Conditions: Hypercholesterolemia Familial Hypercholesterolemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 381
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of enclitide chloride, an oral PCSK9 inhibitor, in lowering low-density lipoprotein cholesterol (LDL-C) in participants with hypercholesterolemia. The primary hypothesis is that at least one of the four doses of enclitide chloride tested in this study is superior to placebo on percent change from baseline in LDL-C at Week 8.

Detailed description:

Arms:
arm 1: Participants will receive 6 mg of enlicitide chloride orally QD for 8 weeks arm 2: Participants will receive 12 mg of enlicitide chloride orally QD for 8 weeks arm 3: Participants will receive 18 mg of enlicitide chloride orally QD for 8 weeks arm 4: Participants will receive 30 mg of enlicitide chloride orally QD for 8 weeks arm 5: Participants will receive enlicitide chloride-matching placebo orally QD for 8 weeks

Interventions: intervention 1: Enclitide Chloride intervention 2: Placebo
Intervention descriptions: intervention 1: Enclitide Chloride administered orally intervention 2: Placebo matching enclitide chloride administered orally

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT05261126
Document Date:            24-May-2022
A Phase 2b, Randomized, Double-Blind,
Placebo-Controlled Study to Evaluate the
Efficacy and Safety of MK-0616 in Adults With
Hypercholesterolemia


