Clinical trial NCT05070390
Conditions: Moderate Renal Impairment
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-11-16; Completion date: 2023-05-03
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study evaluated the safety, tolerability and pharmacokinetic (PK) effects of enlicitide chloride in participants with moderate renal impairment (RI) to those of healthy matched control participants. Moderate RI was defined as the estimated glomerular filtration rate (eGFR) ≥30 and \<60milliliter/minute/1.73meters\^2 (ml/min/1.73m\^2). There is no formal hypothesis.

Detailed description:

Arms: arm 1: Single dose of enlicitide chloride 10 mg arm 2: Single dose of enlicitide chloride 10 mg
Interventions: intervention 1: Enlicitide Chloride
Intervention descriptions: intervention 1: 10 mg capsule administered orally

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT05070390 
Document Date: 
22-Feb-2023
An Open-Label Clinical Study to Evaluate the Pharmacokinetics of
MK-0616 Following Administration of a Single Dose to Participants 
with Moderate Renal
Impairment


PRODUCT: MK-0616  
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PROTOCOL/AMENDMENT NO.: 007-02
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22-FEB-2023
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: An Open-Label Clinical Study to Evaluate the Pharmacokinetics of 
MK-0616 Following Administration of a Single Dose to Participants with Moderate Renal 
Impairment
Protocol Number: 007-02
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):
IND
To Be Determined
Approval Date: 22 February 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 02
22-FEB-2023
This study protocol is being amended to modify 1 eligibility criteria (estimated 
glomerular filtration rate) for the healthy participant’s panel in order to support the 
inclusion of suitable participants. 
Amendment 01
17-JUN-2022
The primary reason for this amendment is to add two additional participants to 
Panel A (Moderate renal impairment panel).
Original Protocol
10-AUG-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
This study protocol is being amended to modify 1 eligibility criteria (eGFR) for the healthy participant’s panel in order to support the 
inclusion of suitable participants.
Because the MDRD equation was used in the original protocol to calculate eGFR for inclusion/exclusion for both Panel A (moderate 
renal impairment) and Panel B (healthy matched controls), the eGFR for healthy matched controls is likely to be an underestimation as 
described in reference [Stevens, L. A., et al 2010] [Levey, A.S., et al 2009]. For this reason, the eGFR criteria for enrollment of 
healthy matched controls (Panel B) was lowered from 90 mL/min/1.73 m2 to 80 mL/min/1.73 m2.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
4.1 Overall Design
Change of the term “mild” to “moderate”
This was a typographical error. Only participants with
moderate RI are enrolled in this study.
4.1 Overall Design 
(Table 1  Renal Function 
Panels)
5.1 Inclusion Criteria
(Additional Categories)
Change in eGFR criteria for enrollment of 
healthy matched controls (Panel B) from
90 mL/min/1.73 m2 to 80 mL/min/1.73 m2.
Because the MDRD equation was used in the original 
protocol to calculate eGFR for inclusion/exclusion for 
both Panel A (moderate renal impairment) and Panel B 
(healthy matched controls), the eGFR for healthy 
matched controls is likely to be an underestimation as 
described in reference [Stevens, L. A., et al 2010] 
[Levey, A.S., et al 2009]. For this reason, the eGFR 
criteria for enrollment of healthy matched controls 
(Panel B) was lowered from 90 mL/min/1.73 m2 to 80 
mL/min/1.73 m2.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................20
2.2.1
Pharmaceutical and Therapeutic Background .............................................20
2.2.2
Ongoing Clinical Studies.............................................................................20
2.3
Benefit/Risk Assessment......................................................................................21
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................21
4
STUDY DESIGN............................................................................................................22
4.1
Overall Design......................................................................................................22
4.2
Scientific Rationale for Study Design.................................................................23
4.2.1
Rationale for Endpoints ...............................................................................24
4.2.1.1
Efficacy Endpoints.............................................................................24
4.2.1.2
Safety Endpoints................................................................................24
4.2.1.3
Pharmacokinetic Endpoints ...............................................................24
4.2.1.4
Pharmacodynamic Endpoints.............................................................24
4.2.1.5
Planned Exploratory Biomarker Research.........................................24
4.2.1.5.1
Planned Genetic Analysis ........................................................24
4.2.1.6
Future Biomedical Research..............................................................25
4.2.2
Rationale for Control ...................................................................................25
4.3
Justification for Dose...........................................................................................25
4.4
Beginning and End-of-Study Definition ............................................................25
4.4.1
Clinical Criteria for Early Study Termination .............................................26
5
STUDY POPULATION ................................................................................................26
5.1
Inclusion Criteria.................................................................................................26
5.2
Exclusion Criteria................................................................................................28
5.3
Lifestyle Considerations......................................................................................30
5.3.1
Meals and Dietary Restrictions....................................................................30
5.3.1.1
Diet Restrictions.................................................................................30
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................31
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5.3.2.1
Caffeine Restrictions..........................................................................31
5.3.2.2
Alcohol Restrictions...........................................................................31
5.3.2.3
Tobacco Restrictions..........................................................................31
5.3.3
Activity Restrictions ....................................................................................31
5.4
Screen Failures.....................................................................................................32
5.5
Participant Replacement Strategy......................................................................32
6
STUDY INTERVENTION............................................................................................32
6.1
Study Intervention(s) Administered...................................................................32
6.2
Preparation/Handling/Storage/Accountability .................................................34
6.2.1
Dose Preparation..........................................................................................34
6.2.2
Handling, Storage, and Accountability........................................................34
6.3
Measures to Minimize Bias: Randomization and Blinding..............................35
6.3.1
Intervention Assignment..............................................................................35
6.3.2
Stratification.................................................................................................35
6.3.3
Blinding........................................................................................................35
6.4
Study Intervention Compliance..........................................................................35
6.5
Concomitant Therapy..........................................................................................36
6.5.1
Rescue Medications and Supportive Care ...................................................37
6.6
Dose Modification (Escalation/Titration/Other)...............................................37
6.6.1
Stopping Rules.............................................................................................37
6.7
Intervention After the End of the Study............................................................38
6.8
Clinical Supplies Disclosure................................................................................38
6.9
Standard Policies..................................................................................................38
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................38
7.1
Discontinuation of Study Intervention...............................................................38
7.2
Participant Withdrawal From the Study...........................................................38
7.3
Lost to Follow-up .................................................................................................39
8
STUDY ASSESSMENTS AND PROCEDURES........................................................39
8.1
Administrative and General Procedures ...........................................................40
8.1.1
Informed Consent.........................................................................................40
8.1.1.1
General Informed Consent.................................................................40
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................41
8.1.2
Inclusion/Exclusion Criteria ........................................................................41
8.1.3
Participant Identification Card.....................................................................41
8.1.4
