micronodular and 
macronodular hyperplasia])

Hyperthyroidism, and is currently being treated.

Hypothyroidism, and is on thyroid hormone replacement therapy that has not been at 
a stable dose for at least 12 weeks prior to Visit 1/Screening.
Note: Participants who meet this exclusion criterion may be rescreened after being on 
a stable dose of thyroid hormone replacement therapy for at least 12 weeks.

Alpha-1-antitrypsin deficiency

Hemochromatosis or iron overload

Spontaneous bacterial peritonitis

Known bile duct obstruction

Hepatocellular carcinoma

Untreated obstructive sleep apnea

Hemostasis disorder (eg, Von Willebrand disease, hemophilia, Factor V Leiden 
thrombophilia, sickle-cell disease, polycythemia, leukemia)

Hematological disorder (eg, aplastic anemia, myeloproliferative or myelodysplastic 
syndromes, thrombocytopenia)
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7. Has significant systemic or major illnesses other than liver disease, including recent 
events (≤6 months before Visit 1/Screening) of congestive heart failure (NYHA 
functional class III to IV of the American Heart Association), unstable coronary artery 
disease, arterial revascularization, pulmonary disease, renal failure, stroke, transient 
ischemic attack, or organ transplantation.
8. Has a known hypersensitivity to any of the ingredients or excipients of the IMP.
9. Has experienced any bone trauma, fracture, or bone surgery ≤2 months before
Visit 1/Screening.
10. Has a history of osteoporosis or an indication that requires treatment with a bone-active 
pharmacological agent in the classes listed in exclusion criterion #18 at Visit 1/Screening.
Note: Participants will not be excluded from study participation if an indication requires
treatment with a bone-active pharmacological agent in the classes listed in exclusion 
criterion #18 that is identified after completion of Visit 1/Screening. This includes any 
participant diagnosed with osteoporosis by DXA imaging performed during placebo 
run-in (see Section 4.3.3).
11. Has current or history of significant alcohol consumption for a period of more than 
3 consecutive months ≤24 months before Visit 1/Screening. 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.
Note: For participants whose baseline liver biopsy was obtained before Visit 1/Screening, 
there must be no history of significant alcohol consumption, as defined above, for a 
period of more than 3 consecutive months ≤24 months before the date of the liver biopsy 
and through Visit 1/Screening.
12. Has an inability to reliably quantify alcohol consumption.
13. Has a recent history of drug abuse (defined as ≤3 years) or is a current user of 
recreational or illicit drugs at the time of Visit 1/Screening.
14. Has a known psychiatric or any other cognitive disorder per the opinion of the 
investigator, that would interfere with the participant’s ability to cooperate with the 
requirements of the study.
15. Is at imminent risk of self-harm, based on clinical interview and responses on the 
C-SSRS, or of harm to others in the opinion of the investigator. Participants must be 
excluded if they report suicidal ideation with intent, with or without a plan or method 
(eg, positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in 
the past 2 months or suicidal behavior in the past 6 months. See Section 8.3.11.1.1 for 
further details.
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16. Has a total score >12 on the PHQ-9 (see Section 8.3.11.1.2).
Note: If a participant’s score on Question #9 of the PHQ-9 is ≥1 (see Appendix 11), but 
the participant answered “No” to all the questions on the C-SSRS, the investigator must 
reconcile the discrepancy to determine a participant’s study eligibility.
Prior/Concomitant Therapy
17. Is on treatment with or has been treated with the following agents:

Within ≤12 months before Visit 1/Screening:
o
Thiazolidinediones (ie, pioglitazone, rosiglitazone)
o
Investigational agents:
-
Investigational PPAR-gamma activators (eg, lanifibranor)
-
FXR agonists (eg, obeticholic acid, cilofexor [GS-9674], tropifexor [LJN452])
-
FGF21 analogs (eg, pegbelfermin [BMS-986036], efruxifermin [AKR-001], 
BIO89-100)
-
Aldafermin (NGM282)
-
BFKB8488A (KLB/FGFR1c-activating antibody)
Note: For participants whose baseline liver biopsy was obtained before 
Visit 1/Screening, the use of these agents is prohibited ≤12 months before the date of 
the liver biopsy and through Visit 1/Screening.

Within ≤6 months before Visit 1/Screening:
o
L-ornithine L-aspartate
o
Investigational agents:
-
Thyroid hormone receptor beta-agonists including resmetirom (MGL-3196) 
and VK2809
-
DGAT2 inhibitors including PF-06865571 and ION224
-
ACC inhibitors including firsocostat (GS-0976) and PF-05221304
Note: For participants whose baseline liver biopsy was obtained before 
Visit 1/Screening, the use of these agents is prohibited ≤6 months before the date of 
the liver biopsy and through Visit 1/Screening.
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18. Is on treatment with or has used bone-active agents in the classes listed below 
≤24 months before Visit 1/Screening:

Bisphosphonates

Calcitonin

Selective estrogen receptor modulator (estrogen receptor agonist/antagonist)

PTH and PTH analogs

RANK ligand inhibitor

Anti-sclerostin antibody

Aromatase inhibitors

GnRH agonists
Note: Participants will not be excluded from study participation if agents from these 
classes are initiated based on an indication identified after completion of the 
Visit 1/Screening. This includes any participant diagnosed with osteoporosis by DXA 
imaging performed during the placebo run-in (see Section 4.3.3).
19. Is on treatment with or has used drugs associated with NAFLD ≤6 months before
Visit 1/Screening:

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

Nucleoside reverse transcriptase inhibitors

Tetracycline (intravenous administration at high doses)

Valproic acid
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
Other known hepatotoxins
Notes:

Drugs known to be hepatotoxic (ie, drugs with a warning of hepatotoxicity in the 
package insert) should be avoided during the administration of study intervention.

The maximum allowable dose of acetaminophen is 4000 mg/day.

For participants whose baseline liver biopsy was obtained before Visit 1/Screening, 
the use of these agents is prohibited ≤6 months before the date of the liver biopsy and 
through Visit 1/Screening.
20. Is on treatment or likely to require treatment for ≥14 consecutive days or repeated courses 
of pharmacologic doses of corticosteroids (eg, prednisone 5 mg or equivalent doses of 
other glucocorticoids).
Note: Inhaled, nasal, ophthalmic, and topical corticosteroids, and physiological 
replacement doses of adrenal steroids are permitted.
21. Is on treatment with anticoagulants (eg, warfarin, heparin).
22. Is on treatment with an AHA or other medications listed in Table 1, and is not on a stable 
dose according to Table 1.
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Table 1
Stability Definitions for Medications and Other Substances
Medications: Antihyperglycemic Agents
Stability Definition

Insulin
Stable dose (defined as ≤20% variance in total daily 
dose) required for ≥3 months: (1) before
Visit 1/Screening or (2) from the date of historical 
liver biopsy.

Alpha glucosidase inhibitors

DPP-4 inhibitors

Meglitinides

Metformin

Sulfonylureas
Stable dose required for ≥3 months: (1) before
Visit 1/Screening or (2) from the date of historical 
liver biopsy.

GLP-1 agonistsa

SGLT2 inhibitorsa
Stable dose required for ≥6 months: (1) before
Visit 1/Screening or (2) from the date of historical 
liver biopsy.
Medications: Other
Stability Definition

Weight loss medication (eg, orlistat, phentermine, 
topiramate, lorcaserin, naltrexone/bupropion, 
GLP-1 agonists)

Medications associated with weight changes 
(eg, anti-psychotic medications [eg, olanzapine, 
risperidone, quetiapine fumarate])
Stable dose required for ≥6 months: (1) before
Visit 1/Screening or (2) from the date of historical 
liver biopsy.

Lipid lowering agents (eg, statins, ezetimibe, fibric 
acid derivatives [fibrates], icosapent ethyl)
Stable dose required for ≥3 months: (1) before
Visit 1/Screening or (2) from the date of historical 
liver biopsy.

Doses of vitamin E >100 IU/day
Stable dose required for ≥6 months: (1) before 
Visit 1/Screening or (2) from the date of historical 
liver biopsy.

Chronic prescription pharmacotherapy initiated 
and/or a recent change in prescription medication, 
dose, or frequency of medication which in the 
opinion of the investigator may potentially 
interfere with the study.
Stable dose required for ≥1 month before
Visit 5/Randomization.
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; IU=international units; SGLT2=sodium-glucose 
cotransporter-2.
a If a participant should require additional medications for control of diabetes, the initiation of SGLT2 inhibitors and 
GLP-1 agonists are prohibited.
Prior/Concurrent Clinical Study Experience
23. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device ≤3 months before participating in this current study.
Participants enrolled in observational studies may be included and will be reviewed on a 
case-by-case basis for approval by the Sponsor. Note: See Appendix 7 for Korea-specific
study requirements.
Diagnostic Assessments
24. Has exclusionary laboratory values as listed in Table 2.
Note: If any of the laboratory exclusion criteria in Table 2 are met, the site may have the 
abnormal value retested one time.
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Table 2
Laboratory Exclusion Criteria
Parametera
Population
(if applicable)
Study Limit for Exclusion
ALP
-
>2 × ULN
ALT
-
>5 × ULN
AST
-
>5 × ULN
eGFRb
-
<45 mL/min/1.73 m2
FT4
-
Outside the central laboratory normal range
Hemoglobin
Male
Female
<11 g/dL (110 g/L)
<10 g/dL (100 g/L)
IGF-1
-
Above the central laboratory age-appropriate normal range
INR
-
≥1.3
Bedtime salivary cortisolc
-
>1.5 × ULN
Platelet count
-
<140 × 109/L
Serum albumin
-
<3.5 g/dL
Total bilirubind
-
≥1.3 mg/dL
TSH
-
Outside the central laboratory normal range
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; eGFR=estimated 
glomerular filtration rate; FT4=free thyroxine; IGF-1=insulin-like growth factor-1; INR=international normalized ratio;
MDRD=Modification of Diet in Renal Disease; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.
a
Participants with an exclusionary laboratory value may have one repeat determination performed if the investigator 
considers the Visit 1/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 4-variable MDRD Equation. For the calculation of eGFR for participants 
in Japan, the Japanese 3-variable Equation 4 will be used (Appendix 7) [Matsuo, S., et al 2009]. See Appendix 13 for 
eGFR equations.
c
Bedtime salivary cortisol samples should be collected between 9 PM and midnight.
d
Participants with an elevated total bilirubin but with a direct bilirubin within normal limits are eligible.
25. Has poor venous access that precludes routine peripheral blood sampling required for this 
study.
26. Has received blood products ≤2 months before Visit 1/Screening and/or donated blood 
products ≤1 month before Visit 1/Screening.
Note: Participants are not to donate blood products throughout the duration of the study.
27. Has a clinically significant ECG abnormality that requires further diagnostic evaluation 
or intervention (eg, new, clinically significant arrhythmia, or a conduction disturbance).
28. Has claustrophobia to a degree that prevents tolerance of MRI scanning procedure. 
Sedation is permitted at the discretion of the investigator.
29. Has a metallic implant of any sort that prevents MRI 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 examination.
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Other Exclusions
30. In the opinion of the investigator, the participant has any other condition which would 
impede competence or compliance or possibly hinder completion of the study.
31. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Diet and Activity Counseling
Participants will receive dietary and activity counseling at Visit 4/Placebo Run-in. At 
subsequent visits as detailed in Section 1.3 (SoA), the site staff will review the diet and 
activity guidance sheets with the participant. Detailed dietary and activity information will 
not be captured.
All participants will receive counseling on diet uniformly across the sites. Participants will
also be counseled to maintain a medically appropriate, routine exercise program and 
consistent physical activity level during the study. Participants should not engage in
strenuous exercise (ie, weightlifting, running, bicycling, etc.) for 48 hours before each blood 
collection for clinical laboratory tests for the duration of the study.
Additional registered nutritionist/dietician (or equivalent outside the US) referrals may be 
provided during the study and for up to an additional 3-month (optional) period after study
completion if participants meet certain criteria as described in Section 8.3.3.
5.3.2
Alcohol Restrictions
Participants will be counseled to limit alcohol use to ≤1 standard drink per day or less than 
approximately 7 standard drinks per week in females, and ≤2 standard drinks per day or less 
than 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.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
Any participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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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 3.
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Table 3
Study Interventions
Arm Name
Arm Type
Intervention Name
Type
Dose 
Formulation
Unit Dose 
Strengths Dosage Level(s)
Route of 
Admin
Treatment Period
Use
IMP or 
NIMP/AxMP
Sourcing
Group 1
(Run-in Period)
Experimental
MK-3655 Matching 
Placebo
Drug
Vial
0 mg
2 x 1.5 mL 
injections once
SC
V4 up to V5
(Run-in Period)
Placebo
IMP
Provided centrally by 
the Sponsor
Group 1
Experimental
MK-3655 
33.3 mg/mL
Drug
Vial
50 mg
1 x 1.5 mL 
injection Q4W
SC
V5 to V15 (Double-
Blind Treatment Period)
Test 
Product
IMP
Provided centrally by 
the Sponsor
Group 1
Experimental
MK-3655 Matching 
Placebo
Drug
Vial
0 mg
1 x 1.5 mL 
injection Q4W
SC
V5 to V15 (Double-
Blind Treatment Period)
Placebo
IMP
Provided centrally by 
the Sponsor
Group 2
(Run-in Period)
Experimental
MK-3655 Matching 
Placebo
Drug
Vial
0 mg
2 x 1.5 mL 
injections once
SC
V4 up to V5
(Run-in Period)
Placebo
IMP
Provided centrally by 
the Sponsor
Group 2
Experimental
MK-3655 
33.3 mg/mL
Drug
Vial
100 mg
2 x 1.5 mL 
injections Q4W
SC
V5 to V15 (Double-
Blind Treatment Period)
Test 
Product
IMP
Provided centrally by 
the Sponsor
Group 3
(Run-in Period)
Experimental
MK-3655 Matching 
Placebo
Drug
Vial
0 mg
2 x 1.5 mL 
injections once
SC
V4 up to V5
(Run-in Period)
Placebo
IMP
Provided centrally by 
the Sponsor
Group 3
Experimental
MK-3655 
100 mg/mL
Drug
Vial
300 mg
2 x 1.5 mL 
injections Q4W
SC
V5 to V15 (Double-
Blind Treatment Period)
Test 
Product
IMP
Provided centrally by 
the Sponsor
Group 4
(Run-in Period)
Placebo 
Comparator
MK-3655 Matching 
Placebo
Drug
Vial
0 mg
2 x 1.5 mL 
injections once
SC
V4 up to V5
(Run-in Period)
Placebo
IMP
Provided centrally by 
the Sponsor
Group 4
Placebo 
Comparator
MK-3655 Matching 
Placebo
Drug
Vial
0 mg
2 x 1.5 mL 
injections Q4W
SC
V5 to V15 (Double-
Blind Treatment Period)
Placebo
IMP
Provided centrally by 
the Sponsor
Admin=administration; EEA=European Economic Area; IMP=Investigational Medicinal Product; NIMP/AxMP=Non-Investigational Medicinal Product/Auxiliary Medicinal Product; Q4W=once
every 4 weeks; SC=subcutaneous; V=visit.
Notes:
The classification of IMP and NIMP/AxMP 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 and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
In Japan, administration of study intervention will not be allowed by a caregiver. See Section 8.1.8.3 and Appendix 7.
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All supplies indicated in Table 3 will be provided per the "Sourcing" column depending upon 
local country operational requirements.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
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 4 study 
intervention arms. Participants will be assigned randomly in a 1:1:1:1 ratio to 1 of 3 doses of 
MK-3655 study intervention (50 mg Q4W, 100 mg Q4W, or 300 mg Q4W) or a matching
placebo study intervention Q4W, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Concurrent diagnosis of T2DM at the time of randomization (Yes or No)
2. Fibrosis score (Stage 2 or Stage 3)
3. Region (Japan, East Asia excluding Japan, or Other)