PRODUCT: MK 0616  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-0616 in Adults With Hypercholesterolemia
Protocol Number: 008-04
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
152853
EudraCT
2021-005221-24
Approval Date: 24 May 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
24-MAY-2022
To update Sponsor’s entity name and address change and to add clarifications 
and minor updates.
Amendment 03
10-MAR-2022
United Kingdom-specific amendment created to fulfill health authority request.
Amendment 02
14-FEB-2022
South Korea-specific amendment created to fulfill health authority request.
Amendment 01
04-FEB-2022
Germany-specific amendment created to fulfill health authority request.
Original Protocol
03-NOV-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 4
Overall Rationale for the Amendments:
To update Sponsor’s entity name and address change and to add clarifications and minor updates. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
1.3 Schedule of Activities
Clarification on timing of visit added to 
Visits 4 and 5.
To ensure study participants have access to study 
intervention.
1.1 Synopsis
6.1 Study Intervention 
Administered
‘Test product’ replaced ‘Experimental’ in 
the Study Intervention Table ‘Use’ 
column.
To align with Japan regulatory requirements.
5 Study Population
Clarified the collection, use, and 
confidentiality of demographic data 
provided by participants.
Clarification
8 Study Assessments and 
Procedures
Updated maximum amount of blood 
needed for collection.
To reflect additional blood volume required for beta 
quantification LDL samples and for select countries with 
an additional clinic visit based on country-specific 
amendments.
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Section # and Name
Description of Change 
Brief Rationale 
8.2 Efficacy Assessments
9.4.1 Efficacy Endpoints
10.2 Appendix 2: Clinical 
Laboratory Tests
Updated description of LDL-C 
measurement.
To clarify method of LDL-C measurement.
Section 10.7 Appendix 7: 
Country-specific 
Requirements
Country-specific amendments for 
Germany, South Korea, and the United 
Kingdom were added to this amendment.
Changes are outlined in Section 10.7 and 
referenced in Sections 1.2 Schema, 1.3 
Schedule of Activities, 4.3 Justification for 
Dose, 5 Study Population, 5.1 Inclusion 
Criteria, 5.2 Exclusion Criteria, 5.3.1 
Meals and Dietary Restrictions, 6.5 
Concomitant Therapy, 7.1 Discontinuation 
of Study Intervention, 8 Study 
Assessments and Procedures, 8.3.7 
Pregnancy Testing, 8.4.7 Events of 
Clinical Interest, 8.11.1 Visit Reminders, 
8.11.7 Post-treatment, 10.2 Appendix 2: 
Clinical Laboratory Tests, and 10.5 
Appendix 5: Contraceptive Guidance.
To consolidate country-specific amendments 1, 2, and 3 
into this global amendment. 
Throughout the document
Minor editorial changes 
Editorial changes.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.2
Preclinical and Clinical Studies ...................................................................26
2.2.3
Ongoing Clinical Studies.............................................................................26
2.3
Benefit/Risk Assessment......................................................................................27
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................29
4.1
Overall Design......................................................................................................29
4.2
Scientific Rationale for Study Design.................................................................30
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.2
Safety Endpoints................................................................................31
4.2.1.3
Pharmacokinetic Endpoints ...............................................................32
4.2.1.4
Pharmacodynamic Endpoints.............................................................32
4.2.1.5
Planned Exploratory Biomarker Research.........................................32
4.2.1.5.1
Planned Genetic Analysis ........................................................32
4.2.1.6
Future Biomedical Research..............................................................32
4.2.2
Rationale for the Use of Placebo .................................................................33
4.3
Justification for Dose...........................................................................................33
4.4
Beginning and End-of-Study Definition ............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................34
5.1
Inclusion Criteria.................................................................................................34
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................40
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5.3.3
Activity Restrictions ....................................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................40
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................40
6.1.1
Medical Devices...........................................................................................42
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................43
6.4.1
Background Lipid-lowering Therapy Compliance ......................................44
6.4.2
Fasting Compliance .....................................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................45
6.6
Dose Modification (Escalation/Titration/Other)...............................................45
6.7
Intervention After the End of the Study............................................................45
6.8
Clinical Supplies Disclosure................................................................................45
6.9
Standard Policies..................................................................................................45
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................46
7.1
Discontinuation of Study Intervention...............................................................46
7.2
Participant Withdrawal From the Study...........................................................47
7.3
Lost to Follow-up .................................................................................................47
8
STUDY ASSESSMENTS AND PROCEDURES........................................................48
8.1
Administrative and General Procedures ...........................................................49
8.1.1
Informed Consent.........................................................................................49
8.1.1.1
General Informed Consent.................................................................49
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................49
8.1.2
Inclusion/Exclusion Criteria ........................................................................49
8.1.3
Participant Identification Card.....................................................................50
8.1.4
Medical History ...........................................................................................50
8.1.5
Prior and Concomitant Medications Review...............................................50
8.1.5.1
Prior Medications...............................................................................50
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8.1.5.2
Concomitant Medications..................................................................50
8.1.6
Dietary Counseling/Monitoring...................................................................50
8.1.7
Assignment of Screening Number...............................................................51
8.1.8
Assignment of Randomization Number.......................................................51
8.1.9
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing....................................................................................................51
8.1.10
Study Intervention Administration ..............................................................51
8.1.10.1
Timing of Dose Administration.........................................................51
8.1.11
Witnessed Dose............................................................................................52
8.1.12
Study Intervention Accountability (Overall Population).............................52
8.1.13
Background Lipid-Lowering Therapy Accountability ................................52
8.1.14
Fasting Accountability (Overall Population)...............................................52
8.1.15
Fasting Log (Subset)....................................................................................53
8.1.16
Discontinuation and Withdrawal .................................................................53
8.1.16.1
Withdrawal From Future Biomedical Research ................................53
8.1.17
Participant Blinding/Unblinding..................................................................54
8.1.18
Calibration of Equipment.............................................................................54
8.2
Efficacy Assessments ...........................................................................................55
8.3
Safety Assessments...............................................................................................55
8.3.1
Physical Examinations.................................................................................55
8.3.2
Height and Weight .......................................................................................55
8.3.3
Temperature.................................................................................................56
8.3.4
Vital Signs....................................................................................................56
8.3.5
Electrocardiograms ......................................................................................56
8.3.6
Clinical Safety Laboratory Assessments .....................................................57
8.3.7
Pregnancy Testing........................................................................................57
8.3.7.1
Pretreatment Confirmation of Postmenopausal State ........................58
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................58
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................58
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......60
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...61
8.4.4
Regulatory Reporting Requirements for SAE .............................................61
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................61
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................62
8.4.7
Events of Clinical Interest............................................................................62
8.5
Treatment of Overdose........................................................................................62
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8.6
Pharmacokinetics.................................................................................................62
8.6.1
Blood Collection for Plasma MK-0616 .......................................................62
8.7
Pharmacodynamics..............................................................................................63
8.8
Biomarkers ...........................................................................................................63
8.8.1
Planned Genetic Analysis Sample Collection..............................................63
8.9
Future Biomedical Research Sample Collection...............................................63
8.10
Medical Resource Utilization and Health Economics.......................................63
8.11
Visit Requirements...............................................................................................64
8.11.1
Visit Reminders ...........................................................................................64
8.11.2
Screening......................................................................................................64
8.11.3
Rescreening..................................................................................................64
8.11.4
Treatment Period..........................................................................................65
8.11.5
Unscheduled Visits ......................................................................................65
8.11.6
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................66
8.11.7
Post-treatment ..............................................................................................66
9
STATISTICAL ANALYSIS PLAN .............................................................................67
9.1
Statistical Analysis Plan Summary.....................................................................67
9.2
Responsibility for Analyses/In-house Blinding .................................................68
9.3
Hypotheses/Estimation ........................................................................................68
9.4
Analysis Endpoints...............................................................................................68
9.4.1
Efficacy Endpoints.......................................................................................68
9.4.2
Safety Endpoints..........................................................................................69
9.4.3
Pharmacokinetic Endpoint...........................................................................69
9.4.4
Pharmacodynamic Endpoint........................................................................69
9.5
Analysis Populations............................................................................................69
9.5.1
Efficacy Analysis Population.......................................................................69
9.5.2
Safety Analysis Population..........................................................................69
9.5.3
Pharmacokinetic Analysis Population .........................................................70
9.6
Statistical Methods...............................................................................................70
9.6.1
Statistical Methods for Efficacy Analysis....................................................71
9.6.1.1
Primary Efficacy Endpoint ................................................................71
9.6.1.2
Secondary Efficacy Endpoints...........................................................72
9.6.2
Statistical Methods for Safety Analyses ......................................................73
9.6.2.1
Overall Safety Assessment ................................................................73
9.6.2.2
Assessment of Safety Topics of Special Interest ...............................73
9.6.3
Demographic and Baseline Characteristics .................................................74
9.7
Interim Analyses ..................................................................................................74
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9.8
Multiplicity ...........................................................................................................75
9.9