Medical History ...........................................................................................41
8.1.5
Prior and Concomitant Medications Review...............................................41
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8.1.5.1
Prior Medications...............................................................................41
8.1.5.2
Concomitant Medications..................................................................41
8.1.6
Assignment of Screening Number...............................................................42
8.1.7
Assignment of Treatment/Randomization Number.....................................42
8.1.8
Study Intervention Administration ..............................................................42
8.1.8.1
Timing of Dose Administration.........................................................42
8.1.9
Discontinuation and Withdrawal .................................................................42
8.1.9.1
Withdrawal From Future Biomedical Research ................................42
8.1.10
Participant Blinding/Unblinding..................................................................43
8.1.11
Domiciling ...................................................................................................43
8.1.12
Calibration of Equipment.............................................................................43
8.2
Efficacy/Immunogenicity Assessments ..............................................................43
8.3
Safety Assessments...............................................................................................43
8.3.1
Physical Examinations.................................................................................44
8.3.2
Vital Signs....................................................................................................44
8.3.2.1
Resting Vital Signs ............................................................................44
8.3.2.2
Orthostatic Vital Signs.......................................................................44
8.3.3
Electrocardiograms ......................................................................................45
8.3.4
Clinical Safety Laboratory Assessments .....................................................46
8.3.5
Pregnancy Testing........................................................................................46
8.3.6
Photograph of Rash......................................................................................46
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................47
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................47
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......49
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...49
8.4.4
Regulatory Reporting Requirements for SAE .............................................49
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................49
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................49
8.4.7
Events of Clinical Interest............................................................................49
8.5
Treatment of Overdose........................................................................................50
8.6
Pharmacokinetics.................................................................................................50
8.6.1
Blood Collection for Plasma MK-0616 .......................................................50
8.6.2
Urine Collection for Urinary MK-0616.......................................................50
8.7
Pharmacodynamics..............................................................................................51
8.8
Biomarkers ...........................................................................................................51
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8.8.1
Planned Genetic Analysis Sample Collection..............................................51
8.9
Future Biomedical Research Sample Collection...............................................51
8.10
Visit Requirements...............................................................................................51
8.10.1
Screening......................................................................................................51
8.10.2
Treatment Period Visit.................................................................................52
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........52
8.10.4
Poststudy......................................................................................................52
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......52
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................53
9
STATISTICAL ANALYSIS PLAN .............................................................................55
9.1
Statistical Analysis Plan Summary.....................................................................55
9.2
Responsibility for Analyses.................................................................................56
9.3
Hypotheses/Estimation ........................................................................................57
9.4
Analysis Endpoints...............................................................................................57
9.5
Analysis Populations............................................................................................58
9.6
Statistical Methods...............................................................................................58
9.7
Interim Analyses ..................................................................................................59
9.8
Multiplicity ...........................................................................................................60
9.9
Sample Size and Power Calculations .................................................................60
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................61
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........61
10.1.1
Code of Conduct for Clinical Trials.............................................................61
10.1.2
Financial Disclosure.....................................................................................63
10.1.3
Data Protection.............................................................................................64
10.1.3.1
Confidentiality of Data ......................................................................64
10.1.3.2
Confidentiality of Participant Records...............................................64
10.1.3.3
Confidentiality of IRB/IEC Information............................................64
10.1.4
Publication Policy........................................................................................65
10.1.5
Compliance with Study Registration and Results Posting Requirements ...65
10.1.6
Compliance with Law, Audit, and Debarment ............................................65
10.1.7
Data Quality Assurance ...............................................................................66
10.1.8
Source Documents .......................................................................................67
10.1.9
Study and Site Closure.................................................................................67
10.2
Appendix 2: Clinical Laboratory Tests..............................................................68
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................69
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10.3.1
Definition of AE ..........................................................................................69
10.3.2
Definition of SAE ........................................................................................70
10.3.3
Additional Events Reported.........................................................................71
10.3.4
Recording AE and SAE ...............................................................................71
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................72
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................74
10.5
Appendix 5: Contraceptive Guidance................................................................75
10.5.1
Definitions....................................................................................................75
10.5.2
Contraception Requirements........................................................................75
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................76
10.7
Appendix 7: Country-specific Requirements....................................................81
10.8
Appendix 8: Blood Volume Table ......................................................................82
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................83
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values .....85
10.11 Appendix 11: Abbreviations ...............................................................................86
11
REFERENCES...............................................................................................................89
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LIST OF TABLES
Table 1
Renal Function Panels......................................................................................23
Table 2
Study Interventions..........................................................................................33
Table 3
Allocation of Participants to Treatment...........................................................35
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................48
Table 5
Pharmacokinetic (Blood/Urine) Collection Windows.....................................53
Table 6
Protocol-required Safety Laboratory Assessments..........................................68
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................15
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label Clinical Study to Evaluate the Pharmacokinetics of 
MK-0616 Following Administration of a Single Dose to Participants with Moderate Renal 
Impairment
Short Title: MK-0616 Renal Study
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study will be conducted in male and female (nonchildbearing potential only) 
participants, 18 to 75 years of age with moderate renal impairment and healthy adults.