Japan and East Asia excluding Japan were each added as a separate stratum in region 
stratification to ensure that randomization of the Japan population and overall East-
Asian population (ie, Japan and East Asia excluding Japan) are balanced between-
treatment groups. This stratification will allow for an optimal assessment of the Japan
subpopulation as required by the regulatory agency, as well as the overall East-Asian 
population.
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. Note: In Japan, enrollment 
will not be restricted by this cap, and sites will be able to continue to enroll participants with 
or without T2DM (see Appendix 7).
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. All MK-3655 doses and 
matching placebo will have the same dose volume and be packaged identically so that the 
blind is maintained. The participant, the investigator, and Sponsor personnel or delegate(s) 
who are involved in the study intervention administration or clinical evaluation of the 
participants will be unaware of the intervention assignments.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
When participants self-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 
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participant diary. At all protocol-specified site visits, the investigator or qualified designee is 
to record whether treatment had been taken per protocol. If not, the date(s) and reason for 
each dosing noncompliance must be recorded.
When participants self-administer study intervention at home, compliance with study 
intervention will be assessed at the next site visit. Compliance will be assessed using 
participant diaries. A visual inspection of the vials returned (used and unused) will also be 
performed (when available). Deviation(s) from the prescribed dosage regimen will be 
recorded in the CRF.
A record of the number of vials dispensed to and returned by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF.
Note: In Japan, administration of study intervention will not be allowed by a caregiver. See 
Section 8.1.8.3 and Appendix 7.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the study
(see Section 5.2). If there is a clinical indication for any medications specifically prohibited, 
discontinuation from study intervention may be required. Medications required to be stable 
upon study entry (see Table 1) that require adjustment during the trial may result in 
discontinuation. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy 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 Medical Monitor or appropriate designee should be contacted if there are any questions 
regarding concomitant or prior therapy.
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study. Participants 
should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.
6.6
Dose Modification
Participants will be randomized to a fixed dose regimen of MK-3655 (50 mg Q4W, 100 mg 
Q4W, or 300 mg Q4W) or matching placebo for the duration of the study. Dose 
modifications (ie, delays in the administration of study intervention) are permitted if 
clinically warranted (eg, due to AEs).
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.11). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention randomization system (IRT) should be used to unblind 
participants and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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 prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.11.6.
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 
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investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10 and 
Section 8.11.6.
A participant must be discontinued from study intervention but should 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. The participant has a positive urine pregnancy test and confirmed by positive serum 
pregnancy test.
Clinical Events
4. The participant has a CTCAE Grade 3 clinical AE that is considered drug-related by the 
investigator.
5. 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 AEs are exceptions to #4 and #5. 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 
AE.

Weight gain: Participants will be discontinued from study intervention if body 
weight measured at the study site has increased ≥15% from baseline 
(Visit 5/Randomization) at any time during the study.

Obesity: The CTCAE grading for obesity is not applicable to this study as 
participants with a BMI of 25.0 kg/m2 to 50.0 kg/m2 are eligible for study 
participation (see Section 5.1, inclusion criterion #5). Instead, discontinuation of 
study intervention will be based on weight gain as described above.

Hypoglycemia in participants with T2DM: A participant with T2DM will be 
discontinued from study intervention if the participant has repeated (2 or more 
episodes since the prior visit) FPG or fingerstick glucose <50 mg/dL (<2.8 mmol/L) 
with or without symptoms of hypoglycemia or ≤70 mg/dL (≤3.9 mmol/L) with 
symptoms of hypoglycemia, and without a reasonable explanation (such as increased 
physical activity or skipped meal).
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If a participant is taking any concomitant medications known to cause hypoglycemia 
(ie, insulins, sulfonylureas, and meglitinides), discontinuation of study intervention 
should occur only if hypoglycemia persists after down-titration and discontinuation of 
those medications.
Note: The investigator should ensure that the participant's glucose meter is 
functioning accurately and that the test procedure is being correctly performed by the 
participant before discontinuation of study intervention.

Participants known to have hypertension or with a baseline blood pressure 
>120 mm Hg (systolic) or >80 mm Hg (diastolic) before randomization: Participants 
known to have hypertension or with a baseline blood pressure >120 mm Hg (systolic) 
or >80 mm Hg (diastolic) before randomization will be discontinued from study 
intervention for a persistent increase from baseline of ≥20 mm Hg (systolic blood 
pressure) and/or ≥10 mm Hg (diastolic blood pressure) despite continuation of any 
antihypertensive regimen being used at baseline AND initiation and/or dose increase 
of >2 anti-hypertensive agents are required for management. Note: Multiple changes 
made to a single medication (eg, initiation at lower dose followed by dose increase) 
counts as only one adjustment.
Note: NCI CTCAE, Version 5.0 will not be used for grading AE severity for 
participants known to have hypertension or with a baseline blood pressure 
>120 mm Hg (systolic) or >80 mm Hg (diastolic) before randomization. Instead, the 
investigator will assess AE intensity according to the following modified CTCAE 
grading:

Grade 1: Persistent increase from baseline of 10 mm Hg to 19 mm Hg (systolic 
blood pressure) and/or 5 mm Hg to 9 mm Hg (diastolic blood pressure) despite 
continuation of any anti-hypertensive regimen being used at baseline.

Grade 2: Persistent increase from baseline of ≥20 mm Hg (systolic blood 
pressure) and/or ≥10 mm Hg (diastolic blood pressure) despite continuation of 
any anti-hypertensive regimen being used at baseline AND initiation and/or dose 
increase of ≤2 anti-hypertensive agents required for management.*

Grade 3: Persistent increase from baseline of ≥20 mm Hg (systolic blood 
pressure) and/or ≥10 mm Hg (diastolic blood pressure) despite continuation of 
any anti-hypertensive regimen being used at baseline AND initiation and/or dose 
increase of >2 anti-hypertensive agents required for management.*

Grade 4: Life-threatening consequences (eg, malignant hypertension, transient or 
permanent neurologic deficit, hypertensive crisis); urgent intervention indicated.

Grade 5: Death related to AE.
*Note: Multiple changes made to a single medication (eg, initiation at lower dose 
followed by dose increase) counts as only one adjustment.
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Laboratory Abnormalities
6. 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.
7. 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 #6 and #7. 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 10 and no other cause for the 
combination of laboratory abnormalities is immediately apparent (eg, prolonged INR 
with warfarin use), study intervention will be discontinued.
Note: See Appendix 10 for additional details on management of blinded study 
intervention for participants with elevated liver enzymes.
•
Reduction of renal function: If the participant has an eGFR that is persistently 
<30 mL/min/1.73 m2 as calculated by the MDRD formula, study intervention will be 
discontinued. For participants in Japan, eGFR will be calculated with the Japanese 
3-variable Equation 4 (Appendix 7) [Matsuo, S., et al 2009]. See Appendix 13 for the 
eGFR equations.
Note: A persistent eGFR value is defined as a repeat measurement, performed within 
2 weeks after notification from the central laboratory, that remains 
<30 mL/min/1.73 m2, despite correction of potential causative factors (eg, correction 
of volume depletion, discontinuation of NSAIDs). If the eGFR value continues to 
meet the discontinuation criterion but demonstrates stability or improvement relative 
to the prior result, an additional repeat measurement may be performed within 7 days.
•
Salivary cortisol: If the participant has a bedtime salivary cortisol test value 
>1.5 × ULN AND >50% above baseline during the study, a repeat bedtime salivary 
cortisol will be obtained. If the second test value is also >1.5 × ULN AND >50% 
above baseline, a 24-hour urinary cortisol test will be performed. If the 24-hour 
urinary cortisol value is elevated >1 × ULN, study intervention will be discontinued
(see Section 8.3.9.1).
Note: The baseline assessment for the salivary cortisol test value is considered the 
one closest to but before dosing (Visit 5/Randomization [Day 1]). However, if no 
sample is collected before the Visit 5/Randomization, the Visit 1/Screening test value 
should be used for the baseline assessment.
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•
TSH, FT4: If the participant has TSH and/or FT4 values outside the normal range of 
the assay and any signs or symptoms of hyperthyroidism or hypothyroidism 
accompany the changes in thyroid function tests, study intervention will be 
discontinued (see Section 8.3.9.2).
•
IGF-1: If the participant has 2 sequential IGF-1 values above the age-appropriate 
ULN of the assay AND >30% above baseline during the study, study intervention
will be discontinued (see Section 8.3.9.3).
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 500 mL (Appendix 9). Note: See Appendix 7 for China-specific blood 
volume collection requirements.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative before participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
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requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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 trial protocol number, trial 
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 ICF 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.
8.1.2
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.
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
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randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare 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 Section 5.2 and Table 1), and record prior medication 
taken by the participant before Visit 1/Screening.
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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.3.1.
After all required screening procedures have been completed and a participant’s eligibility 
has been confirmed, the study randomization visit will be registered in IRT.
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 re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Compliance (Intervention/Diet/Activity/Other)
8.1.8.1
Diet and Activity Counseling/Monitoring
Participants will receive diet and activity guidance sheets (see Section 5.3.1). At each site 
visit, site staff will reinforce the information on the diet and activity guidance sheets.
8.1.8.2
Assessment of Alcohol Consumption
Participants will report the average number of drinks consumed per week since the last visit.
Participants who consume more than the recommended amount of alcoholic drinks per week 
(ie, more than approximately 7 standard drinks per week in females or more than 
approximately 14 standard drinks per week in males; see Section 5.3.2) must be counseled by 
the site. If a participant is non-compliant with the alcohol use restrictions for 3 or more visits 
over the course of the study, consultation between the investigator and Sponsor is required 
for a collaborative decision on participant management.
8.1.8.3
Self-injection Training (Participant and/or Caregiver)
Participants/caregivers will be trained by site staff on the proper method for self-injection.
At Visit 4/Week -2
1. Participants/caregivers will receive training from the site staff and will review written 
instructions for self-injection.
2. Participants/caregivers will be expected to administer the single-blind study 
intervention (MK-3655 matching placebo) under the guidance of the site staff.
3. Participants/caregivers will take home the written instructions and will be instructed 
to review these materials at home, before Visit 5/Week 0.
If a participant/caregiver is unable to administer study intervention, the site staff may 
administer the doses of study intervention to the participant.
Note: In Japan, administration of study intervention can only be performed by a medically
qualified person (eg, physician, supporting nurse); self-administration by the participant 
him/herself is the only exception. Therefore, administration of study intervention by a 
caregiver will not be allowed in Japan (see Appendix 7).
8.1.8.4
Witnessed Dosing
Administration of study intervention will be witnessed by the investigator and/or qualified 
study staff at ALL scheduled study visits during the placebo run-in and the double-blind 
treatment period. Dosing should occur after completion of all study procedures including the 
collection of all fasting blood samples.
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During the double-blind treatment period:
1. Participants/caregivers will administer the double-blind study intervention
(MK-3655/matching placebo) in the presence of the site staff except at Weeks 28, 36, 
and 44.

Telephone contacts will be made at Weeks 28, 36, and 44 (see SoA [Section 1.3]) 
to assess for compliance with study intervention administration at home by 
participants/caregivers, and to record AEs, body weight, and concomitant 
medications. See Section 8.1.8.8 for further details.
2. Retraining will be provided and documented by site staff as appropriate.
3. Participants/caregivers should be instructed to refer to the written instructions when 
administering injections of the double-blind study intervention at home.
Notes:

No coaching by site staff will be provided unless deemed necessary.

If a participant/caregiver is unable to administer study intervention, the site staff 
may administer the doses of study intervention to the participant.

In Japan, administration of study intervention will not be allowed by a caregiver. 
See Section 8.1.8.3 and Appendix 7.
8.1.8.5
Dispense Single-Blind and Double-Blind Study Intervention
Participants will be dispensed single-blind study intervention (MK-3655 matching placebo) 
at Visit 4/Week -2.
Participants will be dispensed double-blind study intervention (MK-3655/matching placebo) 
at all scheduled study visits from Visit 5/Week 0 (Day 1) through Visit 14/Week 48.
At Visit 11/Week 24, Visit 12/Week 32, and Visit 13/Week 40, study intervention kits will 
be dispensed to participants to self-administer study intervention at home on Week 28, 
Week 36, and Week 44, respectively.
Refer to Section 8.1.9 for further details.
8.1.8.6
Dispense/Review Participant Dosing Diary
Participants will receive dosing diaries as specified in the SoA (see Section 1.3) to document 
their experience with self-injection; specifically, to collect the date, time, and who is 
administering the injection, as well as any comments related to the injection experience. 
Participants should bring their completed diary to all study visits and be reminded to do so 
(eg, by phone or text) before each visit. Site personnel should review the diaries at each study
visit to monitor compliance and review for any potential AEs from the comments entered.
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8.1.8.7
Investigational Product Accountability
When participants self-administer study intervention at home (ie, Weeks 28, 36, and 44)
accountability for the administration of study intervention will be assessed at the next site 
visit. Compliance will be assessed using participant diaries. A visual inspection of the vials 
returned (used and unused) will also be performed (when available) to ensure accurate drug 
accountability.
Consultation between the investigator and Sponsor is required if a participant misses
2 consecutive doses of study intervention during the double-blind treatment period. 
Refer to Section 6.4 for further details on study intervention compliance.
8.1.8.8
Telephone Contact
During the 6-week (±28 days) screening period, telephone contact by the 
investigator/qualified designee will be made within the 3 days before Visit 2/MRI-PDFF and 
Visit 3/Liver Biopsy to assess for concomitant medications and AEs.
At Week 2 post-randomization, telephone contact by the investigator/qualified designee will 
be made to perform a C-SSRS assessment (see Section 8.3.11.1.1).
During the double-blind treatment period, telephone contact by the investigator/qualified 
designee will be made at the midpoint between study visits from Visit 11 through Visit 14 
(ie, Weeks 28, 36, and 44) to assess weight, concomitant medications, AEs, pregnancy status
(if applicable), and compliance with study intervention administration (see Section 1.3).
Unscheduled visit(s) may be performed as needed if the participant requires retraining on 
study intervention administration.
If the participant reports a weight at the time of telephone contact that is greater than or equal 
to a 10% weight gain from baseline (Visit 5/Randomization), an unscheduled site visit will 
be required to confirm the participant’s body weight and to assess the potential need for 
additional dietary intervention (see Section 8.3.3).
During the post-treatment period, telephone contact by the investigator/qualified designee 
will be made at Weeks 60 and 64 to record AEs and assess pregnancy status, if applicable
(see Section 1.3).
If a participant reports a pregnancy at the time of telephone contact, an unscheduled site visit 
will be required to confirm the participant’s pregnancy status with a serum pregnancy test
(see Section 8.3.10).
Section 6.4 summarizes the approach to assessment of compliance as well as addressing 
noncompliance when necessary.
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8.1.9
Study Intervention Administration
Administration of study intervention will be witnessed by the investigator and/or study staff
at ALL scheduled study visits (see Section 1.3). Beginning at Week 0, participants will be 
instructed to administer two 1.5 mL subcutaneous injections of MK-3655/matching placebo 
once every 4 weeks. Refer to Section 8.1.9.1 for further details.
Note: In Japan, administration of study intervention will not be allowed by a caregiver. See 
Section 8.1.8.3 and Appendix 7.
8.1.9.1
Timing of Dose Administration
After it is confirmed that a participant meets study eligibility criteria, study intervention 
(MK-3655/matching placebo) will be administered subcutaneously once every 4 weeks after 
the completion of predose procedures for the duration of the 52-week double-blind treatment 
period.
Week 0 through Week 24 of the double-blind treatment period:

Study intervention will be administered by participants/caregivers as a witnessed dose 
at the study site.

A study intervention kit will be provided by the site to each participant on Week 24 to 
self-administer study intervention at home on Week 28.
After Week 24 through Week 48 of the double-blind treatment period:

On Weeks 28, 36, and 44, study intervention will be administered at home, 4-weeks 
after the previous dose of study intervention by participants/caregivers.

Telephone contact by the investigator/qualified designee will be made on Weeks 28, 
36, and 44 to assess weight, concomitant medications, AEs, and compliance with
study intervention administration.

On Weeks 32, 40, and 48, study intervention will be administered by 
participants/caregivers as a witnessed dose at the study site.

Study intervention kits will be provided by the site to participants at the Week 32 and 
Week 40 visits to self-administer study intervention at home on Weeks 36 and 44, 
respectively.
If necessary, administration of study intervention by site personnel is acceptable. Participants 
will be re-instructed on appropriate injection technique as needed based on observed 
injection experience.
Note: In Japan, administration of study intervention will not be allowed by a caregiver. See 
Section 8.1.8.3 and Appendix 7.
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8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the double-blind 
treatment period should be encouraged to continue to be followed for all remaining study 
visits as outlined in the SoA (Section 1.3) and Section 8.11.6.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the DC visit at the time of withdrawal. Section 8.11.6 outlines 
specific instructions for collection of the end of study MRI-PDFF, DXA imaging, and liver 
biopsy for participants who withdraw from the study. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in
Section 8.4.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@msd.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, they will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
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the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
For participants whose treatment assignment has been unblinded by the investigator or 
medically qualified designee and/or non-study treating physician, discontinuation from study 
intervention is only required if deemed medically necessary. Participants who are 
discontinued from study intervention should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Critical equipment for this study includes a digital body weight scale. The study site is 
responsible for conducting accuracy checks at least monthly to ensure the scale to measure 
body weight is working correctly. Additional details are provided in the operations manual.
8.2
Efficacy Assessments
8.2.1
Liver Fat Content by MRI-Estimated Proton Density Fat Fraction
LFC will be assessed by MRI-PDFF during screening (Visit 2/MRI-PDFF) and at
Visit 11/Week 24. The process for image collection and transmission to the iCRO is in the 
Site Imaging Manual. The same imaging technique and MRI scanner should be used for a 
participant throughout the study to minimize variability.
The screening MRI-PDFF must be performed at Visit 2. All participants must have safety 
laboratory tests (ie, liver function, renal function, and hematological parameters) that meet 
Visit 1/Screening eligibility criteria before imaging can be performed.
Note: Other pending Visit 1/Screening laboratory results are not required to proceed to 
Visit 2/MRI-PDFF. Participants will be screen failed for any exclusion criteria identified 
during Screening.
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For participants who discontinue study intervention before Visit 11/Week 24, an MRI-PDFF 
should be performed at the time of study intervention discontinuation if at least 4 weeks have 
passed since the first dose of double-blind study intervention (see Section 8.11.6).
All scheduled MRI-PDFF images/data for all participants will be submitted to the iCRO for
LFC assessment by BICR (see Section 8.11.3.2). The iCRO will communicate to the site 
whether a participant has met the MRI-PDFF entry criterion (ie, LFC ≥8%). A specific LFC 
score will not be communicated to the sites or participants during the study.
Clinically significant findings in the local interpretation of the MRI-PDFF images at baseline 
and during the double-blind treatment period that are reported by the site investigator should 
be recorded appropriately.
For further information see Section 8.11.3.2.
8.2.2
Liver Biopsy (Histology) and Assessment of Disease
Full instructions concerning the number and type of samples to be collected at each visit, the 
sample collection methods, sample processing, labeling, and shipping will be provided in the 
laboratory manual.
All liver biopsy assessments, including determination of study eligibility based on NASH 
diagnosis, NAS, and fibrosis staging during the 6-week (±28 days) screening period, will be 
performed centrally by independent pathologists. Participants should be fasted for at least 
8 hours before liver biopsy collection. Biopsy tissue is recommended to be of adequate size 
(≥2.0 cm in length; obtained with at least a 16-gauge instrument) and of adequate quality for 
interpretation. For study eligibility, the central pathologists must confirm at baseline, the
histological presence of NASH based on a NAS score ≥4 with a score of at least one in each 
component (steatosis, ballooning, and lobular inflammation) and a fibrosis score of Stage 2 
or 3. NAS and fibrosis staging will be graded in accordance with the NASH CRN criteria for 
scoring [Kleiner, D. E., et al 2005] and as summarized in Appendix 12.
For participants who discontinue study intervention before Visit 15/Week 52, a liver biopsy 
should be performed at the time of study intervention discontinuation if at least 12 weeks 
have passed since the first dose of double-blind study intervention (see Section 8.11.6).
For further information see Section 8.11.3.3.
8.2.3
Glycemic and Lipid Metabolism
The laboratory efficacy endpoints for glycemic metabolism (A1C and FPG) and lipid 
metabolism (cholesterol [total, HDL-C, LDL-C], TG, apoA1, and apoB) should be collected 
as specified in the SoA (see Section 1.3). Participants should be fasted for at least 8 hours
before collection and should take their non-AHA medications as prescribed (see 
Section 8.11.1).
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Sample collection, storage, and shipment instructions for samples will be provided in the 
laboratory manual.
8.2.4
Patient-Reported Outcomes
The CLDQ NAFLD-NASH, PGI-S, and EQ-5D-5L questionnaires will be administered by 
trained site personnel and completed by participants at Visit 5/Week 0 and Visit 15/Week 52 
in the following order: CLDQ NAFLD-NASH first, followed by PGI-S, then EQ-5D-5L. The 
questionnaires should be administered before administration of study intervention and 
according to the SoA (see Section 1.3).
It is best practice and strongly recommended that PROs are administered to randomized 
participants before study intervention administration, AE evaluation, and disease status 
notification.
If a participant discontinues early from study intervention but agrees to be followed for the 
remaining study visits, the participant will be asked to complete the PROs at the DC Visit.
For further information see Section 4.2.1.2.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes per period, can be found in 
Appendix 9. Note: See Appendix 7 for China-specific blood volume collection requirements.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Complete and directed physical examinations will be conducted by an investigator or 
medically qualified designee (consistent with local requirements) as per institutional standard 
and as outlined in the SoA (see Section 1.3). The complete physical examinations will at 
minimum include assessments of general appearance, skin, lymphatic system, eyes, ears, 
nose, throat, CV system, respiratory system, abdomen/gastrointestinal system, urological 
system, musculoskeletal system, and neurological system. Unless the study investigator feels 
there is a specific need, genitourinary, rectal, and breast examination should be omitted from 
the full physical examination.
The directed physical examinations will at a minimum include assessment of the heart, lungs, 
abdomen, skin, and extremities. Other body systems may be evaluated with either type of 
examination. Abnormalities considered clinically significant should be reported as AEs.
A physical examination (complete or directed) may be performed at any unscheduled visit if 
deemed necessary by the investigator or medically qualified designee.
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8.3.2
Height
Height will be measured without shoes using a calibrated stadiometer at Visit 1/Screening.
Document height in meters to the nearest 0.01 meter (0.01 meter = 1 cm).
8.3.3
Body Weight Assessment and Monitoring
Body weight (kg) will be measured in duplicate using a standardized, digital scale as outlined 
in the SoA (Section 1.3). Detailed information regarding the collection of body weight can be 
found in the operations manual.
At Visit 11/Week 24, all participants will be dispensed a digital weight scale (provided by the 
Sponsor) to measure body weight at home on Weeks 28, 36, and 44. Telephone contact by 
the investigator/qualified designee will be made at Weeks 28, 36, and 44 to record the weight 
reported by the participant. Participants should weigh themselves on the day of the scheduled 
telephone contact wearing underwear and socks, first thing in the morning, and after voiding 
(ie, emptying their bladder). If the participant reports a weight at the time of telephone 
contact that is greater than or equal to a 10% weight gain from baseline
(Visit 5/Randomization), an unscheduled site visit will be required to confirm the 
participant’s body weight and potential need for intervention as described below.
Interventions Triggered by Weight Gain
If at any time during the study, a participant has weight gain ≥10% from the 
Visit 5/Randomization baseline measured at the study site using the methodology described 
above, the following will occur:

Local site diet and activity counseling will continue to be provided at each site visit.

A referral to a registered nutritionist/dietician (or equivalent outside the US) will be 
provided, and the investigator must promptly notify the Sponsor. The nutritional/dietary 
consult is recommended to occur within approximately 2 weeks of the initial referral. The 
Sponsor recommends that the registered nutritionist/dietician (or equivalent outside the 
US) encourages the participant to achieve a 0.5 to 0.9 kg (1 to 2 lb) weight loss per week.
If a participant has a weight gain ≥15% from baseline (Visit 5/Randomization) at any time 
during the study:

Study intervention will be discontinued.

Local site diet and activity counseling will continue to be provided at each site visit.

A referral to a registered nutritionist/dietician (or equivalent outside the US) will be 
provided (if not provided already) for the remainder of the study, and the investigator 
must promptly notify the Sponsor.
Poststudy, participants should work with their primary care physician/equivalent physician 
for further weight management, as appropriate. Any participant who has been referred to a 
registered nutritionist/dietician (or equivalent outside the US) at any point during the study 
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for having weight gain ≥10% from randomization will be eligible to continue with their 
nutritional/dietary consult for up to an additional 3 months following completion of the 
study. Specific information regarding this additional nutritional/dietary consultation 
following study completion will be provided in a separate procedure manual.
8.3.4
Body Mass Index
BMI will be calculated (weight/height2 in kg/m2) by the investigator or qualified designee 
based on participant’s height and weight at Visit 1/Screening to ensure the participant meets 
study inclusion criteria (see Section 5.1). Document BMI to the nearest 0.1 kg/m2.
8.3.5
Model for End-Stage Liver Disease-Sodium Score
MELD-Na score will be calculated by the laboratory vendor based on the participant’s 
bilirubin, INR, creatinine, and sodium levels at Visit 1/Screening and communicated to the 
site to ensure the participant meets study inclusion criteria (see Section 5.1).
Note: Should the laboratory vendor be unable to perform the MELD-Na score calculation, 
consult the operations manual.
8.3.6
12-Lead Electrocardiogram
A standard supine 12-lead ECG will be obtained and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) according to the SoA (see 
Section 1.3). Clinically significant abnormal findings during the 6-week (±28 days) screening 
period should be recorded as medical history. Assessments may be repeated during the study, 
as clinically indicated.
•
Participants should avoid the ingestion of caffeine and nicotine-containing products for at 
least 30 minutes before the scheduled ECGs.
•
ECGs should be performed after the participant has rested quietly for at least 10 minutes 
in a supine position and before the assessment of blood pressure and heart rate as well as 
before blood collection.
All ECGs performed should be reviewed at the investigative site for participant safety 
monitoring. The investigator is responsible for retaining all copies of the ECG reports.
8.3.7
Vital Signs
Vital signs will be measured at all scheduled site visits, except Visit 2/MRI-PDFF and 
Visit 3/Liver Biopsy (see Section 1.3 [SoA]). Oral temperature (in centigrade) will only be 
measured at Visit 5/Randomization. At all scheduled visits, blood pressure and heart rate 
should be measured under the following conditions:
•
Triplicate assessment of sitting systolic and diastolic blood pressure (mm Hg) and heart 
rate (beats per minute) will be collected at approximate 2-minute intervals using 
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automated devices. The time, positioning, and arm used should be recorded for each 
measurement.
•
Measurements must be conducted after a 10-minute resting period with the participant 
comfortably seated in a chair with the legs uncrossed and the back and arm supported. 
Measurements should not be made while the participant is on an examination table. The 
participant should be instructed to relax as much as possible and to not talk during the 
measurement procedure.
•
Site personnel should ensure that the middle of the cuff on the upper arm is at the level of 
the right atrium (the midpoint of the sternum).
•
The participant should be asked to remove all clothing that covers the location of cuff 
placement.
•
Site personnel should use the same blood pressure measuring device (ie, automated 
device) and under the same external conditions throughout the study for each participant.
•
Other procedures should not be performed during the time of the blood pressure and heart 
rate measurements.
Detailed information regarding blood pressure and heart rate monitoring is contained in the 
operations manual. After the first dose of study intervention, new clinically significant 
abnormal findings should be recorded as AEs.
8.3.8
Dual-Energy X-ray Absorptiometry
DXA images to monitor whole body composition and BMD should be collected from all 
participants/sites willing and able to have the test performed and according to country law.
These participants will undergo DXA of the total body, lumbar spine, and hip for BMD as 
well as body composition. All scheduled DXA images will be submitted to the iCRO.
Participants will not be excluded from participation in the study if unable to have DXA 
imaging performed.
Only participants who are confirmed eligible at Visit 1/Screening will undergo DXA imaging 
during the Visit 4/Placebo Run-in period (baseline). If iCRO DXA quality control should 
fail, no repeat DXA imaging will be performed. Only participants with valid baseline DXA 
images should have DXA imaging performed at Visit 15 (Week 52 ±5 days). For participants 
who discontinue study intervention after Visit 11/Week 24, DXA imaging should be 
performed at the time of study intervention discontinuation (DC visit). Refer to 
Section 8.11.6 for end of study DXA collection recommendations.
All scheduled DXA images will be evaluated by BICR. The BICR will not be performed in 
real-time and analysis results will not be provided to the site/participant. For clinical 
management of the participant, the DXA images should be reviewed and interpreted by a 
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qualified individual. Clinically significant findings noted in the local interpretation of the 
DXA images at baseline and during the double-blind treatment period should be recorded 
appropriately.
For each participant, the same imaging equipment should be used throughout the study to 
optimize assessment. Details on DXA acquisition and quality assurance will be included in 
the iCRO manual for DXA.
8.3.9
Clinical Laboratory Assessments (Hematology, Chemistry, Urinalysis, and 
Other)
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (see Section 1.3).
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study, every attempt should be made to perform repeat assessments 
until the values return to normal or baseline or if a new baseline is established as 
determined by the investigator.
•
Participants will be counseled to fast (ie, no food, double-blind study intervention, or 
drink except water and non-AHA medications as prescribed) for at least 8 hours before 
study visits requiring fasted blood collections or procedures (see Section 8.11.1).
•
Serum hCG testing will be performed in female participants where a pregnancy is 
suspected.
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8.3.9.1
Bedtime Salivary Cortisol
Salivary cortisol testing kits will be provided to the participant as described in the SoA (see 
Section 1.3).

At Visit 1/Screening:
o
Participants will be provided with the salivary cortisol testing kit on the day of the 
visit (unless provided in advance if the informed consent is obtained before the visit).
o
Participants should be instructed to collect the sample at bedtime between 9 PM and 
midnight that evening and return the sample to the site the next day if possible but no 
later than 72 hours from the time of collection.

All visits after Visit 1/Screening:
o
Participants will be provided with the salivary cortisol testing kit at the visit prior to 
the next required sample collection timepoint.
o
Participants should be instructed to collect the sample at bedtime between 9 PM and 
midnight the evening prior to the visit and return the sample to the site the next day 
but no later than 72 hours from the time of collection.
If the bedtime salivary cortisol test value is >1.5 × ULN AND >50% above baseline during
the study, a repeat bedtime salivary cortisol test should be performed within 1 week to 
confirm the value. If the second test value is also >1.5 × ULN AND >50% above baseline, a 
24-hour urinary cortisol test will be performed. If the 24-hour urinary cortisol value is 
elevated >1 × ULN, study intervention will be discontinued and the participant should be 
referred to an endocrinologist, or an appropriate medical provider when an endocrinologist is 
not available.
Sample collection, storage, and shipment instructions for samples will be provided in the 
laboratory manual.
8.3.9.2
TSH and FT4
TSH and FT4 will be measured as detailed in the SoA (see Section 1.3). If a participant
develops TSH and/or FT4 values outside the normal range of the assay during the study, 
repeat testing and further evaluation by an endocrinologist, or an appropriate medical 
provider when an endocrinologist is not available, are warranted. Study intervention should
be discontinued if any treatment-emergent signs or symptoms of hyperthyroidism or 
hypothyroidism accompany the changes in thyroid function tests.
Sample collection, storage, and shipment instructions for samples will be provided in the 
laboratory manual.
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8.3.9.3
IGF-1
IGF-1 will be measured as detailed in the SoA (see Section 1.3). If a participant develops 
IGF-1 values during the study that are both above the age-appropriate ULN of the assay 
AND >30% above baseline, a repeat IGF-1 test should be performed. If both test values are 
above the age-appropriate ULN AND >30% above baseline, study intervention will be 
discontinued and the participant should be referred to an endocrinologist, or an appropriate 
medical provider when an endocrinologist is not available.
Sample collection, storage, and shipment instructions for samples will be provided in the 
laboratory manual.
8.3.10
Pregnancy Testing
-
Pregnancy testing for WOCBP:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum) should be conducted at monthly intervals 
during intervention.
o
At all scheduled site visits (except Visits 2 and 3) a urine pregnancy test will 
be performed (see Section 1.3).
o
At Visit 11/Week 24, Visit 12/Week 32, and Visit 13/Week 40, the site will 
also dispense a urine pregnancy test kit for use at home on Weeks 28, 36, and 
44.
o
At Visit 16/Week 56, the site will dispense urine pregnancy test kits for use at 
home on Weeks 60 and 64.
o
Telephone contact by the investigator/qualified designee will be made at the 
midpoint between study visits from Visit 11 through Visit 14 (ie, Weeks 28, 
36, and 44) and Weeks 60 and 64 to assess AEs and pregnancy status (see 
Section 8.1.8.8). If the participant reports a pregnancy at the time of telephone 
contact, an unscheduled site visit will be required to confirm the participant’s 
pregnancy status with a serum pregnancy test.
-
Pregnancy testing (urine and/or serum) should be conducted as per the SoA for 
the time required to eliminate systemic exposure after the last dose of study 
intervention and should correspond with the time frame for participant’s
contraception as noted in Section 5.1. The length of time required to continue 
pregnancy testing for study intervention is 16 weeks after the last dose of study 
intervention.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study.
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8.3.11
Suicidal Ideation and Behavior Monitoring
8.3.11.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
8.3.11.1.1
Columbia-Suicide Severity Rating Scale
Suicidal ideation and behavior will be prospectively assessed during this study using the 
C-SSRS. The C-SSRS should be administered by trained raters at specified time points, as 
indicated in the SoA, as well as at unscheduled visits as clinically indicated. Site staff should 
review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, the completed 
C-SSRS should be provided to the investigator for review before their assessment of the 
participant to further inform their evaluation.
During the Visit 1/Screening visit, the participant’s suicidal symptoms and actions over the 
past 6 months should be evaluated with the C-SSRS. The C-SSRS is not explicit about 
whether the participant specifically has suicidal ideation at the time of Visit 1/Screening. If a 
participant reports a prior history of suicidal ideation/behavior, the assessor should also 
inquire and document if this is also present at the time of Visit 1/Screening. For all other 
assessments, the participant’s suicidal symptoms and actions since the last assessment should 
be evaluated.
Participants must be excluded if they report suicidal ideation meeting the description of 
C-SSRS items 4 or 5 (ie, suicidal ideation with intent with or without a plan) within the 
past 2 months or suicidal behavior within the past 6 months at Visit 1/Screening.
Additionally, participants must be excluded at Visit 4/Placebo Run-in or 
Visit 5/Randomization if they report suicidal ideation of items 4 or 5 or suicidal behavior, 
as measured by the C-SSRS since the last assessment. Excluded participants who meet the 
description of C-SSRS items 4 or 5 or suicidal behavior will be immediately referred to a 
qualified mental health professional and must be evaluated that day.
Participants who, at any time during this study (ie, pre- or post-randomization), report 
suicidal ideation or behavior that is considered to be an AE, either between visits or during 
visit interviews, must be assessed by the investigator. Participants who report suicidal 
ideation with intent, with or without a plan or method (ie, a positive response to items 4 or 5 
in the assessment of suicidal ideation on the C-SSRS) or ANY suicidal behavior must be 
evaluated that day by a psychiatrist or other trained mental health professional who is a 
licensed psychologist, social worker, or mental health nurse practitioner (or comparable 
professional qualification in countries outside the US). Participants whose suicidal ideation is 
considered to be passive, and who expressly deny any intent to act, and who, after evaluation
by a psychiatrist or mental health professional, are not judged to be at serious risk for self-
harm during the course of the study may continue on study intervention; others must be 
interrupted from study intervention and receive appropriate clinical follow-up care to ensure 
their safety. If after appropriate follow-up care, the investigator judges that the participant 
can safely resume study intervention, re-dosing can be considered with Sponsor approval. If 
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after appropriate follow-up care, the investigator judges it is not appropriate for a participant 
to resume dosing, the participant should be discontinued from study intervention.
All AEs of suicidal ideation or behavior must be recorded as an ECI (see Section 8.4.7). 
Even if suicidal ideation is present at Visit 1/Screening and has not changed or worsened by 
Visit 4/Placebo Run-in, the site should still report the suicidal ideation as an ECI. Sites are to 
designate which health care professionals are to be responsible for acute care on-site and to 
specify referral center(s) to be used for further evaluation.
Notes:

The Sponsor Clinical Director or appropriate qualified designee should be contacted at 
any time during the study if a participant reports a positive response to items 1, 2, or 3 in 
the assessment of suicidal ideation on the C-SSRS.

Unscheduled assessments can be conducted for individual participants as considered 
appropriate by study investigators and, if warranted by emerging data during the conduct 
of the study, more frequent assessments can be implemented.
8.3.11.1.2
Patient Health Questionnaire – 9
The PHQ-9 is a 9-item self-reported depression screening tool which takes approximately 
10 minutes to complete and will be used as a clinical assessment and monitoring tool.
Before Randomization
The investigator must assess the PHQ-9 score at Visit 1/Screening, Visit 4/Placebo-Run-in,
and Visit 5/Randomization:

Actions:
o
Participants with a total score >12 should be excluded from participating in the study.
o
Participants with a total score ≥15 will be referred to a mental health professional.
o
Investigator is expected to exercise good clinical judgment to ensure participant’s 
safety.
Notes:

The PHQ-9 should be scored and evaluated before all other assessments/procedures.

If a participant’s score on Question #9 of the PHQ-9 is ≥1 (see Appendix 11), but the 
participant answered “No” to all the questions on the C-SSRS, the investigator must 
reconcile the discrepancy to determine a participant’s study eligibility.
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After Randomization
The PHQ-9 will be administered at ALL clinic visits to take appropriate action based on 
score.

Actions While on Study Intervention:
o
Participants will be referred to a mental health professional if they have a total score 
≥15 on the PHQ-9. The investigator will be expected to comply with local/state 
clinical practice mandates if in the opinion of the investigator the event is deemed an
emergency.
o
The Sponsor Clinical Director should be contacted for any score ≥15 on the PHQ-9.
Note: The PHQ-9 should be scored and evaluated before all other assessments/procedures.
8.3.12
Adverse Event Monitoring
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the SoA (Section 1.3) and more frequently if clinically 
indicated. AEs will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE, Version 5.0 (see Section 10.14). Note: For AEs that are an 
exception to the NCI CTCAE grading, see Section 7.1.
The criteria for the discontinuation of study intervention for individual participants are 
described in Section 7.1.
Please refer to Section 8.4 for detailed information regarding assessing and reporting AEs, 
SAEs, and other reportable safety events.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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 participant is receiving placebo run-in or other run-in treatment, 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.
For all participants, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator from the time of intervention randomization through Week 64.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time 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 the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor. This includes any cardiovascular SAE or 
any malignancy an investigator learns about in a participant who has been discharged from 
the study through the last participant’s last treatment visit in the study must be promptly 
reported to the Sponsor for adjudication regardless of whether the event is considered related 
to the study intervention.
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 4.
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Table 4
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:
Nonserious Adverse Event 
(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
Serious Adverse Event 
(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)
Report all
Previously reported – Follow 
to completion/termination; 
report outcome
Within 24 hours of 
learning of event
Event of Clinical Interest 
(require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of Clinical Interest 
(do not require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs
- ECIs not requiring 
regulatory reporting
- Suicidal ideation, 
suicidal behaviors
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
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.
Certain patient reported outcomes, observer reported outcomes and/or surveys designed for 
patient respondents that are included in the study require review for SAE identification and 
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reporting by the investigator or a qualified designee. The assessment of these SAEs should 
follow the requirements outlined in Section 8.4. The specific patient reported outcomes, 
observer reported outcomes and /or surveys designed for patient respondents that need to be 
reviewed for SAE identification, assessment and reporting are listed below: 
1. CLDQ NAFLD-NASH
2. PGI-S
3. EQ-5D-5L
4. PHQ-9
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, events of clinical interest (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 suspected unexpected serious adverse 
reactions (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.
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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.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. For participants with ALT and AST ≤ULN at baseline who meet ANY of the following 
criteria*:
• ALT or AST >3 × ULN
• Total bilirubin >2 × ULN (if direct bilirubin is elevated)
• Alkaline phosphatase >3 × ULN
• INR >1.5 × ULN**
• Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, 
rash, or eosinophilia >5%)
2. For participants with ALT and/or AST >ULN at baseline who meet ANY of the 
following criteria*:
• ALT and/or AST >2 × baseline***
• Total bilirubin >1.5 × baseline AND >ULN (if direct bilirubin is elevated)
• Alkaline phosphatase >3 × ULN
• INR >1.5 × ULN**
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• Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, 
rash, or eosinophilia >5%).
*Note: The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File Binder 
(or equivalent). During a period of close observation for DILI, study intervention can be 
continued, if desired, at the discretion of investigator in consultation with the Sponsor 
Clinical Director.
**Note: For participants who initiate anticoagulant therapy after study initiation, the INR 
threshold does not apply.
***Note: If only one of the analytes (ie, ALT or AST) was >ULN at baseline, this criterion 
(ie, >2 × baseline) would only apply to the analyte that is >ULN at baseline while the 
criterion noted under #1 above (ie, >3 × ULN) would apply to the analyte that was ≤ULN at 
baseline.
3. Suicidal ideation, suicidal behaviors
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the prescribed dose of MK-3655 or 
matching placebo as defined in the protocol.
No specific information is available on the treatment of overdose of MK-3655. In the event 
of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
The decision as to which serum samples collected will be assayed for evaluation of PK will 
be collaboratively determined by the Sponsor. If indicated, these samples may also be 
assayed and/or pooled for assay in an exploratory manner for additional PD markers.
8.6.1
Blood Collection for Serum MK-3655
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the laboratory manual.
PK samples will be collected from all randomized participants according to the PK sampling 
scheme shown in Table 5 and as outlined in the SoA (Section 1.3). A total of 7 PK samples 
will be taken from each participant. At all study visits during the double-blind treatment 
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period where a PK sample will be collected, the participant must withhold their 
MK-3655/matching placebo dose until after PK sample collection. During the double-blind 
treatment period, the date and time of the last dose of MK-3655/matching placebo will be 
recorded. Throughout the study, the date and time of each PK sample will also be recorded.
All PK samples will be used to evaluate not only PK exposures, but also to assess the PK/PD 
and PK/AE relationships of MK-3655, as appropriate.
Note: In Japan, administration of study intervention will not be allowed by a caregiver. See 
Section 8.1.8.3 and Appendix 7.
Table 5
Pharmacokinetic Sampling Time Points
Visit Number
Week/Study Day
Visit 5
Week 0/Day 1
Visit 6
Week 4/Day 28
Visit 7
Week 8/Day 56
Visit 8
Week 12/Day 84
Visit 11
Week 24/Day 168
Visit 15
Week 52/Day 364
Visit 16
Week 56/Day 392
ADA=anti-drug antibodies; eCRF=electronic case report form; PK=pharmacokinetic.
Notes:

Approximately 2 mL of blood will be collected for the PK only timepoint at Visit 7 (Week 8/Day 56). At 
all other prespecified timepoints, approximately 4 mL of blood will be collected for assessment of ADA 
and PK.

The date and time of the PK sample collection for all MK-3655 PK samples must be recorded in the 
eCRF.

At the time of PK sample collection, participants will be asked to provide information regarding the 
time/date of the last dose of MK-3655/matching placebo before the PK sample collection.
8.7
Immunogenicity
ADA samples will be collected from all randomized participants according to the ADA
sampling scheme outlined in the SoA (Section 1.3). A total of 6 ADA samples will be taken 
from each participant. At all study visits during the double-blind treatment period where an 
ADA sample will be collected, the participant must withhold their MK-3655/matching 
placebo dose until after ADA sample collection. During the double-blind treatment period,
the date and time of the last dose of MK-3655/matching placebo will be recorded.
Throughout the study, the date and time of each ADA sample will be recorded.
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the laboratory manual.
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8.8
Pharmacodynamics
PD assessments will be conducted as outlined in the SoA (Section 1.3).
8.8.1
Plasma and Serum Pharmacodynamic Samples
Plasma or serum samples will be used for measurement of the following PD assessments:

Adiponectin

Fasting insulin

HOMA-IR (calculated from fasting glucose and fasting insulin)

Fasting FFA
Sample collection, storage, and shipment instructions for PD samples will be provided in the 
laboratory manual.
8.8.2
Biomarkers/Panels Reflecting Liver Inflammation and Fibrosis
The following biomarkers/composite scores will be used to assess liver inflammation and 
fibrosis:

The FIB-4 is an index with high clinical utility as it can be calculated by using the 
patient’s age and 3 indirect markers: ALT, AST, and PLT levels. The FIB-4 formula is 
(((age expressed in years) × (AST [U/L])) / ((PLT [109/L]) × (square root of ALT 
[U/L]))) [Shah, A. G., et al 2011].

The NFS is a validated serum-based model used for identifying patients with advanced 
fibrosis. The NFS uses 6 variables: age, BMI, IFG/diabetes, AST/ALT ratio, PLT, and 
albumin. The algorithm for NFS = −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) 
+ 1.13 × IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio – 0.013 × PLT (× 109/L) 
– 0.66 × albumin (g/dL) [Angulo, P., et al 2007].

The APRI is an algorithm that uses serum biomarkers for staging fibrosis risk and is 
calculated using the following equation ([AST level/AST ULN]/PLT count) × 100
[Fallatah, H. I. 2014].

Pro-C3 levels in serum have been demonstrated to increase with worsening of fibrosis 
and decrease with fibrosis improvement/regression; suggesting that Pro-C3 may be a 
potentially useful biomarker in identifying patients with advanced fibrosis and active 
fibrogenesis, as well as in assessing changes in fibrosis over time. Pro-C3 may also be 
used to monitor disease progression and therapeutic response [Nielsen, M. J., et al 2015].
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Sample collection, storage, and shipment instructions for serum samples will be provided in 
the laboratory manual. Composite scores will be calculated during data analysis and will not 
be calculated by the study site.
8.9
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for genetic analysis
•
Blood for serum biomarkers
•
Blood for plasma biomarkers
•
Liver Biopsy
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
8.9.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for PNPLA3, TM6SF2, MBOAT7, 
GCKR, HSD17B13, PPP1R3B, and LYPLAL1 genotyping and for planned analysis of the 
association between genetic variants in DNA and drug response. If the IRB/IEC does not 
approve of the planned analysis of the association between DNA variation and drug response, 
or if there is a local law or regulation prohibiting the same, data analysis will be limited to
PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13, PPP1R3B, and LYPLAL1. If the 
participant provides documented informed consent for FBR, the leftover extracted DNA will 
be stored for FBR.
Genetic analysis samples will only be collected from randomized participants. If a sample for 
genetic analysis is not collected at Visit 5/Randomization, it can be collected at a subsequent 
visit.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the laboratory manual.
8.10
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
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•
Leftover main study serum biomarkers for future research
•
Leftover main study plasma biomarkers for future research
•
Leftover main study liver biopsy for future research
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Fasting Before Scheduled Visits
Participants should be counseled to fast (ie, no food or drink except water) for at least 8 hours
before study visits requiring fasted blood collections or procedures (see Section 1.3).
Participants who have not fasted for the Visit 1/Screening should have all blood collections 
rescheduled and completed before the Visit 2/MRI-PDFF. After randomization 
(Visit 5/Week 0), participants who do not fast before a scheduled visit will be required to 
return fasted for a study visit within 3 days.
Note: Participants should take their non-AHA medications as prescribed before study visits 
requiring fasted blood collections or procedures (see Section 1.3).
8.11.2
Scheduling Visits
At Visit 1/Screening, the Visit 2/MRI-PDFF, Visit 3/Liver Biopsy, and Visit 4/Placebo 
Run-in (including DXA imaging), will be scheduled in advance.
At the end of each study visit from the placebo run-in through the double-blind treatment 
period, the next study visit should be scheduled. Every effort should be made to adhere to the 
visit schedule (see Section 1.3). Visit 5/Week 0 (Day 1) should be scheduled 2 weeks 
±3 days after Visit 4/Placebo Run-in. Visits during the double-blind treatment period should 
be scheduled within ±3 days (Visit 5/Week 0 [Day 1] through Visit 11/Week 24) and ±5 days 
(Visit 12/Week 32 through Visit 15/Week 52). If unavoidable and after consultation with the 
Sponsor, a visit may be scheduled at a time outside this recommended range. After Visit 
5/Week 0 (Day 1), the schedule for subsequent visits must be adjusted so that the total 
duration of the double-blind treatment period is as close as possible to 52 weeks. Visits
during the double-blind treatment period should be scheduled relative to the date of 
Visit 5/Week 0 (Day 1). If a visit is scheduled at a time other than the protocol designated 
time, careful consideration must be given to the amount of investigational product the 
participant has available.
Study sites should contact IVRS at the timepoints outlined in the SoA (see Section 1.3) for 
purposes of enrollment tracking.
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8.11.2.1
Visit Reminders
Before each study visit, participants should be called and be reminded of:

The date and time of next appointment.

The requirement:
-
To not engage in physically strenuous exercise (ie, weightlifting, running, bicycling, 
etc.) within 48 hours before their study visit.
-
To fast for at least 8 hours before all study visits requiring fasting laboratory 
collections.
-
To not take AHA medications at home the morning of the study visit. Non-study
medications that are not AHA medications should be taken as directed by the
prescribing physician.
-
To bring blinded study intervention (used and unused vials) on Weeks 32, 40, and 48.
-
To bring participant dosing diaries to each site visit.
-
That administration of study intervention will be witnessed by the investigator and/or 
study staff at the study visit.
8.11.3
Screening
The interval from Visit 1 through Visit 3 will constitute a screening period of approximately 
6 weeks (±28 days). The screening period may be extended under special circumstances 
(eg, scheduling issues, delays in obtaining MRI-PDFF or liver biopsy results) with the 
explicit approval of the Sponsor Clinical Director.
8.11.3.1
Visit 1/Screening
Determination of eligibility will be based mostly on medical history of standard of care tests 
and procedures that were completed before Visit 1/Screening. Potential participants will be 
evaluated at Visit 1/Screening to determine if they fulfill the entry requirements as described
in Sections 5.1 and 5.2. For participants assessed as eligible to participate in the study, blood 
and urine samples will be obtained according to the SoA (see Section 1.3). Participants who 
have not fasted for the Visit 1/Screening should have all blood collections rescheduled and 
completed before Visit 2/MRI-PDFF.
Note: All participants at study sites in Argentina must be tested for Hepatitis B, Hepatitis C, 
and HIV at Visit 1/Screening (see Appendix 7).
If any participant fails to meet the study entry criteria, Visit 1/Screening procedures may be 
repeated based on investigator judgment after initial screening, and after consultation with 
the Sponsor. Participants may only be rescreened once.
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See Section 8.11.3.3.1 for managing participants with a historical liver biopsy.
8.11.3.2
Visit 2/MRI-PDFF
LFC will be measured by MRI-PDFF in consented participants whose safety laboratory tests 
(ie, liver function, renal function, and hematological parameters) meet study eligibility 
criteria assessed at Visit 1/Screening. Other pending Visit 1/Screening laboratory assessment 
results are not required to proceed to Visit 2/MRI-PDFF. Participants will be screen failed for 
any exclusion criteria identified during Screening.
All MRI-PDFF scans will be evaluated by BICR. The appointed iCRO will review all 
baseline scans and confirm participants meet the MRI-PDFF entry criteria (see Section 5.1) 
before Visit 3/Liver Biopsy.
Note: A second MRI-PDFF will be performed at 24 weeks after Visit 5/Randomization.
8.11.3.3
Visit 3/Liver Biopsy
8.11.3.3.1
Participants With Historical Liver Biopsies
For consented participants who have had a historical liver biopsy performed within 6 months 
of Visit 1/Screening and whose safety laboratory tests (ie, liver function, renal function, and 
hematological parameters) satisfy Visit 1/Screening entry criteria, biopsy samples will be 
submitted to the central laboratory vendor for processing and BICR to confirm study 
eligibility.
Notes:

Other pending Visit 1/Screening laboratory assessment results are not required for 
submission of biopsy samples to the central laboratory vendor. Participants will be screen 
failed for any exclusion criteria identified during Screening.

An MRI-PDFF can be performed in consented participants with pending historical liver 
biopsy assessments.

If the historical liver biopsy does not meet study eligibility criteria, the participant will be 
screen failed.

If the historical liver biopsy cannot be assessed for any reason (including sample quality), 
the participant, if agreeable, may have a liver biopsy performed at Visit 3/Liver Biopsy; 
however, all Visit 1/Screening assessments/procedures and LFC by MRI-PDFF must 
meet study eligibility criteria before performing the liver biopsy.
8.11.3.3.2
Participants Who Require an In-Study Liver Biopsy
Participants who have not had a liver biopsy within 6 months of Visit 1/Screening, or whose 
previous liver biopsy is not available for review by the central pathology vendor, or whose 
previous liver biopsy is of inadequate quality, must have a liver biopsy completed at 
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Visit 3/Liver Biopsy to be eligible to participate in this study. The biopsy should be 
performed once the participant has been found to be eligible with respect to all other 
inclusion and exclusion criteria (see Sections 5.1 and 5.2).
Participants should be fasted (ie, no food or drink except water) for at least 8 hours before the 
liver biopsy procedure. Biopsy tissue should be of adequate size and of adequate quality for 
interpretation (see Section 8.2.2). All biopsies will be read by BICR by the central pathology 
vendor.
Note: A second liver biopsy sample will be collected at Visit 15/Week 52.
8.11.4
Placebo Run-in Period
At Visit 4/Week -2, participants who meet all enrollment criteria as described in Sections 5.1 
and 5.2 will be eligible to enter the 2-week, single-blind, placebo run-in period.
After completion of all other study procedures as specified in the SoA (see Section 1.3),
eligible participants will be provided instruction and be witnessed in the administration of 
2 subcutaneous injections of single-blind investigational product at a volume of 1.5 mL each.
Note: Participants will be re-instructed on appropriate injection technique as needed based on 
observed injection experience. See Section 8.1.8.3 for further details.
Participants will have a baseline DXA scan performed. If quality control fails and a repeat
DXA is required, one will not be performed. The data point will be recorded as a missing 
value.
8.11.5
Double-Blind Treatment Period
At Visit 5/Randomization (Day 1), participants who meet all study entry criteria will enter 
the double-blind treatment period of approximately 52 weeks. Participants will be 
randomized in a 1:1:1:1 ratio to MK-3655 50 mg Q4W, MK-3655 100 mg Q4W, MK-3655 
300 mg Q4W, or MK-3655 matching placebo Q4W and assigned a unique
treatment/randomization number.
On Day 1 (Visit 5/Randomization) participants will have all study procedures, including the 
collection of fasting blood samples, performed as described in the SoA (see Section 1.3) 
before the administration of the double-blind study intervention. Study intervention will be 
administered by participants/caregivers as a witnessed dose at the study site.
At all scheduled site visits from Visit 6/Week 4 through Visit 14/Week 48, study 
intervention will be dispensed, and participants will administer study intervention as a 
witnessed dose at the study site after all study procedures have been performed as described 
in the SoA (see Section 1.3).
After Visit 11/Week 24, once administration of study intervention at home applies, 
participants will be expected to self-administer study intervention as specified in the SoA 
(ie, Weeks 28, 36, and 44). Therefore, at Visit 11/Week 24, Visit 12/Week 32, and
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Visit 13/Week 40, the site will also dispense (supported by IRT) a study intervention kit for 
administration at home.
On Weeks 28, 36, and 44, participants will record in their diary the date, time, and who 
administered the injection as well as any comments related to the injection experience. 
Participants will return their diary, used and unused medication, and the study intervention 
kit packaging at their next scheduled site visit.
Participants will return to the study site approximately 4 weeks after the last dose of double-
blind study intervention (MK-3655/matching placebo) for Visit 15/Week 52.
See Section 8.1.9.1 for timing of dosing study intervention on the day of study visits.
8.11.6
Participants Discontinued From Study Intervention but Continuing to Be 
Monitored in the Study
It is intended that all randomized participants should be followed through completion of the
study, regardless of premature discontinuation of treatment, unless the participant withdraws
consent from any study follow-up. Thus, participants who discontinue from study
intervention before completion of the study should continue to be monitored after the DC 
visit procedures are completed to obtain relevant information through the end of the study.
If a participant is discontinued from the study intervention early:

A DC visit should be completed as specified in the SoA (see Section 1.3) except as noted 
below:

For participants who have completed at least 24 weeks of treatment, DXA imaging 
should be encouraged as part of the DC visit procedures. For participants who 
withdraw from the study before completing 24 weeks of treatment, end of study DXA 
imaging should not be performed at the time of withdrawal.

For participants who have completed at least 12 weeks of treatment, completion of 
the end of study liver biopsy should be encouraged as part of the DC visit procedures. 
For participants who withdraw from the study before completing 12 weeks of 
treatment, an end of study liver biopsy should not be performed at the time of 
withdrawal.

For participants where at least 4 weeks have passed since the first dose of 
double-blind study intervention, the end of study MRI-PDFF should be encouraged as 
part of the DC Visit procedures. Note, MRI-PDFF assessed in these participants will 
potentially be used for further evaluation of the kinetics of LFC reduction from the 
onset of treatment. For participants where less than 4 weeks have passed since the 
first dose of study intervention, an end of study MRI-PDFF should not be performed 
at the time of withdrawal.
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
Study site visits/telephone contacts should continue to be performed for all participants as 
outlined in the SoA through Week 64.

For WOCBP pregnancy testing should continue to be performed monthly until 16 weeks 
have passed since the last dose of study intervention.
For those participants who have discontinued study intervention early and who miss the 
remaining study visits, sites will be instructed to make diligent efforts to continue to contact 
them. To enable sites to reach participants, the participants should provide primary and 
secondary contact information (eg, home telephone, work telephone, mobile telephone). Sites 
must document the outcome of the telephone contact(s) to demonstrate diligent efforts have 
been made.
Additionally, the ICF will explain the importance of continued data collection from 
participants, including the use of continued contact by telephone.
8.11.7
Post-Treatment Visit and Telephone Contacts
The final scheduled site visit (Visit 16) will occur approximately 4 weeks after Visit 15.
Post-treatment follow-up telephone contacts will be performed at Weeks 60 and 64.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study that are 
considered principal in nature. If changes are made to primary and/or key secondary 
hypotheses or the statistical methods related to those hypotheses after the study has begun but 
before any unblinding, then the protocol will be amended (consistent with ICH 
Guideline E9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized 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.
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Study Design 
Overview
A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-3655 in Individuals With 
Pre-cirrhotic Nonalcoholic Steatohepatitis
Treatment
Assignment
Participants (82 per group) will be randomized in a 1:1:1:1 ratio 
among 4 treatment groups: (1) MK-3655 50 mg Q4W, (2) MK-3655 
100 mg Q4W, (3) MK-3655 300 mg Q4W, and (4) matching placebo.
Primary Analysis 
Populations
Efficacy: FAS
Safety: APaT
Primary 
Endpoint

NASH resolution without worsening in fibrosis by histology 
(evaluated by BICR) after 52 weeks
Key Secondary 
Endpoints

Percent relative reduction in LFC based on MRI-PDFF (evaluated 
by BICR) after 24 weeks

≥1 stage improvement in fibrosis without worsening of 
steatohepatitis by histology (evaluated by BICR) after 52 weeks

≥2 point reduction in NAS with ≥1 point reduction in 
inflammation or ballooning without worsening of fibrosis by 
histology (evaluated by BICR) after 52 weeks
Statistical 
Methods for Key
Efficacy 
Analyses
Primary:

The differences in proportions and the associated 95% CI and 
p-values will be provided (MK-3655 minus placebo; 3 pair-wise 
comparisons) based on the stratified M&N method [Mehrotra, D. 
V. 2000].
Key Secondary:

For LFC, the differences in means and the associated 95% CIs and 
p-values will be provided (MK-3655 minus placebo; 3 pair-wise 
comparisons) based on a cLDA model.