Sample Size and Power Calculations .................................................................75
9.9.1
Efficacy........................................................................................................75
9.9.2
Safety ...........................................................................................................75
9.10
Subgroup Analyses...............................................................................................75
9.11
Compliance (Medication Adherence).................................................................76
9.12
Extent of Exposure...............................................................................................76
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................77
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........77
10.1.1
Code of Conduct for Clinical Trials.............................................................77
10.1.2
Financial Disclosure.....................................................................................79
10.1.3
Data Protection.............................................................................................80
10.1.3.1
Confidentiality of Data ......................................................................80
10.1.3.2
Confidentiality of Participant Records...............................................80
10.1.3.3
Confidentiality of IRB/IEC Information............................................80
10.1.4
Committees Structure...................................................................................81
10.1.4.1
Internal Data Monitoring Committee.................................................81
10.1.4.2
Scientific Advisory Committee (SAC)..............................................81
10.1.5
Publication Policy........................................................................................81
10.1.6
Compliance with Study Registration and Results Posting Requirements ...81
10.1.7
Compliance with Law, Audit, and Debarment ............................................82
10.1.8
Data Quality Assurance ...............................................................................82
10.1.9
Source Documents .......................................................................................83
10.1.10
Study and Site Closure.................................................................................84
10.2
Appendix 2: Clinical Laboratory Tests..............................................................85
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................88
10.3.1
Definition of AE ..........................................................................................88
10.3.2
Definition of SAE ........................................................................................89
10.3.3
Additional Events Reported.........................................................................90
10.3.4
Recording AE and SAE ...............................................................................90
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................94
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................95
10.5
Appendix 5: Contraceptive Guidance................................................................96
10.5.1
Definitions....................................................................................................96
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10.5.2
Contraception Requirements........................................................................97
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................98
10.7
Appendix 7: Country-specific Requirements..................................................103
10.7.1
Country-specific Requirements for Japan:.................................................103
10.7.2
Country-specific Requirements for Germany:...........................................103
10.7.3
Country-specific Requirements for South Korea.......................................104
10.7.4
Country-specific Requirements for the United Kingdom..........................105
10.7.4.1
DILI Site Guidance Document for Assessment and Follow-up ......107
10.7.4.1.1
Purpose...................................................................................107
10.7.4.1.2
Introduction............................................................................107
10.7.4.1.3
Close Observation Recommendations...................................108
10.7.4.1.4
Hepatic Assessment Flow Chart............................................109
10.7.4.1.5
Factors to Consider in Assessing Potential DILI...................109
10.7.4.1.5.1
Study Medication.........................................................110
10.7.4.1.5.2
Treatment .....................................................................110
10.7.4.1.5.3
Signs and Symptoms (Associated With the Potential 
DILI Event)..................................................................110
10.7.4.1.5.4
Confounding Variables ................................................110
10.7.4.1.5.5
Evaluation Algorithm for Potential DILI if There are 
no Other Clinical Reasons ...........................................111
10.7.4.1.5.6
Potential Diagnosis ......................................................114
10.7.4.1.5.7
Overall Clinical Impression.........................................115
10.7.4.1.5.8
Treatment Plan.............................................................115
10.7.4.1.6
Preapproved Tests..................................................................115
10.7.4.1.7
Contacts..................................................................................116
10.7.4.1.8
DILI Site Guidance Document References............................117
10.8
Appendix 8: ASCVD Risk Calculator..............................................................118
10.9
Appendix 9: Statin Intensity Chart Based on Total Daily Dose....................119
10.10 Appendix 10: Abbreviations .............................................................................120
11
REFERENCES.............................................................................................................123
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LIST OF TABLES
Table 1
ASCVD Status/Risk Categories and Corresponding LDL-C Ranges for 
Inclusion.....................................................................................................35
Table 2
Study Interventions....................................................................................41
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................59
Table 4
Analysis Strategy for Key Efficacy Endpoints..........................................72
Table 5
Analysis Strategy for Safety Parameters....................................................74
Table 6
Examples of AE Incidences for Which the 95% CI for the Difference 
Would Exclude Zero..................................................................................75
Table 7
Protocol-required Laboratory Assessments...............................................85
Table 8
PK and PD Sample Collection Times........................................................87
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-0616 in Adults With Hypercholesterolemia
Short Title: A Phase 2b Study of MK-0616 in Adults With Hypercholesterolemia
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In adults with hypercholesterolemia:
Objectives
Endpoints
Primary
•
Objective: To compare the effect of MK-
0616 with the effect of placebo on percent 
change from baseline in LDL-C at Week 
8.
•
Hypothesis: At least 1 of the 4 doses of 
MK-0616 is superior to placebo on 
percent reduction from baseline in LDL-C 
at Week 8.
•
LDL-C
•
Objective: To evaluate the safety and 
tolerability of each dose of MK-0616.
•
AEs
•
Discontinuation of study intervention due 
to AEs
Secondary
•
Objective: To compare the effect of MK-
0616 with the effect of placebo on percent 
change from baseline in ApoB and 
non-HDL-C at Week 8.
•
ApoB and non-HDL-C
•
Objective: To compare the effect of MK-
0616 with the effect of placebo on the 
proportion of participants with LDL-C 
value at goal at Week 8.
•
LDL-C (LDL-C goals are defined in 
Section 9.4.1)
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Hypercholesterolemia
Population
Male and female participants ≥18 and ≤80 years of age with 
hypercholesterolemia
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 13 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s last 
study-related contact.
Number of Participants:
Approximately 375 participants will be randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Study intervention will be administered in the fasted state, as described in 
Section 5.3.1.
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Treatment 
Period
Use
Group 1
MK 0616
6 mg
QD
oral
8 weeks 
(V2 to V5)
Test Product
Group 2
MK 0616
12 mg
QD
oral
8 weeks 
(V2 to V5)
Test Product
Group 3
MK 0616
18 mg
QD
oral
8 weeks 
(V2 to V5)
Test Product
Group 4
MK 0616
30 mg
QD
oral
8 weeks 
(V2 to V5)
Test Product
Group 5
Placebo
0 mg
QD
oral
8 weeks 
(V2 to V5)
Placebo
Abbreviations: QD once daily; V visit
Note: Each dose of MK 0616 is formulated with
of sodium caprate, a permeation enhancer.
Total 
Number of 
Intervention 
Groups/
Arms
5
Duration of 
Participation
Each participant will participate in the study for approximately 19 weeks from 
the time the participant provides documented informed consent through the 
final contact. After an up-to 21-day screening phase, each participant will 
receive assigned intervention for 8 weeks. After the end-of-treatment, each 
participant will be followed for 8 weeks for safety.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
CCI
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Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 10.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
a. Country specific requirements are in Appendix 7.
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1.3
Schedule of Activities
Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
Administrative Procedures
Informed Consent
X
Informed Consent for FBR
X
Participants remain eligible 
for the main study if they opt 
out of FBR.
Inclusion/Exclusion 
Criteria
X
X
Participant Identification 
Card
X
X
Add randomization number 
at V2/Day 1.
Medical History 
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
Dietary 
Counseling/Monitoring
X
X
X
X
X
See Section 5.3.1.
IRT Visit Registration
X
X
X
X
X
IRT Randomization
X
Dispense Study 
Intervention
X
X
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Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
Witnessed Dose
X
X
Study Intervention 
Accountability 
(overall population)
X
X
X
X
See Section 6.4 for details. 
Background Lipid-
lowering Therapy 
Accountability 
X
X
X
X
X
X
Only applicable for 
participants on background 
lipid-lowering therapy. See 
Section 6.4.1 for details.
Fasting Accountability 
(overall population)
X
X
X
X
Participants’ compliance 
with fasting guidelines 
(Section 5.3.1) relative to 
administration of study 
intervention will be assessed 
(Section 6.4.2). 
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Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
Provide or Configure 
Electronic Device for 
Fasting Log and Train on 
Completion of Fasting Log
(subset)
X
Between V2/Day 1 and 
V5/Wk 8 (or SI Discon 
Visit), a subset of 
participants will complete a 
daily Fasting Log (Section 
8.1.15). Use of a personal or
Sponsor-provided device for 
the Fasting Log will be 
determined at V1/Screening. 
Compliance with the Fasting
Log should be reinforced at 
each visit.
Collect Electronic Device 
From Participant (subset)
X
X
For participants who 
received an electronic device 
for the Fasting Log. 
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Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
Dispense Urine Pregnancy 
Test Kits (WOCBP only)
X
X
WOCBP will perform a
urine pregnancy test 
approximately 4 and 8 weeks 
after the last dose of study 
intervention. A serum test 
will be performed if a urine 
test is not acceptable per 
local regulations 
(Section 8.3.7).  
Efficacy Assessments
Lipid Panel
X
X
X
X
X
X
Lipid panel parameters are 
listed in Appendix 2. 
VLDL-C, ApoB, ApoA1, 
Lp(a), hsCRP
X
X
X
Safety Assessments
Full Physical Examinationa
X
X
X
Directed Physical 
Examination
X
Height
X
Weight
X
X
X
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Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
Temperature
X
Vital Signs (blood 
pressure, pulse rate)
X
X
X
X
X
X
12-lead ECG (local)a
X
X
X
Chemistry (including CK)
X
X
X
X
X
X
A1C
X
X
X
X
A1C will only be assessed in 
participants with a history of 
diabetes mellitus.
Hematology
X
X
X
X
X
X
Urine or Serum hCG, 
(WOCBP only, per local 
requirements)
X
X
X
X
X
In addition to the visits 
shown here, WOCBP will 
perform urine pregnancy 
tests approximately 4 and 8 
weeks after the last dose of 
study intervention using site-
provided kits. A serum test 
will be performed if a urine 
test is not acceptable per 
local regulations 
(Section 8.3.7 for details).
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Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
FSH
X
FSH may be measured to 
confirm postmenopausal 
state (Appendix 5). Testing 
requirements for FSH are in 
Section 8.3.7.1.
TSH
X
FT4
X
Only in participants with 
hypothyroidism.
AE Monitoring
X
X
X
X
X
X
X
X
PK, PD, and Biomarkers
PK Sample Collection
X
X
X
X
Refer to Appendix 2 and the 
laboratory manual for details 
on collection of PK samples, 
and Section 8.9 for details on 
FBR.
Plasma PCSK9 Sample 
Collection
X
X
X
X
Refer to Appendix 2 and the 
laboratory manual for details 
on collection of PCSK9 
samples, and Section 8.9 for 
details on FBR. 
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Study Period:
Screening
Treatment
Post-Treatment 
Follow-up
SI
Discon
Notes
Visit Number/Title:
1
2
3
4
5
6 (TC)
7 
(TC)a
Participants who discontinue 
study intervention 
prematurely will have an SI 
Discon Visit. These 
participants will be 
encouraged to remain in the 
study despite discontinuation 
of study intervention 
(Section 7.1).
Week/Day:
Day
-21 to -1
Day
1
Wk
2
Wk
4
Wk
8
Wk
10
Wk
16
N/A
Visit Windows (Days):
N/A
N/A
+5
±5b
±5b
+7
+7
N/A
Blood for Genetic Analysis
X
Collect predose at V2/Day 1. 
See Section 8.8.1.
Plasma for FBR
X
X
X
Collect predose at V2/Day 1.
A1C glycosylated hemoglobin, AE adverse event, ApoA1 apolipoprotein A1, ApoB apolipoprotein B, CK creatine kinase, 
FBR future biomedical research, FSH follicle stimulating hormone, FT4 free T4 test, hCG human chorionic gonadotropin,
hsCRP high-sensitivity C-reactive protein, IRT interactive response technology, Lp(a) lipoprotein (a), N/A not applicable, 
PCSK9 protein convertase subtilisin/kexin type 9, PD pharmacodynamic, PK pharmacokinetic, QD once daily, SI Discon study 
intervention discontinuation, TC telephone call, TSH thyroid stimulating hormone, V visit, VLDL-C very low-density lipoprotein 
cholesterol, Wk week, WOCBP woman of childbearing potential.
a. Country-specific requirements are in Appendix 7.
b. The maximum time between on-treatment visits must not exceed 35 days since study intervention supplies contain 35 capsules to be 
taken QD.
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2
INTRODUCTION
2.1
Study Rationale
Cardiovascular disease, principally ASCVD, is the leading cause of global mortality and a 
major contributor to disability [Roth, G. A., et al 2021]. Epidemiologic, genetic, and clinical 
intervention studies have shown that LDL-C is causally associated with ASCVD, and that 
lifestyle and pharmacologic reductions in LDL-C lower the risk of myocardial infarction, 
stroke, and death from cardiovascular disease [Ference, B. A., et al 2017]. Despite the 
availability of several proven LDL-C-lowering therapies (eg, statins, ezetimibe, bile acid 
sequestrants, PCSK9 inhibitors), a substantial proportion of patients with 
hypercholesterolemia are not at guideline-recommended LDL-C targets [Fox, K. M., et al 
2018]. This information supports the need for additional LDL-C-lowering therapies for the 
treatment of hypercholesterolemia.
PCSK9 is a well-validated target for lowering LDL-C and reducing ASCVD risk, with strong 
human genetics implicating an important role for PCSK9 in regulating LDL-C. Circulating 
PCSK9 molecules bind to cell surface LDL receptors and direct the receptors to intracellular 
lysosomes for degradation instead of back to the surface, resulting in reduced clearance of 
LDL-C from the circulation. Thus, blockade of the PCSK9-LDL receptor interaction 
increases steady state levels of cell surface hepatic LDL receptors, which enhances LDL-C 
clearance and lowers circulating levels of LDL-C. 
Several injectable PCSK9 inhibitors have received regulatory approval for the treatment of 
hypercholesterolemia. Unlike these injectable therapies, MK-0616 is an orally administered
PCSK9 inhibitor for the treatment of hypercholesterolemia. An oral PCSK9 inhibitor, that 
can achieve equivalent LDL-C-lowering as the injectable PCSK9 inhibitors, offers potential 
advantages in simplicity of dosing, patient preference, and access.
The principal objectives of this Phase 2b study are to evaluate the LDL-C-lowering efficacy 
and safety of MK-0616 in participants with hypercholesterolemia. This study will also be 
used to support dose selection of MK-0616 for future development.
2.2
Background
Refer to the IB for detailed background information on MK-0616.
2.2.1
Pharmaceutical and Therapeutic Background
MK-0616 is a cyclic peptide that binds to human PCSK9 and prevents interaction of PCSK9 
with the LDL receptor. This action results in a reduction in PCSK9-mediated degradation of 
the LDL receptor and a resultant increase in clearance of LDL particles and reduction in 
plasma LDL-associated cholesterol.
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Objectives
Endpoints
•
Objective: To evaluate the safety and 
tolerability of each dose of MK-0616.
•
AEs
•
Discontinuation of study intervention due 
to AEs
Secondary
•
Objective: To compare the effect of MK-
0616 with the effect of placebo on percent 
change from baseline in ApoB and 
non-HDL-C at Week 8.
•
ApoB and non-HDL-C
•
Objective: To compare the effect of MK-
0616 with the effect of placebo on the 
proportion of participants with LDL-C 
value at goal at Week 8.
•
LDL-C (LDL-C goals are defined in 
Section 9.4.1)
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Objectives
Endpoints
•
Germline genetic variation and 
association to clinical data collected in 
this study
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2b, randomized, double-blind, placebo-controlled, multi-site study of 
MK-0616 in participants with hypercholesterolemia. Participants with a range of ASCVD 
risk are eligible for the study, including those who are not on any lipid-lowering therapy 
(including participants who stopped prior treatment and treatment naïve participants), as well 
as those on 1 or more lipid-lowering therapies, and those with or without heterozygous FH.
Participants with homozygous FH and those on treatment with a PCSK9 inhibitor 
are not eligible for the study.
This study consists of an up-to 21-day screening period (Visit 1 [Screening] to Visit 2
[Day 1]), an 8-week treatment period (Visit 2 [Day 1] to Visit 5 [Week 8]), and an 8-week 
post-treatment follow-up period (Visit 5 [Week 8] to Visit 7 [Week 16]) for safety
assessment. Participants who discontinue study intervention prematurely will be encouraged
to continue in the study off-treatment and to complete all remaining visits as outlined in the 
SoA.
After completing the screening period, approximately 375 participants meeting eligibility 
criteria will be randomized in a 1:1:1:1:1 ratio to treatment with either 1 of 4 doses of 
MK-0616 (6, 12, 18, or 30 mg) or placebo. Randomized participants will administer 1 
capsule of study intervention daily (Table 2) in the fasted state according to the guidelines 
provided in Section 5.3.1. 
Randomization will be stratified by renal function (eGFR ≥60 or <60 ml/min/1.73 m2) at 
Visit 1 (Screening) and by dose of background statin therapy (Sections 4.2 and 6.3.2), with 
an aim to enroll approximately one-third of participants in each of the following statin 
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4.2.1.3
Pharmacokinetic Endpoints
Trough concentrations of MK-0616 will be summarized to inform on MK-0616 exposure in 
participants. 
4.2.1.4
Pharmacodynamic Endpoints
PCSK9 inhibition reduces free plasma PCSK9 concentrations. In the Phase 1 single 
ascending-dose study, all doses of MK-0616 led to maximum mean reductions of >90% from 
baseline in free plasma PCSK9. The effects of MK-0616 on free plasma PCSK9 will be 
measured in the current study to inform on dose selection for the Phase 3 program.
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.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
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4.2.2
Rationale for the Use of Placebo
This study will be placebo-controlled in order to avoid bias in the collection and evaluation 
of data during its conduct and to assess whether any observed effects are treatment-related or 
an effect of study participation. Use of placebo is considered acceptable in this study given 
the short study duration, the frequent evaluation of participants at scheduled visits, and 
because higher-risk participants with ASCVD or ASCVD risk-equivalents are expected to be 
on stable treatment with background LDL-C-lowering therapy (per local guidelines) and to 
continue this therapy throughout the study. 
4.3
Justification for Dose
Four doses of MK-0616 (6, 12, 18, and 30 mg) will be tested in this study. In the Phase 1 
multiple ascending-dose study in participants on background statin therapy (P003), the mean 
reduction from baseline in LDL-C at Day 14 was >50% with both the 10 and 20 mg fasting 
doses of MK-0616. Although a lower dose could not be tested, a 10 mg fed dose, which is 
presumed to behave like a 5 mg fasted dose given the food effect (Section 2.2.2), did not 
attain similar LDL-C reductions.
In the current study of MK-0616, the planned doses will allow for refinement of the 
exposure-response relationship and selection of a Phase 3 dose by populating the ascending 
and descending phases of the exposure-response curve and characterizing EC50 and the 
Emax plateau, and will also ensure that there is an adequate safety margin for the anticipated 
clinical dose in the projected patient population.
Additional country-specific justification for dose is in Appendix 7.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1) our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data are to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Male and female participants ≥18 and ≤80 years of age with hypercholesterolemia and a 
range of ASCVD risk, including those who are not on any lipid-lowering therapy (including 
participants who stopped prior treatment and treatment naïve participants), as well as those 
on 1 or more lipid-lowering therapies, and those with or without heterozygous FH will be 
enrolled in this study.
Participants with an exclusionary laboratory value (see Sections 5.1 and 5.2) may have 1
repeat determination performed if the investigator considers the Visit 1 (Screening) result to 
be inconsistent with prior determinations. Only the laboratory test not meeting entry criterion 
should be repeated (not the entire panel). The last laboratory draw/result should be used to 
assess eligibility.
Country-specific inclusion and exclusion criteria are in Appendix 7.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. Meets 1 of the following ASCVD status/risk categories AND has a fasted LDL-C value 
in the corresponding LDL-C range at Visit 1 (Screening) (Table 1).
Note 1: ASCVD status/risk categories are mutually exclusive, therefore, the highest 
applicable ASCVD status/risk category should be used to determine participant eligibility
and corresponding LDL-C range.
Note 2: See Appendix 7 for additional eligibility requirements for participants in Japan.
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Table 1
ASCVD Status/Risk Categories and Corresponding LDL-C Ranges for Inclusion
ASCVD Status/Risk Category
Corresponding LDL-C Range
(mg/dL)
(mmol/L)
Has clinical ASCVD1
≥70 and ≤160 
≥1.81 and ≤4.14
Has an ASCVD risk equivalent2
and/or a 10-year risk of having 
an ASCVD event that is ≥7.5%3
≥100 and ≤200 
≥2.59 and ≤5.18
Has a 10-year risk of having an 
ASCVD event that is ≥5.0% and 
<7.5%3
≥130 and ≤250
≥3.37 and ≤6.48
1 Clinical ASCVD is defined as having a history of 1 or more of the following: acute coronary syndrome,
myocardial infarction, angina pectoris, coronary revascularization, arterial revascularization, stroke, transient 
ischemic attack, peripheral arterial disease [Grundy, S. M., et al 2019].
2 ASCVD-risk equivalents include diabetes mellitus and heterozygous FH. The diagnosis of heterozygous FH 
should be definitive and based on an established diagnostic algorithm (eg, US MEDPED, Simon Broome, Dutch 
Lipid Network, or Japanese Atherosclerosis Society Guidelines) [McGowan, M. P., et al 2019] [Kinoshita, M., 
et al 2018]. 
3 The 10-year risk percentage for having an ASCVD event will be determined using an ASCVD risk calculator 
(Appendix 8).
2. Is either on a stable dose of 1 or more lipid-lowering therapies for ≥30 days before 
Visit 1 (Screening) or has not received treatment with any lipid-lowering therapy for 
≥30 days before Visit 1 (Screening). Those who are not on a lipid-lowering therapy at 
Visit 1 (Screening) can either have been previously treated or be treatment naïve.
Note 1: Lipid-lowering therapies include medications (eg, statins, ezetimibe, 
bempedoic acid, niacin, fibrates) and supplements (eg, omega-3 fatty acids) that can 
affect cholesterol levels. 
Note 2: For all participants, there should be no planned lipid-lowering therapy additions 
or dose changes during the study (Visit 1 [Screening] to Visit 7 [Week 16]).
Country-specific requirements for inclusion criterion #2 are in Appendix 7.
Demographics
3. Is male or a female, ≥18 years and ≤80 years of age, at the time of providing documented 
informed consent.
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Female Participants
4. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses an acceptable contraceptive method, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 8 weeks after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies
-
Has a negative highly sensitive pregnancy test (urine or serum as required by local 
regulations) within 72 hours before the first dose of study intervention. If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. Additional requirements for pregnancy testing 
during and after study intervention are in Section 8.3.7.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Country-specific contraception requirements are in Appendix 7.
Informed Consent
5. The participant (or legally acceptable representative) provides 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.
Country-specific information for participants in Germany is provided in Appendix 7.
Additional Categories
6. Is willing and considered able by the investigator to comply with study procedures, 
including adherence with study intervention, fasting guidelines (Section 5.3.1), and visit 
schedule.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has a history of homozygous FH based on genetic or clinical criteria [Cuchel, M., et al 
2014].
2. Has a history of nephrotic syndrome.
3. Has any clinically significant malabsorption condition.
4. Had unstable angina, a myocardial infarction, percutaneous transluminal coronary 
angioplasty, transient ischemic attack, or stroke within 3 months before Visit 1 
(Screening).
5. Has a planned coronary revascularization procedure within the next 3 months after 
Visit 1 (Screening).
6. Has poorly controlled diabetes mellitus, defined as A1C ≥9.0%, at Visit 1 (Screening).
7. Has a known allergy or intolerance to any of the ingredients in the study intervention. 
8. Has a history of malignancy ≤3 years before Visit 1 (Screening), except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer, which have no 
timeframe limitations relative to Visit 1 (Screening).
9. Has a severe, acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or administration of study 
intervention or may interfere with the interpretation of study results and, in the opinion of 
the investigator, would make the participant inappropriate for entry into this study.
Prior/Concomitant Therapy
10. Is undergoing or previously underwent an LDL-C apheresis program within 3 months 
before Visit 1 (Screening). 
11. Is receiving treatment with oral semaglutide at Visit 1 (Screening).
12. Meets 1 or more of the following criteria:
•
Is on treatment with a PCSK9 inhibitor (siRNA or mAb), an ANGPTL3 inhibitor, or 
an MTP inhibitor (eg, lomitapide) at Visit 1 (Screening).
•
Was previously treated with an siRNA PCSK9 inhibitor within 1 year before Visit 1
(Screening).
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•
Was previously treated with a mAb PCSK9 inhibitor within 6 months before Visit 1 
(Screening).
•
Was previously treated with an ANGPTL3 inhibitor within 6 months before Visit 1 
(Screening).
•
Was previously treated with an MTP inhibitor (eg, lomitapide) within 1 month before 
Visit 1 (Screening).
Prior/Concurrent Clinical Study Experience
13. Is currently participating in or has previously participated in an interventional clinical 
study within 3 months (or 5 half-lives for agents in the previous study, whichever is 
longer) before Visit 1 (Screening). 
Diagnostic Assessments
14. Has moderate or greater renal insufficiency defined as eGFR <45 mL/min/1.73 m2 at 
Visit 1 (Screening); eGFR will be calculated according to Appendix 2. (Germany-specific 
criterion is in Appendix 7).
15. Has laboratory or clinical evidence of clinically significant hepatic conditions, including 
1 or more of the following:

ALT or AST >2X ULN at Visit 1 (Screening).

A history of hepatitis or liver disease that, in the opinion of the investigator, 
has been active within the 6 months before Visit 1 (Screening) and may 
increase the risk associated with study participation or administration of study 
intervention.
Country-specific exclusion requirements are in Appendix 7.
16. Has elevated CK >3X ULN at Visit 1 (Screening).
17. Has a fasting triglyceride value ≥400 mg/dL (≥4.52 mmol/L) at Visit 1 (Screening).
18. Has an abnormal TSH value at Visit 1 (Screening) without a history of hypothyroidism. 
Participants with a history of hypothyroidism are eligible if their treatment for this 
condition is stable for ≥3 months before Visit 1 (Screening) and their FT4 value at 
Visit 1 (Screening) is normal. 
Other Exclusions
19. Routinely consumes >3 alcoholic drinks per day. One standard drink is defined as any 
beverage containing 14 g of pure alcohol (ie, 12 oz of beer, 8 to 9 oz of malt liquor, 5 oz 
of wine, 1.5 oz of distilled spirits).
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20. Has a recent history of drug abuse (within the last year) or is a current user of recreational 
or illicit drugs at the time of Visit 1 (Screening).
21. 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.
22. Country-specific exclusion criterion is in Appendix 7.
23. Country-specific exclusion criterion is in Appendix 7.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Fasting Guidance for Clinic Visits
In order to ensure laboratory parameters are collected in the fasted state, participants will be 
contacted approximately 3 days before each clinic visit and instructed to fast (ie, no food, 
study intervention [if applicable], or beverages, except small amounts of water) for ≥8 hours 
before the visit. Non-study medications should be taken as prescribed.
Country-specific requirements are in Appendix 7.
At Visit 1 (Screening), the fast may be broken after laboratory samples are collected. For 
other clinic visits, the fast may be broken 30 minutes after administration of study 
intervention. Timing of dosing study intervention is described in Section 8.1.10.1.
Fasting Guidance on Days With no Clinic Visit
After Visit 2 (Day 1), on days with no clinic visit, participants should:
1. Take their dose of study intervention (with water) first thing in the morning following an 
overnight fast (≥8 hours), and 
2. Withhold food and beverages (except water) until 30 minutes after administration of 
study intervention.
Note: Non-study medications should be taken as prescribed.
Dietary Counseling/Monitoring
At Visit 1 (Screening), participants will receive counseling from a qualified healthcare 
professional on a diet consistent with local guidelines. At each subsequent visit, participants
will be asked about their diet and exercise, and further counseling should be provided, as 
appropriate. Detailed dietary information will not be captured in the database.
Country-specific requirements are in Appendix 7.
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
Participants will be counseled to limit alcohol use to moderate amounts while participating in 
the study (ie, ≤3 drinks per day and not more than 21 drinks per week). One standard drink is 
defined as any beverage containing 14 g of pure alcohol (ie, 12 oz of beer, 8 to 9 oz of malt 
liquor, 5 oz of wine, 1.5 oz of distilled spirits).
Participants should be advised to refrain from nicotine-containing products and ingesting 
caffeine for at least 30 minutes before blood pressure, pulse rate, and ECG determinations
(Sections 8.3.4 and 8.3.5).
5.3.3
Activity Restrictions
Participants will be instructed not to initiate a strenuous exercise program during the study. 
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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 (MK-0616 and matching placebo) provided by the Sponsor will be 
packaged to support enrollment.  Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study will be administered in the fasted state 
(Section 5.3.1) and are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Group 
1 
Experi-
mental
MK-0616
Drug
Capsule
6 mg
6 mg QD
Oral
8 weeks (V2 to V5)
Test 
Product
IMP
Central
Group 
2
Experi-
mental
MK-0616
Drug
Capsule
12 mg
12 mg QD
Oral
8 weeks (V2 to V5)
Test 
Product
IMP
Central
Group 
3
Experi-
mental
MK-0616
Drug
Capsule
18 mg
18 mg QD
Oral
8 weeks (V2 to V5)
Test 
Product
IMP
Central
Group 
4
Experi-
mental
MK-0616
Drug
Capsule
30 mg
30 mg QD
Oral
8 weeks (V2 to V5)
Test 
Product
IMP
Central
Group 
5
Placebo 
Com-
parator
Placebo
Drug
Capsule
0 mg
0 mg QD
Oral
8 weeks (V2 to V5)
Placebo
IMP
Central
EEA European Economic Area; IMP investigational medicinal product; NIMP noninvestigational medicinal product; QD once daily; V visit.
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to
the definition/classification of IMP/NIMP may exist (Appendix 7). In these circumstances, local legislation is followed.
Note: Each dose of MK 0616 is formulated with
of sodium caprate, a permeation enhancer.
CCI
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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 (not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.10 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.1.1
Medical Devices
No medical devices are tested in this study. 
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 5 study 
intervention arms. Participants will be assigned randomly in a 1:1:1:1:1 ratio to once-daily 
treatment with 1 of the 4 doses of MK-0616 (6, 12, 18, or 30 mg) or placebo.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Background statin dose (no statin therapy vs. low- to moderate-intensity statin
therapy vs. high-intensity statin therapy [Appendix 9]). Details on enrollment by 
statin category are in Section 4.1.
2. Renal function (eGFR ≥60 vs <60 mL/min/1.73 m2) at Visit 1 (Screening); eGFR will 
be calculated according to Appendix 2.
The rationale for the stratification factors used in this study is in Section 4.2.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-0616 and placebo will 
be packaged identically so that blind is maintained. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the intervention assignments.
The Sponsor will be unblinded to participants’ treatment assignments after the first database 
lock. Participants and investigators will remain blinded to participants’ treatment 
assignments until after the second database lock (Section 4.1).
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan that result in <80% compliance with 
study intervention will require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
•
Compliance with study intervention will be assessed by counting returned capsules,
corroborated with participant reporting. To facilitate this, participants will be instructed 
to bring unused study intervention and empty bottles to each clinic visit after Visit 2
(Day 1). Those who are non-compliant with study intervention will receive additional 
counseling by site staff.
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•
Any discrepancies between the actual and expected amount of unused study intervention 
will be discussed with the participant at the time of the visit, and any explanation will be 
documented in the source records. Intervention start and stop dates, including dates for 
intervention delays will be recorded in the eCRF.
6.4.1
Background Lipid-lowering Therapy Compliance
Compliance with lipid-lowering therapy (medications and/or supplements), in those on 
lipid-lowering therapy at Visit 1 [Screening], will be assessed by direct questioning. Those 
who report non-compliance with taking their lipid-lowering therapy in the screening or 
double-blind treatment period will receive additional counseling by site staff.
6.4.2
Fasting Compliance
Participants in the overall population will be instructed to fast before and after administration 
of study intervention according to the guidance provided in Section 5.3.1. Compliance with 
the fasting guidance during the week before each visit will be assessed by direct questioning. 
Those whose compliance with fasting guidance is <80% during the week before each visit 
will receive additional counseling by site staff. Compliance with fasting guidance will also be 
assessed via a Fasting Log in a subset of participants (see Section 8.1.15 for details). 
6.5
Concomitant Therapy
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.
Any lipid-lowering therapies (medications and/or supplements) the participant was receiving 
within 30 days before Visit 1 (Screening) should be recorded on the concomitant therapy 
CRF. No lipid-lowering therapy additions or dose changes are permitted during the study
(Visit 1 [Screening] to Visit 7 [Week 16]). Acceptable lipid-lowering therapies include, but 
are not limited to the following (Country-specific requirements are in Appendix 7):

statins

niacin

bempedoic acid

fibrates

ezetimibe

omega-3 fatty acids
Treatment with any nonstudy PCSK9 inhibitor, an ANGPTL3 inhibitor, an MTP inhibitor 
(eg, lomitapide), LDL-C apheresis, or oral semaglutide is prohibited during the study (Visit 1 
[Screening] to Visit 7 [Week 16]); there are no other prohibited medications for this study.
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Additionally, 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 (Visit 1 [Screening]) or receives during 
the study must be recorded on the concomitant therapy CRF. 
Any licensed COVID-19 vaccine (including for emergency use) in a particular country is 
permitted in the study as long as they are mRNA vaccines, adenoviral vaccines, or 
inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. 
Investigational vaccines (ie, those not licensed or approved for emergency use) are not 
permitted.
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modifications are permitted.
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
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity . The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.17). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 (see Section 8.11.6 for exceptions), unless the 
participant has withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
After prolonged study intervention interruption that prohibits restarting study intervention 
if agreed upon with the Sponsor.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a positive serum pregnancy test.
Note: A positive urine pregnancy test during the double-blind treatment period requires 
immediate interruption of study intervention until a serum test can be performed. If the 
serum test is positive, the participant must be permanently discontinued from study 
intervention and followed per Section 8.4.5.
•
The participant has an eGFR consistently <35 mL/min/1.73 m2; eGFR will be calculated 
according to Appendix 2.
Note 1: For eGFR, a consistent value is defined as a repeat measurement performed 
within 7 days of notification from the central laboratory.
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Note 2: If the eGFR value continues to meet discontinuation criterion but demonstrates 
stability or improvement relative to the prior result, an additional repeat may be 
performed (within 7 days). If this repeat continues to meet the discontinuation criterion, 
the participant must be discontinued from study intervention.

The participant has an ALT or AST result ≥3X ULN, a total bilirubin result ≥2X ULN, 
and, at the same time, an alkaline phosphatase result <2X ULN (guidance on follow-up of 
participants with laboratory values meeting this criterion is in the Investigator Study File 
Binder, or equivalent).
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
Country-specific discontinuation requirements are in Appendix 7.
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 or a participant’s legally acceptable representative requests to withdraw from 
the study, the investigator will clarify whether the participant wishes to withdraw completely 
from study (eg, no further site contact) or whether the participant is willing to be contacted 
for additional follow-up by phone. If the participant is willing to be contacted about their 
health status at a future timepoint, then the participant is not withdrawn from study follow-
up.
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 8.1.16. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
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•
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.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant at scheduled visits over the 
duration of the study will not exceed approximately 140 mL (see the laboratory 
documentation). This blood volume does not account for unscheduled visits or the Study 
Intervention Discontinuation Visit. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Country-specific requirements are in Appendix 7.
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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.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator (or qualified designee) at Visit 1 
(Screening).
Clinically significant findings in physical examinations, laboratory tests, ECGs, or other 
evaluations during the screening period will be recorded in the participant’s medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator (or qualified designee) will review and record any prior lipid-lowering 
therapies (medications and/or supplements) the participant was receiving within 30 days 
before Visit 1 (Screening). Other prior medications/vaccines taken by the participant at the 
time of enrollment (Visit 1 [Screening]) will also be recorded.
Participants treated with 1 or more of the excluded therapies in Section 5.2 are not eligible 
for the study.
8.1.5.2
Concomitant Medications
The investigator (or qualified designee) will review and record medications taken by the 
participant during the study. No lipid-lowering therapy additions or dose changes are 
permitted during the study (Visit 1 [Screening] to Visit 7 [Week 16]). Treatment with any
non-study PCSK9 inhibitor, an ANGPTL3 inhibitor, an MTP inhibitor (eg, lomitapide), 
LDL-C apheresis, or oral semaglutide is prohibited during the study (Visit 1 [Screening] to 
Visit 7 [Week 16]); there are no other prohibited medications for this study. 
8.1.6
Dietary Counseling/Monitoring
Refer to Section 5.3.1 for guidance on dietary counseling and monitoring.
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8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Sections 8.11.2 and 8.11.3.
8.1.8
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing
The investigator (or designee) will register the participant in IRT at the visits specified in the 
SoA. Participants who satisfy all entry criteria will be assigned a randomization number via 
IRT at Visit 2 (Day 1). Participants who do not meet eligibility criteria will be entered into 
IRT as screen failures. IRT will also be used to identify the study intervention supplies that 
will be dispensed to participants at the visit specified in the SoA. Refer to the IRT user 
manual for details about the IRT system.
8.1.10
Study Intervention Administration
Study intervention will be administered as oral capsules. At Visit 2 (Day 1), participants will 
be educated by a trained member of the site staff on appropriate dosing (Section 8.1.10.1) 
and fasting instructions (Section 5.3.1), and the requirement to bring all remaining study 
intervention supplies to each clinic visit to assess compliance (Section 6.4). Documentation 
of participant training will be filed with the participant’s source documents.
Details on appropriate handling, storage, and accountability of study intervention are 
provided in Section 6.2.2.
8.1.10.1
Timing of Dose Administration
Except for days with scheduled clinic visits during the double-blind treatment period, study 
intervention will be administered by the participant once-daily at home. Dosing will occur 
first thing in the morning (with water) following an overnight fast (ie, no food, study 
intervention, or beverages, except small amounts of water) of ≥8 hours. Participants will 
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withhold food and beverages (except water) until 30 minutes after administration of study 
intervention (Section 5.3.1). 
Participants will be instructed to fast for ≥8 hours before scheduled clinic visits
(Section 8.11.1). Study intervention will be administered as follows on the day of scheduled 
clinic visits:
•
Visit 2 (Day 1): Study intervention will be administered (with water) as a witnessed dose 
after all visit procedures are complete (except collection of post-dose PK/PD samples). 
•
Visit 3 (Week 2): Study intervention will be administered (with water) after laboratory 
samples are collected. 
•
Visit 4 (Week 4): Study intervention will be administered (with water) as a witnessed 
dose after laboratory samples are collected (except collection of post-dose PK/PD
samples). 
•
Visit 5 (Week 8): No study intervention will be administered. The last dose of study 
intervention will be taken on the day before Visit 5 (Week 8). 
If a participant misses a dose of study intervention, the participant should fast as long as 
possible, preferably at least 4 hours before dosing, and withhold food and beverages 
(except water) until 30 minutes after administration of study intervention. Participants should 
not take 2 doses of study intervention on the same day.
8.1.11
Witnessed Dose
Administration of study intervention will be witnessed by a member of the site staff at 
Visit 2 (Day 1) and Visit 4 (Week 4) for collection of PK/PD samples. The time of dosing 
will be recorded.
8.1.12
Study Intervention Accountability (Overall Population)
Accounting for compliance with study intervention in the overall population is described in 
Section 6.4.
8.1.13
Background Lipid-Lowering Therapy Accountability
Accounting for compliance with background lipid-lowering therapy (for those on 
lipid-lowering therapy at Visit 1 [Screening]) is described in Section 6.4.1. 
8.1.14
Fasting Accountability (Overall Population)
Accounting for compliance with fasting guidelines relative to administration of study 
intervention in the overall population is described in Section 6.4.2.
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8.1.15
Fasting Log (Subset)
At Visit 2 (Day 1), a subset of participants will either receive an electronic device or have 
their own electronic device configured (if compatible) to complete a daily Fasting Log. Use 
of a personal or Sponsor-provided device for the Fasting Log will be determined at 
Visit 1 (Screening).
At Visit 2 (Day 1), participants will be educated by a trained member of the site staff on how 
to record the time of study intervention administration and the time of the first meal of the 
day in the Fasting Log. The Fasting Log will be completed each day up to the day before 
Visit 5 (Week 8) or Study Intervention Discontinuation Visit. Participants who received an 
electronic device to complete the Fasting Log will return it at Visit 5 (Week 8) or the Study 
Intervention Discontinuation Visit.
Site personnel should reinforce compliance with the Fasting Log at each visit.
8.1.16
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.6.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Study Intervention Discontinuation Visit at the time of 
withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.16.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
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8.1.17
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue treatment and be 
monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.18
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.
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8.2
Efficacy Assessments
Lipid parameters (LDL-C, HDL-C, non-HDL-C, total cholesterol, triglycerides, VLDL-C, 
ApoB, and Lp[a]), ApoA1, and hsCRP will be measured at the visits specified in the SoA. 
The rationale for efficacy endpoints is provided in Section 4.2.1.1. LDL-C will be calculated 
based on the Friedewald formula; If the calculated LDL-C is ≤40 mg/dL or triglycerides are 
≥400 mg/dL, or calculated LDL-C is missing then LDL-C will be directly measured using 
beta-quantification. For analysis, LDL-C will be based on the beta-quantification method 
when available, or calculated based on the Friedewald formula when no beta-quantification is 
available.  
Because the effects of study intervention on efficacy endpoints could inform on participants’ 
treatment assignments, efficacy results will be masked by the central laboratory after 
Visit 2 (Day 1) through the end of the study. Unless clinically urgent, investigators should 
not evaluate efficacy endpoints locally during the study. Non-study physicians should also be 
encouraged not to evaluate efficacy endpoints locally during the study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood to be drawn over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in the laboratory documentation.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A full physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements), per institutional standard, at the visits specified 
in the SoA.
A directed physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements), per institutional standard, at the visit specified 
in the SoA.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Height and Weight
Height and body weight will be measured at the visits specified in the SoA. 
Height measurements should be rounded to the nearest inch/centimeter (without shoes).
Body weight will be measured using a standardized scale (provided by the Sponsor if 
requested) and should be rounded to the nearest pound/kilogram. Participants’ weight should 
be measured after voiding and while wearing light clothing (eg, no coats or heavy 
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sweatshirts). The site should follow their local procedures to ensure the body weight scale is 
working properly.
8.3.3
Temperature
Participant’s temperature will be measured at Visit 1 (Screening). It is recommended that 
individual sites use the same method for measuring temperature (eg, oral, tympanic) in all 
participants throughout the study
8.3.4
Vital Signs
Vital signs (blood pressure and pulse rate) will be assessed at the visits specified in the SoA.
•
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of 
rest with the participant in the seated position. Measurements should be performed using 
a completely automated device. Manual techniques may be used if an automated device is 
not available.
•
Whenever possible, blood pressure measurements should be obtained using the same 
arm, the same blood pressure monitoring device, and the same examiner at each visit.
•
The participant should be asked to remove all clothing that covers the location of the cuff 
placement.
•
The examiner should ensure that the middle of the cuff on the upper arm is at the level of 
the right atrium (the midpoint of the sternum).
•
When performed manually, pulse rate must be measured in the brachial/radial artery for 
at least 30 seconds.
•
Participants should be advised to refrain from nicotine-containing products and ingesting 
caffeine for at least 30 minutes before blood pressure and pulse rate determinations
(Section 5.3.2).
8.3.5
Electrocardiograms
ECG measurements will be performed at the visits specified in the SoA.
•
Single 12-lead ECGs will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and QTc intervals.
•
ECGs should be performed after the participant has rested quietly for at least 10 minutes.
•
Participants should be advised to refrain from nicotine-containing products and ingesting 
caffeine for at least 30 minutes before ECG measurements (Section 5.3.2). 
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8.3.6
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 8 weeks 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.
8.3.7
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
-
A positive urine pregnancy test during the double-blind treatment period requires 
immediate interruption of study intervention until a serum test can be performed. If 
the serum test is positive, the participant must be permanently discontinued from 
study intervention (Section 7.1) and followed per Section 8.4.5.
-
Sites will provide WOCBP urine pregnancy test kits to assess pregnancy status. The 
tests will be performed approximately 4 and 8 weeks after the last dose of study 
intervention. Participants will contact the site if the result is either positive or unable 
to be confirmed as negative. These participants will have a confirmatory serum 
pregnancy test (locally or centrally). Otherwise, sites will confirm that both urine 
pregnancy tests were performed during the Visit 7 (Week 16) telephone contact 
(or post-treatment telephone contact corresponding to 8 weeks after the last dose of 
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study intervention for participants who discontinued study intervention prematurely). 
Results from the urine and serum (if applicable) pregnancy tests will be recorded in 
participants’ source files. 
-
If urine pregnancy tests are not acceptable per local regulations, then a serum 
pregnancy test will be performed (locally or centrally) for the 4- and 8-week 
post-treatment pregnancy assessment.
Country-specific Visit 7 pregnancy testing requirements are in Appendix 7.
8.3.7.1
Pretreatment Confirmation of Postmenopausal State
Female participants whose postmenopausal status is in question are required to have 2 
pretreatment FSH measurements (approximately 2 weeks apart with a minimum interval of 
10 days) in the postmenopausal range or adhere to contraception guidelines in Appendix 5. 
The first FSH measurement will be obtained at Visit 1 (Screening). Participants whose first 
FSH measurement is in the postmenopausal range, but who cannot have a second 
measurement within approximately 2 weeks of Visit 1 (Screening), should be excluded if 
they are unwilling to adhere to the contraception guidelines in Appendix 5. These 
participants may be rescreened after consulting with the Sponsor (Section 8.11.3).
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
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
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specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the time of intervention randomization through the final study contact (Visit 7 [Week 16]).
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including placebo 
run-in)
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event.
Report all
Previously reported –
Follow to 
completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 calendar 
days of learning 
of event
DILI drug induced liver injury; ECI event of clinical interest; NSAE nonserious adverse event; SAE serious adverse 
event.
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.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events or disease-related outcomes that do not qualify as an AE 
or SAE.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
a.
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).
Country-specific requirements are in Appendix 7. 
8.5
Treatment of Overdose
In this study, an overdose is any dose that exceeds the prescribed daily dose of study 
intervention in Section 6.1 (ie, >1 capsule/day of study intervention is an overdose). 
The Sponsor does not recommend specific treatment for an overdose.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma MK-0616
PK samples will be collected at the timepoints specified in Appendix 2 (Table 8). Blood 
samples may be stored for further analysis, if required.
Sample collection, storage, and shipment instructions for PK samples will be provided in a 
laboratory manual.
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8.7
Pharmacodynamics
Free and total plasma PCSK9 samples will be collected at the timepoints specified in 
Appendix 2 (Table 8). Blood samples may be stored for further analysis, if required.
Sample collection, storage, and shipment instructions for free and total plasma PCSK9 
samples will be provided in a laboratory 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:
•
Plasma for FBR
•
Leftover DNA for future research
•
Leftover plasma PK samples for future research
•
Leftover plasma PCSK9 samples for future research
8.10
Medical Resource Utilization and Health Economics
Not applicable. 
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Visit Reminders
Approximately 3 days before scheduled clinic visits, participants will be contacted and 
reminded to do the following:
•
On the days before clinic visits (applicable after Visit 2 [Day 1]): Take their daily dose of 
study intervention (with water) first thing in the morning following an overnight fast 
(≥8 hours), and to withhold food and beverages (except water) until 30 minutes after 
dosing.
•
On the day of the clinic visit (applicable to all scheduled clinic visits): Fast for ≥8 hours 
before the visit. At Visit 1 (Screening), the fast may be broken after laboratory samples 
are collected. For other clinic visits, the fast may be broken 30 minutes after 
administration of study intervention (Section 5.3.1).
While fasting, participants should not eat any food, take study intervention, or drink any 
beverages, except small amounts of water. Non-study medications should be taken as 
prescribed.
Country-specific Visit 7 requirements are in Appendix 7.
8.11.2
Screening
Procedures and assessments at Visit 1 (Screening) will be performed per the SoA to 
determine if potential participants satisfy all eligibility criteria listed in Section 5. Those who 
qualify for randomization will have Visit 2 (Day 1) within 21 days after Visit 1 (Screening). 
Participants with an exclusionary laboratory value may have 1 repeat determination 
performed if the investigator considers the Visit 1 (Screening) result to be inconsistent with 
prior determinations (see Section 5 for details). Participants who have not fasted before 
Visit 1 (Screening) should have all blood collections rescheduled and completed before 
Visit 2 (Day 1). 
Site staff will reinforce participant compliance with background lipid-lowering therapy
(medications and/or supplements), if applicable, at Visit 1 (Screening) (Section 6.4.1).
For participants in the subset who will complete the Fasting Log, site personnel will 
determine if these participants will either receive an electronic device or have their own 
device configured to complete the Fasting Log (Section 8.1.15).
8.11.3
Rescreening
If a participant screen-fails (Section 5.4), the participant may be rescreened once based on 
investigator judgment, and after consultation with the Sponsor. Participants who are 
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rescreened will retain the same screening number assigned at the initial Screening Visit 
(Section 8.1.7).
8.11.4
Treatment Period
Each visit should be performed as specified in the SoA. Participants who satisfy all entry 
criteria will be randomized (via IRT) to double-blind study intervention at Visit 2 (Day 1). 
Participants will be educated by a trained member of the site staff on appropriate dosing 
instructions (including missed doses, Section 8.1.10) and fasting guidance (Section 5.3.1). A 
subset of participants will either receive an electronic device or have their own electronic 
device configured (if compatible) to complete a daily Fasting Log (Section 8.1.15). These 
participants will be educated by a trained member of the site staff on accurate completion of 
the Fasting Log. 
The first dose of study intervention will be witnessed by a member of the site staff in the 
clinic at Visit 2 (Day 1) for collection of PK/PD samples. Administration of study 
intervention will also be witnessed at Visit 4 (Week 4) for collection of PK/PD samples
(Section 8.1.11).
Compliance with study intervention (Section 6.4), background lipid-lowering therapy 
(medications and/or supplements, if applicable) (Section 6.4.1), and fasting guidance 
(Section 6.4.2) will be assessed and reinforced throughout the study. Compliance with the 
Fasting Log, in the subset of participants completing this log, will also be reinforced 
throughout the study (Section 8.1.15).
Scheduled clinic visits will be conducted at the study site. If a participant has not fasted 
before Visit 2 (Day 1), the entire visit should be rescheduled to occur within 21 days of 
Visit 1 (Screening). If a participant has not fasted before any other visits during the 
double-blind treatment period, all efficacy and safety laboratory collections, the witnessed 
dose at Visit 4 (Week 4), and PK/PD sample collections (Visit 4 [Week 4] and Visit 5 
[Week 8]) should be rescheduled to occur within the allowable visit window (specified in the 
SoA). 
If there are extenuating circumstances that do not enable the participant to attend a scheduled 
clinic visit (ie, incapacitating health conditions or local or national emergency situations), a 
telephone, video, or home visit using site staff or a nursing service may be used, if allowed 
by local regulations, following consultation with the Sponsor.
8.11.5
Unscheduled Visits
Unscheduled visits may be utilized at any time during the study at the discretion of the 
investigator. The following should be performed at unscheduled visits:

AE review and reporting (Section 8.4 and Appendix 3)
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
Concomitant medication review (Sections 6.5 and 8.1.5.2) and reinforcement of 
compliance with background lipid-lowering therapy (medications and/or supplements), 
if applicable (Section 6.4.1)

Review and reinforcement of compliance with study intervention (Section 6.4), fasting 
guidelines (Section 6.4.2), and the Fasting Log (in the subset completing this log; 
Section 8.1.15)
8.11.6
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who prematurely discontinue study intervention will undergo the assessments 
and procedures outlined in the SoA at the Study Intervention Discontinuation Visit. After this 
visit, participants should continue to undergo the assessments and procedures outlined in the 
SoA at all remaining visits, with the following exceptions, which are not applicable after 
study intervention is discontinued:

Witnessed dose (Visit 4 [Week 4]) and PK/PD sample collection (Visit 4 [Week 4] 
and Visit 5 [Week 8])

Study intervention accountability (overall population)

Fasting accountability (overall population)

Plasma collection for FBR
Additionally, the subset of participants completing the Fasting Log will no longer complete 
the log after the Study Intervention Discontinuation Visit. Those using a Sponsor-provided 
device for the Fasting Log will return it at the Study Intervention Discontinuation Visit
(Section 8.1.15). 
Participants who agree to continue in the study after discontinuation of study intervention, 
but who do not agree to attend clinic visits, may have follow-up contacts conducted via 
phone (Section 7.2). 
8.11.7
Post-treatment
Participants will be contacted approximately 2 and 8 weeks after the last dose of study 
intervention to assess safety (Section 1.3). Additionally, WOCBP will perform at-home urine 
pregnancy tests approximately 4 and 8 weeks after the last dose of study intervention to 
assess pregnancy status (Section 8.3.7). 
Country-specific Visit 7 requirements are in Appendix 7.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to unblinding the database addressing all study objectives (first 
database lock), changes are made to primary hypotheses, or the statistical methods related to 
those hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). 
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, but prior to unblinding the database addressing all study objectives (first database 
lock), will be documented in an sSAP and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR. Other planned analyses (ie, those 
specific to the analysis of PK data and FBR) will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design 
Overview
A Phase 2b, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of MK-0616 in Adults with Hypercholesterolemia
Treatment 
Assignment
Participants will be assigned randomly in a 1:1:1:1:1 ratio to 1 of 4 doses of MK-0616 
(6, 12, 18, or 30 mg) or matching placebo. Randomization will be stratified by 
background statin dose (no statin therapy vs. low- to moderate-intensity statin therapy 
vs. high-intensity statin therapy) and renal function (eGFR ≥60 vs <60 ml/min/1.73 
m2) at Visit 1 (Screening). 
Analysis Populations
Efficacy: FAS 
Safety: APaT
Primary Endpoint(s)
Percent change from baseline in LDL-C at Week 8
Secondary Endpoints
1.
Percent change from baseline in ApoB and non-HDL-C at Week 8
2.
Proportion of participants with LDL-C value at goal at Week 8
Statistical Methods 
for Key Efficacy 
Analyses
For the primary and secondary endpoints of percent change from baseline in LDL-C
(primary), ApoB, and non-HDL-C at Week 8, the differences in means and the 
associated 95% CIs and p-values will be provided (MK-0616 minus placebo; 
4 pairwise comparisons per endpoint) based on a cLDA model. For the secondary 
endpoint of proportion of participants with LDL-C value at goal at Week 8, 95% CIs 
(based on the M&N method) and p-values will be provided for between-treatment 
differences.
Statistical Methods 
for Key Safety 
Analyses
Analyses for which 95% CIs will be provided for between-treatment differences 
(MK-0616 minus placebo) in the percentage of participants with events will be 
performed using the M&N method.
Interim Analyses
No interim analyses are planned.  
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Multiplicity
There are 4 pairwise treatment group comparisons that may be tested to address the 
primary hypothesis. Testing will be performed in order of descending randomized 
dose and will stop with the first comparison that has a one-sided p-value ≥0.025.
Sample Size and 
Power
The sample size for this Phase 2b trial is driven primarily by safety and exposure 
considerations. Based on an assumed standard deviation of 25%, a -50% treatment 
difference (MK-0616 minus placebo) with respect to mean percent change from 
baseline in LDL-C at Week 8, and a discontinuation rate of <2% at or before Week 8, 
a sample size of 75/arm provides >99% power at a one-sided alpha of 0.025 for each 
of the treatment comparisons. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule for study intervention 
assignment for this protocol, and the randomization will be implemented in IRT.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The database addressing all study objectives (first database lock) will not be unblinded until 
medical/scientific review has been performed, protocol deviations have been identified, and 
data have been declared final and complete.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary Efficacy Endpoint
•
Percent change from baseline in LDL-C at Week 8
LDL-C will be based on the beta-quantification method when available, or calculated based 
on the Friedewald formula when no beta-quantification is available.
Secondary Efficacy Endpoints
•
Percent change from baseline in ApoB and non-HDL-C at Week 8
•
Proportion of participants with LDL-C value at goal at Week 8. LDL-C goal is defined 
as:
-
LDL-C <70 mg/dL (<1.81 mmol/L) in participants with clinical ASCVD
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-
LDL-C <100 mg/dL (<2.59 mmol/L) in participants with an ASCVD risk-equivalent 
and/or a 10-year risk of having an ASCVD event that is ≥7.5%
-
LDL-C <130 mg/dL (<3.37 mmol/L) in participants with a 10-year risk of having an 
ASCVD event that is ≥5.0% and <7.5%
Efficacy endpoints are further described in Section 4.2.1.1.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, ECG measurements, and vital signs. Safety endpoints are further 
described in Section 4.2.1.2.
9.4.3
Pharmacokinetic Endpoint
The PK endpoint is MK-0616 plasma concentration (Cmin). The PK endpoint is further 
described in Section 4.2.1.3.
9.4.4
Pharmacodynamic Endpoint
The PD endpoint is MK-0616 free plasma PCSK9 levels. The PD endpoint is further 
described in Section 4.2.1.4.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The FAS population will serve as the population for the analysis of efficacy data in this 
study. The FAS population consists of all randomized participants who:
•
receive at least 1 dose of double-blind study intervention
•
have at least 1 observation for the analysis endpoint 
•
have baseline data for those analyses that require baseline data
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of double-blind study intervention. Participants will 
be included in the treatment group corresponding to the study treatment they actually 
received for the analysis of safety data. This will be the treatment group to which they are 
randomized except for participants who take incorrect study intervention for the entire 
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treatment period; such participants will be included in the treatment group corresponding to 
the study treatment actually received. 
At least 1 laboratory, vital sign, or ECG measurement obtained subsequent to at least 1 dose 
of double-blind study intervention is required for inclusion in the analysis of the respective 
safety parameter. To assess change from baseline, a baseline measurement is also required.
9.5.3
Pharmacokinetic Analysis Population
Participants from the active MK-0616 treatment population who received at least 1 dose of 
active study intervention and complied with the protocol sufficiently will be included in the 
PK analysis population. Compliance includes exposure to treatment, availability of 
measurements and documentation of dose and sample collection time, and absence of 
important protocol deviations. 
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the exploratory objectives will be described in the sSAP.
P-values for the key secondary efficacy endpoints will be provided as an assessment of 
strength of evidence without intent to make inferential claims.
For analysis purposes, the baseline assessment is considered the one closest to, but before or 
on the day of randomization (Visit 2 [Day 1]).
For stratified analyses, the stratification factors used for randomization (background statin 
dose and renal function at Visit 1 [Screening], Section 6.3.2) will be applied to the 
analysis. If it is expected that statistical models may not converge on account of small strata, 
the baseline renal function factor will be dropped from the models. A decision to drop this 
factor will be based on blinded data and documented in the sSAP prior to database lock.
Two database locks are planned for this study in order to facilitate program planning. The 
first will occur after the efficacy cutoff date, defined as the date when all randomized 
participants complete Visit 5 (Week 8) (or otherwise discontinue the study prematurely). The 
second database lock will occur after all participants complete their participation in the study 
through Visit 7 (Week 16) (or otherwise discontinue the study prematurely). All study 
objectives will be addressed based on the first database lock, which will include complete 
efficacy, PK, and PD data. Analyses of safety based on the first database lock will include all 
available data (including post-Visit 5 [Week 8]). Additional safety analyses will be 
performed using the comprehensive data in the second database lock.
The Sponsor will be unblinded to participants’ treatment assignments after the first database 
lock. Participants and investigators will remain blinded to participants’ treatment 
assignments until after the second database lock.
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9.6.1
Statistical Methods for Efficacy Analysis
This section describes the statistical methods that address the primary and key secondary 
objectives related to the efficacy endpoints.
The primary efficacy estimand following the guidance in ICH E9 (R1) [European Medicines 
Agency 2020] has the following 5 attributes:
1. The treatment condition of interest and the alternative treatment condition to which 
comparison will be made: intervention with MK-0616 or placebo.
2. The population of participants targeted by the clinical question: adults with 
hypercholesterolemia.
3. The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question: percent change from baseline in LDL-C at Week 8.
4. The specification of how to account for other intercurrent events to reflect the scientific 
question of interest: a treatment policy approach will be used for intercurrent events 
(defined as discontinuation of study intervention and/or initiation of non-study 
intervention). No observed data will be excluded from analyses.
5. The population-level summary for the endpoint which provides the basis for a 
comparison between treatment conditions: the difference (MK-0616 - placebo) in the 
mean percent change from baseline in LDL-C at Week 8.
9.6.1.1
Primary Efficacy Endpoint
To address the primary hypothesis, the percent change from baseline in LDL-C will use a 
cLDA method proposed by Liang and Zeger [Liang, K-Y and Zeger, S. L. 2000]. This model 
assumes a common baseline mean across treatment groups and a different mean for each 
treatment group at post-baseline time points. In this model, the response vector consists of 
the baseline value and the percent change observed at the post-baseline time points. Time is 
treated as a categorical variable so that no restriction is imposed on the trajectory of the 
means over time. The analysis model will include terms for treatment, time, background 
statin dose (no statin therapy, low- to moderate-intensity statin therapy, or high-intensity 
statin therapy), baseline renal function (eGFR ≥60 vs <60 ml/min/1.73 m2), and the 
interaction of treatment by time. The treatment difference for each of the 4 pairwise
comparisons of MK-0616 versus placebo in terms of mean percent change from baseline in 
LDL-C at Week 8 will be estimated and tested from this model. An unstructured covariance 
matrix will be used to model the correlation among repeated measurements.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups. Of note, in the event that there are no missing data, the estimated treatment 
difference from the above cLDA model will be identical to that from a traditional 
longitudinal ANCOVA model which uses the baseline value as a covariate. However, unlike 
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longitudinal ANCOVA, the cLDA model accounts for variability in the baseline values, thus 
providing more accurate standard errors and CIs for individual treatment effects. Details of 
the model specification, assumptions, and SAS implementation code will be provided in the 
sSAP.
The cLDA method assumes that the mechanism for missing data is MAR. It is expected that 
<2% of participants will be missing their LDL-C value at Week 8. Sensitivity analyses to
assess the robustness of the MAR-based analysis to deviations from this assumption will be 
described in the sSAP.
The model-based least squares mean and empirical mean change (with 95% CIs) from 
baseline for each treatment group and difference between treatment groups at the Week 8 
post-baseline time point will be summarized.
9.6.1.2
Secondary Efficacy Endpoints
The analysis of secondary efficacy endpoints regarding percent change from baseline in 
ApoB and non-HDL-C at Week 8 will follow the same approach as the primary efficacy 
analysis.
For the secondary endpoint of the proportion of participants with LDL-C value at goal at 
Week 8, the 95% CIs and p-values will be provided based on the stratified M&N method
(with sample size weighting) for the difference in proportions between treatment groups 
(MK-0616 minus placebo). Any participant who does not have a Week 8 assessment will be 
considered as not being at the LDL-C goal at Week 8.  
Table 4 summarizes the key analysis strategies for the primary and key secondary efficacy 
endpoints.
Table 4
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Percent change from baseline in LDL-C at Week 8
cLDA
FAS
Model-based
Key Secondary Endpoints
Percent change from baseline in ApoB and non-HDL-C at 
Week 8
Proportion of participants with LDL-C value at goal at 
Week 8
cLDA
M&N
FAS
FAS
Model-based
M=F
ApoB apolipoprotein B, cLDA constrained longitudinal data analysis method, FAS full analysis set, LDL C low
density lipoprotein cholesterol, M&N Miettinen and Nurminen, M F: Missing Failure, non HDL C non high density 
lipoprotein cholesterol
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory tests, vital signs, and ECG measurements. The primary 
assessment of safety will use all data through the efficacy cutoff date including 8 weeks after 
last dose of study intervention, if available.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least 1 AE, drug-related AE, serious AE, serious 
drug-related AE, and moderate or severe AE; discontinuation from study intervention due to 
an AE; and an AE resulting in death. Point estimates and 95% CIs for the differences 
between treatment groups in the percentages of participants with the event will be provided 
based on the criteria described below for specific AEs.
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 95% CIs for the differences between treatment groups in the percentages of 
participants with specific AEs will be provided for AEs that occur in at least 5% of 
participants in any treatment group.
CIs for between treatment group differences will be provided using the M&N method. These 
CIs will not be adjusted for multiplicity and should be regarded as helpful descriptive 
measures for the review of the safety profile and not as a formal method for assessing 
statistical significance of between-group differences. Rainfall plots with point estimates and 
95% CIs will be displayed for AEs that occur in at least 5% participants in any treatment 
group. Point estimates and 95% CIs will be provided for the percentage of participants with 
safety parameters that meet predefined limits of change based on the same criteria used 
above for the specific AEs.
For continuous safety measures, such as change from baseline in laboratory, vital signs, and 
ECG parameters, summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by treatment group. 
9.6.2.2
Assessment of Safety Topics of Special Interest
There are no safety topics of special interest in this study.
Table 5 summarizes analysis strategy for safety endpoints in this study. 
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Table 5
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% 
Between-
group CI
Graphical 
Display
Overall Safety 
Assessment
Any AE
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious drug-related AE
X
X
Any moderate or severe AE
X
X
Discontinued study treatment 
due to AE 
X
X
Discontinued study treatment 
due to a drug-related AE
X
X
AE that resulted in death
X
Specific AEs (≥5% of 
participants in any treatment 
group)
X
Xa
Xa
SOCs, PDLCs (≥5% of 
participants in any treatment 
group)
X
Xa
Change from Baseline Results 
(Labs, ECGs, Vital Signs)
X
AE adverse event; CI confidence interval; ECG electrocardiogram; PDLC predefined limit of change; SOC system 
organ class.
a Threshold for incidence will be applied for CI and graphical display.
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, gender), baseline characteristics, 
primary and secondary diagnoses, and prior and concomitant therapies will be summarized 
by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned. Unblinded safety summaries will be reviewed on a periodic 
basis by the Sponsor’s siDMC (see Section 10.1.4.1) and will be specified in the siDMC 
charter. These summaries will be provided by an internal unblinded statistician and 
programmer with no other involvement in the study.
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9.8
Multiplicity
There are 4 pairwise treatment group comparisons (MK-0616 vs placebo) that may be tested 
to address the primary hypothesis. Testing will be performed in order of descending 
randomized MK-0616 dose and will stop with the first comparison that has a one-sided 
p -value ≥0.025.
The multiplicity strategy strongly controls the Type I error at 0.025 (one-sided) to address the 
primary hypothesis.
9.9
Sample Size and Power Calculations
9.9.1
Efficacy
The sample size for this Phase 2b study is driven primarily by safety and exposure 
considerations. Based on an assumed standard deviation of 25%, a -50% treatment difference 
(MK-0616 minus placebo) with respect to mean percent change from baseline in LDL-C at 
Week 8, and a discontinuation rate of <2% at or before Week 8, a sample size of 75 per arm 
(375 total) would provide >99% power at a one-sided alpha of 0.025 for each of the 
treatment comparisons (MK-0616 vs. placebo, based on nQuery software version 7). 
9.9.2
Safety
Given the sample size of 75 per group, Table 6 provides examples of minimum differences in 
proportions in AEs between each MK-0616 dose and placebo that would have a 95% CI that 
excludes zero. 
Table 6
Examples of AE Incidences for Which the 95% CI for the Difference Would 
Exclude Zero
MK-0616
n/N (%)
Placebo
n/N (%)
4/75 (5.3%)
0/75 (0%)
10/75 (13.3%)
3/75 (4.0%)
16/75 (21.3%)
7/75 (9.3%)
AE  adverse event; CI confidence interval; n number of participants with an AE; N population size. 
Based on the M&N method
9.10
Subgroup Analyses
The primary efficacy endpoint will be summarized for each of the following baseline defined 
subgroups:
•
Stratification factor: background statin dose (no statin therapy, low- to moderate-intensity 
statin therapy, or high-intensity statin therapy)
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•
Stratification factor: renal function (eGFR ≥60 vs <60 ml/min/1.73 m2) at Visit 1 
(Screening)
•
Diagnosis of heterozygous familial hypercholesterolemia (Yes, No)
•
Baseline risk category (clinical ASCVD, ASCVD-risk equivalents and/or a 10-year risk 
of having an ASCVD event that is ≥7.5%, or 10-year risk of having an ASCVD event 
that is ≥5.0% and <7.5%)
•
Baseline BMI (≥30 kg/m2 vs <30 kg/m2)
•
Diabetes mellitus (Yes, No)
•
Region (North America, Western Europe, Eastern Europe, Asia Pacific)
•
Age (≥65 vs <65 years)
•
Gender (male vs female)
9.11
Compliance (Medication Adherence)
A day within the double-blind treatment period will be considered a compliant day if the 
participant takes 1 capsule of treatment intervention (MK-0616 or matching placebo). 
For each participant, the compliance rate, based on time until study treatment 
discontinuation, will be calculated using the following formulas:
Compliance rate (%) =
Number of Compliant Days
× 100%.
Number of Days in the Double-blind Treatment Period
For each participant the “Number of Days in the Double-blind Treatment Period” is the total 
number of days from the first dose of double-blind study treatment to the date of the last dose 
of study treatment. 
9.12
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics and 
frequencies for the Number of Days on Therapy by treatment group. 
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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
Committees Structure
10.1.4.1
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, the Sponsor's siDMC will 
monitor the interim data from this study. The siDMC is comprised of members of Sponsor 
Senior Management, none of whom are directly associated with the conduct of this study. 
The siDMC will monitor the study at an appropriate frequency (specified in the siDMC 
charter ) for evidence of adverse effects of study intervention. The siDMC will determine 
whether the study should continue (or other modifications, prespecified or otherwise, should 
be made) according to the protocol, considering the overall risk and benefit to study 
participants. The siDMC will also make recommendations to the Sponsor protocol team 
regarding steps to ensure both participant safety and the continued ethical integrity of the 
study.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
10.1.4.2
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
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 
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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.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
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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 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
Except for pregnancy tests, which may be performed locally, the tests in Table 7 will be 
performed by the central laboratory.
•
Efficacy results will be masked by the central laboratory after Visit 2 (Day 1) through the 
end of the study (Section 8.2). Unless clinically urgent, investigators should not evaluate 
efficacy endpoints locally during the study. Non-study physicians should also be 
encouraged not to evaluate efficacy endpoints locally during the study.
•
Protocol-specific laboratory-based requirements for inclusion or exclusion of participants 
are detailed in Section 5 of the protocol. Country-specific inclusion or exclusion 
requirements are in Appendix 7.
•
The investigator (or medically qualified designee) must document their review of each
laboratory safety report.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Country-specific requirements for Visit 7 pregnancy testing are in Appendix 7.
Table 7
Protocol-required Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
-
MCV
-
MCH
-
MCHC
-
MPV
-
RDW
-
Nucleated RBC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Immature 
Granulocyte
RBC Count
Reticulocytes
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
above the ULN)
Albumin
Bicarbonate
ALT/SGPT
Phosphorous
Creatinine
Sodium
Alkaline 
phosphatase
Total Protein
eGFR
Calcium
Chloride
Creatine Kinase
Glucose
Potassium
Uric Acid
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Laboratory Assessments
Parameters
Lipid Panel
LDL-C
HDL-C
Non-HDL-C
Total 
Cholesterol
Triglycerides
Other Efficacy 
Parameters
VLDL-C
ApoB
ApoA1
Lp(a)
hsCRP
Pregnancy Testing
•
Highly sensitive serum or urine hCG pregnancy test (WOCBP only).
•
WOCBP will be given urine pregnancy test kits to assess pregnancy 
status approximately 4 and 8 weeks after the last dose of study 
intervention.  
•
If urine pregnancy tests are not acceptable per local regulations, then 
a serum pregnancy test will be performed (locally or centrally) for 
the 4- and 8-week post-treatment pregnancy assessments.
PK
•
Plasma for PK (Section 8.6)
PD
•
Plasma for Free and Total PCSK9 (Section 8.7)
Other Tests
•
A1C (only in participants with diabetes mellitus)
•
FSH (as needed to assess menopausal status)
•
TSH
•
FT4 (only in participants with hypothyroidism)
A1C hemoglobin A1c, ALT alanine aminotransferase, ApoA1 apolipoprotein A1, ApoB apolipoprotein B, AST aspartate 
aminotransferase, BUN blood urea nitrogen, CKD EPI Chronic Kidney Disease Epidemiology Collaboration,
eGFR estimated glomerular filtration rate, FSH follicle stimulating hormone, FT4 free T4 test, hCG human chorionic 
gonadotropin, HDL C high density lipoprotein cholesterol, hsCRP high sensitivity C reactive protein, LDL C low
density lipoprotein cholesterol, Lp(a) lipoprotein (a), MCH mean corpuscular hemoglobin, MCHC mean corpuscular 
hemoglobin concentration, MCV mean corpuscular volume, MPV mean platelet volume, PCSK9 protein convertase 
subtilisin/kexin type 9, PD pharmacodynamic, PK pharmacokinetic, RBC red blood cell, RDW red cell distribution 
width, SGOT serum glutamic oxaloacetic transaminase, SGPT serum glutamic pyruvic transaminase, TSH thyroid 
stimulating hormone, ULN upper limit of normal, VLDL C very low density lipoprotein cholesterol, WBC white blood 
cell, WOCBP women of childbearing potential
Note 1: eGFR will be calculated using CKD EPI Creatinine or, for participants in Japan, the Japanese 3 variable Equation 4; 
see Appendix 7.
Note 2: LDL C will be calculated based on the Friedewald formula; If the calculated LDL C is ