An Open-Label, Single-Dose Clinical Study to Evaluate the Pharmacokinetics of MK-0616 in Participants With Varying Degrees of Renal Impairment
Phase: PHASE1
Conditions: Hypercholesterolaemia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:  
    NCT05934292
Document Date:  
    10-AUG-2023
An Open-Label, Single-Dose Clinical Study to
Evaluate the Pharmacokinetics of MK-0616 in
Participants with Varying Degrees of Renal
Impairment

PRODUCT: MK-0616
1
PROTOCOL/AMENDMENT NO.: 020-01
MK-0616-020-01 FINAL PROTOCOL
10-AUG-2023
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 Clinical Study to Evaluate the Pharmacokinetics of MK-0616
in Participants with Varying Degrees of Renal Impairment
Protocol Number: 020-01
Compound Number: MK-0616
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):
NCT
To be determined
EU CT
Not applicable
EudraCT
Not applicable
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
152853
Approval Date:  10 August 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
Amendment 01
10-AUG-2023
The original protocol was amended to change 
the collection of dialysate samples from spot 
collections to interval collections, in an effort to 
align with standard practice.
Original Protocol
17-MAY-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
This protocol was amended to change spot collections for dialysate samples to interval 
collections.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.3, 
Schedule of 
Activities for 
Panel C
Updated original footnote ‘j’, now footnote ‘h’,
to reflect that the Dialysate Samples for MK-
0616 and/or Metabolites Assay are to be 
collected at the end of every 30-minute interval 
from the start of hemodialysis until immediately 
before completion of hemodialysis.
This change was made to address 
investigator/site feedback: It is understood that 
the collection of dialysate samples is typically an 
interval collection, rather than a spot collection, 
therefore, this update was made to comply with 
standard practice.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.3, 
Schedule of 
Activities for 
Panels A, B, and D
All references to BDS/UDS were changed to 
Drug Screen
To allow flexibility for sites to conduct a drug 
screen that is in alignment with their standard 
practice, given the participant population
Section 1.3, 
Schedule of 
Activities for 
Panels A, B, and D
Modified original footnote ‘g’, now footnote 
‘e’
To emphasize that the Day 1 Predose Scheduled 
Time is the only timepoint when triplicate 
semirecumbent VS (HR, BP) and 12-lead ECGs 
are taken
Section 1.3, 
Schedule of 
Activities for Panel 
C
Removed reference to ‘~15’ under Post-study
Correction of a typo
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Section Number 
and Name
Description of Change
Brief Rationale
Section 1.3, 
Schedule of 
Activities for Panel 
C
Removed Screening Visit 2
This visit is no longer necessary, given the 
removal of the need to calculate baseline eGFR 
values for participants in Panel C
Section 1.3, 
Schedule of 
Activities for Panel 
C
Removed original footnotes ‘b’ and ‘c’; 
Footnotes ‘d’ through ‘k’ are now ‘b’ through 
‘i’
These footnotes are no longer necessary, given 
the removal of the need to calculate baseline
eGFR values for participants in Panel C
Section 1.3, 
Schedule of 
Activities for Panel 
C
Removed ‘(ie, ~8 am in both periods)’ from 
notes for Study Intervention Administration
To allow flexibility for sites regarding timing of 
study drug administration
Section 1.3, 
Schedule of 
Activities for Panel 
C
Updates were made to the notes for both ‘On-
site HD’ entries (ie, Period 1 only and Period 2 
only)
To reflect the fact that the length and timing of 
hemodialysis sessions varies from participant to 
participant and from session to session but 
needs to last a minimum of 3 hours
Section 1.3, 
Schedule of 
Activities for Panel 
C
All references to BDS/UDS were changed to 
Drug Screen
To allow flexibility for sites to conduct a drug 
screen that is in alignment with standard 
practice, given the participant population
Section 1.3, 
Schedule of 
Activities for Panel 
C
Specified in the Notes for Urinalysis that the 
urine sample is only to be collected if the 
participant can produce urine
To reflect that some participants with ESRD on 
HD are unable to produce urine and under those 
circumstances, would not be expected to 
produce urine for a urinalysis
Section 1.3, 
Schedule of 
Activities for Panel 
C
Removed ‘Plasma’ from ‘Dialysate Samples 
for Plasma MK-0616 and/or Metabolites Assay 
– Period 2 Only’
Correction of a typo where ‘Plasma’ was 
included in error
Section 1.3, 
Schedule of 
Activities for Panel 
C
Modified original footnote ‘g’, now footnote 
‘e’
To emphasize that the Day 1 Predose Scheduled 
Time is the only timepoint when triplicate 
semirecumbent VS (HR, BP) and 12-lead ECGs 
are taken
Section 1.3,
Schedule of 
Activities for Panel 
C
Modified original footnote ‘k’, now footnote ‘i’
To reflect that some participants with ESRD on 
HD are unable to produce urine and under those 
circumstances, would not be expected to 
produce interval urine samples for PK analysis.
Section 4.1, 
Overall Design
Replaced ‘< 15 requiring HD’ with ‘Not 
applicable’ in Table 1 Renal Function Group 
for participants in Panel C
To reflect that the calculated eGFR value is not
relevant in participants with ESRD on HD, due 
to the fluctuation in the creatinine values 
between hemodialysis sessions
Section 4.1, 
Overall Design
Removed all reference to the timing of 
hemodialysis sessions
To allow flexibility in the timing of 
hemodialysis sessions to reflect the fact that the 
length and timing of hemodialysis sessions 
varies from participant to participant and from 
session to session
Section 4.1, 
Overall Design
Modified wording regarding dialysate sample 
collection, emphasizing collection at the end of 
every 30-minute interval from the start of 
hemodialysis until immediately before 
hemodialysis completion
To comply with standard practice regarding 
collection of dialysate sample for PK analysis
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Section Number 
and Name
Description of Change
Brief Rationale
Section 5.1, 
Inclusion Criteria
Inclusion criterion 1 - Removed the need for 
the investigator to consult with the Sponsor 
regarding inclusion of participants with RI that 
have stable, chronic medical or psychiatric 
conditions
To allow the investigators to determine 
eligibility
Section 5.1, 
Inclusion Criteria
Inclusion criterion 5 – Removed criterion for 
participants with ESRD on HD (Panel C) by 
making it ‘not applicable’
The calculated eGFR value is not relevant for
participants with ESRD on HD due to the 
fluctuation in the creatinine values between 
hemodialysis sessions 
Section 5.2, 
Exclusion Criteria
Exclusion criterion 2 – Modified exclusion of 
all participants with a history of renal 
transplant to only exclude participants with a 
functioning renal transplant in the past 5 years, 
taking transplant medication
To allow for enrollment of participants that 
have had a failed renal transplant
Section 5.2, 
Exclusion Criteria
Exclusion criterion 3 – Modified this criterion 
so that it only applies to participants in Panels 
A, B, and D
To reflect that this criterion should not apply to 
participants in Panel C, due to the fluctuation in 
the creatinine values between hemodialysis 
sessions
Section 5.2, 
Exclusion Criteria
Exclusion criterion 8 – Added ‘2021’ before 
CKD-EPIcr_R and added the word ‘equation’
after CKD-EPIcr_R
Correction of typos where ‘2021’ and ‘equation’
were previously omitted
Section 5.2, 
Exclusion Criteria
Exclusion criterion 21 – replaced all references 
to UDS with drug screen
To allow flexibility for sites to conduct a drug 
screen that is in alignment with their standard 
practice, given the participant population
Section 5.3.1.1, 
Diet Restrictions
Corrected ‘24-hr postdose’ to ‘4-hr postdose’
Correction of a typo
Section 5.3.2.1, 
Caffeine 
Restrictions
Corrected ‘Screening 2 Visit’ to ‘Screening 
Visit 2’
Correction of typos
Section 5.3.2.2, 
Alcohol 
Restrictions
Corrected ‘participations’ to ‘participants’
Corrected ‘Screening 2 Visit’ to ‘Screening 
Visit 2’
Correction of typos
Section 6.5, 
Concomitant 
Therapy
Removed the requirement to consult with the 
Sponsor regarding participants who are taking 
certain prescription medications to treat 
manifestations of renal disease or medications 
needed to treat stable diseases.
The list of example medications noted in that 
sentence are later noted as being allowed, 
therefore, there is no need to consult with the 
Sponsor.
Section 8.1.1, 
Informed Consent
Moved around wording between Section 8.1.1 
and 8.1.1.1
To provide further clarity
Section 8.1.1.1, 
General Informed 
Consent
Moved around wording between Section 
8.1.1.1 and 8.1.1
To provide further clarity
Section 8.1.6, 
Assignment of 
Screening Number
Updated ‘individual’ to ‘participant’
Deleted ‘initial’ prior to ‘Screening Visit’
Minor editorial changes
Section 8.1.8.1, 
Timing of Dose 
Administration
Removed all reference to the timing of 
hemodialysis sessions
To allow flexibility in the timing of 
hemodialysis sessions to reflect the fact that the 
length and timing of hemodialysis sessions 
varies from participant to participant and from 
session to session
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Section Number 
and Name
Description of Change
Brief Rationale
Section 8.3.2.1, 
Resting Vital Signs
Specified that Screening VS measurements will 
be single measurements
To emphasize that the Day 1 Predose Scheduled 
Time is the only timepoint when triplicate 
semirecumbent VS (HR, BP) and 12-lead ECGs 
are taken
Section 8.3.3, 
Electrocardiograms
Removal of word ‘telemetry’
Because only 12-lead ECGs are standardly 
taken for safety
Section 8.3.6, 
Photograph of 
Rash
Reference made to the Investigator Site Binder 
for additional rash guidance.
To provide the site(s) additional resources on 
how to manage participant rash
Section 8.6.2, 
Dialysate Samples 
for MK-0616 
and/or Metabolites
Removed ‘Plasma’ from Section Name
Correction of a typo where ‘Plasma’ was 
included in error
Section 8.11.3, 
Participants 
Discontinued From 
Study Intervention 
but Continuing to 
be Monitored in 
the Study
Replaced ‘a PCL’ with ‘an official memo’
Provide more flexibility in document(s) to be 
used to describe subset of study procedures to 
be completed for participants who discontinue 
treatment but continue to be monitored in the 
study
Section 10.2, 
Appendix 2: 
Clinical 
Laboratory Tests
Replaced reference to serum or urine drug 
screen with just drug screen
To allow flexibility for sites to conduct a drug 
screen that is in alignment with their standard 
practice, given the participant population
Section 10.8, 
Appendix 8: 
Approximate 
Blood Volume 
Tables
Table for Panel C: Removed row for 
‘Chemistry test for Second Creatinine 
Value…’ and re-calculated total blood volumes
This blood draw is no longer necessary, given 
the removal of the need to calculate baseline
eGFR values for participants in Panel C
Section 10.11, 
Appendix 11: 
Abbreviations
Removed ‘BDS’ and ‘UDS’
These abbreviations are no longer used in the 
document
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................30
2.2.1
Pharmaceutical and Therapeutic Background .............................................30
2.2.2
Information on Other Study-related Therapy ..............................................30
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................35
4.2.1.1
Efficacy Endpoints.............................................................................35
4.2.1.2
Safety Endpoints................................................................................35
4.2.1.3
Pharmacokinetic Endpoints ...............................................................35
4.2.1.4
Pharmacodynamic Endpoints.............................................................35
4.2.1.5
Planned Exploratory Biomarker Research.........................................35
4.2.1.5.1
Planned Genetic Analysis ........................................................35
4.2.1.6
Future Biomedical Research..............................................................36
4.2.2
Rationale for Control ...................................................................................36
4.3
Justification for Dose...........................................................................................36
4.4
Beginning and End-of-Study Definition ............................................................37
4.4.1
Clinical Criteria for Early Study Termination .............................................38
5
STUDY POPULATION ................................................................................................39
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................41
5.3
Lifestyle Considerations......................................................................................44
5.3.1
Meals and Dietary Restrictions....................................................................44
5.3.1.1
Diet Restrictions.................................................................................44
5.3.1.2
Fruit Juice Restrictions ......................................................................45
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................45
5.3.2.1
Caffeine Restrictions..........................................................................45
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5.3.2.2
Alcohol Restrictions...........................................................................46
5.3.2.3
Tobacco Restrictions..........................................................................46
5.3.3
Activity Restrictions ....................................................................................46
5.4
Screen Failures.....................................................................................................46
5.5
Participant Replacement Strategy......................................................................47
6
STUDY INTERVENTION............................................................................................48
6.1
Study Intervention(s) Administered...................................................................48
6.2
Preparation/Handling/Storage/Accountability .................................................50
6.2.1
Dose Preparation..........................................................................................50
6.2.2
Handling, Storage, and Accountability........................................................50
6.3
Measures to Minimize Bias: Randomization and Blinding..............................51
6.3.1
Intervention Assignment..............................................................................51
6.3.2
Stratification.................................................................................................51
6.3.3
Blinding........................................................................................................51
6.4
Study Intervention Compliance..........................................................................51
6.5
Concomitant Therapy..........................................................................................52
6.5.1
Rescue Medications and Supportive Care ...................................................53
6.6
Dose Modification ................................................................................................53
6.6.1
Stopping Rules.............................................................................................53
6.7
Intervention After the End of the Study............................................................54
6.8
Clinical Supplies Disclosure................................................................................54
6.9
Standard Policies..................................................................................................54
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................55
7.1
Discontinuation of Study Intervention...............................................................55
7.2
Participant Withdrawal From the Study...........................................................55
7.3
Lost to Follow-up .................................................................................................56
8
STUDY ASSESSMENTS AND PROCEDURES........................................................57
8.1
Administrative and General Procedures ...........................................................57
8.1.1
Informed Consent.........................................................................................57
8.1.1.1
General Informed Consent.................................................................58
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................58
8.1.2
Inclusion/Exclusion Criteria ........................................................................58
8.1.3
Participant Identification Card.....................................................................58
8.1.4
Medical History ...........................................................................................59
8.1.5
Prior and Concomitant Medications Review...............................................59
8.1.5.1
Prior Medications...............................................................................59
8.1.5.2
Concomitant Medications..................................................................59
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8.1.6
Assignment of Screening Number...............................................................59
8.1.7
Assignment of Treatment/Allocation Number.............................................59
8.1.8
Study Intervention Administration ..............................................................59
8.1.8.1
Timing of Dose Administration.........................................................60
8.1.9
Discontinuation and Withdrawal .................................................................60
8.1.9.1
Withdrawal From Future Biomedical Research ................................60
8.1.10
Participant Blinding/Unblinding..................................................................61
8.1.11
Domiciling ...................................................................................................61
8.1.12
Calibration of Equipment.............................................................................61
8.2
Efficacy/Immunogenicity Assessments ..............................................................61
8.3
Safety Assessments...............................................................................................61
8.3.1
Physical Examinations.................................................................................62
8.3.2
Vital Signs....................................................................................................62
8.3.2.1
Resting Vital Signs ............................................................................62
8.3.2.2
Orthostatic Vital Signs.......................................................................63
8.3.3
Electrocardiograms ......................................................................................63
8.3.4
Clinical Safety Laboratory Assessments .....................................................65
8.3.5
Pregnancy Testing........................................................................................65
8.3.6
Photograph of Rash......................................................................................65
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................65
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................66
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......68
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...68
8.4.4
Regulatory Reporting Requirements for SAE .............................................68
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................69
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................69
8.4.7
Events of Clinical Interest............................................................................69
8.5
Treatment of Overdose........................................................................................70
8.6
Pharmacokinetics.................................................................................................70
8.6.1
Blood Collection for Plasma MK-0616 and/or Metabolites........................70
8.6.2
Dialysate Samples for MK-0616 and/or Metabolites ..................................70
8.6.3
Urine Collection for Urinary MK-0616 and/or Metabolites........................70
8.7
Pharmacodynamics..............................................................................................70
8.8
Biomarkers ...........................................................................................................71
8.8.1
Planned Genetic Analysis Sample Collection..............................................71
8.9
Future Biomedical Research Sample Collection...............................................71
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8.10
Health Economics, Medical Resource Utilization and Health Economics......71
8.11
Visit Requirements...............................................................................................71
8.11.1
Screening......................................................................................................72
8.11.2
Treatment Period Visit.................................................................................72
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................72
8.11.4
Poststudy......................................................................................................72
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......72
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................73
9
KEY STATISTICAL CONSIDERATIONS ...............................................................75
9.1
Responsibility for Analyses.................................................................................76
9.2
Hypotheses/Estimation ........................................................................................76
9.3
Analysis Endpoints...............................................................................................76
9.3.1
Primary Endpoints .......................................................................................76
9.3.2
Secondary Endpoints ...................................................................................76
9.4
Analysis Populations............................................................................................77
9.4.1
All Participants as Treated (APaT) Population............................................77
9.4.2
Per-Protocol (PP) Population.......................................................................77
9.5
Statistical Methods...............................................................................................77
9.5.1
Statistical Methods for Pharmacokinetic Analyses......................................77
9.5.2
Statistical Methods for Safety Analyses ......................................................78
9.6
Interim Analyses ..................................................................................................79
9.7
Multiplicity ...........................................................................................................79
9.8
Sample Size and Power Calculations .................................................................79
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................80
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........80
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................80
10.1.2
Financial Disclosure.....................................................................................83
10.1.3
Data Protection.............................................................................................84
10.1.3.1
Confidentiality of Data ......................................................................84
10.1.3.2
Confidentiality of Participant Records...............................................84
10.1.3.3
Confidentiality of IRB/IEC Information............................................85
10.1.4
Publication Policy........................................................................................85
10.1.5
Compliance with Study Registration and Results Posting Requirements ...85
10.1.6
Compliance with Law, Audit, and Debarment ............................................86
10.1.7
Data Quality Assurance ...............................................................................86
10.1.8
Source Documents .......................................................................................87
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10.1.9
Study and Site Closure.................................................................................88
10.2
Appendix 2: Clinical Laboratory Tests..............................................................89
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................90
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................90
10.3.2
Definition of AE ..........................................................................................90
10.3.3
Definition of SAE ........................................................................................91
10.3.4
Additional Events Reported.........................................................................92
10.3.5
Recording AE and SAE ...............................................................................93
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................96
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................97
10.5
Appendix 5: Contraceptive Guidance................................................................98
10.5.1
Definitions....................................................................................................98
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................101
10.7
Appendix 7: Country-specific Requirements..................................................105
10.8
Appendix 8: Approximate Blood Volume Tables ...........................................106
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................108
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...110
10.11 Appendix 11: Abbreviations .............................................................................111
11
REFERENCES.............................................................................................................116
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LIST OF TABLES
Table 1
Renal Function Group..................................................................................33
Table 2
Study Interventions......................................................................................49
Table 3
Allocation of Participants to Treatment.......................................................51
Table 4
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ............................................................................67
Table 5
Pharmacokinetic (Blood/Urine) Collection Windows.................................73
Table 6
Protocol-required Safety Laboratory Assessments......................................89
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LIST OF FIGURES
Figure 1
Study Design................................................................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Single-Dose Clinical Study to Evaluate the 
Pharmacokinetics of MK-0616 in Participants with Varying Degrees of Renal Impairment
Short Title: MK-0616 Renal Impairment Study 2
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in male and female participants, 18 to 85 years of 
age (inclusive), with moderate RI, severe RI, ESRD on HD, and healthy adults.
Primary Objective
Primary Endpoint
To compare the plasma PK of MK-0616 
following a single 20 mg dose in 
participants on a background of statin 
therapy with varying degrees of renal 
impairment (moderate, severe, ESRD) to 
those of healthy mean matched control 
participants on a background of statin 
therapy.
Estimation: MK-0616 AUC0-inf following 
a single dose of MK-0616 administered to 
participants with varying degrees of renal 
impairment (moderate, severe, ESRD) will 
be estimated and compared to MK-0616 
AUC0-inf when administered to healthy 
mean matched control participants.
Plasma MK-0616 AUC0-inf, AUClast, 
Cmax, Tmax, t1/2, CL/F, and Vz/F
Secondary Objectives
Secondary Endpoints
To investigate the extent MK-0616 is 
removed by hemodialysis.
Estimation: The extent to which MK-0616 
is removed from the plasma by 
hemodialysis [eg, CLD, CD, AED, AED
(%dose)] will be estimated.
CLD, CD, AeD, AeD (%dose)
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PRODUCT: MK-0616
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10-AUG-2023
To compare the urine PK of MK-0616 
following a single dose of MK-0616 to 
participants with varying degrees of renal 
impairment, where possible, to those of 
healthy matched control participants.
Estimation: MK-0616 Ae0-24, Fe, and CLr 
following a single dose of MK-0616 
administered to participants with varying 
degrees of renal impairment, as appropriate, 
will be estimated and compared to those 
estimated in healthy mean matched control 
participants.
Urine MK-0616 Ae0-24, Fe, and CLr
To evaluate the safety and tolerability of the 
administration of a single dose of MK-0616 
in participants with varying degrees of renal 
impairment.
Adverse Events, Discontinuations due to 
Adverse Events
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Hypercholesterolaemia
Population
Participants with varying degrees of renal 
impairment and Healthy Participants
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 1 year from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
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Number of Participants:
Up to 36 participants will be allocated as described in Section 9.4.
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 RI 
Group
MK-0616
20 mg
20 mg
Oral
Panel A: 
Single dose 
on Day 1
Test Product
Severe RI 
Group
MK-0616
20 mg
20 mg
Oral
Panel B: 
Single dose 
on Day 1
Test Product
ESRD on HD 
Group
MK-0616
20 mg
20 mg
Oral
Panel C: 
Single Dose 
on Day 1 of 
Periods 1 and 
2
Test Product
Healthy 
Control 
Group
MK-0616
20 mg
20 mg
Oral
Panel D: 
Single Dose 
on Day 1
Test Product
Total Number of Intervention Groups/Arms
4
Duration of Participation
Each participant with moderate renal 
impairment, severe renal impairment, and 
each healthy participant will participate in 
the study for approximately 6 weeks from 
the time the participant provides 
documented informed consent through the 
final contact. 
Each participant with end-stage renal 
disease on hemodialysis will participate in 
the study for approximately 8 weeks from 
the time the participant provides 
documented informed consent through the 
final contact.
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical, and study oversight 
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 Design
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1.3
Schedule of Activities
Schedule of Activities for Panels A, B, and D
Panels A, B, and D
Study Period:
Screening
Intervention (Period 1)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
~15
Scheduled Hour
Screen-
ing 
Visit 1
Screen-
ing 
Visit 2b
Check-
In
Pre-
dose
0
0.5
1
1.5
2
4
8
12 24 36 48 72 120 168 240
Post-
study
Administrative/Study 
Procedures
Informed Consent
X
Sec. 5.1, 
8.1.1.1
Informed Consent 
for FBR
X
Sec. 5.1, 
8.1.1.2
Inclusion/
Exclusion Criteria
Xc
Xc
Xc
Review to
occur at 
Screening and 
after predose 
procedures.
Sec. 5.1, 5.2, 
8.1.2
Participant ID Card
X
Sec. 8.1.3
Medical History
X
X
Includes 
history of 
illicit drug, 
alcohol, 
tobacco, and 
caffeine use. 
Sec. 8.1.4
Prior/
Concomitant 
Medication Review
X---------------------------------------------------------------------------------------------------------------------------------------X
Sec. 5.2, 6.5, 
8.1.5
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Panels A, B, and D
Study Period:
Screening
Intervention (Period 1)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
~15
Scheduled Hour
Screen-
ing 
Visit 1
Screen-
ing 
Visit 2b
Check-
In
Pre-
dose
0
0.5
1
1.5
2
4
8
12 24 36 48 72 120 168 240
Post-
study
Assignment of 
Screening Number
X
Sec. 8.1.6
Assignment of 
Treatment/
Allocation Number
X
Within 24 
hours prior to 
study 
intervention 
administration. 
Sec. 5.5, 8.1.7
Study Intervention 
Administration
X
Sec. 8.1.8
Participant Visit to 
CRU
X
Xc
X
X
X
X
X
X
Domicilingd
X-------------------------------------------------------------------------------X
Sec. 8.1.11
Standard Mealse
X----------------------------------------------------X
Sec. 5.3.1
Safety Procedures
Full physical 
examination
X
Xf
X
X
Sec. 8.3.1
Height
X
Sec. 8.3.1
Weight
X
X
BMI and BSA 
to be assessed
only at 
Screening. 
Sec. 8.3.1
Semirecumbent VS 
(HR, BP)
X
Xg
X
X
X
Sec. 8.3.2, Sec. 
8.3.2.1
VS (RR, BT)
X
Xg
X
X
X
Sec. 8.3.2, Sec. 
8.3.2.1
Orthostatic VS (HR, 
BP)
X
Xg
X
X
Sec. 8.3.2.2
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Panels A, B, and D
Study Period:
Screening
Intervention (Period 1)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
~15
Scheduled Hour
Screen-
ing 
Visit 1
Screen-
ing 
Visit 2b
Check-
In
Pre-
dose
0
0.5
1
1.5
2
4
8
12 24 36 48 72 120 168 240
Post-
study
12-lead ECG
X
Xg
X
X
X
Sec. 8.3.3
Serum or Urine hCG 
– POCBP only
X
Xf
X
Result to be 
reviewed prior 
to dosing on 
Day 1. Sec. 
5.1, Sec. 8.3.5, 
Appendix 2
Serum FSH –
postmenopausal 
PONCBP only
X
Appendix 2
HIV, hepatitis B and 
C screen (per site 
SOP)
X
Sec. 8.3.4, 
Appendix 2
Drug Screen (per 
site SOP)
X
Xf
Sec. 8.3.4, 
Appendix 2
Hematology/
Chemistry
X
Xc
Xc,f
X
X
Fast for at least 
8 hours prior 
to sample 
collection. Sec. 
8.3.4, 
Appendix 2
Urinalysis
X
Xf
X
X
Sec. 8.3.4
AE/SAE review
X---------------------------------------------------------------------------------------------------------------------------------------X
Sec. 8.4
Pharmacokinetics
Blood for Plasma 
MK-0616 and/or 
Metabolites Assay
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Sec. 8.6.1
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10-AUG-2023
Panels A, B, and D
Study Period:
Screening
Intervention (Period 1)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
~15
Scheduled Hour
Screen-
ing 
Visit 1
Screen-
ing 
Visit 2b
Check-
In
Pre-
dose
0
0.5
1
1.5
2
4
8
12 24 36 48 72 120 168 240
Post-
study
Urine for Urinary 
MK-0616 and/or 
Metabolites Assayi
X
X-----------------------------X----X---X---X--------X
Sec. 8.6.3
Pharmacodynamics
Blood for Plasma 
for PCSK9 (free) 
Assay
X
X
X
X
Xh
Sec. 8.7
Biomarkers
Blood for Genetic 
Analysis
X
Collect
predose on 
Day 1, but may 
be collected at 
the next 
scheduled 
blood draw, if 
needed from 
enrolled 
participants 
only. Sec. 8.8.
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AE=adverse event; BMI=body mass index; BP=blood pressure; BSA=body surface area; BT=body temperature; CKD-EPI=Chronic Kidney Disease Epidemiology 
Collaboration; CRU=clinical research unit; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FBR=future biomedical research; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HR=heart rate; ID=identification; PCSK9=proprotein convertase subtilisin/kexin 
type 9; POCBP=participant of childbearing potential; PONCBP=participant of non-childbearing potential; RR=respiratory rate; SAE=serious adverse event; SOP=standard 
operating procedure; VS=vital signs.
a
Poststudy Visit should occur approximately 14 days postdose. If the visit occurs prior to 14 days postdose, verbal contact should be made to assess for AEs 14 days 
postdose.
b
Screening Visit 2 is optional. If Screening Visit 2 is conducted, it must occur at least 72 hours after Screening Visit 1.
c
Baseline eGFR will be obtained twice (at least 72 hours apart as part of participant screening) based on the 2021 CKD-EPI Creatinine (CKD-EPIcr_R) equation. This 
second baseline eGFR may be obtained at the optional Screening Visit 2 or on Day -1 within 24 hours of dosing (Predose Day 1 chemistry labs) but data must be available 
before dosing on Day 1 to ensure eligibility.
d
Participants will report to the CRU on Day -1, at the time indicated by the CRU (~24 hours prior to dosing on Day 1). Participants will be discharged after completion of the 
48-hour postdose procedures on Day 3.
e
A standard meal will be provided as follows relative to study intervention administration: breakfast at least 30 minutes postdose, lunch at approximately 4 hours postdose. 
After the 4-hour postdose standard meal is completed, subsequent meals and snacks will be unrestricted in terms of caloric content, composition, and timing.
f
Predose full physical examination, Drug Screen, serum or urine hCG for POCBP only, hematology/chemistry, and urinalysis may be conducted/collected upon admission to 
the CRU on Day -1 but within 24 hours of study drug administration. Results must be back prior to study intervention administration to confirm eligibility.
g
Predose VS and 12-lead ECG to be measured within 3 hours prior to study intervention administration. Semirecumbent predose VS (HR and BP) and ECG measurements 
will be done in triplicate. All other scheduled timepoints and measurements, including Screening VS and Screening 12-lead ECG, and Predose RR and BT, will be single 
measurements.
h
The sample drawn at the Poststudy Visit corresponds to the Day 1 336 hour postdose sample.
i
Urine samples will be collected at predose (baseline) and at the following intervals postdose: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, and 24 to 48 hours.
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Schedule of Activities for Panel C
All Participants in Panel C
Study Period:
Screening
Intervention (Periods 1 and 2)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
Scheduled Hour
Screening Visit 1
Check-
In
Pre-
dose
0
0.5
1
1.5
2
3
4
8
12
24 36 48 72 120 168 240
Post-
study
Administrative/Study 
Procedures
Informed Consent
X
Sec. 5.1, 8.1.1.1
Informed Consent 
for FBR
X
Sec. 5.1, 8.1.1.2
Inclusion/Exclusion 
Criteria
X
X
Review to occur at 
Screening and after 
predose procedures 
in both periods. 
Sec. 5.1, 5.2, 8.1.2
Participant ID Card
X
Sec. 8.1.3
Medical History
X
X
Includes history of 
illicit drug, alcohol, 
tobacco, and 
caffeine use. Sec. 
8.1.4
Prior/Concomitant 
Medication Review
X---------------------------------------------------------------------------------------------------------------------------------X
Sec. 5.2, 6.5, 8.1.5
Assignment of 
Screening Number
X
Sec. 8.1.6
Assignment of 
Treatment/
Allocation Number
X
To be assigned 
within 24 hours 
prior to study 
intervention 
administration in 
Period 1 only. Sec. 
5.5, 8.1.7
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All Participants in Panel C
Study Period:
Screening
Intervention (Periods 1 and 2)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
Scheduled Hour
Screening Visit 1
Check-
In
Pre-
dose
0
0.5
1
1.5
2
3
4
8
12
24 36 48 72 120 168 240
Post-
study
Study Intervention 
Administration
X
After at least an 
8-hour overnight 
fast; to be dosed 
immediately 
following HD 
session in Period 1 
and ~ 0.5 hours 
prior to HD in 
Period 2. Sec. 8.1.8
Participant Visit to 
CRU
X
X
X
X
X
X
X
Domicilingb
X------------------------------------------------------------------------X
Sec. 8.1.11
Standard Mealsc
X-----------------------------------------------X
Starting at least 30 
minutes after study 
intervention 
administration. Sec. 
5.3.1
On-Site HD –
Period 1 Only
X-----X
X
X
HD to last a 
minimum of 3 
hours on Days 1, 4, 
and 6. Day 1 to 
occur on either a 
Friday or Saturday. 
Sec. 4.1
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All Participants in Panel C
Study Period:
Screening
Intervention (Periods 1 and 2)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
Scheduled Hour
Screening Visit 1
Check-
In
Pre-
dose
0
0.5
1
1.5
2
3
4
8
12
24 36 48 72 120 168 240
Post-
study
On-Site HD –
Period 2 Only
X---------------------X
X
X
HD starting ~ 0.5 
hours postdose on 
Day 1. HD to last a 
minimum of 3 
hours on Days 1, 4, 
and 6. Day 1 to 
occur on either a 
Friday or Saturday. 
Sec. 4.1
Safety Procedures
Full physical 
examination
X
Xd
X
X
Sec. 8.3.1
Height
X
Sec. 8.3.1
Weight
X
X
BMI to be assessed 
only at Screening. 
Sec. 8.3.1
Semirecumbent VS 
(HR, BP)
X
Xe
X
X
X
Sec. 8.3.2, Sec. 
8.3.2.1
VS (RR, BT)
X
Xe
X
X
X
Sec. 8.3.2, Sec. 
8.3.2.1
Orthostatic VS (HR, 
BP)
X
Xe
X
X
Sec. 8.3.2.2
12-lead ECG
X
Xe
X
X
X
Sec. 8.3.3
Serum or Urine hCG 
– POCBP only
X
Xd
X
Result to be 
reviewed prior to 
dosing on Day 1, 
both periods. Sec. 
5.1, Sec. 8.3.5, 
Appendix 2
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All Participants in Panel C
Study Period:
Screening
Intervention (Periods 1 and 2)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
Scheduled Hour
Screening Visit 1
Check-
In
Pre-
dose
0
0.5
1
1.5
2
3
4
8
12
24 36 48 72 120 168 240
Post-
study
Serum FSH –
postmenopausal 
PONCBP only
X
Appendix 2
HIV, hepatitis B and 
C screen (per site 
SOP)
X
Sec. 8.3.4, 
Appendix 2
Drug Screen (per 
site SOP)
X
Xd
Sec. 8.3.4, 
Appendix 2
Hematology/
Chemistry
X
Xd
X
X
Fast for at least 8 
hours prior to 
sample collection. 
Sec. 8.3.4, 
Appendix 2
Urinalysis
X
Xd
X
X
Only if participant 
is able to produce 
urine. Sec. 8.3.4
AE/SAE review
X--------------------------------------------------------------------------------------------------------------------------------X
Sec. 8.4
Pharmacokinetics
Blood for Plasma 
MK-0616 and/or 
Metabolites Assayf
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
Xg
Sec. 8.6.1
Dialysate Samples 
for MK-0616 and/or 
Metabolites Assay –
Period 2 Onlyh
X--------------------------------Xh
Sec. 4.1, Sec. 8.6.2
Urine for Urinary 
MK-0616 and/or 
Metabolites Assayi
X
X---------------------------X--X---X---X--------X
Sec. 8.6.3
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All Participants in Panel C
Study Period:
Screening
Intervention (Periods 1 and 2)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
Scheduled Hour
Screening Visit 1
Check-
In
Pre-
dose
0
0.5
1
1.5
2
3
4
8
12
24 36 48 72 120 168 240
Post-
study
Pharmacodynamics
Blood for Plasma 
for PCSK9 (free) 
Assay
X
X
X
X
Xi
Sec. 8.7
Biomarkers
Blood for Genetic 
Analysis
X
Collect predose on 
Day 1 of Period 1 
only, but may be 
collected at the next 
scheduled blood 
draw, if needed 
from enrolled 
participants only. 
Sec. 8.8.
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All Participants in Panel C
Study Period:
Screening
Intervention (Periods 1 and 2)
Post-
studya Notes
Scheduled Day
Up to -28
-1
1
2
3
4
6
8
11
Scheduled Hour
Screening Visit 1
Check-
In
Pre-
dose
0
0.5
1
1.5
2
3
4
8
12
24 36 48 72 120 168 240
Post-
study
AE=adverse event; BMI=body mass index; BP=blood pressure; BSA=body surface area; BT=body temperature; CKD-EPI=Chronic Kidney Disease Epidemiology 
Collaboration; CRU=clinical research unit; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FBR=future biomedical research; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; HD=hemodialysis; HIV=human immunodeficiency virus; HR=heart rate; ID=identification; PCSK9=proprotein convertase 
subtilisin/kexin type 9; PK=pharmacokinetic; POCBP=participant of childbearing potential; PONCBP=participant of non-childbearing potential; RR=respiratory rate;
SAE=serious adverse event; SOP=standard operating procedure; VS=vital signs.
a
Poststudy Visit should occur approximately 14 days postdose. If the visit occurs prior to 14 days postdose, verbal contact should be made to assess for AEs 14 days 
postdose.
b
Participants will report to the CRU on Day -1, at the time indicated by the CRU (~24 hours prior to dosing on Day 1). Participants will be discharged after completion of the 
48-hour postdose procedures on Day 3.
c
A standard meal will be provided as follows relative to study intervention administration: breakfast at least 30 minutes postdose, lunch at approximately 4 hours postdose. 
After the 4-hour postdose standard meal is completed, subsequent meals and snacks will be unrestricted in terms of caloric content, composition, and timing.
d
Predose full physical examination, Drug Screen, serum or urine hCG (POCBP only), hematology/chemistry, and urinalysis may be conducted/collected upon admission to 
the CRU on Day -1 but within 24 hours of study drug administration. Results must be back prior to study intervention administration to confirm eligibility.
e
Predose VS and 12-lead ECG to be measured within 3 hours prior to study intervention administration. Semirecumbent predose VS (HR and BP) and ECG measurements 
will be done in triplicate. All other scheduled timepoints and measurements, including Screening VS and Screening 12-lead ECG, and Predose RR and BT, will be single 
measurements.
f
In addition to the PK sampling timepoints noted, one Pre-HD PK sample and one Post-HD PK sample must be drawn in Period 1 on Study Days 4 and 6 and one Pre-HD PK 
sample and one Post-HD PK sample must be drawn in Period 2 on Study Days 1, 4, and 6.
g
The sample drawn at the Poststudy Visit corresponds to the Period 2 Day 1 336 hour postdose sample.
h
The duration of the HD session will vary from participant to participant, based on individual needs, but should last at minimum 3 hours. A Pre-HD dialysate sample is to be 
collected at the start of HD. During the HD session, dialysate samples to be collected at the end of every 30-minute interval as follows: 0 to 0.5 hours, 0.5 to 1 hour, 1 to 1.5 
hours, 1.5 to 2 hours, 2 to 2.5 hours, 2.5 to 3 hours, 3 to 3.5 hours, 3.5 to 4 hours, 4 to 4.5 hours, etc…from the start of HD until immediately before HD completion.
i
Urine samples will be collected at predose (baseline) and at the following intervals postdose: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, and 24 to 48 hours, 
only if the participant can produce urine.
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2
INTRODUCTION
2.1
Study Rationale
MK-0616 is a small molecule cyclic peptide inhibitor of PCSK9 being developed for the 
treatment of hypercholesterolemia. MK-0616 is a low clearance drug which is excreted as 
unchanged parent peptide in rat and cynomolgus monkeys predominately by renal clearance. 
As such, this study is being conducted to assess the impact of moderate renal impairment, 
severe renal impairment, and end-stage renal disease on the PK of MK-0616.
2.2
Background
Refer to the IB for detailed background information on MK-0616.
2.2.1
Pharmaceutical and Therapeutic Background
MK-0616 is a cyclic peptide inhibitor of PCSK9 being developed for reduction of LDL-C.
2.2.2
Information on Other Study-related Therapy
There is no other study-related therapy 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 following objectives will be evaluated in male and female participants, 18 to 85 years of 
age (inclusive), with moderate RI, severe RI, ESRD on HD, and healthy adults.
Primary Objective
Primary Endpoint
To compare the plasma PK of MK-0616 
following a single 20 mg dose in 
participants on a background of statin 
therapy with varying degrees of renal 
impairment (moderate, severe, ESRD) to 
those of healthy mean matched control 
participants on a background of statin 
therapy.
Estimation: MK-0616 AUC0-inf following 
a single dose of MK-0616 administered to 
participants with varying degrees of renal 
impairment (moderate, severe, ESRD) will 
be estimated and compared to MK-0616 
AUC0-inf when administered to healthy 
mean matched control participants.
Plasma MK-0616 AUC0-inf, AUClast, 
Cmax, Tmax, t1/2, CL/F, and Vz/F
Secondary Objectives
Secondary Endpoints
To investigate the extent MK-0616 is 
removed by hemodialysis.
Estimation: The extent to which MK-0616 
is removed from the plasma by 
hemodialysis [eg, CLD, CD, AED, AED
(%dose)] will be estimated.
CLD, CD, AeD, AeD (%dose)
To compare the urine PK of MK-0616 
following a single dose of MK-0616 to 
participants with varying degrees of renal 
impairment, where possible, to those of 
healthy matched control participants.
Estimation: MK-0616 Ae0-24, Fe, and CLr 
following a single dose of MK-0616 
administered to participants with varying 
degrees of renal impairment, as appropriate, 
will be estimated and compared to those 
estimated in healthy mean matched control 
participants.
Urine MK-0616 Ae0-24, Fe, and CLr
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To evaluate the safety and tolerability of the 
administration of a single dose of MK-0616 
in participants with varying degrees of renal 
impairment.
Adverse Events, Discontinuations due to 
Adverse Events
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To explore the relationship between genetic 
variation and response to the treatment 
administered. Variation across the human 
genome will be analyzed for association 
with clinical data collected in this study
Germline genetic variation and association 
to clinical data collected in this study
To explore the % change in plasma free 
PCSK9 from baseline following 
administration of a single oral 20 mg dose 
of MK-0616 in participants on a 
background of statin therapy with varying 
degrees of renal impairment (moderate, 
severe, ESRD), compared to healthy mean 
matched control participants on a 
background of statin therapy.
Percent reduction in free PCSK9 from 
baseline
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4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, parallel-group, multi-site, open-label study of MK-0616 in adult
male and female participants with moderate renal impairment (Panel A; n=8), severe renal 
impairment (Panel B; n=8), end-stage renal disease on HD (Panel C; n=8), and healthy mean 
matched control participants (Panel D; n=8 to 12), all on a background of statin therapy. 
Healthy control participants will be matched for mean age (± 15 years) and BMI 
(± 3.5 kg/m2) of participants with RI. In addition, the ratio of males and females of the 
healthy participants will be generally matched to the ratio of males and females of RI 
participants. Enrollment into the healthy mean matched control panel (Panel D) will begin 
once 8 participants with RI have been enrolled across all RI panels (8 participants from 
Panels A, B, and C combined). Up to an additional 4 healthy participants may be enrolled as 
needed, to maintain the mean-matching of the healthy participant panel to the RI panels. If 
additional healthy matched control participants are enrolled (beyond the minimum 
8 participants), the overall ratio of males and females in the healthy panel should be as close 
as possible to the overall ratio of males and females in the RI panels. 
The study will evaluate safety, PK, and pharmacodynamic effects of a single oral 20 mg dose 
of MK-0616. The dose of MK-0616 will be administered in a fasted state (ie, following an 
overnight fast of at least 8 hours, with no food for at least 30 minutes following the oral 
dose).
Assignment to a renal function group will be as shown in Table 1:
Table 1
Renal Function Group
Panel
Renal Impairment Stage
n
eGFR (mL/min)a,b
A
Moderate
8
≥ 30 but ≤ 60c
B
Severe
8
≥ 15 but < 30 not on dialysis
C
ESRD requiring HD
8
Not applicable
D
Healthy
8 to 12d
≥ 90
BSA=body surface area; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; cr=creatinine; 
eGFR=estimated glomerular filtration rate; ESRD=end-stage renal disease; HD=hemodialysis
a
eGFR based on the 2021 CKD-EPI Creatinine (CKD-EPIcr_R) equation that does not require use of race. Baseline 
eGFR will be obtained twice (at least 72 hours apart as part of participant screening) and the mean of the 2 values 
will be used for group assignment. The second baseline eGFR sample may be obtained on Day -1 but within 24 
hours of study intervention administration, as long as data are available in time to confirm eligibility.
b
eGFR criteria will use de-indexed values to correct for participant BSA. To convert indexed eGFR expressed as 
mL/min/1.73 m2, this value will be divided by 1.73 and multiplied by participant BSA.
c
Reasonable efforts will be made to enroll at least 2 participants in the moderate renal impairment group who have 
eGFR values of 30 to 40 mL/min.
d
May need to enroll more than 8 to enable mean matching of the healthy mean match controls to the participants with 
RI.
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Participants with moderate RI (Panel A), participants with severe RI (Panel B), and healthy 
mean matched control participants (Panel D), will receive a single oral dose of 20 mg 
MK-0616, followed by PK sampling until 48 hours postdose in the clinic. There will be 
additional outpatient visits through 240 hours postdose for PK assessments and a follow up 
visit approximately 14 days postdose. Safety will be monitored throughout the study by 
repeated clinical and laboratory evaluations.
ESRD participants (Panel C), will receive a single oral dose of 20 mg MK-0616 on 2 
separate occasions. In Period 1 on Day 1, ESRD participants will receive a single oral dose of 
20 mg MK-0616 immediately following completion of the scheduled HD, followed by PK 
sampling until 48 hours postdose in the clinic. There will be additional outpatient visits 
through 240 hours postdose for PK assessments and HD sessions. For participants following 
a Monday, Wednesday, Friday HD schedule, MK-0616 will be administered immediately 
following the Friday HD session (Study Day 1). For participants following a Tuesday, 
Thursday, Saturday HD schedule, study intervention will be administered immediately 
following their Saturday HD session (Study Day 1). The participant’s next scheduled HD 
sessions will occur either Monday or Tuesday (Study Day 4) and either Wednesday or 
Thursday (Study Day 6). A PK sample for MK-0616 analysis will be collected prior to HD
(Pre-HD) and after HD (Post-HD) on Study Days 4 and 6. There will be a washout period of 
at least 14 days between MK-0616 administrations in each period, due to the need to collect 
PK samples out to 240-hours postdose in each period and to stay on the HD schedule.
In Period 2 on Day 1, ESRD participants (Panel C) will receive a single oral dose of 20 mg 
MK-0616 approximately 0.5 hours prior to their scheduled HD followed by PK sampling 
until 48 hours postdose in the clinic. There will be additional outpatient visits through 240 
hours postdose for PK assessments of MK-0616 and HD sessions. For participants following 
a Monday, Wednesday, Friday HD schedule, MK-0616 will be administered approximately 
0.5 hours prior to the Friday HD session (Study Day 1). For participants following a 
Tuesday, Thursday, Saturday HD schedule, MK-0616 will be administered approximately 
0.5 hours prior to the Saturday HD session (Study Day 1). The HD session should initiate 
immediately following the 0.5-hour PK blood draw. The participant’s next scheduled HD 
sessions will occur either Monday or Tuesday (Study Day 4) and either Wednesday or 
Thursday (Study Day 6). A PK sample for MK-0616 analysis will be collected prior to HD
(Pre-HD) and after HD (Post-HD) on Study Days 1, 4, and 6. A Pre-HD dialysate sample 
will be collected at the start of HD. During the HD session, dialysate samples will be 
collected at the end of every 30-minute interval from the start of HD until immediately 
before HD completion, for MK-0616 analysis.
Because this is a Phase 1 assessment of MK-0616 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.
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4.2
Scientific Rationale for Study Design
MK-0616 is likely to be used in patients with varying degrees of RI. The primary purpose of 
this trial is to understand the impact of moderate RI, severe RI and ESRD on the PK of 
MK-0616.
This study will evaluate and compare MK-0616 PK 
in participants with moderate RI, severe RI and ESRD patients requiring HD to healthy 
control participants with normal renal function that are reasonably matched to the mean 
demographic parameters of participants with varying degrees of RI to control for the 
influence of covariates. In addition, the impact of HD on MK-0616 PK will also be assessed.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
No efficacy endpoints will be evaluated.
4.2.1.2
Safety Endpoints
Safety will be assessed by monitoring AEs, physical examinations, VS, 12-lead ECGs, and 
laboratory safety tests (chemistry, hematology, urinalysis). Based on the data from preclinical 
safety studies and clinical studies to date, no specific concerns or target organ toxicities have 
been identified. Therefore, standard safety monitoring has been deemed adequate.
4.2.1.3
Pharmacokinetic Endpoints
Pharmacokinetic parameters selected for evaluation in this study will effectively inform the 
pharmacokinetic profile of MK-0616 and include the following: AUC0-inf, AUClast, Cmax, 
Tmax, t1/2, CL/F, Vz/F, CLr (renal clearance), Ae (amount excreted).
4.2.1.4
Pharmacodynamic Endpoints
Reduction of free PCSK9 relative to baseline will be included as an exploratory endpoint. 
Inhibition of PCSK9 results in reduction of plasma LDL-C, therefore the percent reduction of 
plasma LDL-C from baseline/pre-dose levels will be used as a pharmacodynamic endpoint.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
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tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for Control
Healthy participants with normal renal function, matched by mean age, mean BMI, and sex, 
will serve as the control group. Comparison of data from participants with renal impairment 
to data from healthy participants will effectively inform the differences of safety and PK 
between the groups.
4.3
Justification for Dose
The proposed clinical dose for MK-0616 is 20 mg taken once daily, which will be evaluated 
in this study. Single doses of 20 mg MK-0616 will be sufficient to characterize the impact of 
RI on the PK of MK-0616.
In healthy controls, a single oral dose of 20 mg is anticipated to result in plasma AUC0-inf of 
This projection is based upon observed 18 to 20 mg fasted PK in 
normal healthy participants from previous Phase 1 studies (ie, P005, P009), with the 
additional assumption of
 With above 
assumptions regarding severe/ESRD, the MK-0616 AUC0-inf could be up to
with a 20 mg single dose. In the FIH study (P001), single doses of 300 mg 
were associated with mean plasma AUC0-inf of 2260 nM*hr and were well-tolerated, so it is 
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anticipated that existing clinical safety is sufficient to justify the 20 mg dose in this study 
across all renally impaired groups.
In the Phase 2b study, plasma levels of
The target population for MK-0616 will be on 
standard of care/statin therapy, and a large proportion of renally impaired patients are 
receiving concomitant medications, including statins.
Participants will not be limited to any particular type of statin (atorvastatin, rosuvastatin, etc), 
which is a similar approach as used in previous studies with MK-0616. In P008 (Ph2b study), 
at the 18 mg dose,
 Therefore, we do not plan to limit or restrict 
participants to a particular dose level (ie, high/medium/low intensity statin).
As this is a Phase 1 assessment of MK-0616 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
1. Be in good health based on medical history, physical examination, VS measurements, 
and ECGs performed before allocation, with the exception of RI for participants in Panels 
A, B, and C. Participants with RI that have stable, chronic medical or psychiatric 
conditions, including but not limited to hypertension, hypercholesterolemia, diabetes 
mellitus, hyper- or hypothyroidism, gout, and chronic anxiety or depression may be 
included at the discretion of the investigator.
Appendix 9 provides a table of the 12-Lead Electrocardiogram Evaluation Criteria, to be 
used for healthy participants only (Panel D).
2. Be in good health based on laboratory safety tests obtained at the screening visit and prior 
to study intervention administration (Period 1 only for ESRD participants, Panel C), 
with the exception of RI for participants in Panels A, B, and C. 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.
3. BMI ≥ 18 kg/m2 and ≤40 kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to 
the nearest whole number. BMI = weight (kg)/height (m)2. 
For participants with ESRD (Panel C), dry weight (body weight after hemodialysis) 
should be used for BMI calculation.
Healthy Mean Matched Controls (Panel D): BMI must be ± 3.5 kg/m2 of the mean 
BMI of participants within the RI panels.
4. Be on a stable dose of any statin therapy defined as: no changes to dose or type of statin 
therapy for at least 2 months prior to Screening Visit 1 and participant anticipates no 
changes to statin therapy throughout the study until the poststudy visit.
5. Has a baseline eGFR as follows based on 2021 CKD-EPI Creatinine equation [Inker, L. 
A., et al 2021] [Delgado, C., et al 2021]:
For participants with moderate RI (Panel A): ≥30 mL/min but ≤ 60 mL/min;
For participants with severe RI (Panel B): ≥15 mL/min but < 30 mL/min (but not on 
dialysis);
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For participants with ESRD on HD (Panel C): not applicable;
2021 CKD-EPI Creatinine (CKD-EPIcr_R) Equation:
eGFR = 142 X min(Scr/k,1)α X max(Scr/k,1)-1.200 X 0.9938age X 1.012 [if female]
where Scr is serum creatinine, k is 0.7 for females and 0.9 for 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.
Baseline eGFR will be obtained twice (at least 72 hours apart as part of participant 
screening), and the mean of the two values will be used. The second baseline eGFR 
sample may be obtained at the time of check-in as long as the result is available in time to 
determine eligibility prior to study intervention administration.
eGFR values indexed to BSA 1.73 m2 will be de-indexed by dividing the value obtained 
from the equation by 1.73 and then multiplying by participant BSA.
6. For participants with ESRD (Panel C), participant has ESRD maintained on stable 
outpatient regimen at a healthcare center for > 3 months prior to dosing, using an 
established and normally functioning, regular flow, uninfected mature AV fistula or AV 
graft and skin consistent with standard HD access injuries, and HD stability defined as 
Kt/V ≥ 1.2 within 3 months prior to the initial administration of the study intervention.
7. For participants with ESRD (Panel C), participant is on a HD regimen at least 3 times 
per week for a minimum of 3 hours per dialysis session, using a complication-free well-
maintained AV fistula or AV graft, expected and planning to continue this during the 
study and at least up to the poststudy visit.
Demographics
8. Is an individual of any sex/gender, from 18 years to 85 years of age inclusive, at the time 
of providing the informed consent.
Healthy Mean Matched Controls (Panel D): Age must be within ± 15 years of the 
mean age of participants within the RI panels.
Female Participants
9. 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
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•
Is a POCBP and:
-
Uses an acceptable contraceptive method, or is abstinent from penile-vaginal 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 8 weeks after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
POCBPs should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions are more stringent 
than the requirements above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the 
first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
10. 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.
Other Inclusion Criteria
11. Willing to comply with the study restrictions (see Section 5.3 for a complete summary of 
study restrictions).
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. History or presence of renal artery stenosis.
2. Had a functioning renal transplant in the past 5 years and is taking transplant medication.
3. Participants in Panels A, B and D: Has rapidly fluctuating renal function as determined 
by historical measurements. Rapidly fluctuating renal function is defined as > 30 % 
difference between two measurements of eGFR taken at least 72 hours apart as part of 
participant screening.
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4. Has a history of gastrointestinal disease which might affect food and drug absorption, as 
determined by the investigator, or has had gastric bypass or similar surgery. For example, 
recurrent vomiting, inflammatory bowel disease, chronic intestinal disease accompanied 
by a disturbance in digestion and absorption, Roemheld’s syndrome, severe hernia, etc.
5. Healthy Participants (Panel D): History of clinically significant endocrine, GI, 
cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, 
or major neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (eg, uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
Participants with RI (Panels A, B, and C): History of any illness, other than RI, 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.
6. Mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
7. 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.
8. Healthy Participants (Panel D): Estimated eGFR ≤90 mL/min based on the 2021 
CKD-EPIcr_R equation (see Section 5.1 for equation and de-indexing values to correct 
for participant BSA).
9. History of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or 
has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or nonprescription drugs or food.
10. Has a known hypersensitivity to the active substance or any of the excipients of the study 
drug.
11. Has received an anti-PCSK9 small molecule treatment, mAb, or small interfering siRNA 
or RNAi (ie, Inclisiran) within 12 months prior to Screening Visit 1.
12. 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.
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
14. Healthy Participants (Panel D): 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 dose of 
study intervention, throughout the study, until the poststudy visit. There may be certain 
medications that are permitted (see Section 6.5).
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Participants with RI (Panels A, B, and C): Taking medications to treat chronic medical 
conditions and/or conditions associated with renal disease, if participant has not been on a 
stable regimen for at least 1 month (other than statins, which require a stable dose for at 
least 2 months) prior to administration of the initial dose of study intervention, and/or is 
unable to withhold the use of the medication(s) within 4 hours prior to and 4 hours after 
administration of study intervention. Exceptions may be granted for participants in whom 
a medication regimen has been adjusted within a one-month window prior to 
administration of the initial dose of study intervention, at the discretion of the 
Investigator and following consultation with the Sponsor. See Section 5.1.2 for allowed 
medical conditions, and Section 6.5 for allowed medications.
Prior/Concurrent Clinical Study Experience
15. 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
16. Healthy Participants (Panel D): QTc interval ≥470 msec (for males) or ≥480 msec 
(for females).
Participants with RI (Panels A, B, and C): The participant meets the following criteria 
for ECG:
-
Heart rate < 40 or > 110 bpm
-
QTc interval > 500 msec
-
Any significant arrhythmia or conduction abnormality, (including but not specific to 
atrioventricular block [2nd degree or higher], Wolff Parkinson White syndrome 
[unless curative radio ablation therapy]), which, in the opinion of the Investigator and 
Sponsor, could interfere with the safety for the individual participant.
-
Non-sustained or sustained ventricular tachycardia (> 2 consecutive ventricular 
ectopic beats at a rate of > 1.7/second).
Other Exclusions
17. Under the age of legal consent.
18. Healthy participants (Panel D): The participant is a smoker and/or has used nicotine or 
nicotine-containing products (eg, nicotine patch and electronic cigarette) within 3 months 
of screening.
Participants with RI (Panels A, B, and C): Does not agree to follow the smoking 
restrictions as defined by the CRU.
19. Consumes greater than 3 servings of alcoholic beverages (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. Participants who consume 4 servings of alcoholic beverages 
per day may be enrolled at the discretion of the investigator.
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20. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
21. Healthy participants (Panel D): A regular user of cannabis, any illicit drugs or has a 
history of drug (including alcohol) abuse within approximately 3 months. Participants 
must have a negative drug screen prior to allocation.
Participants with RI (Panels A, B, and C): A regular user of cannabis (refer to 
exception below for use of cannabis) or any illicit drugs or has a history of drug 
(including alcohol) abuse within approximately 3 months. Participants must have a 
negative drug screen prior to treatment allocation, but may be allowed for inclusion with 
a positive drug screen due to the use of physician-prescribed medications (eg., opioids, 
benzodiazepines, antidepressants) at the discretion of the investigator. In addition, 
participants with a positive THC may be enrolled at the discretion of the investigator if 
the participants’ THC use is under 4 times/month and the participant agrees to not use 
during study participation. Participants with positive THC on screening may have 
rechecks performed at the discretion of the investigator to ensure compliance with 
abstinence from THC use during study participation.
22. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
23. The investigator has any concern regarding safe participation in the study or for any other 
reason the investigator considers the participant inappropriate for participation in the 
study.
24. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Participants will fast from all food and drinks, except water, for at least 8 hours before study 
intervention administration. Participants will fast from all food and drinks, except water, 
between study intervention administration and the first scheduled meal. Meals and snack(s) 
will be provided by the site staff at time points indicated in the SoA. Participants will fast 
from all food and drinks, except water, between meals and snacks. The caloric content and 
composition (macronutrients) of meals will be approximately the same in each treatment 
period for Panel C. The meal content should be consistent within a given clinical site. After 
the 4-hour postdose procedures have been completed, subsequent meals and snacks will be 
unrestricted in caloric content, composition, and timing.
Approximately 240 mL of water will be provided during study intervention administration. 
Additional water may be provided in 50-mL increments if desired. Water will be restricted 
1 hour before and 1 hour after study intervention administration.
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Approximately 30 minutes after study intervention administration, participants will begin to 
consume a breakfast. The contents of the breakfast are listed below.
The nutritional content of the breakfast is as follows:
•
~15% to 19% kcal from fat
The exact meal contents may be substituted with agreement between Sponsor and 
investigator, and must be documented in an administrative letter.
This breakfast should be consumed in its entirety in 30 minutes or less. The start and stop 
time of the breakfast will be recorded.
Instructions on whether to take MK-0616 with or without food and/or drink may be modified 
during the study based on newly available data.
Fasting requirements for laboratory safety evaluations are at least 8 hours prior to collection.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the initial dose of study 
intervention, throughout the study including the washout interval between treatment periods
(Panel C only) and until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours before and 
after study intervention administration. On all other days during the study, consumption of 
fruits and fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is 
allowed.
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 1. A recheck may be needed if 
participants did not refrain from consuming caffeinated beverages or xanthine-containing 
products 12 hours prior to the Screening Visit 1.
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from:
•
12 hours before the Screening Visit 2.
•
12 hours before and after study intervention administration (for Panel C, applies to each 
treatment period).
•
12 hours before poststudy visit.
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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 1. A recheck may be needed if participants did not refrain from consuming 
alcohol 24 hours prior to the Screening Visit 1.
Participants will refrain from consumption of alcohol from:
•
24 hours before the Screening Visit 2.
•
24 hours before and after study intervention administration (for Panel C, applies to each 
treatment period).
•
24 hours before poststudy visit.
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
Healthy Mean Matched Control Participants (Panel D): Smoking (and/or the use of 
nicotine/nicotine-containing products) is not permitted during the study.
Moderate RI, Severe RI, and ESRD Participants (Panels A, B, and C): 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 in Panels A, B, and D will avoid unaccustomed strenuous physical activity (ie, 
weightlifting, running, bicycling, etc) from the prestudy (screening) visit until administration 
of the dose of study intervention, throughout the study, and until the poststudy visit.
ESRD participants in Panel C 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 the washout interval 
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 discontinues from study intervention or 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 treatment/allocation number.
The study site should contact the Sponsor for the replacement participant’s 
treatment/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(s) to be used in this study is outlined in Table 2.
Country-specific requirements are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Moderate 
RI Group
Experimental MK-0616
Drug
Tablet
20 mg
20 mg
Oral
Panel A: 
Single dose 
on Day 1
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Severe RI 
Group
Experimental MK-0616
Drug
Tablet
20 mg
20 mg
Oral
Panel B: 
Single dose 
on Day 1
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
ESRD on 
HD 
Group
Experimental MK-0616
Drug
Tablet
20 mg
20 mg
Oral
Panel C: 
Single Dose 
on Day 1 of 
Periods 1 
and 2
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Healthy 
Control 
Group
Experimental MK-0616
Drug
Tablet
20 mg
20 mg
Oral
Panel D: 
Single Dose 
on Day 1
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
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 2 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.
6.2
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.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
A sample allocation table is provided below in Table 3.
Table 3
Allocation of Participants to Treatment
Panel
Renal Impairment Stage
N
Period 1
Period 2a
A
Moderate
8
20 mg MK-0616
Not applicable
B
Severe
8
20 mg MK-0616
Not applicable
C
ESRD on HD
8
20 mg MK-0616 
(immediately after HD)
20 mg MK-0616 
(approximately 
30 minutes prior to HD)
D
Healthy
8 to 12
20 mg MK-0616
Not applicable
ESRD=end-stage renal disease; HD=hemodialysis
a
There will be at least 14 days of washout between study intervention administration in each period
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
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study-site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study-site staff other than the person administering the study 
intervention. Study-site personnel will examine each participant’s mouth to ensure that the 
study intervention was ingested.
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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 the 
first dose of study intervention, 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 (up to 2 g total per day for participants with RI or up to 4 g total 
per day for healthy participants) may be used for minor ailments without prior consultation 
with the Sponsor.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are not to be used 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.
•
Hormone replacement therapy
•
Contraceptives
•
Statins (any statin, any dose), but must be on a stable, unchanged dose for at least 
2 months prior to screening
In addition, for participants with RI (Panels A, B, and C):
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medications specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant’s primary physician. For ESRD participants 
(Panel C), however, the decision to continue the participant on study intervention requires the 
mutual agreement of the investigator, the Sponsor, and the participant.
Participants who are taking certain prescription medications to treat manifestations of renal 
disease or medications needed to treat stable diseases (eg, angiotensin converting enzyme 
inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics) may be allowed to 
participate in the study at the discretion of the investigator. Participants must be on a stable 
regimen for at least 2 weeks (or 5 half-lives of the concomitant medication, whichever is 
longer) prior to administration of study intervention and be able to withhold the use for 4 
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hours prior to and 4 hours after study intervention administration. If a participant is 
prescribed prohibited medication, upon discussion between the Sponsor and the investigator, 
the investigator may substitute the previously prescribed medication to an allowed one for 
the purpose of this study. Examples of the types of medications that would be allowed 
include (but are not limited to) the following:
•
Angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, diuretics
•
Beta blockers
•
Metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, alpha-glucosidase 
inhibitors, incretin mimetics
•
Synthroid
•
Colchicine, allopurinol
•
SSRIs, tricyclic antidepressants
•
Proton pump inhibitors
Participants using medical marijuana will be allowed to participate in the study at the 
discretion of the investigator, however, the use of medical marijuana should be restricted 
during study participation.
Any medication (including over-the-counter) that would significantly alter eGFR, which, by 
the determination of the investigator, might interfere with the study (eg, cimetidine) must be 
discontinued at least 2 weeks (or 5 half-lives of the compound, whichever is longer) prior to 
administration of study intervention.
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
CRUs will be staffed with medically trained personnel with appropriate access to full-service 
acute care hospitals to facilitate rapid institution of medical intervention.
6.6
Dose Modification
Dose modifications are not applicable to this study.
6.6.1
Stopping Rules
The 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. To continue the study 
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(on joint agreement with the Sponsor and investigator), a substantial amendment will be 
submitted for approval.
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.
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 (ie, participants in Panels A, B, and D).
For ESRD Participants only (Panel C):
Discontinuation of study intervention does not represent withdrawal from the study. As 
certain data on clinical events beyond study intervention discontinuation may be important to 
the study, they must be collected through the participant’s last scheduled follow-up, even if 
the participant has discontinued study intervention. Therefore, all participants who 
discontinue study intervention before completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.1.9, or 
if available, a PCL.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a positive drug screen at any time during the course of the study (with 
the exception for positive drug screen due to prescription drug use that is approved by the 
investigator and Sponsor). The drug screen can be confirmed by a recheck at the 
discretion of the investigator after discussion with the Sponsor.
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.
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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 providing documented informed consent 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.
•
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
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The 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.
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 their legally acceptable 
representative) and of the person conducting the consent discussion.
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A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
The 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.
8.1.1.1
General Informed Consent
Specifics about the study and the study population are to be included in the ICF.
The participant (or their 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.
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
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/allocation 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.
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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 first dose of study intervention.
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 Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1. Pre-trial screening logs may be collected for review by 
the Sponsor. If applicable, any information that would make the participant identifiable will 
be removed.
8.1.7
Assignment of Treatment/Allocation 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
Participants with moderate RI (Panel A), severe RI (Panel B), and healthy participants 
(Panel D):
On Day 1, 20 mg (1 x 20 mg tablet) MK-0616 will be given to participants at Hour 0.
Participants with ESRD:
On Day 1 of Period 1, 20 mg (1 x 20 mg tablet) MK-0616 will be given to participants at 
Hour 0, immediately following completion of the scheduled HD session. On Day 1 of Period 
2, 20 mg (1 x 20 mg tablet) MK-0616 will be given to participants at Hour 0, approximately 
0.5 hours prior to the scheduled HD session.
All participants:
The study interventions will be administered with approximately 240 mL of water following 
at least an 8-hour fast and participants will continue to fast for at least 30 minutes postdose.
See Section 5.3.1 for additional information on meal restrictions throughout the study.
The exact clock time of study intervention 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 and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, 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 
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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.
8.1.11
Domiciling
All participants (Panels A to D) will be admitted to the CRU on Day -1, at the time indicated 
by the CRU, and will be housed until after the 48 hours postdose study procedures are 
completed on Day 3. Panel C participants with ESRD will follow the same domiciling 
schedule in a 2nd treatment period.
At all times, a participant may be required to remain at the CRU for longer at the discretion 
of the investigator or designee.
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 or immunogenicity 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 to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn 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.
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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 (Section 1.3).
Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the investigator or designee.
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.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
BSA
In order to correct eGFR for individual BSA, the DuBois formula will be used to calculate 
BSA:
BSA (m2) = Weight (kg)0.425 x Height (cm)0.725 x 0.007184
8.3.2
Vital Signs
•
Body temperature, HR, RR, and BP will be assessed.
•
Body temperature will be measured with an appropriate thermometer.
•
BP and HR measurements will be assessed in a semirecumbent position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
•
BP and HR measurements should be preceded by at least 10 minutes of rest for the 
participant in a quiet setting without distractions.
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 
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indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participant’s arm is essential to increase the accuracy of BP measurements.
The predose (baseline) HR and BP will be triplicate measurements, obtained at least 1 to 2 
minutes apart within 3 hours of dosing MK-0616. The mean of these measurements will be 
used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed). Screening and postdose VS measurements will be single measurements.
Participants will continue to rest semirecumbent from dosing until 4 hours postdose except to 
stand for the measurement of orthostatic VS (if needed) or other study-related procedure.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained. 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
•
Triplicate 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. For healthy participants (Panel D), refer to Appendix 9 for evaluation and 
potentially significant findings.
•
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.
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.
The correction formula to be used for QTc is Fridericia.
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.
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Before each period, predose ECGs will be obtained in triplicate at least 1 minute apart within 
3 hours before dosing MK-0616. The mean of these measurements will be used as the 
baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed).
During the treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with mean predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the mean QTc interval increase from baseline for any postdose 
time point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc interval is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study cardiologist 
may be appropriate and the Sponsor should be notified.
During each treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The mean value of the QTc 
interval from the 3 ECGs will represent the value at that time point. If the mean QTc interval 
is ≥500 msec, 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 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.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted, 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.
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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.
-
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. See 
Investigator Site Binder for additional guidance.
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.
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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.
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 4.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 4
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to Allocation
Reporting Period:
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
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 (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does 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
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Type of Event
Reporting Period:
Consent to Allocation
Reporting Period:
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
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, 
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.
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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.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable to this study.
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).
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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.
8.5
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 plasma and/or urine samples collected will be measured for 
evaluation of PK/pharmacodynamics 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 Plasma MK-0616 and/or Metabolites
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations Manual.
8.6.2
Dialysate Samples for MK-0616 and/or Metabolites
Sample collection, storage, and shipment instructions for dialysate samples will be provided 
in the Operations Manual.
8.6.3
Urine Collection for Urinary MK-0616 and/or Metabolites
Sample collection, storage, and shipment instructions for urine samples will be provided in 
the Operations Manual.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples (free 
PCSK9) will be in the Operations Manual.
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8.8
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
•
Blood for Plasma for PCSK9 (free) Assay
8.8.1
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 FBR is 
approved and consent is given, 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.
8.9
Future Biomedical Research Sample Collection
All sample collections for study-specific assessments shown in the SoA are described within
the main Informed Consent.
If the participant has provided documented informed consent for FBR, leftover samples will 
be used for FBR. The following specimens will be included for FBR:
•
Leftover samples from Section 8.8
8.10
Health Economics, Medical Resource Utilization and Health Economics
Health Economics, Medical Resource Utilization and Health Economics are not evaluated in 
this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.11.1
Screening
Within approximately 4 weeks; 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.
8.11.2
Treatment Period Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
8.11.3
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, all 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 an official memo. 
8.11.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for MK-0616 is the critical procedure.
At any postdose time point, the blood sample for MK-0616 needs to be collected as close to 
the exact time point 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 Collection as outlined in Table 5.
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Table 5
Pharmacokinetic (Blood/Urine) Collection Windows
PK Collection
PK Collection Window
0 to <1 h
5 min
1 to <24 h
15 min
24 to <48 h
1 h
48 to 168 h
2 h
>168 h
24 h
h=hour, min=minute; PK=pharmacokinetic.
Predose and Postdose Procedures
•
Predose standard safety evaluations: VS and ECG within 3 hours; laboratory safety tests 
and physical examination within 24 hours
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
examination
-
Procedures scheduled within the 24-hours after dosing may be obtained within 
15 minutes of the theoretical sampling time
-
Procedures scheduled between 24-hours and 48-hours postdose may be obtained 
within 1 hour of the theoretical sampling time
-
Procedures scheduled from 48-hours postdose to 168-hours postdose may be obtained 
within 2 hours of the theoretical sampling time
Note: Visit windows defined by ±1 day refers to calendar days.
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-0616 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.
•
Decrease in the dose of the study intervention administered in any given period/panel
•
Entire period(s) or panel(s) may be omitted
•
Lengthening of the washout period between doses
•
Addition of PK pause
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•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK/pharmacodynamic 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 plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to an 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).
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 contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 9.2 through 9.9).
If a different group of healthy matched control participants is needed to match the mean age 
and BMI for the RI and ESRD groups, then separate analyses will be performed for the 
populations as follows:
• Moderate RI versus an appropriate group of healthy matched control participants;
• Severe RI versus an appropriate group of healthy matched control participants;
• ESRD participants versus an appropriate group of healthy matched control participants.
If a single set of healthy matched control participants can be used for comparison with all RI 
and ESRD groups, the following analysis pooled over all populations will be used.
Separately for each pharmacokinetic parameter, individual values of plasma MK-0616 
AUC0-inf and Cmax will be natural log-transformed and evaluated with a linear mixed-
effects model containing a fixed effect for populations. An unstructured covariance matrix 
will be used to allow for unequal population variances and to model the correlation between 
repeated measures (before and after HD) within each ESRD participant via the REPEATED 
statement in SAS PROC MIXED.
Ninety-five percent (95%) CIs 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% CIs will yield estimates for the population 
GMs and CIs about the GMs on the original scale.
To compare participants with RI in each of the renal categories (moderate RI, severe RI, 
ESRD before HD and ESRD after HD) to matching participants with normal renal function, a 
2- sided 90% CI for the true difference in means (RI - normal renal function) will be 
calculated for each PK parameter (AUC0-inf and Cmax) using the mean square error from 
the model and referencing a t-distribution. For each of the RI populations, these confidence 
limits will be exponentiated to obtain the 90% CI for the true GMRs (RI/normal renal 
function) for each PK parameter.
The same approach will be used to address the secondary estimation objective. The extent to 
which MK-0616 is removed from plasma by HD will be evaluated with the difference in 
means (ESRD before HD – ESRD after HD), the geometric mean ratio (ESRD before 
HD/ESRD after HD) and their 90% CIs.
A natural log transformation will be applied to AUC0-inf and Cmax. For each PK parameter, 
95% confidence intervals for the least squares means will be constructed on the natural log 
scale and will reference the t-distribution. Exponentiating the least-squares means and their 
corresponding 95% CIs will yield estimates for the population GMs and CIs about the GMs 
on the original scale. A 2-sided 90% CI for the true difference in means (before HD –after 
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HD) will be calculated for each pharmacokinetic parameter (AUC0-inf 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 (GMR) of 
geometric means (before HD/ after HD) for each PK parameter. A scatter plot of AUC0-inf 
and Cmax by renal function will also be provided.
Urine PK: MK-0616 Ae0-24, Fe, and CLr following a single dose of MK-0616 administered 
to participants with moderate and severe renal impairment and ESRD, will be estimated and 
compared to those estimated in healthy matched control participants.
Separately for each urine PK parameter, where possible, individual values of Ae0-24, Fe and 
CLr will be natural log-transformed and evaluated with a linear fixed-effects model, which is 
described in the primary analysis. Ninety five percent CIs intervals for the least square means 
for each population will be constructed. To compare participants with varying degrees of RI 
(moderate, severe and ESRD) to matching participants with normal renal function, a 2-sided 
90% CI for the true ratio of means (RI/normal renal function) will be calculated for each 
urine PK parameter (Ae0-24, Fe and CLr).
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 
Pharmacology Department of the Sponsor.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3
9.3
Analysis Endpoints
9.3.1
Primary Endpoints
Pharmacokinetics: The primary PK endpoints are plasma MK-0616 AUC0-inf, AUClast, 
Cmax, Tmax, t1/2, CL/F and Vz/F following a single dose of MK-0616 administered to 
participants with varying degrees of renal impairment (moderate, severe, ESRD) and healthy 
matched control participants.
9.3.2
Secondary Endpoints
The secondary PK endpoints are MK-0616, CLD, CD, AeD, AeD (%dose)] and urine MK-
0616 Ae0-24, Fe, and CLr following a single dose of MK-0616 administered to participants 
with varying degrees of renal impairment (moderate, severe, ESRD) and healthy matched 
control participants.
The secondary safety endpoints are Adverse Events, Discontinuations due to Adverse Events.
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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 treatment(s) they actually received.
9.4.1
All Participants as Treated (APaT) Population
The All Participants as Treated Population  consists of all participants who received at least 
one dose of treatment. This population will be used for assessments of safety and tolerability.
9.4.2
Per-Protocol (PP) Population
The Per-Protocol Population consists of the set of data generated by the subset of participants 
who comply with the protocol sufficiently to ensure that these 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 participant or data value 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 from at least one 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 Pharmacokinetic Analyses
If a different group of healthy matched control participants is needed to match the mean age 
and BMI for the RI and ESRD groups, then separate analyses will be performed for the 
populations as follows:
• Moderate RI versus an appropriate group of healthy matched control participants;
• Severe RI versus an appropriate group of healthy matched control participants;
• ESRD participants versus an appropriate group of healthy matched control participants.
If a single set of healthy matched control participants can be used for comparison with all RI 
and ESRD groups, the following analysis pooled over all populations will be used.
Separately for each pharmacokinetic parameter, individual values of plasma MK-0616 
AUC0-inf and Cmax will be natural log-transformed and evaluated with a linear mixed-
effects model containing a fixed effect for populations. An unstructured covariance matrix 
will be used to allow for unequal population variances and to model the correlation between 
repeated measures (before and after HD) within each ESRD participant via the REPEATED 
statement in SAS PROC MIXED.
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Ninety-five percent (95%) CIs 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% CIs will yield estimates for the population 
GMs and CIs about the GMs on the original scale.
To compare participants with RI in each of the renal categories (moderate RI, severe RI, 
ESRD before HD and ESRD after HD) to matching participants with normal renal function, a 
2- sided 90% CI for the true difference in means (RI - normal renal function) will be 
calculated for each PK parameter (AUC0-inf and Cmax) using the mean square error from 
the model and referencing a t-distribution. For each of the RI populations, these confidence 
limits will be exponentiated to obtain the 90% CI for the true GMRs (RI/normal renal 
function) for each PK parameter.
The same approach will be used to address the secondary estimation objective. The extent to 
which MK-0616 is removed from plasma by HD will be evaluated with the difference in 
means (ESRD before HD – ESRD after HD), the geometric mean ratio (ESRD before 
HD/ESRD after HD) and their 90% CIs.
A natural log transformation will be applied to AUC0-inf and Cmax. For each PK parameter, 
95% confidence intervals for the least squares means will be constructed on the natural log 
scale and will reference the t-distribution. Exponentiating the least-squares means and their 
corresponding 95% CIs will yield estimates for the population GMs and CIs about the GMs 
on the original scale. A 2-sided 90% CI for the true difference in means (before HD –after 
HD) will be calculated for each pharmacokinetic parameter (AUC0-inf 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 (GMR) of 
geometric means (before HD/ after HD) for each PK parameter. A scatter plot of AUC0-inf 
and Cmax by renal function will also be provided.
Urine PK: MK-0616 Ae0-24, Fe, and CLr following a single dose of MK-0616 administered 
to participants with moderate and severe renal impairment and ESRD, will be estimated and 
compared to those estimated in healthy matched control participants.
Separately for each urine PK parameter, where possible, individual values of Ae0-24, Fe and 
CLr will be natural log-transformed and evaluated with a linear fixed-effects model, which is 
described in the primary analysis. Ninety five percent CIs intervals for the least square means 
for each population will be constructed. To compare participants with varying degrees of RI 
(moderate, severe and ESRD) to matching participants with normal renal function, a 2-sided 
90% CI for the true ratio of means (RI/normal renal function) will be calculated for each 
urine PK parameter (Ae0-24, Fe and CLr).
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. 
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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.
9.6
Interim Analyses
No formal interim analyses are planned for this study.
9.7
Multiplicity
Not applicable.
9.8
Sample Size and Power Calculations
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 6 will be performed by the local laboratory.
•
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.
•
Because the glucose is part of the standard chemistry laboratory tests and requires fasting, 
participants should fast (approximately 8 hours) prior to all chemistry laboratory 
collections. If the individual comes to the screening visit and is not fasting, a recheck 
may be needed at the discretion of the investigator and the participant may be asked to 
return at a later time for the safety laboratory collection.
Table 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes
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
Glucose 
(fasting)
Calcium
Alkaline 
phosphatase
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 for PONCBP only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids, and benzodiazepines) per site SOP
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HIV=human 
immunodeficiency virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
POCBP=participant of childbearing potential; PONCBP=participant of non-childbearing potential; RBC=red blood 
cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; SOP=standard 
operating procedure; ULN=upper limit of normal; WBC=white blood cell
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.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of 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.
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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.
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.
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/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).
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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.
•
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 
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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.
•
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.
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•
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).
-
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
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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.
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.
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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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Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant b
IUS c
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception b
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Penile/external or vaginal/internal condom with or without spermicided
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
c
IUS is a progestin releasing IUD
d
Vaginal/internal condom used for contraceptive purposes
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction) d  
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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 8.9 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, 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: Approximate Blood Volume Tables
Panels A, B, and D
Prestudy
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/
Test
Laboratory Safety Tests
2
1
1
4
10.5
42
Serum hCG (POCBP only)
2
-
1
3
4
12
Serum FSH 
(postmenopausal PONCBP 
only)
1
-
-
1
4
4
HIV/Hepatitis Screen (per 
site SOP)
1
-
-
1
9
9
Chemistry test for Second 
Creatinine Value (if 
conducted between 
Screening Visit 1 and Day 1 
Predose)
1
-
-
1
8
8
Blood for MK-0616
-
15
1
16
3
48
Blood for Plasma PCSK9 
(free)
-
4
1
5
3
15
Blood for Planned Genetic 
Analysis
-
1
-
1
8.5
8.5
Approximate Total Blood Volume per Male Participant for Panels A, B, and Da
130.5
Approximate Total Blood Volume per POCBP for Panels A, B, and Da
142.5
Approximate Total Blood Volume per PONCBP for Panels A, B, and Da
134.5
FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
POCBP=participant of childbearing potential; PONCBP=participant of non-childbearing potential; SOP=standard 
operating procedure
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (no more than 
50 mL in total) may be obtained.
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Panel C
Prestudy
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/
Test
Laboratory Safety 
Tests
2
3
1
6
10.5
63
Serum hCG (POCBP 
only)
2
1
1
4
4
16
Serum FSH 
(postmenopausal 
PONCBP only)
1
-
-
1
4
4
HIV/Hepatitis Screen 
(per site SOP)
1
-
-
1
9
9
Blood for MK-0616
-
40
1
41
3
123
Blood for Plasma 
PCSK9 (free)
-
8
1
9
3
27
Blood for Planned 
Genetic Analysis
-
1
-
1
8.5
8.5
Approximate Total Blood Volume per Male Participant for Panel Ca
230.5
Approximate Total Blood Volume per POCBP for Panel Ca
246.5
Approximate Total Blood Volume per PONCBP for Panel Ca
234.5
FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
POCBP=participant of childbearing potential; PONCBP=participant of non-childbearing potential; SOP=standard 
operating procedure
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (no more than 
50 mL in total) may be obtained.
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10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria
Screen Failure Criteria
Potentially Significant 
Postallocation 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
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
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Screen Failure Criteria
Potentially Significant 
Postallocation Findings
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 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
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
Ae
amount excreted
Ae0-24
amount excreted at 0 to 24 hours
AeD
amount excreted in dialysate
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-inf
area under the curve from 0 to infinity
AUClast
area under the curve last
AV
Atrioventricular/arteriovenous
BMI
body mass index
BP
blood pressure
BSA
body surface area
BT
body temperature
BUN
blood urea nitrogen
CCU
Cardiac care unit
CD
concentration in dialysate
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
oral clearance
CLr
renal clearance
Cmax
maximum plasma concentration
COVID-19
Coronavirus Disease 2019
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
cr
creatinine
CRF
Case Report Form
CRU
clinical research unit
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Abbreviation
Expanded Term
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase 4
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ESRD
end stage renal disease
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
Fe
fraction excreted unchanged
FAS
Full Analysis Set
FIH
first in human
FSH
follicle-stimulating hormone 
FSR
First Site Ready
GCP
Good Clinical Practice
GI
gastrointestinal
GM
geometric mean
GMR
geometric mean ratio
h
hour
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HD
hemodialysis
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Abbreviation
Expanded Term
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
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
ICRBBB
incomplete right bundle branch block
ICU
intensive care unit
ID
identification
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JRCT
Japan Registry of Clinical Trials
LAHB
left anterior hemiblock
LAM
lactational amenorrhea method
LDL-C
low-density lipoprotein cholesterol
LPHB
left posterior hemiblock
LVH
left ventricular hypertrophy
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MI
multiple imputation
mm
millimeter
ms
milliseconds
NIMP/AxMP
noninvestigational/auxiliary medicinal product
NSAE
nonserious adverse event
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Abbreviation
Expanded Term
NSAID
nonsteroidal anti-inflammatory drugs
OBS
observed GMR
P
primary approach
PCL
Protocol Clarification Letter
PCSK9
Proprotein convertase subtilisin/kexin type 9
PK
pharmacokinetic
POCBP
participant of childbearing potential
PONCBP
participant of non-childbearing potential
PP
per-protocol
PR
pulse rate
QTcB
QT correction using Bazett’s formula
QTcF
QT correction using Fredericia formula
RBBB
right bundle branch block
RBC
red blood cell
RI
renal impairment
RNA
ribonucleic acid
RNAi
RNA interference
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
siRNA
short interfering RNA
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOP
Standard Operating Procedures
SSRI
selective serotonin uptake inhibitors
ST/T
segment/T wave
SUSAR
suspected unexpected serious adverse reaction
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Abbreviation
Expanded Term
THC
Delta-9-tetrahydrocannabinol
Tmax
time to maximum plasma concentration
t1/2
half life
ULN
upper limit of normal
UTN
Universal Trial Number
VS
vital signs
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
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REFERENCES
[Delgado, C., et al 2021]
Delgado C, Baweja M, Crews DC, Eneanya ND, 
Gadegbeku CA, Inker LA, et al. A unifying 
approach for GFR estimation: recommendations 
of the NKF-ASN Task Force on reassessing the 
inclusion of race in diagnosing kidney disease. J 
Am Soc Nephrol. 2021;32:2994–3015.
[07ZP4L]
[Inker, L. A., et al 2021]
Inker LA, Eneanya ND, Coresh J, Tighiouart H, 
Wang D, Sang Y, et al. New creatinine- and 
cystatin C-based equations to estimate GFR 
without race. N Engl J Med. 2021 Nov 
4;385(19):1737-49. Supplemental material; 87 p.
[07ZRQ6]
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