An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Efinopegdutide (MK-6024) in Participants With Moderate and Severe Hepatic Impairment
Phase: PHASE1
Conditions: Non-alcoholic Steatohepatitis, Hepatic Impairment
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT06052566 
Document Date: 
31-Jul-2023
An Open-Label, Single-Dose Study to Evaluate the 
Pharmacokinetics of Efinopegdutide (MK-6024) in Participants with 
Moderate and Severe Hepatic Impairment

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title:
An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Efinopegdutide 
(MK-6024) in Participants with Moderate and Severe Hepatic Impairment
Protocol Number: 014-00
Compound Number: MK-6024
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called 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
153,067
Approval Date:   31 July 2023
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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
Original Protocol
31-JUL-2023
Not applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................14
1.3
Schedule of Activities...........................................................................................15
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................20
2.2.1
Pharmaceutical and Therapeutic Background .............................................20
2.2.2
Preclinical and Clinical Studies ...................................................................21
2.2.2.1
Efinopegdutide Preclinical Overview................................................21
2.2.2.2
Efinopegdutide Clinical Overview ....................................................22
2.2.3
Ongoing Clinical Studies.............................................................................23
2.2.4
Information on Other Study-related Therapy ..............................................24
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................25
4
STUDY DESIGN............................................................................................................27
4.1
Overall Design......................................................................................................27
4.2
Scientific Rationale for Study Design.................................................................29
4.2.1
Rationale for Endpoints ...............................................................................30
4.2.1.1
Efficacy Endpoints.............................................................................30
4.2.1.2
Safety Endpoints................................................................................30
4.2.1.3
Pharmacokinetic Endpoints ...............................................................30
4.2.1.4
Pharmacodynamic Endpoints.............................................................30
4.2.1.5
Immunogenicity Endpoints................................................................31
4.2.1.6
Planned Exploratory Biomarker Research.........................................31
4.2.1.6.1
Planned Genetic Analysis ........................................................31
4.2.1.7
Future Biomedical Research..............................................................31
4.2.2
Rationale for the Use of Comparator/Placebo .............................................31
4.3
Justification for Dose...........................................................................................32
4.4
Beginning and End-of-Study Definition ............................................................32
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................34
5.1
Inclusion Criteria.................................................................................................34
5.2
Exclusion Criteria................................................................................................36
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
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5.3.1.1
Diet Restrictions.................................................................................39
5.3.1.2
Fruit Juice Restrictions ......................................................................40
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................40
5.3.2.1
Caffeine Restrictions..........................................................................40
5.3.2.2
Alcohol Restrictions...........................................................................40
5.3.2.3
Tobacco Restrictions..........................................................................40
5.3.3
Activity Restrictions ....................................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................41
6
STUDY INTERVENTION............................................................................................42
6.1
Study Intervention(s) Administered...................................................................42
6.1.1
Medical Devices...........................................................................................44
6.2
Preparation/Handling/Storage/Accountability .................................................44
6.2.1
Dose Preparation..........................................................................................44
6.2.2
Handling, Storage, and Accountability........................................................44
6.3
Measures to Minimize Bias: Randomization and Blinding..............................45
6.3.1
Intervention Assignment..............................................................................45
6.3.2
Stratification.................................................................................................45
6.3.3
Blinding........................................................................................................45
6.4
Study Intervention Compliance..........................................................................45
6.5
Concomitant Therapy..........................................................................................46
6.5.1
Rescue Medications and Supportive Care ...................................................47
6.6
Dose Modification ................................................................................................47
6.6.1
Stopping Rules.............................................................................................47
6.7
Intervention After the End of the Study............................................................47
6.8
Clinical Supplies Disclosure................................................................................48
6.9
Standard Policies..................................................................................................48
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................49
7.1
Discontinuation of Study Intervention...............................................................49
7.2
Participant Withdrawal From the Study...........................................................49
7.3
Lost to Follow-up .................................................................................................49
8
STUDY ASSESSMENTS AND PROCEDURES........................................................50
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................51
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................51
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
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8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................52
8.1.5
Prior and Concomitant Medications Review...............................................52
8.1.5.1
Prior Medications...............................................................................52
8.1.5.2
Concomitant Medications..................................................................52
8.1.6
Assignment of Screening Number...............................................................52
8.1.7
Assignment of Treatment/Randomization Number.....................................52
8.1.8
Study Intervention Administration ..............................................................52
8.1.8.1
Timing of Dose Administration.........................................................53
8.1.9
Discontinuation and Withdrawal .................................................................53
8.1.9.1
Withdrawal From Future Biomedical Research ................................53
8.1.10
Participant Blinding/Unblinding..................................................................53
8.1.11
Domiciling ...................................................................................................54
8.1.12
Calibration of Equipment.............................................................................54
8.2
Efficacy/Immunogenicity Assessments ..............................................................54
8.3
Safety Assessments...............................................................................................54
8.3.1
Physical Examinations.................................................................................54
8.3.2
Vital Signs....................................................................................................55
8.3.2.1
Resting Vital Signs ............................................................................55
8.3.2.2
Orthostatic Vital Signs.......................................................................55
8.3.3
Electrocardiograms ......................................................................................55
8.3.4
Clinical Safety Laboratory Assessments .....................................................57
8.3.5
Pregnancy Testing........................................................................................57
8.3.6
Photograph of Rash......................................................................................58
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................58
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................58
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......60
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...60
8.4.4
Regulatory Reporting Requirements for SAE .............................................61
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................61
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................62
8.4.7
Events of Clinical Interest............................................................................62
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions......................................................................................62
8.5
Treatment of Overdose........................................................................................63
8.6
Pharmacokinetics.................................................................................................63
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8.6.1
Blood Collection for Serum Efinopegdutide ...............................................63
8.7
Pharmacodynamics..............................................................................................63
8.8
Immunogenicity Assessment...............................................................................63
8.9
Biomarkers ...........................................................................................................63
8.9.1
Planned Genetic Analysis Sample Collection..............................................64
8.10
Future Biomedical Research Sample Collection...............................................64
8.11
Medical Resource Utilization and Health Economics.......................................64
8.12
Visit Requirements...............................................................................................64
8.12.1
Screening......................................................................................................64
8.12.2
Treatment Period..........................................................................................64
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................65
8.12.4
Poststudy......................................................................................................65
8.12.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......65
8.12.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................66
9
KEY STATISTICAL CONSIDERATIONS ...............................................................68
9.1
Responsibility for Analyses.................................................................................68
9.2
Hypotheses/Estimation ........................................................................................68
9.3
Analysis Endpoints...............................................................................................68
9.3.1
Primary Endpoints .......................................................................................68
9.3.2
Secondary Endpoints ...................................................................................68
9.3.3
Exploratory Endpoints .................................................................................68
9.4
Analysis Populations............................................................................................69
9.4.1
Safety Analysis Populations ........................................................................69
9.4.2
PK Analysis Populations..............................................................................69
9.5
Statistical Methods...............................................................................................69
9.5.1
Statistical Methods for PK Analyses ...........................................................69
9.5.2
Statistical Methods for Safety Analyses ......................................................70
9.5.3
Statistical Methods for Pharmacodynamic Analyses...................................70
9.5.4
Statistical Methods for Immunogenicity Endpoints ....................................70
9.6
Interim Analyses ..................................................................................................71
9.7
Multiplicity ...........................................................................................................71
9.8
Sample Size and Power Calculations .................................................................71
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................72
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........72
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................72
10.1.2
Financial Disclosure.....................................................................................75
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10.1.3
Data Protection.............................................................................................76
10.1.3.1
Confidentiality of Data ......................................................................76
10.1.3.2
Confidentiality of Participant Records...............................................76
10.1.3.3
Confidentiality of IRB/IEC Information............................................77
10.1.4
Publication Policy........................................................................................77
10.1.5
Compliance with Study Registration and Results Posting Requirements ...77
10.1.6
Compliance with Law, Audit, and Debarment ............................................78
10.1.7
Data Quality Assurance ...............................................................................78
10.1.8
Source Documents .......................................................................................79
10.1.9
Study and Site Closure.................................................................................80
10.2
Appendix 2: Clinical Laboratory Tests..............................................................81
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................82
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................82
10.3.2
Definition of AE ..........................................................................................82
10.3.3
Definition of SAE ........................................................................................83
10.3.4
Additional Events Reported.........................................................................84
10.3.5
Recording AE and SAE ...............................................................................84
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................87
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................89
10.4.1
Definitions....................................................................................................89
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....90
10.5
Appendix 5: Contraceptive Guidance................................................................92
10.5.1
Definitions....................................................................................................92
10.5.2
Contraceptive Requirements........................................................................94
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................95
10.7
Appendix 7: Country-specific Requirements....................................................99
10.8
Appendix 8: Blood Volume Table ....................................................................100
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................101
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...103
10.11 Appendix 11: Abbreviations .............................................................................104
11
REFERENCES.............................................................................................................112
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LIST OF TABLES
Table 1
Group Assignment ...........................................................................................28
Table 2
Child-Pugh Score for Severity of Liver Disease Classification.......................28
Table 3
Study Interventions..........................................................................................43
Table 4
Allocation of Participants to Treatment...........................................................45
Table 5
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................59
Table 6
PK and ADA Collection Windows..................................................................65
Table 7
Protocol-required Safety Laboratory Assessments..........................................81
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................14
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of 
Efinopegdutide (MK-6024) in Participants with Moderate and Severe Hepatic Impairment
Short Title: Efinopegdutide (MK-6024) Hepatic Impairment Study
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study population includes male and female participants with moderate and severe hepatic 
impairment between the ages of 18 and 75 years (inclusive) and healthy mean-matched 
controls.
Primary Objective
Primary Endpoint
To evaluate the serum pharmacokinetics of 
efinopegdutide after a single dose in 
participants with moderate hepatic 
impairment compared to matched healthy 
control participants
Estimation: The serum PK (AUC0-inf and 
Cmax) of efinopegdutide following a single 
7 mg dose of efinopegdutide in participants 
with moderate hepatic impairment will be 
estimated and compared to those in healthy 
matched control participants.
AUC0- ∞, AUC0-last, Cmax, Tmax, 
apparent terminal t1/2, CL/F, and Vz/F
To evaluate the serum pharmacokinetics of 
efinopegdutide after a single dose in 
participants with severe hepatic impairment 
compared to healthy matched control 
participants
Estimation: The serum PK (AUC0-inf and 
Cmax) of efinopegdutide following a single 
7 mg dose of efinopegdutide in participants 
with severe hepatic impairment will be 
estimated and compared to those in healthy 
matched control participants
AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t1/2, CL/F, and Vz/F
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Secondary Objectives
Secondary Endpoints
To evaluate the safety and tolerability of 
efinopegdutide in participants with hepatic 
impairment
Adverse experiences and discontinuations 
due to adverse events.
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Non-alcoholic steatohepatitis
Population
Participants with moderate or severe hepatic 
impairment, Healthy participants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 8 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 24 participants will be allocated as described in Section 9.8.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Moderate HI
Efinopegdutide
14 mg/mL
7 mg
SC
Single dose, 
Day 1
Test 
Product
Severe HI
Efinopegdutide
14 mg/mL
7 mg
SC
Single dose, 
Day 1
Test 
Product
Healthy 
Matched 
Control
Efinopegdutide
14 mg/mL
7 mg
SC
Single dose, 
Day 1
Test 
Product
HI=hepatic impairment; SC=subcutaneous
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
MK-6024, HM1252A, JNJ-64565111, and efinopegdutide.
Total Number of Intervention Groups/Arms
3
Duration of Participation
Each participant will participate in the study 
for approximately 9 weeks from the time 
the participant provides documented 
informed consent through the final contact. 
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: Yes
A list of abbreviations is in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
CRU=clinical research unit; PK=pharmacokinetic
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1.3
Schedule of Activities
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2
INTRODUCTION
2.1
Study Rationale
Efinopegdutide is a dual GLP-1/glucagon receptor agonist being developed for treatment of 
NASH. 
The liver is involved in drug clearance through multiple oxidative and conjugative metabolic 
pathways and through biliary excretion. Hepatic insufficiency from acute or chronic liver 
disease may affect excretion and metabolism, leading to accumulation of drug and 
metabolites. Hepatic disease can therefore alter the levels of drugs, potentially leading to an 
effect on efficacy and/or safety.  In accordance with FDA hepatic impairment guidance, a 
Sponsor should evaluate the PK of its investigational drug in hepatic impaired participants 
when hepatic metabolism and/or excretion accounts for a substantial portion (>20% of the 
absorbed drug) of the elimination of the parent or active metabolite. It is not yet known how 
hepatic impairment will affect the PK of efinopegdutide. Previous studies evaluating the 
effect of hepatic impairment in the setting of the GLP-1 agonist semaglutide, demonstrated 
no effect on exposure and concluded that no dose modification would be required [Jensen, 
L., et al 2018][Baekdal, T. A., et al 2018]. 
This Phase 1 study will evaluate the general PK, safety, and tolerability of a single dose of 
efinopegdutide in participants with moderate and severe hepatic impairment, compared to 
participants in good health.
2.2
Background
Refer to the IB for detailed background information on efinopegdutide.
2.2.1
Pharmaceutical and Therapeutic Background
NAFLD is a condition associated with an increased accumulation of triglycerides in the liver
that affects approximately 25% of the global adult population. NAFLD has been recognized 
as the hepatic manifestation of overarching metabolic dysregulation and is considered a 
consequence of obesity-related insulin resistance resulting in increased trafficking of fatty 
acids from the adipose tissue to the liver and increased de novo hepatic lipogenesis [Fabbrini, 
E., et al 2010].
NAFLD encompasses a spectrum of disease, ranging from simple steatosis to NASH that is 
associated with chronic inflammation within the liver described histologically as 
steatohepatitis with or without fibrosis [Kechagias. S., et al 2020]. An increasing proportion 
of NAFLD cases are expected to progress to NASH, rising from 20% to 27% between the 
years 2015 and 2030 [Friedman, S. L., et al 2018].
Patients with NASH are usually asymptomatic. A diagnosis of NASH is typically considered 
when patients have abnormal liver tests without alternate explanation or when abdominal 
imaging incidentally detects hepatic fat. 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 assessments cannot definitively diagnose NASH 
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or fibrosis stage but are useful in evaluating the risk of advanced fibrosis. A definitive 
diagnosis of NASH requires liver biopsy [Friedman, S. L., et al 2018].
In general, patients with NASH are diagnosed between the ages of 40 and 60 years and have 
associated metabolic comorbidities that include obesity, dyslipidemia, T2DM, and metabolic 
syndrome [Younossi, Z. M., et al 2016][Younossi, Z., et al 2018][Chalasani, N., et al 2018]. 
Approximately 20% of the patients with NASH will progress to cirrhosis with increases in 
all-cause- and liver-related mortality, including increased rates of hepatocellular carcinoma 
[Sheka, A. C., et al 2020]. Additionally, some patients develop hepatocellular carcinoma 
without cirrhosis [Stine, J. G., et al 2018][Perumpail, R. B., et al 2015].
Lifestyle modifications directed at weight loss and exercise remain the most recommended 
treatment for NAFLD and NASH; however, even in well-organized settings, only a minority 
of patients achieve and sustain weight loss. Presently, there are no approved medications for 
the treatment of NASH. According to evidence-based practice guidelines for the treatment of 
patients with biopsy-proven NASH, pioglitazone and GLP-1 receptor agonists are 
recommended as pharmacotherapies for patients with T2DM and high-dose vitamin E 
(800 IU/day) is recommended for nondiabetic patients [Cusi, K., et al 2022][Sumida, Y. and 
Yoneda, M. 2018]. However, neither pioglitazone nor vitamin E have demonstrated a robust 
histologic efficacy in patients with NASH, have been studied long-term to assess their impact 
on liver-related outcomes, or have fully characterized safety profiles in this patient 
population. Given the growing global prevalence of NASH, the absence of well-
characterized, safe, and highly effective NASH treatments is a significant unmet medical 
need recognized by both medical societies and regulatory agencies [Friedman, S. L., et al 
2018][Chalasani, N., et al 2018].
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Efinopegdutide Preclinical Overview
The preclinical safety profile of efinopegdutide has been assessed in safety pharmacology 
studies, single-dose toxicity studies, 2 repeat-dose toxicology studies in rats for 4- and 
26 weeks duration, and 2 repeat-dose toxicology studies in monkeys for 4- and 16-weeks 
duration.
The predominant treatment-related effects of efinopegdutide in 4-week repeat-dose toxicity 
studies in rats and monkeys are attributable to exaggerated pharmacological actions of 
efinopegdutide on GLP-1R and GCGR receptors that caused pronounced dose-related 
decreases in body weight, body weight gain, and food consumption compared with controls. 
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In turn, these effects led to
 
 
 
 
Findings in the 26-week rat study were consistent with those in the shorter term 4-week rat 
study. 
 
 
 
2.2.2.2
Efinopegdutide Clinical Overview
Based on completed clinical studies, at least 1 dose of efinopegdutide has been administered 
to a total of 
 
 
 
 
 
 
 
 
 
 
Key safety data are summarized below.
In the 
 studies, efinopegdutide was generally well tolerated at doses up to 
The most common AEs were GI-related, primarily nausea and vomiting, and 
appeared to be dose-related.
 
 
 in the same individual were considered treatment related. 
 