Objectives
Endpoints
Primary
•
Objective: To compare the plasma PK of 
MK-0616 following a single dose in 
participants with moderate renal 
impairment to those of healthy matched 
control participants.
•
Estimation: MK-0616 AUC0-inf 
following a single dose of MK-0616 
administered to participants with 
moderate real impairment will be 
estimated and compared to MK-0616 
AUC0-inf when administered to healthy 
matched control participants.
•
Plasma MK-0616 AUC0-inf, AUClast, 
Cmax, Tmax, t1/2, CL/F and Vz/F
Secondary
•
Objective: To evaluate the safety and 
tolerability of the administration of a 
single dose MK-0616 in participants with 
moderate renal impairment.
•
Adverse events, vital signs, 12-lead 
electrocardiograms, laboratory safety 
tests
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Objectives
Endpoints
•
Objective: To compare the urine PK of 
MK-0616 following a single dose of 
MK-0616 to participants with moderate
renal impairment 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 
moderate renal impairment, will be 
estimated and compared to those 
estimated in healthy matched control 
participants.
•
Urine MK-0616 Ae0-24, Fe, and CLr
Objective: To evaluate the % reduction of 
free PCSK9 from baseline following 
administration of a single dose of MK-0616
•
Percent reduction in free PCSK9 from 
baseline
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Hypercholesterolemia
Population
Healthy Participants and Participants with Moderate Renal 
Impairment
Study Type
Interventional
Intervention Model
Sequential
This is a multi-site study.
Type of Control
No Treatment Control, Matched Healthy Participants
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of 
Study
The Sponsor estimates that the study will require approximately
6 months from the time the first participant (or their legally 
acceptable representative) provides documented informed 
consent until the last participant’s last study-related contact.
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Number of Participants:
Approximately 18 participants will be allocated such that 16 evaluable participants complete 
the study as described in Section 9.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Treatment 
Period 
Use
Panels A 
and B
MK-0616
10 mg
Once
Oral
Single 
Dose
Experimental
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: N/A
Total 
Number of 
Intervention 
Groups/
Arms
2
Duration of 
Participation
Each participant will participate in the study for approximately 8 weeks 
from the time the participant provides documented informed consent 
through the final contact. After a screening phase of approximately 4 weeks, 
each participant will receive assigned intervention for 1 day. After the end-
of-treatment each participant will be followed for 14 days.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations is in Appendix 11.
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1.2
Schema
The study design is depicted in [Figure 1].
Figure 1
Study Schema
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1.3
Schedule of Activities
Panels A and B
Study Period:
Screening
Intervention
Scheduled Hour
Screening Day -1 a
Pre-
dose
0
0.5 1 1.5 2
3
4
5
8 12 24 36 48 72 120 168
240
Post-
studyb
Notes
Administrative Procedures
Informed Consent
X
Obtained prior to 
any study 
mandated 
procedures 
(Sec. 8.1.1)
Informed Consent 
for FBR
X
Sec. 8.1.1.2
Participant 
Identification Card
X
Sec. 8.1.3
Inclusion/
Exclusion Criteriac
X
X
X
Sec. 5.1 and 5.2
Medical History
X
Includes any 
Substance use: 
Drugs, alcohol, 
tobacco, and 
caffeine 
(Sec. 8.1.4)
Prior/Concomitant 
Medication Review
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
Sec. 5.2, 6.5 and 
8.1.5
Assignment of a 
Screening Number
X
Sec. 8.1.6
Assignment of 
Randomization 
Number
X
Sec. 8.1.7
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Panels A and B
Study Period:
Screening
Intervention
Scheduled Hour
Screening Day -1 a
Pre-
dose
0
0.5 1 1.5 2
3
4
5
8 12 24 36 48 72 120 168
240
Post-
studyb
Notes
MK-0616
Administration
X
Sec. 8.1.8, and 
8.10.2
Standard Mealsd
X
-
-
-
-
-
X
Sec. 5.3.1
Domiciling in the 
CRUe
X
-
-
-
-
-
-
-
-
-
-
-
-
X
Sec. 8.1.11
Safety Procedures
Full physical 
examination
X
X
X
X
Sec. 8.3.1
Height
X
Sec. 8.3.1
Weight
X
X
BMI to be taken 
only at Screening
Orthostatic VS (BP 
and HR)
X
X
X
X
X
Sec. 8.3.2.2
Semirecumbent VS 
(BP and HR)f
X
X
X
X
X
Sec. 8.3.2.1
Body Temperature
X
X
X
X
X
Sec. 8.3.2.1
Respiratory Rate
X
X
X
X
X
Sec. 8.3.2.1
12-lead ECGg
X
X
X
X
X
Sec. 8.3.3
Serum FSH
X
Postmenopausal 
women only. See 
Appendix 2 and 5.
HIV, hepatitis B and 
C screen
X
Sec. 5.2
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Panels A and B
Study Period:
Screening
Intervention
Scheduled Hour
Screening Day -1 a
Pre-
dose
0
0.5 1 1.5 2
3
4
5
8 12 24 36 48 72 120 168
240
Post-
studyb
Notes
UDS/BDS
X
X
Screening 
UDS/BDS is 
mandatory, any 
additional 
assessments are 
conducted per site 
SOP
Alcohol Screen
X
X
Any additional 
alcohol screen may 
be conducted per 
site SOP.
Laboratory Safety: 
Hematology, 
Chemistry, 
Urinalysis
X
X
X
X
Sec 8.3.4 & 
Appendix 2
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
X
Sec. 8.6.1 & 
Operations Manual
Urine for MK-0616 
and/or Metabolites 
Assay
X
X
-
-
-
-
-
X
-
X X
X
X
X
Collected predose, 
0-4, 4-8, 8-12, 12-
24, 24-36, and 36 -
48 hr postdose. 
(Sec. 8.6.2) & 
Operations Manual
08HKVC


PRODUCT: MK-0616  
19
PROTOCOL/AMENDMENT NO.: 007-02
MK-0616-007-02 FINAL PROTOCOL
22-FEB-2023
Panels A and B
Study Period:
Screening
Intervention
Scheduled Hour
Screening Day -1 a
Pre-
dose
0
0.5 1 1.5 2
3
4
5
8 12 24 36 48 72 120 168
240
Post-
studyb
Notes
Pharmacodynamics and Target Engagement
Blood for Plasma 
for PCSK9 (free) 
Assay
X
X
X
X X
X
X X
X
X
X
X
Sec. 8.7 & 
Operations Manual
Blood for Genetic 
Analysis
X
Collect predose 
from enrolled 
participants only.
See Sec. 8.1 & 
Operations Manual
AE=adverse event; BDS=blood drug screen; BP=blood pressure; CRU=clinical research unit; ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle 
stimulating hormone; HIV=human immunodeficiency virus; HR=heart rate; ID=identification; PCSK9=proprotein convertase subtilisin kexin 9; RR=respiratory rate; 
SAE=serious adverse event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs.
a Day -1 procedures may occur predose
b 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.
c Review of inclusion/exclusion criteria will occur at Screening and after predose procedures (if applicable). Based on IC/EC, only specific criteria will be reviewed at predose 
prior to randomization.
d Standardized meals/snacks to be provided after procedure completion at Day 1: ~ 4 (lunch), ~ 7 (snack), ~ 10 (dinner) and ~ 13 (snack) ~ 24 (breakfast Day 2) hrs postdose.
After the 24-hour postdose procedures have been completed, subsequent meals and snacks will be unrestricted in caloric content, composition, and timing.
e Domiciling beginning on the evening of Day -1 followed by discharge after completion of 48-hrs postdose (Day 3) procedures.
f Predose vital signs (HR/BP) to be measured in triplicate on Day 1, within 3 hours predose of study medication. All other measurements will be single measurements.
g ECG measurements obtained in triplicate on Day 1 predose. All other measurements will be single measurements.
08HKVC


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CCI
CCI
CCI
CCI
CCI
CCI
CCI
+.9&


PRODUCT: MK-0616  
21
PROTOCOL/AMENDMENT NO.: 007-02
MK-0616-007-02 FINAL PROTOCOL
22-FEB-2023
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.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study will be conducted in male and female (nonchildbearing potential only) 
participants, 18 to 75 years of age with moderate renal impairment and healthy adults.
Objectives
Endpoints
Primary
•
Objective: To compare the plasma PK of 
MK-0616 following a single dose in 
participants with moderate renal 
impairment to those of healthy matched 
control participants.
•
Estimation: MK-0616 AUC0-inf 
following a single dose of MK-0616 
administered to participants with 
moderate real impairment will be 
estimated and compared to MK-0616 
AUC0-inf when administered to healthy 
matched control participants.
•
Plasma MK-0616 AUC0-inf, AUClast, 
Cmax, Tmax, t1/2, CL/F and Vz/F
Secondary
•
Objective: To evaluate the safety and 
tolerability of the administration of a 
single dose MK-0616 in participants with 
moderate renal impairment.
•
Adverse events, vital signs, 12-lead 
electrocardiograms, laboratory safety 
tests
08HKVC


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CCI
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CCI
+.9&


PRODUCT: MK-0616  
24
PROTOCOL/AMENDMENT NO.: 007-02
MK-0616-007-02 FINAL PROTOCOL
22-FEB-2023
Given the limited developmental and reproductive toxicity data available for MK-0616,
enrollment shall be restricted to adult males and females of nonchildbearing potential who
meet the study’s eligibility criteria.  
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 
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.
08HKVC


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completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/female participants with moderate renal impairment and healthy matched participants 
between the ages of 18 and 75 years (inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is in good health based upon medical history, physical examination, VS measurements, 
and ECGs performed before randomization.
2. Is in good health based on laboratory safety tests obtained at the screening visit and 
before administration of the initial dose of study intervention. 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.
Demographics
3. Is male or female, from 18 years to 75 years of age inclusive, at the time of providing
informed consent.
Healthy Matched Controls (Panel B): Age must be within ± 15 years of the mean age 
of participants within the RI panel(s) to which the participant is matched.
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4. Has a BMI ≥18 kg/m2 and ≤40 kg/m2. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.
Healthy Matched Controls (Panel B): BMI must be within ± 10% of the mean BMI of 
participants within the moderate RI (panel A) to which the participant is matched.
Male Participants
5. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of study intervention:
Refrain from donating sperm
PLUS either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men 
with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile-vaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
Female Participants
6. A female participant is eligible to participate if: 
She is a WONCBP, as defined in Appendix [5].
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
8. Moderate RI (Panel A): Has a baseline eGFR ≥30 and <60 mL/min/1.73 m2 based on 
the MDRD equation. Reasonable efforts will be made to enroll at least 4 participants with 
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eGFR values ≤45 mL/min/1.73 m2 and at least 1 participant with eGFR ≤ 37.5
mL/min/1.73 m2.
9. Moderate RI (Panel A): Has had no clinically significant change in renal status at least 
1 month prior to dosing and is not currently receiving or has not previously been on 
hemodialysis.
10. Healthy Matched Controls (Panel B): Has an eGFR ≥80 mL/min/1.73 m2 based on the 
MDRD equation.
MDRD Equation:
eGFR (mL/min/1.73 m2) = 
175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if Black or African 
American])
Moderate RI (Panel A): Baseline eGFR will be obtained by taking the mean of the eGFR 
obtained from screening and from historical values within a 3-month period prior to 
screening. If no historical measurement is available, a second baseline eGFR sample will be 
taken during the screening period (≥72 hours apart) and the mean of the 2 values will be used 
for group assignment; the second baseline eGFR sample may be obtained at the time of 
check-in.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Moderate RI (Panel A): Has a history of any clinically significant concomitant disease 
or condition (including treatment for such conditions) or diseases whose current 
condition is considered clinically unstable that, in the opinion of the investigator, could 
either interfere with the study drug, compromise interpretation of study data, or pose an 
unacceptable risk to the patient.
Healthy Matched Controls (Panel B): Has a 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.
2. Is 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.
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3. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies that have 
been successfully treated ≥10 years prior to the prestudy screening visit).
4. Has a 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.
5. Is positive for HBsAg, hepatitis C antibodies or HIV.
6. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
7. Moderate RI (Panel A): Is unable to refrain from or anticipates the use of any 
medication, including prescription and nonprescription drugs or herbal remedies as 
indicated in Section 6.5 for the prohibited time period.  
8. Healthy Matched Controls (Panel B): Is unable to refrain from or anticipates the use of 
any medication, including prescription and nonprescription drugs or herbal remedies 
beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial 
dose of study intervention, throughout the study (including washout intervals between 
treatment periods), until the poststudy visit. There may be certain medications that are 
permitted (see Section 6.5).
9.
Has received any nonlive vaccine starting from 14 days prior to study intervention or is 
scheduled to receive any nonlive vaccine through 30 days following study intervention.
Exception: 

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.
Investigational COVID-19 vaccines (ie, those not licensed or approved for 
Emergency Use) are not allowed.
Prior/Concurrent Clinical Study Experience
10. Has 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.
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Diagnostic Assessments
11. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females).
Other Exclusions
12. Moderate RI (Panel A): Does not agree to follow the smoking restrictions as defined 
by the CRU.
Healthy Matched Controls (Panel B): Is a smoker and/or has used nicotine or nicotine-
containing products (eg, nicotine patch and electronic cigarette) within 3 months of 
screening.
13. Is under the age of legal consent.
14. 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.
15. 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.
16. Is 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 UDS prior to 
randomization.
17. Is unwilling to comply with study restrictions.
18. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
19. 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
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2.
In each treatment period, 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 
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drinks, except water, between study intervention administration and the first scheduled meal. 
Meals and snack(s) will be provided by the investigator at time points indicated in the study 
flowchart. Participants will fast from all food and drinks, except water, between meals and 
snacks. The caloric content and composition of meals will be the same in each treatment 
period. After the 24-hour postdose procedures have been completed, subsequent meals and 
snacks will be unrestricted in caloric content, composition, and timing.
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.
Water will be provided during study intervention administration. Water will be restricted 
1 hour before and 1 hour after study intervention administration.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours before the prestudy and poststudy visits and from 12 hours before
and after study intervention administration in each treatment period. At all other times, 
caffeinated beverages or xanthine-containing products will be limited to no more than 6 units 
per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours before the prestudy and 
poststudy visits and from 24 hours before and after study intervention administration in each 
treatment period. At all other times, alcohol consumption is limited to no more than 
approximately 3 alcoholic beverages or equivalent servings (1 serving is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Healthy Matched Controls (Panel B): Smoking (and/or the use of nicotine/nicotine-
containing products) is not permitted during the study.
Moderate RI (Panel A): Participants will follow the smoking restrictions (and if applicable,
the use of nicotine/nicotine-containing products) defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc) from the prestudy (screening) visit and until the poststudy visit.
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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.
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/randomization number.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies study intervention(s) provided by the Sponsor will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in [Table 2].
08HKVC


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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
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. The rationale 
for selection of doses to be used in this study is in Section 4.3.
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.
Participants will be assigned an allocation number for a single treatment using the allocation 
schedule shown in [Table 3].
Table 3
Allocation of Participants to Treatment
Panel 
Impairment Stage 
n 
Treatment 
A
Moderate RI
10
Single dose of MK-0616 10 mg
B
Healthy Control
8
Single dose of MK-0616 10 mg
RI=renal impairment
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 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 identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention. 
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
Healthy Matched Controls (Panel B):
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 may be used for minor ailments without prior consultation with 
the Sponsor.
Moderate RI (Panel A): 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 Clinical Director. 
The final decision on any supportive therapy rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
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 and following consultation with 
the Sponsor Clinical Monitor. 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 dosing and be 
able to withhold the use 4 hours prior to and 4 hours postdose of study drug. 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. 
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 
dosing.
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
Panels A and B: 
Listed below are specific restrictions for concomitant therapy or vaccination:

Nonlive vaccines may only be administered in consultation with the Sponsor prior to 
or following the receipt of study intervention according to the time frames specified 
in Exclusion Criteria (Section 5.2).
Exception: 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.
Investigational COVID-19 vaccines (ie, those not licensed or approved for 
Emergency Use) are not allowed.
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 (Escalation/Titration/Other)
See Section 8.11.6 for modifications permitted within protocol parameters.
6.6.1
Stopping Rules
The following stopping rules will be used during the conduct of this study.
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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 
(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
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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
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for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
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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 ~200 mL (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
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
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed
consent form.
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Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 2 weeks before the 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.
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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.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation.  Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff.
8.1.8.1
Timing of Dose Administration
Study intervention will be administered in the morning.
Approximately 240 mL of water will be provided during study intervention administration. 
Additional water may be provided in ~50 mL increments if necessary.
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 8.10.4 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 
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(clinical.specimen.management@merck.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Domiciling
Participants will report to the CRU the evening before the scheduled day of study 
intervention administration for each treatment period and remain in the unit until 48 hours 
postdose. At the discretion of the investigator, participants may be requested to remain in the 
CRU longer
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy assessments in this study; surrogate markers of efficacy are 
outlined in Section 8.7.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood volumes drawn/collected by 
visit and by sample type per participant, can be found in Appendix 10.8.
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Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
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.
8.3.2
Vital Signs
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent
position for at least 10 minutes before having VS measurements obtained. Semirecumbent 
VS will include HR, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participants' 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). 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 2 minutes before
measurement of orthostatic VS.
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8.3.3
Electrocardiograms
•
Triplicate 12-lead ECG will be obtained predose, single measurements will be obtained at 
postdose timepoints 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. 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 to 2 minutes apart, but no more than 2 minutes 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 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.
Before each period, predose ECGs will be obtained in triplicate at least 1 to 2 minutes 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 each treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with median predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The median value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the median 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 median value of the 
QTc interval from the 3 ECGs will represent the value at that time point. If the median 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 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.
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If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and 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
This section is not applicable.
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 drug relationship.
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators 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 for randomized participants only if the event causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including, but 
not limited to washout or discontinuation of usual therapy, diet, 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 he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in [Table 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 Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified 
Follow-up Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or run-
in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event.
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 24 hours of 
learning of event
ECI 
(require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do 
not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
(unless serious)
Overdose
Report if:
- receiving placebo run-in 
or other run-in medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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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 towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are WONCBP or males and 
partner pregnancy/lactation information is not required.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not Applicable
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
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Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
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.
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 (eg, 
samples at lower doses may not be measured if samples at higher doses reveal undetectable 
drug concentrations). If indicated, these samples may also be measured and/or pooled for 
assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-0616
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations Manual.
8.6.2
Urine Collection for Urinary MK-0616
Sample collection, storage, and shipment instructions for urine samples will be provided in 
the Operations Manual.
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For participants with RI, urine samples will be collected whenever possible, as participants 
may not be able to produce urine at each interval.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples (PCSK9 
free) will be in the Operations Manual.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
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.
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
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research 
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 4 weeks before intervention allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5.
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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/randomization if 
there are Day -1 procedures planned per protocol.
8.10.2
Treatment Period Visit
Following confirmation that each participant meets inclusion/exclusion criteria and that all 
predose procedures have been completed, participants will be assigned a unique allocation 
number associated with a specific treatment sequence as defined by a computer allocation 
schedule. 
Before each treatment, participants will report to the CRU on Day -1 or at a time specified by 
the investigator. Participants will fast from all food and drink except for water, for a at least 
8 hours before study drug administration and at least 1 hour after study drug administration 
(refer to Section 5.3.1 for specific dietary restrictions during dosing).
Participants will remain in the CRU up to 48 hours postdose. Participants may be required to 
remain in the CRU for longer than 48-hours postdose at the discretion of the investigator. 
Participants will be administered the assigned treatment in the morning. The exact clock time 
of dosing should be recorded. 
8.10.3
Discontinued Participants 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 a PCL.
8.10.4
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.
8.10.5
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.
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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].
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
Predose standard safety evaluations: 
•
VS and ECG up to 3 hours predose
•
laboratory safety tests and physical exam up to 24 hours predose
Postdose standard safety evaluations:
•
VS, ECG, laboratory safety tests, and physical exam
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical 
sampling time
-
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time
-
From 48-hours to 168-hours postdose may be obtained within 2 hours of the 
theoretical sampling time
8.10.6
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 
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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 panel
•
Entire panel(s) may be omitted
•
Adjustment of the dosing interval (eg, divided doses [bid to qd, qd to bid, tid, or vice 
versa])
•
Remove a planned PK pause if agreed by Sponsor and investigator if no further increases 
in total daily dose
•
Addition of PK pause
•
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
•
Modification of urine sample collection
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 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
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
Primary
Pharmacokinetics
Objective:
To compare the plasma PK of MK-0616 following a single dose administration in 
participants with moderate renal impairment to those of healthy matched control participants.
Separately for each PK parameter, individual values of plasma MK-0616 AUC0-inf and 
Cmax will be natural log-transformed and evaluated with a linear fixed-effects model 
containing a categorical effect for populations. The REPEATED statement with the 
GROUP=Population option will be used in SAS PROC MIXED to estimate separate 
variances for each population. The Kenward and Roger adjustment will be used to calculate 
the denominator degrees of freedom for the fixed-effect (DDFM=KR).
Ninety-five percent 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 geometric 
means and CIs about the geometric means on the original scale.
To compare participants with moderate RI to matching participants with normal renal 
function, a 2-sided 90% confidence interval for the true difference in means (moderate RI-
normal renal function) will be calculated for each PK parameters (AUC0-inf and Cmax) 
using the mean square error from the model and referencing a t-distribution. The confidence 
limits will be exponentiated to obtain the 90% CI for the true ratio of geometric means 
(moderate RI/normal renal function) for each PK parameter.
Figures showing individual PK values with GMs (95% CIs) by population, plotted on the 
natural log scale, will be provided for AUC0-inf and Cmax.
Secondary
Safety 
Objective:
To evaluate the safety and tolerability of the administration of a single dose MK-0616 in 
participants with moderate renal impairment. 
The safety and tolerability of MK-0616 will be monitored by clinical assessment of adverse 
experiences and other safety measurements (eg, labs, vital signs, ECGs).
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Urine
Objective:
To compare the urine PK of MK-0616 following a single dose of MK-0616 to participants 
with moderate renal impairment to those of healthy matched control participants.
MK-0616 Ae0-24, Fe, and CLr following a single dose of MK-0616 administered to 
participants with moderate renal impairment, 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 for the least square means for each 
population will be constructed. To compare participants with moderate RI 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).
% Reduction of Free PCSK9
Objective: To evaluate the % reduction of free PCSK9 from baseline following 
administration of a single dose of MK-0616
Estimation: The difference between % reduction of free PCSK9 from baseline following
administration of a single dose of MK-0616 among participants with moderate renal 
impairment and in healthy matched control participants will be estimated. 90% CIs will also 
be reported for this difference.
Sample Size and Power Calculations
The precision of the estimated GMR (moderate renal impairment/normal renal function) of 
PK parameters obtained from this study can be assessed by calculating the halfwidth of the 
90% CIs expected for the given sample size and assumed variability. The pooled between-
subject standard deviation (on the natural log scale) for MK-0616 AUC0-inf as estimated 
from P001 and P004 is 0.29 ln(μM•hr). 
Assuming a sample size of 8 participants per population and observed between-subject SDs 
as given above, then the half width of the 90% CIs of GMRs for MK-0616 AUC0-inf on the 
log scale will be 0.294. The lower and upper 90% confidence limits for the true GMRs will 
be given by OBS/1.34 and OBS*1.34 for AUC0-inf, where OBS is the observed GMR. Thus, 
for example, if the observed GMR for AUC0-inf was 2, then the 90% CI for the GMR would
be 1.49 to 2.68.
9.2
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
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with the Quantitative Pharmacology and Pharmacometrics Department and Translational
Medicine Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below,
then these deviations to the plan will be listed, along with an explanation as to why they
occurred, in the CSR.
9.3
Hypotheses/Estimation
Pharmacokinetics
Objective:
To compare the plasma PK of MK-0616 following a single dose administration in 
participants with moderate renal impairment to those of healthy matched control participants.
Estimation: MK-0616 AUC0-inf following a single dose of MK-0616 administered to 
participants with moderate renal impairment will be estimated and compared to MK-0616 
AUC0-inf when administered to healthy matched control participants.
Urine
Objective:
To compare the urine PK of MK-0616 following a single dose of MK-0616 to participants 
with moderate renal impairment 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 moderate renal impairment, will be estimated and compared 
to those estimated in healthy matched control participants.
% Reduction of free PCSK9
Estimation: The difference between % reduction of free PCSK9 from baseline caused due to 
administration of a single dose of MK-0616 among participants with moderate renal 
impairment and in healthy matched control participants will be estimated. 90% Confidence 
intervals will also be reported for this difference.
9.4
Analysis Endpoints
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 
moderate renal impairment or in healthy matched control participants.
The urine MK-0616 Ae0-24, Fe, and CLr following a single MK-0616 dose in participants 
with moderate renal impairments or in healthy matched control participants.
The secondary safety endpoints are AEs, VS, 12-lead ECGs, and laboratory safety tests.
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9.5
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.
All Participants as Treated (APaT): 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.
Per-Protocol (PP): The Per-Protocol Population consists of the subset of participants who
comply with the protocol sufficiently to ensure that generated data will be likely to exhibit
the effects of treatment, according to the underlying scientific model. Compliance covers
such considerations as exposure to treatment, availability of measurements and absence of
important protocol deviations. Important protocol deviations will be identified to the extent
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be
identified, along with the reason for exclusion, in the CSR. At the end of the study, all
participants who are compliant with the study procedure as aforementioned and have
available data considered sufficient to exhibit the effect of treatment will be included in the
Per-Protocol dataset. This population will be used for the PK analyses.
9.6
Statistical Methods
Primary
Pharmacokinetics:
Separately for each PK parameter, individual values of plasma MK-0616 AUC0-inf and 
Cmax will be natural log-transformed and evaluated with a linear fixed-effects model 
containing a categorical effect for populations. The REPEATED statement with the
GROUP=Population option will be used in SAS PROC MIXED to estimate separate
variances for each population. The Kenward and Roger adjustment will be used to calculate
the denominator degrees of freedom for the fixed-effect (DDFM=KR).
Ninety-five percent 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 moderate RI 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 parameters (AUC0-inf and Cmax) using the mean square error 
from the model and referencing a t-distribution. For each population, these confidence limits 
will be exponentiated to obtain the 90% CI for the true GMRs (RI/normal renal function) for 
each PK parameter.
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Figures showing individual PK values with GMs (95% CIs) by population, plotted on the
natural log scale, will be provided for AUC0-inf and Cmax.
Secondary
Safety
The safety and tolerability of MK-0616 will be monitored by clinical assessment of adverse 
experiences and other safety measurements (eg, labs, VS, ECGs).
Urine PK
MK-0616 Ae0-24, Fe, and CLr following a single dose of MK-0616 administered to 
participants with moderate renal impairment, 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 moderate RI 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).
% Reduction of free PCSK9
Estimation: The difference between % reduction of free PCSK9 from baseline caused due to 
administration of a single dose of MK-0616 among participants with moderate renal 
impairment and in healthy matched control participants will be estimated. Ninety percent CIs
will also be reported for this difference.
Summary Statistics using BSA un-normalized eGFR: The participants will be recategorized
into different renal categories based on their BSA un-normalized eGFR and non-model based
summary statistics by population will be provided for (plasma AUC0-inf, Cmax, Tmax,
elimination terminal t1/2, CL/F, and Vz/F, and urine Ae0-24, Fe, and CLr, as applicable).
Individual values will be listed for each PK parameter (plasma MK-0616 AUC0-inf, Cmax,
Tmax, elimination terminal t1/2, CL/F, and Vz/F, , and urine MK-0616 Ae0-24, Fe, and CLr) 
by population, and the following (non-model-based) descriptive statistics will be provided: N
(number of subjects with non-missing data), arithmetic mean, standard deviation, arithmetic
percent CV (calculated as 100 x standard deviation/arithmetic mean), median, minimum,
maximum, geometric mean, and geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), 
where s2 is the observed variance on the natural log-scale).
9.7
Interim Analyses
Not applicable.
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9.8
Multiplicity
There is no prespecified hypothesis; therefore, no multiplicity adjustment is needed.
9.9
Sample Size and Power Calculations
The sample size selected for each population to evaluate the effect of RI on the PK of 
MK-0616 was not chosen to satisfy any a priori statistical requirement. This sample size (n= 
8 participants per panel) has historically been shown to be sufficient for studies of this type 
and should provide adequate data to support the planned analyses. Nevertheless, estimates of 
the expected precision of the estimates, based on these sample sizes are presented below.
The precision of the estimated ratios of geometric means (moderate renal impairment / 
normal renal function) of PK parameters obtained from this study can be assessed by 
calculating the halfwidth of the 90% CIs expected for the given sample size and assumed 
variability. The pooled between-subject standard deviation (on the natural log scale) for MK-
0616 AUC0-inf after as observed in P001 and P004 is 0.29 ln(μM•hr). 
Assuming a sample size of 8 participants per population and observed between-subject SDs 
as given above, then the half width of the 90% CIs of GMRs for MK-0616 AUC0-inf on the 
log scale will be 0.294. The lower and upper 90% confidence limits for the true GMRs will 
be given by OBS/1.34 and OBS*1.34 for AUC0-inf, where OBS is the observed GMR. Thus, 
for example, if the observed GMR for AUC0-inf was 2, then the 90% CI for the GMR would
be 1.49 to 2.68.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. 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.
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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.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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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.
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 
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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 trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
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.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
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.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
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.
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.
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
eGFR (CKD-EPI)
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other 
Screening Tests
•
FSH (as needed in WONCBP only)
•
Serum or urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) if applicable]
•
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; HIV=human immunodeficiency virus; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; 
SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; WBC=white blood cell; WONCBP=women 
of nonchildbearing potential
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
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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, 
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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.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of causality
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
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•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not Applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
10.5.2
Contraception Requirements
Not Applicable
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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 Research
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 Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
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 Research
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 
(clinical.specimen.management@merck.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 Specimens
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 utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
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 Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
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 Research
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@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not Applicable
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10.8
Appendix 8: Blood Volume Table
Panels A and B
Prestudy
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory 
Safety Tests
2
1
1
4
12.5
50
HIV/Hepatitis 
Screen including 
FSH (if 
applicable)
1
1
6
6
Blood for 
Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for 
MK-0616
16
16
3
48
Blood for 
plasma PCSK9 
(free) assay
12
12
3
36
Total Blood Volume per Participant for Panels A, and Ba
148.5 mL
a If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up 
to 50 mL) may be obtained. Note: never to exceed 50 mL.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
Screen Failure 
Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
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 Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 
10 ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 
60 ms From Baseline
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Screen Failure 
Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
Female
QTc 480 ms
QTc 500 ms or Increase of 
60 ms From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P Mitrale or 
P Pulmonale
Ventricular Abnormalities
Voltage Criteria for 
LVH Plus Strain 
Pattern
Voltage Criteria for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more 
contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive 
of Myocardial Ischaemia 
In 2 or more 
contiguous leads
In 2 or more contiguous leads
T-wave Inversions 
Suggestive of Myocardial 
Ischaemia 
In 2 or more 
contiguous leads
In 2 or more contiguous leads
Non-specific 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 of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat 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:
a.
The participant may be excluded from the study;
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety 
test source document).
c.
The participant may be included in the study if the abnormality is consistent with 
a pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical
condition should be annotated on the laboratory report.
OR
d. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may 
enter the study.
b. 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
ADA
anti drug antibodies
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
Ae0-24
amount recovered in urine from 0 to 24 hours
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
BDS
blood drug screen
bid
twice daily
BMI
body mass index
BP
blood pressure
CCU
Cardiac care unit
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CLr
renal clearance
Cmax
maximum plasma concentration
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
DDI
drug-drug interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
Fe
fraction of dose recovered in urine
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
GI
gastrointestinal
GLP
good laboratory practices
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
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Abbreviation
Expanded Term
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
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
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug 
IRB
Institutional Review Board
ITP
idiopathic thrombocytopenic purpura
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
IWG
International Working Group
LDL-C
Low density lipoprotein - cholesterol
LLN
lower limit of normal
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
messenger RNA
MTD
maximum tolerated dose 
N/A
not applicable
NCI
National Cancer Institute
NCS
not clinically significant
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
OTC
over-the-counter
PCL
Protocol Clarification Letter
PCSK9
proprotein convertase subtilisin kexin 9
PK
Pharmacokinetic(s)
po
orally
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Abbreviation
Expanded Term
PP
per-protocol
PQC
product quality complaint
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RI
renal impairment
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transminase
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
SUSAR
suspected unexpected serious adverse reaction
t1/2
half life
Tmax
Time to maximum plasma concentration
UDS
urine drug screen
ULN
upper limit of normal
VS
vital signs
WBC
white blood cell
WONCBP
woman/women of nonchildbearing potential
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REFERENCES
[Levey, A.S., et al 2009]
Levey AS, Stevens LA, Schmid CH, 
Zhang Y, Castro AF III, Feldman HI, et al. 
A new equation to estimate glomerular 
filtration rate. Ann Intern Med 
2009;150(9):604-12.
[058SRV]
[Stevens, L. A., et al 2010]
Stevens LA, Schmid CH, Greene T, Zhang 
YL, Beck GJ, Froissart M, et al. 
Comparative performance of the CKD 
Epidemiology Collaboration (CKD-EPI) 
and the Modification of Diet in Renal 
Disease (MDRD) Study equations for 
estimating GFR levels above 60 
mL/min/1.73 m2. Am J Kidney Dis. 2010 
Sep;56(3):486-95.
[087F9Z]
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