Other key secondary endpoints will follow methods for the 
primary efficacy endpoint.
Statistical 
Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for between-
treatment differences (MK-3655 minus placebo) 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
A single IA is planned for administrative purposes and to assess 
futility. The IA is planned to be performed once ≥25 participants per 
group have completed an MRI-PDFF at the Week 24 post-
randomization assessment. Results will be reviewed by an eDMC. 
Key endpoints to be evaluated include LFC (efficacy), body weight, 
AEs, and PDLC in laboratory parameters.
The study may stop for futility if the posterior probability is <5% that 
the true mean difference (MK-3655 minus placebo) in percent 
reduction from baseline in LFC is ≥40% for all active treatment 
groups.
Multiplicity
There are 3 pair-wise treatment group comparisons that may be tested 
to address the primary hypothesis. Testing will be performed in order 
of descending dose and will stop with the first comparison that has a 
one-sided p-value >0.025.
Sample Size and 
Power
The sample size was chosen based on the proportion of participants 
with NASH resolution without worsening in fibrosis after 52 weeks. 
Assuming the proportion with this endpoint based on a 
non-completer = failure approach is 30% for each MK-3655
dose/modality versus 10% for placebo, a sample size of 
82 participants per group provides 90% power for each of the 
3 pair-wise treatment comparisons using a one-sided alpha = 0.025.
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.
The Sponsor will generate the randomized allocation schedule for study intervention
assignment for this protocol, and the randomization will be implemented in IVRS.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and
complete.
Blinding procedures related to the planned IA are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
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9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary Efficacy Endpoint

Proportion of individuals with NASH resolution (defined as a score of 0-1 for lobular 
inflammation, 0 for ballooning, and any grade of steatosis) without worsening of fibrosis 
by histology (evaluated by BICR) after 52 weeks
Secondary Efficacy Endpoints

Mean percent relative reduction from baseline in LFC measured by MRI-PDFF 
(evaluated by BICR) after 24 weeks

Proportion of individuals with ≥1 stage improvement in fibrosis without worsening of 
steatohepatitis (defined as no increase in the NAS for ballooning, inflammation, or 
steatosis) by histology (evaluated by BICR) after 52 weeks

Proportion of individuals with ≥2 point improvement in NAS with ≥1 point improvement 
in inflammation or ballooning without worsening of fibrosis by histology (evaluated by 
BICR) after 52 weeks
Efficacy endpoints are further described in Section 4.2.1.1.
9.4.2
Patient-Reported Outcome Endpoints
PRO endpoints (eg, score change from baseline over time) include CLDQ NAFLD-NASH, a 
participant’s specific quality of life total and domain scores; PGI-S, a participant’s rating of 
global severity of symptoms; and EQ-5D-5L, health state description and evaluation. 
Week 52 is the primary timepoint of interest. The PRO endpoints are described in 
Section 4.2.1.2 and Section 8.2.4.
9.4.3
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory safety tests, vital signs, and body weight.
Safety parameters are described in Section 4.2.1.3.
9.4.4
Pharmacokinetic Endpoint
The key exploratory PK endpoint for MK-3655 is Ctrough.
Additional details are in Section 4.2.1.4.
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9.4.5
Immunogenicity Endpoints
The exploratory immunogenicity endpoints are the incidence and magnitude (titer) of ADA 
to MK-3655.
Additional details are in Section 4.2.1.5.
9.4.6
Pharmacodynamic Endpoints
The exploratory PD endpoints are adiponectin, fasting insulin, HOMA-IR, FFA, body 
composition assessed by DXA, and biomarkers/composite scores reflecting liver 
inflammation and fibrosis (ie, ALT, AST, FIB-4, NFS, APRI, and Pro-C3).
Additional details are in Section 4.2.1.6.
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 one injection (including only partial) of study 
intervention and have at least one assessment will be included in this population. Participants 
will be included in the treatment group to which they are randomized.
9.5.2
Patient-Reported Outcome Analysis Population
The primary PRO population will be based on the FAS population. This population consists 
of all randomized participants who had at least one dose of study intervention and had 
completed at least one baseline or post-baseline PRO assessment. The FAS population 
definition is applied separately to each questionnaire. Participants will be included in the 
treatment group to which they are randomized.
9.5.3
Safety Analysis Population
Analyses of safety will be performed in the APaT population, consisting of all randomized 
participants who received at least one injection (including only partial) of study intervention. 
Participants will be included in the treatment group corresponding to the study intervention
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 one laboratory or vital sign measurement obtained after at least one 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.
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9.5.4
Pharmacokinetic Analysis Population
The population for PK data analysis is defined as all participants with at least one measurable 
PK sample.
9.5.5
Immunogenicity Analysis Population
The population for immunogenicity analysis includes all participants with at least one ADA 
assay result following treatment with MK-3655.
9.5.6
Pharmacodynamic Analysis Population
The primary analysis approach for the PD endpoints will be the FAS population. All 
randomized participants who have at least one injection (including only partial) of study 
intervention and have at least one assessment for those analyses for which this is required 
will be included in this population. Participants will be included in the treatment group to 
which they are randomized.
9.6
Statistical Methods
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.
P-values for the key secondary efficacy endpoints may be provided as an assessment of 
strength of evidence without intent to make inferential claims.
For analysis purposes, the baseline assessment is considered the one closest to but before or 
on the day of randomization (Day 1).
For stratified analyses, the stratification factors used for randomization (Section 6.3.2) will 
be applied to the analysis. Small strata will be combined in a way specified by a blinded 
statistician before the analysis, if needed. The stratification for region (Japan, East Asia 
excluding Japan, or Other) will be used for randomization to ensure balance in all treatment 
groups, but it is not considered prognostic and will not be adjusted for in statistical analyses.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and key secondary 
objectives related to the efficacy endpoints.
The primary efficacy estimand used for this study follows the guidance in ICH E9 (R1) 
[European Medicines Agency 2020] and has the following 5 attributes:
1. The treatment condition of interest and, as appropriate, the alternative treatment 
condition to which comparison will be made: intervention with MK-3655 or placebo.
2. The population of patients targeted by the clinical question: individuals with 
pre-cirrhotic NASH.
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3. The variable (or endpoint) to be obtained for each patient that is required to address 
the clinical question: NASH resolution without worsening of fibrosis.
4. The specification of how to account for other intercurrent events to reflect the 
scientific question of interest: the outcome regardless of intercurrent events is of 
primary interest.
5. The population-level summary for the endpoint which provides the basis for a 
comparison between-treatment conditions: difference (MK-3655 minus placebo) in 
the proportion with the primary endpoint at 52 weeks in the effect of being 
randomized regardless of treatment adherence.
9.6.1.1
Primary Efficacy Endpoint
The primary approach for addressing the primary hypothesis will use the stratified M&N 
method with minimum risk weights [Mehrotra, D. V. 2000]. The proportion of participants 
achieving NASH resolution without worsening in fibrosis will be summarized by treatment 
group. The difference in proportion, 95% CI, and p-values will be provided to address the 
primary objective and associated hypothesis (MK-3655 minus placebo; 3 pair-wise 
comparisons).
Participants with missing histology data at Week 52 will be considered as not achieving the 
primary efficacy endpoint.
A p-value for the comparison of MK-3655 versus placebo ≤0.025 (one-sided) will be 
considered statistically significant contingent on the multiplicity strategy (Section 9.8).
Some participants may discontinue before their Week 52 assessment and have a histologic 
assessment post-randomization (Day 1). For the analysis at the Week 52 timepoint, the 
Week 52 assessment used in the analysis will be the assessment that is closest to the Week 52 
nominal visit (Day 364) that is on or after relative Day 84.
Endpoint response assessment will be based on a centrally-read assessment of both baseline 
and end of study specimens, blinded to time, and performed when the end of study specimen 
is available. This post-randomization assessment of the baseline specimen will be considered 
as the primary histologic baseline assessment for assessing treatment response, though it will 
not impact on the inclusion of participants in the primary approach to analysis of the primary
efficacy endpoint.
9.6.1.2
Secondary Efficacy Endpoints
Liver Fat Content
The primary approach for addressing the change in percent relative reduction from baseline
in LFC 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 stratum
and a different mean for each treatment group at the Week 24 post-baseline time point. In 
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this model, the response vector consists of the baseline value and the value observed 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, stratification (Section 6.3.2), and time by stratification interaction.
The treatment difference for each of the 3 pair-wise comparisons of MK-3655 versus placebo
in terms of mean change in percent relative reduction from baseline in LFC after 24 weeks
will be estimated and tested from this model. An unstructured covariance matrix will be used 
to model the correlation among repeated measurements.
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, in the event that 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. 
Details of the model specification, assumptions, and SAS implementation code will be 
provided in the sSAP.
The cLDA method assumes that the mechanism for missing data is MAR. Sensitivity 
analyses that will assess the robustness of the MAR-based analysis to deviations from this 
assumption will be described in the sSAP.
The model-based least squares mean and empirical mean change (with 95% CIs) from 
baseline for each treatment group and difference between-treatment groups at the Week 24 
post-baseline time point will be summarized.
Some participants may discontinue before their Week 24 assessment and have an LFC by 
MRI-PDFF assessed post-randomization. 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 84.
Histologic
The proportion of participants achieving each of the following secondary histologic efficacy 
endpoints will be summarized in a similar manner as the primary efficacy endpoint:

≥1 stage improvement in fibrosis without worsening of steatohepatitis

≥2 point reduction in NAS with ≥1 point reduction in inflammation or ballooning 
without worsening of fibrosis
Table 6 summarizes the key analysis strategies of the primary and secondary efficacy 
endpoints.
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Table 6
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
NASH resolution without worsening in fibrosis after 
52 weeks
M&N
FAS
Missing=Failure
Key Secondary Endpoints
Percent relative reduction from Baseline in LFC after
24 weeks
cLDA
FAS
Model-based
≥1 stage improvement in fibrosis without worsening of 
steatohepatitis after 52 weeks
M&N
FAS
Missing=Failure
≥2 point reduction in NAS score with ≥1 point reduction in 
inflammation or ballooning without worsening of fibrosis
after 52 weeks
M&N
FAS
Missing=Failure
cLDA=constrained longitudinal data analysis method; FAS=full analysis set; LFC=liver fat content; M&N=Miettinen 
and Nurminen method; NAS=nonalcoholic fatty liver disease activity score; NASH=nonalcoholic steatohepatitis.
9.6.2
Analysis Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, body weight, and vital signs.
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
The safety profile of MK-3655 is not understood sufficiently to prespecify any Tier 1 events.
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 
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. Because many 95% CIs
may be provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
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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.
In addition, summary measures of AEs consisting of the percentage of participants with any 
AE, with a drug-related AE, with an 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 provided for between-treatment differences in the percentage of 
participants with each Tier 2 event; these analyses will be performed using the M&N method
[Miettinen, O. and Nurminen, M. 1985].
Weight change from baseline will also be considered a Tier 2 endpoint. This analysis will be 
performed using a cLDA model as described for LFC in Section 9.6.1.2.
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 (CV and malignancy), results of adjudication will be 
summarized. Further details may be provided in the sSAP.
Safety Topics of Special Interest
Safety topics of special interest include suicidal ideation and behavior evaluated by C-SSRS, 
depression severity evaluated by PHQ-9, and AEs reflecting abuse potential. The AEs 
reflecting abuse potential will be analyzed as Tier 2 or Tier 3 analogously to AEs. Further 
details will be provided in the sSAP.
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Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value for 
Treatment 
Comparison
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 Participants in one of the Treatment 
Groups)
-
X
X
Weight Change From Baseline
-
X
X
AEs Reflecting Abuse Potential (Incidence 
≥4 Participants in one of the Treatment 
Groups)
-
X
X
Tier 3
Specific AEs, SOCs, or PDLCs (Incidence 
<4 Participants in all the Treatment 
Groups)
-
-
X
Change From Baseline Results (Laboratory 
Tests, ECGs, Vital Signs) 
-
-
X
ADA
-
-
X
Adjudicated Events (CV and malignancy)
-
-
X
AEs Reflecting Abuse Potential (Incidence 
<4 Participants in one of the Treatment 
Groups)
-
-
X
C-SSRS and PHQ-9
-
-
X
ADA=anti-drug antibodies; AE=adverse event; CI=confidence interval; C-SSRS=Columbia-Suicide Severity 
Rating Scale; CV=cardiovascular; ECG=electrocardiogram; PDLC=predefined limit of change; 
PHQ-9=Patient Health Questionnaire – 9; 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 (eg, age), baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
A single IA is planned for both administrative purposes and to assess futility. The IA is 
planned to be performed once ≥25 participants per group have had LFC measured at the 
Week 24 post-randomization assessment. Key endpoints to be evaluated include LFC 
(efficacy), body weight, AEs, and laboratory PDLC.
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The IA will be conducted by limited Sponsor personnel not otherwise involved in study 
conduct, who will be unblinded to treatment information. Results of the IA will be reviewed 
by an eDMC with recommendations provided to an internal EOC.
The administrative purpose addressed by the IA is to enable the EOC to assess whether the 
interim results are favorable enough to merit initiation of additional programmatic activities. 
The EOC will review unblinded interim results on a recommendation by the eDMC. Criteria 
for this recommendation will be provided in the eDMC charter. If the EOC considers that 
interim data warrant administrative action regarding other aspects of the development 
program, the unblinded interim data may be reviewed by additional individuals with 
responsibility for programmatic oversight. Individuals directly involved in study conduct will 
not have access to unblinded interim results.
The study may stop for futility if the posterior probability is <5% that the true mean 
difference (MK-3655 minus placebo) in percent reduction from baseline in LFC is ≥40% for 
all MK-3655 treatment groups. If this non-binding futility criterion is met, the EOC, and 
possibly additional individuals with responsibility for programmatic oversight, will review 
unblinded interim results on a recommendation by the eDMC. The study will be stopped for 
futility if the EOC considers this to be warranted.
The study will neither stop nor be modified unless the futility criterion is met as defined for 
all MK-3655 groups. There is a 5.0% (<0.1%) chance of observing a posterior probability 
<5% for a given treatment group if the true mean difference is 40% (50%). There is 0.01% 
chance that all MK-3655 doses meet the futility criterion if the true mean difference 
(MK-3655 minus placebo) is 40% for all dose levels. There is a >99% chance that the 
criterion for stopping for futility will be met if MK-3655 doses are not different from
placebo. The posterior probabilities that the true mean difference (MK-3655 minus placebo) 
in percent relative reduction from baseline in LFC is ≥40% for a range of observed 
differences in percent reduction from baseline in LFC are presented in Table 8. An observed 
mean difference <30% for any given MK-3655 dose level would have a posterior probability 
<5%. All calculations assume a common standard deviation of 20% as well as a normal 
distribution for the percent relative reduction in LFC.
Table 8
Posterior Probabilities for Observed Differences in % Relative Reduction in LFC
Observed Difference 
(MK-3655 Minus Placebo)
in % Relative Reduction in LFC
Posterior Probabilitya
30%
4.2%
35%
19.1%
38%
36.3%
40%
50.0%
LFC=liver fat content.
a Posterior probability that the true mean difference (MK-3655 minus placebo) in percent relative reduction from baseline 
in LFC is ≥40%.
Study enrollment is likely to be ongoing at the time of the IA for futility. Blinding to 
intervention assignment will be maintained at all investigational sites. The results of the IA
will not be shared with the investigators before the completion of the study. Participant-level 
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unblinding will be restricted to an internal unblinded statistician and scientific programmer 
performing the IA, who will have no other responsibilities associated with the study.
The eDMC charter will be referenced in the CSR. Before final study unblinding, individuals 
who have been unblinded at any level will not be involved in any discussions regarding 
modifications to the protocol, statistical methods, identification of protocol deviations, or 
data validation efforts after the IA.
The eDMC will also perform rigorous reviews of safety information obtained during the 
clinical study. Details about the frequency and content of these reviews will be provided in 
the eDMC charter.
9.8
Multiplicity
There are 3 pair-wise treatment group comparisons that may be tested to address the primary 
hypothesis. Testing will start with the 300 mg MK-3655 Q4W, then proceed to the 100 mg 
MK-3655 Q4W dose, and then to the 50 mg MK-3655 Q4W dose, stopping after the first test 
with a p-value >0.025 (1-sided).
The multiplicity strategy strongly controls the Type I error at 2.5% (one-sided) to address the 
primary hypothesis.
9.9
Sample Size and Power Calculations
9.9.1
Efficacy
Through 24 weeks post-randomization, drop-out is expected to be approximately 10% in 
each treatment group. The drop-out through 52 weeks post-randomization is expected to be 
approximately 15% in each treatment group. However, based on the approach to missing 
data, all 82 randomized participants per group are expected to be included in the primary and 
key secondary analyses and are the basis for sample size and power calculations.
The sample size was chosen based on the proportion of participants with NASH resolution 
without worsening in fibrosis after 52 weeks. Assuming the true proportion with this 
endpoint is 35% for each MK-3655 dose versus 12% for placebo, the assumed proportion 
using a non-completer = failure approach would be 30% for each MK-3655 versus 10% for 
placebo. Under these assumed proportions, a sample size of 82 participants per group 
provides 90% power to demonstrate superiority for each of the 3 pair-wise treatment 
comparisons using a one-sided alpha = 0.025.
With respect to the secondary endpoint of percent relative reduction from baseline in LFC 
after 24 weeks, a sample size of 82 participants per group provides >99% power (standard 
deviation = 20% and assumed mean difference over placebo ≥40%) using a one-sided 
alpha = 0.025.
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9.9.2
Safety
Given the sample size of 82 per group, Table 9 provides examples of minimum differences in 
proportions in AEs between each MK-3655 dose and placebo that would have a 95% CI that 
excludes zero based on the M&N method [Miettinen, O. and Nurminen, M. 1985].
Table 9
Examples of AE Incidences for Which the 95% CI for the Difference Would 
Exclude Zero
MK-3655
n/N (%)
Placebo
n/N (%)
7/82 (9%)
10/82 (12%)
15/82 (18%)
1/82 (1%)
3/82 (4%)
6/82 (7%)
M&N=Miettinen and Nurminen method; n=sample size; N=population size.
Based on the M&N method [Miettinen, O. and Nurminen, M. 1985].
9.10
Subgroup Analyses
Primary and key secondary efficacy endpoints will be summarized for each of the following 
baseline defined subgroups:

Concurrent diagnosis of T2DM at the time of randomization (Yes or No)

Fibrosis score (Stage 2 or Stage 3)

Region (Japan, East Asia excluding Japan, or Other)

Age (≥65 years vs <65 years)

BMI (>30 kg/m2 vs ≤30 kg/m2)

Region (to be defined in the sSAP)

LFC (>20% vs ≤20%)

Sex (male vs female)
9.11
Compliance (Medication Adherence)
Compliance and accountability data for study intervention will be collected during the study. 
Any deviation from protocol-directed administration will be reported. The primary definition 
of compliance is defined as the proportion of participants who received the expected number 
of injections over the duration of time that they were in the study divided by the total number 
of participants receiving at least one injection. Further detail will be provided in the sSAP.
Drug accountability data for study treatment will be collected during the study. Compliance 
with study treatment administration will be measured by subjects: (1) receiving unscheduled 
study agent injections; (2) missing an injection. Numbers and percentages of subjects and 
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injection visits with any deviation in these measures will be reported for all randomized 
participants.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in terms of number of 
injections. Dose interruption will be summarized. Summary statistics will be provided on 
extent of exposure for the APaT population. Further detail will be provided in the sSAP.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations, (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the eDMC regarding the study.
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Additionally, on a recommendation by the eDMC, the EOC will perform an administrative 
look to assess whether the interim results are favorable enough to merit initiation of 
additional programmatic activities.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an eDMC will monitor 
the interim data from this study. The voting members of the committee are external to the 
Sponsor. The members of the eDMC must not be involved with the study in any other way 
(eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The eDMC will make recommendations to the EOC regarding steps to ensure both 
participant safety and the continued ethical integrity of the study. Also, the eDMC will 
review interim study results, consider the overall risk and benefit to study participants
(Section 9.7 Interim Analyses) and recommend to the EOC whether the study should 
continue in accordance with the protocol. Additionally, the eDMC will inform the EOC if 
interim results meet the criteria to initiate an administrative look (to be defined in the eDMC 
charter).
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of eDMC reports, minutes, and recommendations will be described in the eDMC charter that 
is reviewed and approved by all the eDMC members.
10.1.4.3
Clinical Adjudication Committee (CAC)
A CAC will evaluate the following events for the purposes of confirming them according to 
the criteria in the Adjudication Charter, as well as evaluating the presence of confounding 
factors.
Multiple CACs will evaluate the following events:
1. Malignancy: Thorough evaluation of malignancies is important in the development 
program of all investigational medications; therefore, detailed information will be 
collected for participants who develop a malignancy.
2. Serious CV Events: Patients with NASH often have associated metabolic 
comorbidities that include obesity, dyslipidemia, T2DM, and MetS. Since CV disease 
is a major cause of mortality for individuals with these conditions, serious CV events 
will be adjudicated in this study (including events from participants who continue to 
be followed after discontinuation of double-blinded study intervention).
All personnel involved in the adjudication process will remain blinded to study intervention
allocation throughout the study.
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Specific details regarding endpoint definitions can be found in the Adjudication Charter.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 10 will be performed by the central laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
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Table 10
Protocol-Required Laboratory Assessments
Laboratory Assessments
Hematology
Chemistry
Other Tests
Routine Urinalysisa

Hemoglobin

Hematocrit

RBC count

RBC 
morphology

Mean 
corpuscular 
volume

Platelet count

WBC count

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
BUN
Serum creatinine

eGFR 
calculationb
Glucose
Sodium
Potassium
Chloride

Total carbon 
dioxide 
(bicarbonate)
AST (SGOT)
ALT (SGPT)
ALP
Albumin
Total bilirubin

Direct 
(conjugated) 
bilirubin

Indirect 
(unconjugated
) bilirubin

Hepatitis B (HBsAg) and 
Hepatitis C (anti-HCV)
serologyc

HIVc

FSH

hCG pregnancy test (urine 
and/or serum)d

INR

TSH

FT4

Cortisol (bedtime salivary)

ACTHe

IGF-1

Hemoglobin A1C

FPG

Insulin

Lipid profile (Total 
Cholesterol, non-HDL-C, 
HDL-C, LDL-C, and TG)

apoA1 and apoBf

Ketones (serum)g

Adiponectin

FFA

Bone biomarkers (CTX 
and P1NP)

Pro-C3

Immunogenicity assay (ADA)

Prothrombin time

Blood

Glucose

Protein

Leukocyte 
esterase

Nitrates

Specific gravity

pH

Microscopic 
examination
(if abnormal 
results are 
noted)
A1C=glycated hemoglobin; ACTH=adrenocorticotropic hormone; ADA=anti-drug antibodies; ALP=alkaline 
phosphatase; ALT=alanine aminotransferase; apoA1=apolipoprotein A1; apoB=apolipoprotein B; AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; CTX=collagen type 1 cross-linked telopeptide; eGFR=estimated 
glomerular filtration rate; FFA=free fatty acid; FPG=fasting plasma glucose; FSH=follicle stimulating hormone; 
FT4=free thyroxine; HBsAg=Hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=Hepatitis C virus; 
HDL-C=high density lipoprotein-cholesterol; HIV=human immunodeficiency virus; IGF-1=insulin-like growth factor-1; 
INR=international normalized ratio; LDL-C=low density lipoprotein-cholesterol; MDRD=Modification of Diet in Renal 
Disease; P1NP=procollagen type 1 N terminal propeptide; pH=potential of hydrogen; Pro-C3=propeptide of type III 
collagen; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; RBC=red 
blood cell; TG=triglycerides; TSH=thyroid-stimulating hormone; WBC=white blood cell.
a
Dipstick to be performed at the study site.
b
eGFR calculated using the MDRD formula. For participants in Japan, eGFR will be calculated using the Japanese 
Equation 4 (Appendix 7) [Matsuo, S., et al 2009]. See Appendix 13 for the eGFR equations.
c
For participants in Argentina, Hepatitis B, Hepatitis C, and HIV tests are required at Visit 1/Screening (see 
Appendix 7).
d
A serum pregnancy test should only be performed if the local urine pregnancy test is positive or inconclusive, or if a 
serum pregnancy test is required per local guidelines.
e
ACTH samples should be collected between 7 AM and 10 AM.
f
apoB and apoA1 will not be collected at Visit 1/Screening.
g
Includes acetoacetic acid and beta-hydroxybutyrate.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
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.
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•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE
•
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.
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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
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:
a. Results in death
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b. 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.
c. 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 pre-existing condition that has not 
worsened is not an SAE). A pre-existing 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.
d. 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.
e. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f. 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.
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10.3.4
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
10.3.5
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.
•
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.
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-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living.
-
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 
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.
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◦
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, AND IF REQUIRED, THE 
IRB/IEC.
•
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 their 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.)
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•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
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 their 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.
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.
10.3.6
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 electronic data collection 
(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.
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•
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.
•
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.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
-
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
•
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
-
Progestogen-only subdermal contraceptive implantb
-
IUSc
-
Non-hormonal IUD
-
Bilateral tubal occlusion
-
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. A 
spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.
•
Sexual Abstinence
-
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
a Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for participants of clinical studies.
b If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants 
are limited to those which inhibit ovulation.
c IUS is a progestin releasing IUD.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.10 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@msd.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@msd.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
China-specific Requirements
Section 8 Study Assessments and Procedures
The information in this appendix is added to the main protocol to describe the blood volume 
collection for participants in China.
Parameters Collected
per Participant
Screening
Period
Double-Blind
Treatment 
Period
Post-
Treatment
Follow-up
Total 
Collections
mL per 
Collection
Total (mL)/ 
Test
V5 to V15
V16
FPG
1
7
-
8
2
16
Fasting FFA and P1NP
-
3
-
3
2.5
7.5
PT and INR
1
-
-
1
1.8
1.8
Hepatitis screen (HBsAg, anti-
HCV, and HCV [RNA])
1
-
-
1
8.5
8.5
Hematology laboratory tests and 
when applicable A1C
1
6
-
7
2
14
Chemistry laboratory tests, 
fasting lipid profilea, and when 
applicable apoA1, apoB, and 
hCG
1
4
-
5
3.5
17.5
Chemistry laboratory tests
-
2
-
2
2.5
5
TSH, FT4, and when applicable 
FSH
1
5
-
6
2.5
15
Acetoacetic acid and beta-
hydroxybutyrate
-
6
-
6
5
30
IGF-1
1
5
-
6
2.5
15
ACTH
-
8
-
8
2
16
CTX
-
3
-
3
2.5
7.5
Fasting insulin
-
3
-
3
2
6
Adiponectin
-
3
-
3
2.5
7.5
Blood for serum MK-3655 PK
assay (for PK only timepoint)
-
1
-
1
2
2
Blood for serum MK-3655 PK 
assay and immunogenicity assay 
(ADA)
-
5
1
6
4
24
Total Blood Volume per Participantb
193.3 mL
A1C=glycated hemoglobin; ACTH=adrenocorticotropic hormone; ADA=anti-drug antibodies; apoA1=apolipoprotein A1; 
apoB=apolipoprotein B; CTX=collagen type 1 cross-linked telopeptide; EOT=end of treatment; FFA=free fatty acid; 
FPG=fasting plasma glucose; FT4=free thyroxine; FSH=follicle stimulating hormone; HBsAg=Hepatitis B surface antigen; 
hCG=human chorionic gonadotropin; HCV=Hepatitis C virus; HDL-C=high density lipoprotein-cholesterol; 
IGF-1=insulin-like growth factor-1; INR=international normalized ratio; LDL-C=low density lipoprotein-cholesterol; 
P1NP=procollagen type 1 N-terminal propeptide; PK=pharmacokinetic; PT=prothrombin time; RNA=ribonucleic acid;
TG=triglycerides; TSH=thyroid-stimulating hormone; V=visit.
a Includes total cholesterol, non-HDL-C, HDL-C, LDL-C, and TG.
b If additional pharmacokinetic/pharmacodynamic and/or safety analyses are necessary, additional blood (up to 50 mL) may 
be obtained.
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10.7.2
Argentina-specific Requirements
Section 1.3 Schedule of Activities (SoA), Section 8.11.3.1 Visit 1/Screening and Section 
10.2 Appendix 2: Clinical Laboratory Tests
All participants at study sites in Argentina must be tested for Hepatitis B, Hepatitis C, and 
HIV at Visit 1/Screening before randomization.
10.7.3
Taiwan-specific Requirements
Section 1.1 Synopsis, Section 1.2 Schema, Section 3 Hypotheses, Objectives, and 
Endpoints, Section 4.1 Overall Design, Section 5 Study Population and Section 5.1 
Inclusion Criteria
All participants at study sites in Taiwan must be a male or female aged 20 years to 80 years
with capacity of will, at the time of signing the ICF.
10.7.4
Japan-specific Requirements
Section 1.1 Synopsis, Section 1.2 Schema, Section 3 Hypotheses, Objectives, and 
Endpoints, Section 4.1 Overall Design, Section 5 Study Population, and Section 5.1 
Inclusion Criteria
All participants at study sites in Japan must be a male or female aged 20 years to 80 years, at 
the time of signing the ICF.
Section 1.3 Schedule of Activities (SoA), Section 6.1 Study Intervention(s) 
Administered, Section 6.4 Study Intervention Compliance, Section 8.1.8.3 Self-injection 
Training (Participant and/or Caregiver), Section 8.1.8.4 Witnessed Dosing, Section 8.1.9 
Study Intervention Administration, Section 8.1.9.1 Timing of Dose Administration, and 
Section 8.6.1 Blood Collection for Serum MK-3655
In Japan, administration of study intervention can only be performed by a medically qualified 
person (eg, physician, supporting nurse); self-administration by the participant him/herself is 
the only exception. Therefore, administration of study intervention by a caregiver will not be
allowed in Japan.
Section 4.1 Overall Design and 6.3.2 Stratification
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. In Japan, enrollment will not 
be restricted by this cap, and sites will be able to continue to enroll participants with or 
without T2DM.
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Section 5.2 Exclusion Criteria, Section 7.1 Discontinuation of Study Intervention,
Section 10.2 Appendix 2: Clinical Laboratory Tests, and Section 10.13 Appendix 13:
eGFR Equations
For the calculation of eGFR for participants in Japan, the Japanese 3-variable Equation 4 will 
be used (see Appendix 13) [Matsuo, S., et al 2009].
10.7.5
Korea-specific Requirements
Section 5.2 Exclusion Criteria
Prior/Concurrent Clinical Study Experience
23. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device ≤3 months or ≤5 half-lives (whichever is longer) before 
participating in this current study. Participants enrolled in observational studies may be 
included and will be reviewed on a case-by-case basis for approval by the Sponsor.
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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.
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10.9
Appendix 9: Approximate Blood Volume Table
Parameters Collected
per Participant
Screening
Period
Double-Blind 
Treatment 
Period
Post-
Treatment 
Follow-up
Total 
Collections
mL per 
Collection
Total 
(mL)/Test
V5 to V15
V16
FPG
1
7
-
8
2
16
Fasting FFA and P1NP
-
3
-
3
2.5
7.5
PT and INR
1
-
-
1
1.8
1.8
Hepatitis screen (HBsAg, anti-
HCV, and HCV [RNA])
1
-
-
1
8.5
8.5
Hematology laboratory tests and 
when applicable A1C
1
6
-
7
2
14
Chemistry laboratory tests,
fasting lipid profilea, and when 
applicable apoA1, apoB, and 
hCG
1
4
-
5
3.5
17.5
Chemistry laboratory tests
-
2
-
2
2.5
5
TSH, FT4, and when applicable 
FSH
1
5
-
6
2.5
15
Acetoacetic Acid
-
6
-
6
6
36
Beta-hydroxybutyrate
-
1
-
1
2.5
2.5
Beta-hydroxybutyrate and IGF-1
-
5
-
5
2.5
12.5
IGF-1
1
-
-
1
2.5
2.5
ACTH
-
8
-
8
2
16
CTX
-
3
-
3
2.5
7.5
Adiponectin
-
3
-
3
2.5
7.5
Fasting insulin
-
3
-
3
2
6
Pro-C3
-
3
-
3
2.5
7.5
Blood for serum biomarkers
1
5
-
6
4
24
Blood for plasma biomarkers
1
5
-
6
6
36
Blood for serum MK-3655 PK 
assay (for PK only timepoint)
-
1
-
1
2
2
Blood for serum MK-3655 PK 
assay and immunogenicity assay 
(ADA)
-
5
1
6
4
24
Blood for planned genetic 
analysis 
-
1
-
1
8.5
8.5
Total Blood Volume per Participantb
277.8 mL
A1C=glycated hemoglobin; ACTH=adrenocorticotropic hormone; ADA=anti-drug antibodies; apoA1=apolipoprotein A1; 
apoB=apolipoprotein B; CTX=collagen type 1 cross-linked telopeptide; EOT=end of treatment; FFA=free fatty acid; 
FPG=fasting plasma glucose; FT4=free thyroxine; FSH=follicle stimulating hormone; HBsAg=Hepatitis B surface 
antigen; hCG=human chorionic gonadotropin; HCV=Hepatitis C virus; HDL-C=high density lipoprotein-cholesterol; 
IGF-1=insulin-like growth factor-1; INR=international normalized ratio; LDL-C=low density lipoprotein-cholesterol; 
P1NP=procollagen type 1 N-terminal propeptide; PK=pharmacokinetic; Pro-C3=propeptide of type III collagen; 
PT=prothrombin time; RNA=ribonucleic acid; TG=triglycerides; TSH=thyroid-stimulating hormone; V=visit.
a Includes total cholesterol, non-HDL-C, HDL-C, LDL-C, and TG.
b If additional pharmacokinetic/pharmacodynamic and/or safety analyses are necessary, additional blood (up to 50 mL) 
may be obtained.
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10.10 Appendix 10: Management of Participants With Elevated Liver Enzymes
Although participants enrolled in this study will have baseline liver disease, their hepatic 
function should not be significantly impaired. However, at baseline, some may have liver 
biochemistry levels above the ULN.
The central laboratory report will alert the investigator if a participant meets the thresholds 
outlined in Section 8.4.7. The investigator should initiate close observation and discontinue 
the participant from blinded study intervention if a prespecified criterion for discontinuation
is met.
Close Observation for DILI Guidelines:
•
Repeating liver biochemistries (ALT, AST, ALP, total bilirubin, INR) within 
48 hours
•
Obtaining a more detailed history of symptoms and prior or concurrent disease
•
Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets
•
Obtaining a history of exposure to environmental chemical agents
•
Ruling out other causes of liver disease as needed (obtain viral hepatitis panel, 
imaging for evaluation of biliary tract disease, etc. if required in the opinion of the 
primary investigator)
•
Continuing to monitor liver biochemistries twice weekly. Frequency can decrease to 
once a week or less if abnormalities stabilize or study intervention has been 
discontinued and participant is asymptomatic
•
Reviewing Discontinuation of Study Intervention for Elevated Liver Enzymes (see 
below) to see if a participant meets a given criterion
•
Considering a gastroenterology or hepatology consultation
•
Considering a liver biopsy
Discontinuation of Study Intervention for Elevated Liver Enzymes
However, for all participants, study intervention should be discontinued if any of the 
specified criteria below are met and no other cause for the combination of laboratory 
abnormalities is immediately apparent:
For participants with ALT and AST ≤ULN at baseline who meet ANY of the following 
criteria:
•
ALT or AST >3 × ULN AND either total bilirubin >2 × ULN or INR >1.5*
•
ALT or AST >3 × ULN AND the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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•
ALT or AST >5 × ULN for more than 2 weeks
•
ALT or AST >3 × ULN AND participant is unwilling or unable to undergo repeat 
ALT and AST testing at the frequency defined above in the Close Observation for 
DILI Guidelines
•
ALT or AST >8 × ULN (confirmed by repeat testing)
For participants with ALT and/or AST >ULN at baseline** who meet ANY of the following 
criteria:
•
ALT and/or AST >2 × baseline AND total bilirubin >2 × ULN or INR >1.5*
(confirmed by repeat testing)
•
ALT and/or AST >2 × baseline AND the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
(confirmed by repeat testing)
•
ALT and/or AST >5 × baseline for more than 2 weeks
•
ALT and/or AST >3 × baseline AND participant is unwilling or unable to undergo 
repeat ALT and AST testing at the frequency defined above in the Close Observation 
for DILI Guidelines
•
ALT and/or AST ≥500 U/L (confirmed by repeat testing)
*Note: For participants who initiate anticoagulant therapy after study initiation, the INR 
threshold does not apply.
**Note: If only one of the analytes (ie, ALT or AST) was >ULN at baseline, each criterion
below would only apply to the analyte that was >ULN at baseline.
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10.11 Appendix 11: Patient Health Questionnaire - 9
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10.12 Appendix 12: NASH Clinical Research Network (CRN) Scoring System for 
Determining Eligibility and Assessing Secondary Histological Endpoints
NAFLD Activity Score (NAS)
Fibrosis Staging
Parameter
Scoring Criteria
Parameter
Staging Criteria
Steatosis
0 = <5%
1 = 5% to 33%
2 = >33% to 66%
3 = >66%
Stage 0
No Fibrosis
Lobular 
Inflammation
0 = No Foci
1 = <2 Foci per 200 × field
2 = 2 to 4 Foci per 200 × field
3 = >4 Foci per 200 × field
Stage 1
Stage 1a
Stage 1b
Stage 1c
Perisinusoidal or Periportal
Mild, Zone 3, Perisinusoidal
Moderate, Zone 3, Perisinusoidal
Portal / Periportal
Ballooning
0 = None
1 = Few Balloon Cells
2 = Many Cells / Prominent 
Ballooning
Stage 2
Perisinusoidal and Portal / Periportal
Stage 3
Bridging Fibrosis
Stage 4
Cirrhosis
Source ID: [Kleiner, D. E., et al 2005]
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10.13 Appendix 13: eGFR Equations
MDRD Equation:
•
eGFR = 175 × Serum Creatinine-1.154 × Age-0.203 × 1.212 (if participant is 
black) × 0.742 (if female)
Equation 4 (for participants in Japan only [Appendix 7]):
•
eGFR = 194 × Serum Creatinine-1.094 × Age-0.287 × 0.739 (if female).
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10.14 Appendix 14: Common Terminology Criteria for Adverse Events Version 5.0
The descriptions and grading scales found in the NCI CTCAE, Version 5.0 will be used for 
AE reporting
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Qui
ck_Reference_5x7.pdf) except as noted in Section 7.1.
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10.15 Appendix 15: Abbreviations
Abbreviation
Expanded Term
A1C
Glycated Hemoglobin
ACC
Acetyl-CoA Carboxylase
ACTH
Adrenocorticotropic Hormone
ADA
Anti-drug Antibodies
AE
Adverse Event 
AHA
Antihyperglycemic Agent
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
APaT
All Participants as Treated
apoA1
Apolipoprotein A1
apoB
Apolipoprotein B
APRI
AST/Platelet Ratio Index
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AxMP
Auxiliary Medicinal Product
BICR
Blinded Independent Central Review
BLA
Biologics License Application
BMD
Bone Mineral Density
BMI
Body Mass Index
CAC
Clinical Adjudication Committee
CFR
Code of Federal Regulations
CI
Confidence Interval
cLDA
Constrained Longitudinal Data Analysis
CLDQ-NAFLD-NASH
Chronic Liver Disease Questionnaire for Nonalcoholic Fatty Liver Disease -
NASH
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CRN
Clinical Research Network
CRU
Clinical Research Unit
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
Ctrough
Trough Concentration
CTX
Collagen Type 1 Cross-linked Telopeptide
CV
Cardiovascular
DC
Discontinuation
DGAT2
Diacylglycerol O-Acyltransferase 2
DILI
Drug-induced Liver Injury
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic Acid 
DXA
Dual-energy X-ray Absorptiometry
ECG
Electrocardiogram 
ECI
Event of Clinical Interest
(e)CRF
(Electronic) Case Report Form
EDC
Electronic Data Collection 
eDMC
External Data Monitoring Committee
eGFR
Estimated Glomerular Filtration Rate 
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Abbreviation
Expanded Term
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EOT
End of Treatment
EU
European Union
EU CTR
European Union Clinical Trial Regulation
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIB-4
Fibrosis-4
FFA
Free Fatty Acid
FGF19, -21
Fibroblast Growth Factor-19, -21
FGFR1c
Fibroblast Growth Factor Receptor-1c
FPG
Fasting Plasma Glucose
FSH
Follicle Stimulating Hormone 
FT4
Free Thyroxine
FXR
Farnesoid X Receptor
GCKR
Glucokinase Regulatory Protein
GCP
Good Clinical Practice 
GLP
Good Laboratory Practices
GnRH
Gonadotropin-Releasing Hormone
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HDL-C
High Density Lipoprotein-Cholesterol
HIV
Human Immunodeficiency Virus
HOMA-IR
Homeostatic Model Assessment-Insulin Resistance
HRT
Hormone Replacement Therapy
HSD17B13
Hydroxysteroid 17-Beta Dehydrogenase 13
IA(s)
Interim Analysis(ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
Imaging Clinical Research Organization
IEC
Independent Ethics Committee
IFG
Impaired Fasting Glycemia
IGF-1
Insulin-like Growth Factor-1
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
International Normalized Ratio
IRB
Institutional Review Board 
IRT
Interactive Response Technology 
IUD
Intrauterine Device
IUS
Progestin releasing IUD
IVRS
Interactive Voice Response System
KLB
β-klotho
LDL-C
Low Density Lipoprotein-Cholesterol
LFC
Liver Fat Content
LYPLAL1
Lysophospholipase-like Protein 1
M&N
Miettinen and Nurminen Method
mAb
Monoclonal Antibody
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Abbreviation
Expanded Term
MAD
Multiple Ascending Dose
MAR
Missing at Random
MBOAT7
Membrane Bound O-Acyltransferase Domain-Containing 7
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
MetS
Metabolic Syndrome
MRI
Magnetic Resonance Imaging
MRI-PDFF
MRI-Estimated Proton Density Fat Fraction
MTD
Maximum Tolerated Dose 
Na
Sodium
NAFLD
Nonalcoholic Fatty Liver Disease
NAS
NAFLD Activity Score
NASH
Nonalcoholic Steatohepatitis
NCI
National Cancer Institute
NDA
New Drug Application 
NFS
NAFLD Fibrosis Score
NGM
NGM Biopharmaceuticals, Inc
NHP
Nonhuman Primate
NIMP
Non-Investigational Medicinal Product
NOAEL
No Observed Adverse Effect Level 
NOEL
No Observed Effect Level
NSAID
Nonsteroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
P1NP
Procollagen Type 1 N-terminal propeptide
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PDLC
Predefined Limits of Change
PGI-S
Patient Global Impression of Severity
PHQ-9
Patient Health Questionnaire – 9
PK
Pharmacokinetic
PLT
Platelet
PNPLA3
Patatin-like Phospholipase Domain-Containing Protein 3
PPAR
Peroxisome Proliferator-activated Receptor
PPP1R3B
Protein Phosphatase 1 Regulatory Subunit 3B
PRO
Patient-Reported Outcome
Pro-C3
Propeptide of Type III Collagen
PTH
Parathyroid Hormone
Q1W/Q2W/Q4W
Once Every Week/Once Every 2 Weeks/Once Every 4 Weeks
RANK
Receptor Activator of Nuclear Factor Kappa-Β
RNA
Ribonucleic Acid
SAD
Single Ascending Dose
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard Deviation
siDMC
Standing Internal Data Monitoring Committee
SLAB
Supplemental Laboratory Test(s)
SoA
Schedule of Activities
SOC
System Organ Class
sSAP
Supplementary Statistical Analysis Plan
SUSAR
Suspected Unexpected Serious Adverse Reaction
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Abbreviation
Expanded Term
t1/2
Half-Life
T2DM
Type 2 Diabetes Mellitus
TG
Triglycerides
TM6SF2
Transmembrane 6 Superfamily Member 2
TSH
Thyroid-Stimulating Hormone
ULN
Upper Limit of Normal
US
United States
WOCBP
Woman/Women of Childbearing Potential 
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11
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