 
 
 
 
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In the Phase 2b studies, the most common AEs were also GI-related (nausea and vomiting). 
P009 (Study 64565111OBE2001) was a randomized, double-blind placebo-controlled and 
open-label active-controlled, parallel-group, 5-arm, multicenter Phase 2b study. Nondiabetic, 
obese participants 18 to 70 years of age (inclusive) were assessed. A total of 474 participants 
were randomized to placebo, efinopegdutide at 5.0 mg, 7.4 mg, and 10.0 mg; or open-label 
liraglutide 3.0 mg. P010 (Study 64565111OBE2002) was a randomized, double-blind, 
placebo-controlled, parallel-group, 4-arm, multicenter study that evaluated efinopegdutide in 
obese, 18 to 70-year-old participants with T2DM. A total of 196 participants were 
randomized to placebo, and efinopegdutide at 5.0 mg, 7.4 mg, and 10.0 mg. In both studies 
there was significantly reduced body weight at all dose levels of efinopegdutide compared to 
placebo. In both Phase 2b studies, the overall incidence of TEAEs was higher in each 
efinopegdutide dose group compared with the placebo or liraglutide groups. There were a 
total of 24 SAEs in the Phase 2b studies, of which 3 were considered treatment related in 
efinopegdutide groups and 2 in the liraglutide group.
P001 was a Phase 2a, randomized, active-comparator-controlled, open-label study to evaluate 
the efficacy and safety of efinopegdutide in adult individuals with NAFLD.  Approximately 
145 participants have been randomized in a 1:1 ratio to treatment with efinopegdutide 10.0 
mg SC once weekly or semaglutide 1.0 mg SC once weekly, for a duration of 24 weeks. In 
both treatment groups, study intervention was titrated 3 steps over a period of 8 weeks. The 
primary efficacy objective was to evaluate the effect of efinopegdutide versus semaglutide on 
the mean relative reduction (%) from baseline in LFC, measured by MRI-PDFF, after 24 
weeks of treatment. Treatment with efinopegdutide 10 mg SC once weekly resulted in a 
mean relative reduction in LFC from baseline superior by 30% to that observed with 
semaglutide 1 mg SC weekly. Most AEs were nonserious and of low toxicity grade. 
Gastrointestinal AEs were reported in over half of the participants in the efinopegdutide and 
semaglutide groups, most commonly nausea, diarrhea, and vomiting. Efinopegdutide 10 mg 
SC weekly had an acceptable AE profile that was similar to that of semaglutide 1 mg once 
weekly. Treatment with efinopegdutide SC once weekly for 24 weeks was associated with 
small decreases in hemoglobin and hematocrit.
Refer to the IB for a more extensive summary of the preclinical and clinical data available for 
efinopegdutide.
2.2.3
Ongoing Clinical Studies
P011 is a randomized, placebo -controlled, sequential, single-site, double-blind study of 
MK-6024 in healthy Chinese participants.
 
 
 
 
 
 
 
 
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2.2.4
Information on Other Study-related Therapy
There are no other study-related therapies in this protocol.
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine. 
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.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study population includes male and female participants with moderate and severe hepatic 
impairment between the ages of 18 and 75 years (inclusive) and healthy mean-matched 
controls.
Primary Objective
Primary Endpoint
To evaluate the serum pharmacokinetics of 
efinopegdutide after a single dose in 
participants with moderate hepatic 
impairment compared to matched healthy 
control participants
Estimation: The serum PK (AUC0-inf and 
Cmax) of efinopegdutide following a single 
7 mg dose of efinopegdutide in participants 
with moderate hepatic impairment will be 
estimated and compared to those in healthy 
matched control participants.
AUC0- ∞, AUC0-last, Cmax, Tmax, 
apparent terminal t1/2, CL/F, and Vz/F
To evaluate the serum pharmacokinetics of 
efinopegdutide after a single dose in 
participants with severe hepatic impairment 
compared to healthy matched control 
participants
Estimation: The serum PK (AUC0-inf and 
Cmax) of efinopegdutide following a single 
7 mg dose of efinopegdutide in participants 
with severe hepatic impairment will be 
estimated and compared to those in healthy 
matched control participants
AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t1/2, CL/F, and Vz/F
Secondary Objectives
Secondary Endpoints
To evaluate the safety and tolerability of 
efinopegdutide in participants with hepatic 
impairment
Adverse experiences and discontinuations 
due to adverse events.
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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4
STUDY DESIGN
4.1
Overall Design
This is a non-randomized, parallel-group, multi-center, open-label study to compare the PK 
of efinopegdutide in participants with moderate and severe hepatic impairment (based on the 
Child-Pugh (CP) classification) to healthy control participants reasonably matched to the 
demographics (age, weight, sex) of the group with hepatic impairment.
Screening of participants will occur within 28 days prior to the first dose. Up to 16 adult male 
and female participants with HI, and up to 8 matched healthy control male and female 
participants will be enrolled. Participants with moderate hepatic impairment (Panel A) will 
enroll first. Enrollment of severe hepatic impairment participants (Panel B) will occur after a 
review of safety data of 3 participants from Panel A. Enrollment in Panels A and B will then 
continue until at least 6 PK-evaluable participants are enrolled in each panel. Participants will 
be considered PK-evaluable if sufficient serum concentration data were collected to 
determine the PK parameters of interest (e.g. AUC0-∞, AUC0-last, Cmax, Tmax, apparent 
terminal t1/2, CL/F, Vz/F). Enrollment of healthy matching control participants (Panel C) 
shall commence following the completion of enrollment of either Panel A or B, whichever is 
completed first. Each healthy control participant will be matched to the mean age (±15 years) 
and BMI (±3.5 kg/m2) of the participants in the first HI panel to complete enrollment. A total 
of 6 healthy participants shall be enrolled into Panel C at this stage, and the number of males 
and females shall generally be matched to the numbers of hepatic impairment participants 
within ±1; i.e. if there are 4 males and 4 females in the hepatic insufficient group, every 
effort will be made to ensure a 4:4 ratio in the healthy participants, but 3:5 or 5:3 would be 
acceptable as well.
Following completion of enrollment of the second HI panel, the matching characteristics 
(age, BMI, sex) of the already-enrolled healthy participants in Panel C will be compared 
against the mean values of the HI panel that is completed second. If any of the participants 
already enrolled in Panel C do not also meet the matching criteria for the second completed 
HI panel, additional healthy participants will be enrolled into Panel C in order to provide 6 
healthy control participants who match the mean age (±15 years) and BMI (±3.5 kg/m2) of 
the subjects in the second HI panel. The sex of the additional healthy participant(s) will be 
selected to ensure that there is a minimum of 2 participants of each sex in the group of 
participants within Panel C who match with the second HI panel. The PK comparisons 
between each hepatically impaired panel (A and B) and healthy controls (Panel C) will 
include only control participants who meet the matching criteria for the respective HI panel. 
Assignment to a group will be as per Table 1.
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Table 1
Group Assignment
Panel
Impairment Stage
n
Child-Pugh Scorea
A
Moderate
8
7 to 9
B
Severe
8
10 to 15
C
Healthy
8
0
a Child-Pugh (CP) score based on standard scoring. Baseline CP will be obtained by taking the 
mean of the CP score obtained from screening and from the most recent historical values within a 
6-month period prior to screening. If no historical measurement is available, a second baseline CP 
will be assessed during the screening period (>72 hours apart) and the mean of the 2 values will be 
used for group assignment.
On Day 1, participants will receive a single dose of 7 mg efinopegdutide, followed by PK 
sampling until 72 hours postdose in the clinic. There will be additional visits on Days 5, 6, 7, 
8,11, 14, 21, and 35 for the collection of PK. Safety will be monitored throughout the study 
be repeated clinical and laboratory evaluations.
As noted, the CP classification will be used to categorize hepatic impairment. The CP scale is 
used by clinicians to categorize chronic liver disease and cirrhosis and is also used to 
categorize participants with hepatic impairment for PK studies. In the current study, patients 
with chronic, stable hepatic impairment with features of cirrhosis due to any etiology will be 
enrolled, and the CP scale will be used to classify the severity of liver disease (Table 2). The 
points from each row are summed, leading to the final CP score. Scores of 5 to 6, 7 to 9, and 
10 to 15 are classified as having mild, moderate, or severe hepatic impairment, respectively. 
To ensure an adequate number of study participants with laboratory abnormalities consistent 
with hepatic dysfunction, at least 50% of the participants with hepatic impairment will be 
required to have a score of at least 2 on one of the laboratory parameters (reduced serum 
albumin, increased serum bilirubin, or increased INR), and every effort will be made to 
enroll at least 2 participants with a CP score of >13. Note that the CP score is intended for 
application in individuals who have been diagnosed with liver disease and has a minimum 
starting score of 5. Thus, it is not appropriate to apply this score in participants without liver 
disease, and healthy participants will be assigned a “score” of 0 based on lack of liver disease 
and lab values within normal population limits for albumin, bilirubin, and INR.
Table 2
Child-Pugh Score for Severity of Liver Disease Classification
Points Score for Increasing Abnormality
Assessment
1
2
3
Encephalopathya
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
INR
<1.7
1.7 to 2.3
>2.3
Bilirubin (mg/dL) – not PBCb
Bilirubin (mg/dL) – only for PBCb
<2
<4
2 to 3
4 to 10
>3
>10
INR = international normalized ratio; PBC = primary biliary cirrhosis
a Portal-system encephalopathy is Staged 0 to 4.
b Select only one dependent on type of cirrhosis.
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The CP classification will be used due to its widespread use and acceptance by regulatory 
agencies, including the U.S. FDA. This study design is supported by FDA guidelines for 
drugs which undergo substantial hepatic metabolism and for which an indication is sought 
for patients with hepatic impairment.
Because this is a Phase 1 assessment of efinopegdutide in humans, the PK, 
pharmacodynamic, and safety profiles of the compound are still being elucidated. This 
protocol is therefore written with flexibility to accommodate the inherent dynamic nature of 
Phase 1 clinical studies. Refer to Section 8.11.6 for examples of modifications permitted 
within the protocol parameters.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
An open-label, single-dose study design has been deemed optimal to evaluate the effect of 
hepatic impairment on the PK of efinopegdutide. PK of efinopegdutide have been established 
in previous studies in healthy participants and indicate that steady state is reached after 5 
weeks. Based on preclinical studies, it is anticipated that in humans, efinopegdutide will 
undergo elimination via multiple pathways. It remains unclear how hepatic impairment will 
affect the PK and metabolism of efinopegdutide, and thus the study design will include a 
cohort of individuals with moderate hepatic impairment as well as a cohort of individuals 
with severe hepatic impairment, which will provide important data as the compound 
advances into further clinical development. The study will evaluate and compare 
efinopegdutide PK in participants with moderate HI and severe HI to healthy control 
participants that are reasonably matched to the mean demographic parameters (sex, age, 
BMI) of participants with varying degrees of HI to control for the influence of covariates.
Patients with hepatic impairment often develop elevated circulating glucagon levels [Silva, 
G., et al 1990]. The mechanism of this increase in glucagon is incompletely understood, 
however a potential cause may be an increase in secretion by the pancreas and reduced 
metabolism by the liver. A study evaluating the effects of exogenously administered 
glucagon revealed a mild but significant increase in hepatic portal pressures in patients with 
cirrhosis, but not in control individuals. Exogenous glucagon also caused an increase in heart 
rate and blood pressure, but these changes were significantly attenuated in cirrhotic patients
compared to healthy controls and the dosage of glucagon used in this study is 
 
above the estimated increase in glucagon concentrations with a 7 mg dose of efinopegdutide.
Given these observations and the vulnerability of the hepatically impaired population, 
recruitment of participants will begin with moderate HI. Enrollment of severe HI participants 
will only begin following review of safety and tolerability data from at least 3 moderate HI 
participants. 
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no efficacy endpoints in this trial.
4.2.1.2
Safety Endpoints
The safety data for MK-6024 to date has been described in detail in the IB and summarized 
in Section 2.2.2.
The general safety and tolerability of efinopegdutide will be assessed by clinical evaluation 
of AEs and monitoring of physical examinations, vital signs (HR and BP), 12-lead ECGs, 
glycemic responses (fasting glucose and HbA1c), and standard laboratory safety tests 
(hematology, serum chemistry, and urinalysis).
All procedures will be conducted at the time points specified in the SoA. AEs will be 
recorded throughout the study.
4.2.1.3
Pharmacokinetic Endpoints
The primary endpoints for this study will include the PK parameters of AUC0- ∞, AUC0-
last, and Cmax of efinopegdutide. Serum PK parameters included in this primary endpoint 
will be evaluated and compared between participants with moderate hepatic impairment with 
CP classification 7-9 compared to healthy matched control participants using GMR and CI to 
assess differences between two groups. Similarly, the serum PK parameters will be evaluated 
and compared between participants with severe hepatic impairment with CP classification
10-15 compared to healthy matched control participants. 
For each PK parameter (AUC0- ∞, AUC0-last, Cmax, Tmax, apparent terminal t1/2, CL/F, 
and Vz/F of serum efinopegdutide), descriptive statistics will be provided.
4.2.1.4
Pharmacodynamic Endpoints
Previous clinical studies demonstrate that weekly dosing of efinopegdutide may lead to 
decreases in body weight. While clinically meaningful changes in body weight are not 
expected following a single efinopegdutide dose in this study, to better understand this 
potential impact of efinopegdutide in hepatic impairment participants, the body weight will 
be measured throughout the study. All procedures will be conducted at the time points 
specified in the SoA.
Efinopegdutide is intended to deliver therapeutic benefit through a mechanism of action via 
dual agonism of the GLP-1 and glucagon receptors. However, the mechanisms through 
which these effects are achieved are not completely understood. Therefore, much remains to 
be learned regarding how efinopegdutide works and how it may best be used to treat patients 
with NASH. To aid in these efforts, exploratory assessments of known and/or unknown 
biomarkers may be performed.
 
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4.2.1.5
Immunogenicity Endpoints
Immunogenicity to efinopegdutide will be described as the results of the ADA assay from 
samples taken as described in the SoA (see Section 1.3). ADA samples will be collected from 
all participants. The incidence and magnitude (titer) of ADA positive participants and 
potential effects of ADA on PK and safety will be reported, as appropriate.
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
4.2.1.7
Future Biomedical Research
 
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable.
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4.3
Justification for Dose
The methods used in calculating doses and estimated exposures are detailed in Section 4.3.1 
and Section 4.3.2.
In previous Phase 1 studies of efinopegdutide, single doses of up to 4.0 nmol/kg 
(approximately 20 mg) have been generally well-tolerated. The most common AEs were 
gastrointestinal-related, and most consistently included nausea, vomiting, abdominal 
discomfort/distention/pain and decreased appetite. Dose-dependent increases in GI AEs, 
particularly nausea and vomiting, were observed across the single dose studies and the
multiple dose studies that did not include titration steps from lower to higher doses. Thus, 
while 10 mg may be the eventual clinical dose, a single dose of 7 mg is selected based on 
better tolerability of this dose compared to a 10 mg dose, as is consistent with FDA 
guidelines [U.S.Department of Health and Human Services - Food and Drug Admi 2003].
Based on the sensitivity of the PK assay, single doses lower than 7 mg may fall below the 
LLOQ at earlier postdose time points than would be optimal for the PK analysis. 
As this is a Phase 1 assessment of efinopegdutide in humans, and the PK, pharmacodynamic 
and safety profiles of the compound are still being evaluated, modifications to the dose or 
dosing regimen may be required to achieve the scientific goals of the study objectives and/or 
to ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
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 (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test 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 (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
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4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). 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.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
Moderate or Severe HI 
1. Has a diagnosis of chronic (>6 months), stable, hepatic impairment with features of 
cirrhosis due to any etiology (stability of hepatic disease should correspond to no acute 
episodes of illness within the previous 2 months due to deterioration in hepatic function). 
For the purposes of this study, diagnosis of cirrhosis based on assessment on imaging 
features (ultrasound, transient elastography, or magnetic resonance elastography) 
indicative of cirrhosis in combination with clinical features of cirrhosis or biopsy-
confirmed cirrhosis will be acceptable.
Note: Individuals who have undergone a TIPS (transjugular intrahepatic portosystemic 
shunt) procedure may be considered for inclusion upon consultation with the Sponsor.
2. Moderate HI: Has a score on the CP scale ranging from 7 to 9 at screening.
3. Severe HI: Has a score on the CP scale ranging from 10 to 15 at screening. 
Note: Baseline CP will be obtained by taking the mean of the CP score obtained from 
screening and from historical values within a 6-month period prior to screening. If no 
historical measurement is available, a second baseline CP will be taken during the 
screening period (>72 hours apart) and the mean of the 2 values will be used for group 
assignment; the second CP score may be obtained at the time of check in.
4. With the exception of hepatic impairment, the participant is in generally good health 
based on medical history, physical examination, VS measurements and ECGs performed 
prior to randomization. Participants with stable, chronic medical or psychiatric conditions 
may be included at the discretion of the investigator and the Sponsor. 
5. With the exception of hepatic impairment, baseline health is judged to be stable based on 
laboratory safety tests obtained at the screening visit and prior to study drug 
administration. Appendix 2 provides a table of laboratory safety tests to be performed. 
Appendix 10 provides an algorithm for the assessment of out of range laboratory values.
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Note: The laboratory safety test parameter values for
 
 
Healthy Participants 
6. Is in good health based on medical history, physical examination, VS measurements, and 
ECGs performed before randomization. Appendix 9 provides a table of the 12-lead 
Electrocardiogram Abnormality Criteria.
7. Is in good health based on laboratory safety tests obtained at the screening visit and 
before administration of the of study drug. Appendix 2 provides a table of laboratory 
safety tests to be performed. Appendix 10 provides an algorithm for the assessment of 
out-of-range laboratory values.
All Participants (Panels A, B, and C)
Demographics
8.
 See Section 8.3.1 for criteria on rounding to the nearest whole 
number. BMI= weight (kg)/height (m)2.
9. Is an individual of any sex/gender, from 18 years to 75 years of age inclusive, at the time 
of providing the informed consent.
Participants Assigned Male at Birth
Participants Assigned Female at Birth
11. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
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Informed Consent
12. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
Moderate or Severe HI 
1. Has a history of any illness that, in the opinion of the investigator, might confound the 
results of the study or poses an additional risk to the participant by their participation in 
the study.
4. Is positive for HIV-1 or HIV-2 at the prestudy (screening) visit.
5. Has received antiviral and/or immune modulating therapy for HBV or HCV within 90 
days prior to study start.
.
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2021 CKD-EPI Equation:
eGFR = 142 × min(Scr κ, 1
⁄
)α × max(Scr κ, 1
⁄
). × 0.994Age × 1.012 if female
where Scr is serum creatinine, k is 0.7 for females and 0.9 males, α is  -0.241 for females and 
-0.302 for males, min indicates the minimum of Scr/k or 1, max indicates the maximum of 
Scr/k or 1.
Healthy Participants 
10. Positive test(s) for HBsAg, hepatitis C antibodies or HIV.Note: Participants with a 
documented cure and/or a positive serologic test for HCV with a negative HCV viral load 
may be included upon consultation with the Sponsor.
All Participants (Panels A, B, and C)
11. History of cancer (malignancy). Participants with adequately treated disease deemed as 
“cured,” or who, in the opinion of the study investigator, are highly unlikely to sustain a 
recurrence for the duration of the study may be enrolled at the discretion of the 
investigator.
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13. The participant had a major surgery and/or donated or lost 1 unit of blood (approximately 
500 mL) within 4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
Moderate or Severe HI 
 
Healthy Participants 
15. Unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 
5 half-lives) prior to administration of the initial dose of study intervention, throughout 
the study (including washout intervals between treatment periods), until the poststudy 
visit. There may be certain medications that are permitted (see Section 6.5).
Prior/Concurrent Clinical Study Experience
16. Participated in another investigational study within 4 weeks (or 5 half-lives, whichever is 
greater) prior to the prestudy (screening) visit. The window will be derived from the date 
of the last visit in the previous study.
Diagnostic Assessments
All Participants
17. Participants with HI: The participant meets the following criteria for ECG:
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Other Exclusions
All Participants
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2. 
Participants will fast from all food and drinks, except water, for at least 8 hours prior to study 
drug administration. Participants will fast from all food and drinks except water until 
completing 4-hour postdose procedures. After the 4-hour postdose procedures have been 
completed, subsequent meals and snacks will be unrestricted. Meals will be provided to the 
participants by the site while domiciling.
Water will be restricted 1 hour prior to and 1 hours after study drug administration. 
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5.3.1.2
Fruit Juice Restrictions
There are no specific restrictions for fruit and fruit juice consumption.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants are advised to refrain from consumption of caffeinated beverages or xanthine-
containing products from 12 hours prior to the screening visit, admission, post-dose visits, 
poststudy visit, and during the domiciled period. 
At all other times, caffeinated beverages or xanthine-containing products will be limited to 
no more than 6 units per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants are advised to refrain from consumption of alcohol 24 hours prior to the 
screening visit, admission, post-study visits, poststudy visit, and during the domiciled period. 
At all other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent servings (1 serving is approximately equivalent to: beer 
<354 mL/12 ounces>, wine <118 mL/4 ounces>, or distilled spirits <29.5 mL/1 ounce>) per 
day.
5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study (including washout intervals between treatment 
periods), and until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information may be 
included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
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5.5
Participant Replacement Strategy
If a participant withdraws from the study a replacement participant may be enrolled if 
deemed appropriate by the investigator and Sponsor. The replacement participant will 
generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique allocation
number.
The study site should contact the Sponsor for the replacement participant’s allocation 
number.
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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 will be packaged to support enrollment and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted before dosing the replacement participant. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 3.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Moderate 
HI
Experimental Efinopegdutide Combination 
Product
Injection, 
Solution
14 mg/mL
7 mg
SC
Single 
dose, 
Day 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Severe HI
Experimental Efinopegdutide Combination 
Product
Injection, 
Solution
14 mg/mL
7 mg
SC
Single 
dose, 
Day 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Healthy 
Matched 
Control
Experimental Efinopegdutide Combination 
Product
Injection, 
Solution
14 mg/mL
7 mg
SC
Single 
dose, Day 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
EEA=European Economic Area; HI=hepatic impairment; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
SC=subcutaneous
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.
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All supplies indicated in Table 3 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
The drug-device combination product/combination medicinal product provided for use in this 
study is an efinopegdutide prefilled syringe for SC injection. Refer to Section 8.4.8 and 
Appendix 4 for instructions on reporting events associated with the combination product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
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.
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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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment. A sample allocation 
schedule is shown in Table 4.
Table 4
Allocation of Participants to Treatment
Hepatic Impairment Stage
n
Treatment
Moderatea
8
Efinopegdutide 7.0 mg
Severea
8
Efinopegdutide 7.0 mg
Healthyb
8
Efinopegdutide 7.0 mg
a The participants in the groups defined by hepatic function should be reasonably similar to one another with 
respect to age, gender, and weight. However, participants with normal hepatic function should be matched at the 
group level. In order to make this matching possible, participants with normal hepatic function need to be 
enrolled after the participants with hepatic impairment have been recruited.
b Participants with normal hepatic function are within ±15 years of the mean age and within ± 3.5 kg/m2 of the 
mean BMI for the severe hepatic function group. In addition, the numbers of males and females of the healthy 
participants will be generally matched to the numbers of hepatic insufficient participants within ±1; i.e. if there 
are 4 males and 4 females in the hepatic insufficient group, every effort will be made to ensure a 4:4 ratio in the 
healthy participants, but 3:5 or 5:3 would be acceptable as well.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Participants will be dosed at the site; they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of administration will 
be recorded in the source documents and recorded in the CRF. The dose of study intervention 
and study participant identification will be confirmed at the time of dosing by a member of 
the study-site staff other than the person administering the study intervention.
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6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of 
starting the study, they may be included in the study if the investigator can rationalize that 
the specific use of a prior medication is not clinically relevant within the context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during the ongoing study (ie, after intervention allocation) must first be discussed between 
the investigator and Sponsor before administration, unless appropriate medical care 
necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult. The participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree.
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor.
In addition, the following concomitant medications/vaccinations are permitted:
•
COVID-19 vaccine may be administered. Study intervention must be given at least 72 
hours following or at least 48 hours prior to any COVID-19 vaccination.
For Participants with Moderate or Severe Hepatic Impairment:
Participants who are taking medication to treat general medical conditions and/or conditions 
associated with hepatic disease (e.g., hypertension, non-insulin dependent diabetes mellitus, 
hypercholesterolemia, hypo- or hyperthyroidism, gout, depression) will be allowed to 
participate in the study at the discretion of the Investigator and following consultation with 
the Sponsor Clinical Monitor. Participants must be on a stable regimen for at least 1 month 
prior to study drug administration and able to withhold the use within 4 hours prior to and 8 
hours after study drug administration. Any exceptions to this must first be discussed between 
the Investigator and Sponsor.
Certain prescription medications used to treat manifestations of hepatic disease (e.g., 
lactulose, neomycin, etc.) will be allowed during the study, but the patient must be on a 
steady dose, drug, and regimen for ~ 1 month prior to dosing on Day 1. Lactulose should be 
restricted at least 6 hours prior to and 6 hours after dosing on Day 1 since it may potentially 
affect absorption.
Example of types of medications that would be used for chronic medical conditions that 
would be allowed include (but are not limited to) the following:
•
Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, 
diuretics
•
Beta blockers
•
Metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, alpha-glucosidase 
inhibitors, incretin mimetics
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•
Statins
•
Levothyroxine
•
Colchicine, allopurinol
•
Selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants
•
Proton pump inhibitors
Participants with a valid medical marijuana card will be allowed to participate in the study at 
the discretion of the Investigator, however use of medical marijuana should be restricted at 
least 24 hours prior to, and 24 hours after, study intervention administration.
Any medication (including over-the-counter) that, by the determination of the Investigator, 
might interfere with the study (e.g., cimetidine) must be discontinued at least 2 weeks (or 5 
half-lives of the compound, whichever is longer) prior to the dosing of study drug.
Medications with known effect on QT/QTc prolongation may be allowed following 
discussion with the Sponsor.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
Dose modifications are not applicable to this study.
6.6.1
Stopping RulesThe following stopping rules will be used during the conduct of 
this study.
If any of the below stopping rules are met, the study will be paused, and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. In the case a stopping 
rule is met by adverse drug reactions identified in the MK-6024 IB, the study may be 
continued by addressing an individual participant (e.g. discontinuing the participant based on 
Section 7.1) instead of stopping the entire study. To continue the study, joint agreement with 
the Sponsor and investigator will be needed.
1. An individual participant reports an SAE considered related to the study intervention by 
the investigator
2. Two (2) or more participants within a Panel (at the same dose level) report Severe 
Nonserious AEs considered related to the study intervention by the investigator.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
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6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention. Therefore, participants who receive a single-dose intervention 
cannot discontinue 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 FBR, are outlined in 
Section 8.1.9. 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.
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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 used for screening or baseline purposes 
provided the procedures meet 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 the volume mentioned in Appendix 8. If additional 
pharmacokinetic and/or safety analysis is necessary, additional blood (no more than 50 
mL in total) may be obtained.
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) prior to 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 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
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, 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 
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the participant provides documented informed consent. At the time of intervention allocation, 
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 health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
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 in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment/allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or an appropriately 
qualified designee.
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8.1.8.1
Timing of Dose Administration
After it is confirmed that the participant meets eligibility, study intervention administration 
will occur after the completion of Day 1 predose procedures Study intervention should be 
administered SC to the abdomen. The time of the dose will be designated as time “0” hr and 
the exact time of administration will be recorded.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study. If a participant discontinues for any reason at any 
time during the course of the study, the participant may be asked to return to the clinic (or be 
contacted) for a poststudy visit as per the number of days described in Section 1.3 to have the 
applicable procedures conducted. However, the investigator may decide to perform the 
poststudy procedures at the time of discontinuation or as soon as possible after 
discontinuation. If the poststudy visit occurs prior to the safety follow-up time frame as 
specified in Section 8.4.1, the investigator should perform a follow-up telephone call at the 
end of the follow-up period (Section 8.4.1) to confirm if any AEs have occurred since the 
poststudy clinic visit. Any AEs that are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the 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 
FBR 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the 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.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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8.1.11
Domiciling
Participants will report to the CRU on Day -1 before the scheduled day of study intervention 
administration on Day 1 and remain in the unit until after completion of the postdose 
procedures on Day 4. At the discretion of the investigator, participants may be requested to 
remain in the CRU longer.
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.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded at the timepoints listed in the SoA (Sec. 1.3).
Symptom driven physical examinations may be performed at other times at the Investigator’s 
discretion. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared 
(BMI = kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
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Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, HR, RR, and BP will be assessed.
•
BP and HR will be assessed with a completely automated device. Manual techniques will 
be used only if an automated device is not available. The same arm should be used for all 
measurements for each individual participant if possible. The correct size of the BP cuff 
and the correct positioning of the participant’s arm is essential to increase the accuracy of 
BP measurements.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent 
position for at least 10 minutes before having VS measurements obtained. Semirecumbent 
VS will include HR, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA.
The predose (baseline) HR and BP will be triplicate measurements, obtained at least 1 to 2 
minutes apart within 3 hours of dosing efinopegdutide. The median of these measurements 
will be used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed). Screening and all postdose VS measurements will be single
measurements.
Respiratory Rate and Body Temperature
RR and body temperature will be single measurements per timepoint at all timepoints. The 
same method must be used for all measurements for each individual participant and should 
be the same for all participants at a given site.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will be obtained as single measurements 
per timepoint at all timepoints. Participants should be semirecumbent for at least 10 minutes 
and then stand upright for approximately 2 minutes before measurement of orthostatic VS.
8.3.3
Electrocardiograms
•
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG 
machine that automatically calculates the HR and measures PR, QRS, QT, and QTc 
intervals. The correction formula to be used for QTc is Fridericia. Refer to Appendix 9
for evaluation and potentially significant findings.
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Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semirecumbent position for at least 10 minutes before 
each ECG measurement. At each time point when triplicate ECG are required, 3 individual 
ECG tracings should be obtained at least 1 minute apart. The full set of triplicates should be 
completed in no more than 6 minutes.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
Day 1 predose ECGs will be obtained in triplicate at least 1 minute apart within 3 hours 
before dosing efinopegdutide. The median of these measurements will be used as the baseline 
to calculate change from baseline for safety evaluations (and for rechecks, if needed).
Screening and all postdose ECG measurements (including poststudy visit) will be single 
measurements.
During the treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with median predose baseline measurement, the participant will continue 
to be monitored by at least single repeat 12-lead ECGs every 15 minutes for at least 1 hour or 
until the QTc is within 60 msec of baseline. If prolongation of the QTc interval ≥60 msec
persists, a consultation with a cardiologist may be appropriate and the Sponsor should be 
notified.
If a participant demonstrates a QTc interval ≥500 msec on a postdose ECG, the Sponsor 
should be notified, and the ECGs should be reviewed by a cardiologist. The participant 
should be telemetry monitored (until the QTc interval is <500 msec) or should be considered 
for transfer to a location where closer monitoring and definitive care (eg, a CCU or ICU) is 
available.
If the QRS interval from any postdose ECG is 20% greater than the median baseline QRS 
interval and is >120 msec (and change is not considered rate related or pacing induced) or 
there appears to be new onset intermittent bundle branch block, then the ECG will be 
immediately repeated twice within 5 minutes. The median value of the QRS interval from the 
3 ECGs will represent the value at that time point. If the median QRS interval increase from 
baseline for any postdose time point is >20%, the participant will continue to be monitored 
by repeat 12-lead ECGs every 15 minutes for at least 1 hour or until the QRS interval is 
within 20% of baseline. If a >20% prolongation of the QRS interval persists, a consultation 
with a cardiologist may be appropriate and the Sponsor should be notified.
If at any time the QRS interval is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) is available.
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If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc interval is noted, concomitant medications that prolong QTc 
interval should be held until the QTc interval is within 60 msec of baseline and the QTc 
interval is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
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 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 SoA.
•
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 or within 14 days after the last dose of study intervention, 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.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum) should be conducted as per SoA for the time 
required to eliminate systemic exposure after the last dose of each 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 each study 
intervention is:Efinopegdutide: 35 days
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-
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.
8.3.6
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption, or rash occurrence in determining etiology and study intervention relationship.
8.4
Adverse Events, Serious Adverse Events, 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 safety 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. 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
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator under any of the following circumstances:
•
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,
•
if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention allocation through 14 days after cessation of intervention, all 
AEs, SAEs, and other reportable safety events must be reported by the investigator.
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Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also 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.
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 5.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 5
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
24 hours of 
learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse 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.
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, 
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including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated 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 toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) 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 (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor’s product, as defined in Section 8.5.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. 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).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions
The method of documenting and reporting of such events [complaints associated with 
medical devices including PQCs/malfunctions] will occur as below and in Appendix 4.
To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per 
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions, including those that involve a participant or any user/associated person, 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices and drug-device combination 
products being used in clinical studies.
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The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
Sponsor does not recommend specific treatment for an overdose. 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 will be measured for evaluation of PK will be 
collaboratively determined by the Sponsor. If indicated, these samples may also be measured 
and/or pooled for assay in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers. Blood samples collected may be stored and further analysis may 
be performed, if required.
8.6.1
Blood Collection for Serum Efinopegdutide
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Operations Manual.
8.7
Pharmacodynamics
Pharmacodynamic assessments will be conducted as outlined in the SoA (Section 1.3), 
including for endogenous glucagon. Blood samples collected may be stored and further 
analysis may be performed, if required.
8.8
Immunogenicity Assessment
Serum samples for ADA assessment will be collected to evaluate the incidence and 
magnitude of anti-efinopegdutide antibodies. ADA samples will be collected from all 
participants according to the ADA sampling scheme outlined in the SoA (Section 1.3). 
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 
Operations manual.
8.9
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research will be collected from all participants as specified in the 
SoA:
•
Blood for Genetic Analysis 
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8.9.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but future 
biomedical research is approved, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained pre-dose on Day 1, but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be in the 
Operations/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 samples listed in Section 8.9
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Within approximately 28 days before intervention allocation, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation if there are Day −1 
procedures planned per protocol.
8.12.2
Treatment Period
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1)
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8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.12.4
Poststudy
Participants will be required to return to clinic approximately 35 days after the last dose of 
study intervention for the poststudy visit. 
8.12.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for efinopegdutide is the critical procedure.
At any postdose timepoint, the blood sample for efinopegdutide needs to be collected as 
close to the exact time as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Study procedures can be performed before or after the 
prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the 
Investigator and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
PK and ADA Collection as outlined in Table 6.
Table 6
PK and ADA Collection Windows
Scheduled Sampling Point
Sample Collection Window
Predose
Within 3 hr prior to dosing
0 to < 48 hr post-dose
± 1 hr
48 hr post-dose to Day 8
± 2 hr
Day 11 to Day 21
± 1 day
Poststudy Visit
± 2 day
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•
Pre-dose standard safety evaluations: VS and ECG up to 3 hours prior to dosing; 
laboratory safety tests and physical exam up to 24 hours prior to dosing.
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
exam
•
Prior to 24-hours post dose may be obtained within 15 minutes of the theoretical 
sampling time
•
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time
•
From 48-hours postdose to Day 8 may be obtained within 2 hours of the theoretical 
sampling time
•
From Day 11 to Day 21 may be obtained within 24 hours of the theoretical sampling 
time
•
Poststudy visit samples may be obtained within 2 days of the theoretical sampling 
time
8.12.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of efinopegdutide in humans, and the PK, pharmacodynamic, 
and safety profiles of the compound are still being elucidated. This protocol is written with 
some flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK sample processing and shipping details based on newly available 
data
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak serum concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
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The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
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9
KEY STATISTICAL CONSIDERATIONS
This section details the principal statistical analysis strategy and procedures for the study. If, 
after the study has begun, changes are made to the statistical analysis plan stated below, then 
these deviations to the plan will be listed, along with an explanation as to why they occurred, 
in the Clinical Study Report.
9.1
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine Department of the Sponsor.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 of the protocol.
(Primary Estimation) The serum PK (AUC0-inf, AUC0-last and Cmax) of efinopegdutide 
following a single 7 mg dose of efinopegdutide in participants with hepatic impairment 
(moderate HI and severe HI) will be estimated and compare to those in healthy matched 
control participants.
9.3
Analysis Endpoints
9.3.1
Primary Endpoints
Pharmacokinetics: The pharmacokinetic variables of serum efinopegdutide AUC0-inf, 
AUC0-last, Cmax, Tmax, apparent terminal t1/2, CL/F and Vz/F are of primary interest.
9.3.2
Secondary Endpoints
Safety: The safety endpoints will include all types of adverse events and discontinuation of 
study intervention due to adverse event(s), in addition to laboratory safety tests, ECGs, and 
vital signs. Baseline is defined as measurements obtained pre-dose Day 1.
9.3.3
Exploratory Endpoints
CCI
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9.4
Analysis Populations
The following populations are defined for the analysis and reporting of data.  All participants 
will be reported, and their data analyzed, according to the study intervention(s) they actually 
received.
9.4.1
Safety Analysis Populations
The All Participants as Treatment population consists of all participants who received the 
study intervention. This population will be used for assessments of safety and tolerability.
9.4.2
PK Analysis Populations
The Per-Protocol Population consists of the subset of participants who comply with the 
protocol sufficiently to ensure that generated data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance covers such 
considerations as exposure to treatment, availability of measurements and absence of 
important protocol deviations. Important protocol deviations will be identified to the extent 
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data considered sufficient to exhibit the effect of treatment will be included in the 
Per-Protocol dataset. This population will be used for the PK analyses.
9.5
Statistical Methods
9.5.1
Statistical Methods for PK Analyses
Separately for each pharmacokinetic parameter, individual values of AUC0-∞, AUC0-last, 
and Cmax of serum efinopegdutide will be natural log-transformed and evaluated with a 
linear fixed effects model containing a categorical effect for populations (moderate hepatic 
impairment group, severe hepatic impairment group and healthy matched control group). An 
unstructured covariance matrix will be used to allow for unequal population variances via the 
REPEATED statement with the GROUP=Population in SAS PROC MIXED. The Kenward 
and Roger adjustment will be used to calculate the denominator degrees of freedom for the 
fixed-effect (DDFM=KR). Ninety-five percent (95%) confidence intervals for the least 
squares means for each population will be constructed on the natural log scale and will 
reference the t-distribution. Exponentiating the least-squares means and their corresponding 
95% confidence intervals will yield estimates for the population geometric means and 
confidence intervals about the geometric means on the original scale. Sample SAS code is 
given below:
proc mixed data=data;
class population;
model lnpk = population /ddfm=kr;
repeated/ group= population;
lsmeans population /cl alpha=0.05;
run;
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To compare subjects with HI in each of the hepatic insufficient categories (moderate HI and 
severe HI) to matching subjects with normal hepatic function, a two sided 90% confidence 
interval for the true difference in means (HI – normal hepatic function) will be calculated for 
each PK parameters (AUC0-∞, AUC0-last and Cmax) using the mean square error from the 
model and referencing a t-distribution. These confidence limits will be exponentiated to 
obtain the 90% confidence interval for the true ratio of geometric means (HI/normal hepatic 
function) for each of the insufficient categories. 
Figures showing summary concentration-time profiles by hepatic impairment category 
(linear plot with arithmetic mean (±SD) for concentration and semi-log plot with arithmetic 
mean) will be provided.
Individual values will be listed for each PK parameter (AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t1/2, CL/F, and Vz/F) by population, and the following (non model based) 
descriptive statistics will be provided: N (number of subjects with non-missing data), 
arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 x standard 
deviation/arithmetic mean), median, minimum, maximum, geometric mean, and geometric 
percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 is the observed variance on the 
natural log-scale).
9.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory test results, vital signs, and ECG measurements.
The overall safety endpoints include the number of participants with at least one AE, drug-
related AE, serious AE, serious, drug-related AE, who discontinue from study intervention 
due to an AE, or with an AE resulting in death.
The safety evaluation will include a summary by population group of the number and 
percentage of participants with each type of AE. 
For continuous safety measures, such as change from baseline in laboratory values, vital 
signs, and ECG parameters, summary statistics for baseline, on-treatment, and change from 
baseline values will be provided by group.
9.5.3
Statistical Methods for Pharmacodynamic Analyses
The concentration profile of endogenous glucagon will be plotted across time by group. The 
change from baseline endogenous glucagon will be summarized by group. Similarly, the 
change from baseline body weight will be summarized by group.
9.5.4
Statistical Methods for Immunogenicity Endpoints
The incidence and magnitude (titer) of ADA positive participants will be summarized.
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9.6
Interim Analyses
Not applicable
9.7
Multiplicity
Not applicable
9.8
Sample Size and Power Calculations
The sample size selected for each population to evaluate the effect of hepatic impairment on 
the PK of efinopegdutide was not chosen to satisfy any a priori statistical requirement. This 
sample size (N=6 evaluable per group) has historically been shown to be sufficient for 
studies of this type and should provide adequate data to support the planned analyses. 
Nevertheless, estimates of the expected precision of the estimates, based on these sample 
sizes and the known variability obtained from a hepatic PK study presented below. The 
precision of the estimated GMRs (hepatic impairment / normal hepatic function) of PK 
parameters obtained from this study can be assessed by calculating the half-width of the 90% 
CIs expected for the given sample size and assumed variability. The observed between-
participant coefficients of variation were 
standard deviation on the log scale) 
for AUC0-inf from a SAD study in Healthy Overweight/Obese Adults (Protocol MK-6024-
005). Assuming a sample size of 6 participants per population and observed between-
participant SD is 
on the log scale, then the half width of the 90% CI of GMR for MK-
6024 AUC0-inf on the log scale will be 
. The lower and upper 90% confidence limits 
for the GMR will be given by OBS/
and OBS*
for AUC0-inf, where OBS is the 
observed GMR. Thus, for example, if the observed GMR for AUC0-inf was 
 then the 
approximate 90% CI for the GMR would be 
Similarly, the observed between-participant coefficients of variation were
 
standard deviation on the log scale) for Cmax from Protocol MK-6024-005. Assuming a 
sample size of 6 evaluable participants per population and observed between-participant SD 
is 
 on the log scale, then the half width of the 90% CI of GMR for MK-6024 Cmax on 
the log scale will be 
 The lower and upper 90% confidence limits for the GMR will be 
given by OBS/
 and OBS*
for Cmax. Thus, for example, if the observed GMR for 
Cmax was 1.50, then the approximate 90% CI for the GMR would be [
].
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and 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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. 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. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
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 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.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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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, frequently 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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.
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.
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 before transmission to the Sponsor.
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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
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 ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 trials 
Regulation 536/2014 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 Regulation 536/2014, 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.
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10.1.6
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, ICH 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 Trials.
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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.7
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.
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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 
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.
10.1.8
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.
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10.1.9
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 7 will be performed by the local laboratory.
•
Blood for laboratory tests are to be obtained following at least an 8-hour fasting (except 
water).
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes (Absolute count)
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Fasting plasma 
glucose 
Calcium
Alkaline 
phosphatase
Other safety Tests
HbA1c
Coagulation
PT/INR (International normalized ratio, for hepatic impaired participants only)
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Highly sensitive serum OR urine hCG pregnancy test (as needed for POCBP)
Other Screening Tests
FSH (as needed in postmenopausal PONCBP only)
Serum or urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines) per site SOP
Serology (HIV-1 and HIV-2 antibodies in all participants; HBsAg and hepatitis 
C virus antibody) in healthy participants only)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; POCBP=people of childbearing potential; PONCBP=people of 
nonchildbearing potential; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum 
glutamic-pyruvic transaminase; ULN=upper limit of normal; WBC=white blood cell; 
Notes: Laboratory safety tests will be performed after approximately an 8-hour fast. Predose Day 1 laboratory procedures 
can be conducted up to 24 hours prior to study intervention administration.
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 nontherapeutic 
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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
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
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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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.
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.
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•
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/toxicity
•
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) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? 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 study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention 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; (2) the study is a single-dose drug study; or (3) study 
intervention (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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION 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 study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
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 EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email 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
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination products as listed in 
Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product – A product comprised of 2 or more regulated components (ie, a drug 
and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint – Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part – A drug, device, or biological product that is part of a combination 
product.
Customer Feedback – A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark that may suggest an improvement in the 
functionality or quality of a medical device, or device like features of a drug delivery 
system).
Malfunction – The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device – Any instrument, apparatus, appliance, material, or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment, or alleviation of disease,
•
diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or 
handicap,
•
investigation, replacement, or modification of the anatomy or of a physiological process,
•
control of conception,
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and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological, or metabolic means, but which may be assisted in its 
function by such means.
PQC – Any communication that describes a potential defect related to the identity, strength, 
quality, purity, or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury – An injury or illness that:
1. Is life-threatening,
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
When a complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug-device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 8.4.1 
via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
The investigator will use clinical judgment to determine the relationship.
Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration should 
be considered and investigated.
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Follow-up
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant 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.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal 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, Müllerian 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
-
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 participants assigned female sex at birth who are 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.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal 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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Participants of Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, are considered PONCBP:
•
Premenopausal 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, Müllerian 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
-
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 participants assigned female sex at birth 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.
-
Participants assigned female sex at birth on HRT and whose menopausal status is in 
doubt must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
CCI
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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.
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.
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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 is
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 that 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.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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 FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the 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 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 used 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 
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.
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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.
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
Not applicable.
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10.8
Appendix 8: Blood Volume Table
ADA=antidrug antibodies; FSH=follicle stimulating hormone; HbA1c=hemoglobin A1c; HIV=human 
immunodeficiency virus; INR=international normalized ratio; POCBP= people of childbearing potential; 
PT=prothrombin time; SoA= schedule of activities; SOP= standard operating procedures; 
a
Laboratory safety tests will include serum pregnancy tests at the specified timepoints in the SoA with no 
additional blood volume is required. Serum pregnancy testing will only occur in POCBP, if applicable
b
Serum FSH will be completed for postmenopausal females only
c
To be completed per SOP. HIV-1 and HIV-2 screening will occur for all panels. Hepatitis B/C screening will 
only be conducted for healthy-match control participants
d
Will only be collected for participants in hepatic impairment participants
e
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (no more 
than 50 mL in total) may be obtained.
f
Blood volumes represent the maximum volume to be collected per participant in the study. Certain sites might 
have a lower overall total blood volume per participant based on laboratory blood volumes required to run assays.
CCI
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10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
RHYTHM
Sinus Tachycardia
>110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
>1 beat
≥3 beats
Ventricular Premature Complex
All
≥3 beats
Ectopic Atrial Rhythm
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR <40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR ≥230 ms
PR ≥230 ms + Increase of >15 ms; or 
PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intraventricular Conduction 
Delay
QRS ≥130 ms
QRS ≥130 ms + Increase of ≥10 ms
QTc (B or F)
Male
QTc ≥470 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
Female
QTc ≥480 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P. Mitrale or 
P. Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH Plus Strain 
Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Nonspecific ST-T Changes (In 
2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; 
LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; 
mm=millimeter; ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT 
correction using Fredericia formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1.
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol-specified laboratory value is outside the parameter(s) outlined in the 
inclusion/exclusion criteria (including repeats if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
-
The participant may be excluded from the study.
-
The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
-
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
-
The abnormal test may be repeated (refer to items below for continuation of 
algorithm for repeated values).
◦
If the repeat test value is within the normal range, the participant may enter the 
study.
◦
If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ACCP
American College of Chest Physicians
ADA
antidrug antibodies
ADL
activities of daily living
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
antiretroviral therapy
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
AUC0-inf
area under the curve from 0 to infinity
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
BICR
blinded independent central review
bid
twice daily
BMI
body mass index
BP
blood pressure
CAC
Clinical Adjudication Committee
CCU
Cardiac care unit
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CF
compact flash
CG
Cockcroft-Gault
CHS
cough hypersensitivity syndrome
CI
confidence interval
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Abbreviation
Expanded Term
Cmax
maximum serum concentration
CL/F
apparent clearance
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CP
Child-Pugh
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form
CRU
clinical research unit
CSD
Cough Severity Diary
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
CYP
cytochrome P450
DAIDS
Division of AIDS
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
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Abbreviation
Expanded Term
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ePROs
electronic patient-reported outcomes
E-R
exposure response
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
FVC
forced vital capacity
GCGR
glucagon receptor
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-Stimulating Factor
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GLP
glucagon-like peptide
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
GMR
geometric mean ratio
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
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Abbreviation
Expanded Term
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HI
hepatic impairment
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HSSB
Hepatic-specific Safety Board
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
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug
IO
Immune oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
ITP
idiopathic thrombocytopenic purpura
IUD
intrauterine device
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Abbreviation
Expanded Term
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWG
International Working Group
IWRS
integrated web response system
JRCT
Japan Registry of Clinical Trials
KPS
Karnofsky performance status
LAM
lactational amenorrhea method
LCQ
Leicester Cough Questionnaire
LFC
liver fat content
LLN
lower limit of normal
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose
mTPI
modified Toxicity Probability Interval
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
NCI
National Cancer Institute
NCS
not clinically significant
NEAB
noneosinophilic bronchitis
NDA
New Drug Application
NOAEL
no observed adverse effect level
OR
objective response
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Abbreviation
Expanded Term
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over the counter
PBO
placebo
PBPK
physiologically based PK
PCL
Protocol Clarification Letter
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
PFS
progression free survival
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PP
per-protocol
PQC
product quality complaint
PR
partial response
PRO
patient-reported outcome
QW
once weekly
Q2W
every 2 weeks
Q3W
every 3 weeks
QoL
quality of life
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RCC
refractory chronic cough
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
rP2D
recommended Phase 2 dose
RR
respiratory rate
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Abbreviation
Expanded Term
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SCr
Serum Creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transminase
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
STING
stimulator of interferon genes
SUSAR
suspected unexpected serious adverse reaction
SVR12
sustained viral response
T2DM
type 2 diabetes mellitus
TEA
Treatment Eligibility Assessment (form)
TEAE
treatment-emergent adverse event
Tmax
time to maximum serum concentration
TMDD
target-mediated drug disposition
t½
half life
UACS
upper airway cough syndrome
UCC
unexplained chronic cough
UDS
urine drug screen
ULN
upper limit of normal
URTI
upper respiratory tract infection
UTN
Universal Trial Number
Vd
volume of distribution
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Abbreviation
Expanded Term
VAS
Visual Analog Scale
VS
vital signs
Vz/F
apparent volume of distribution
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
ZAP70
zeta-chain-associated protein kinase
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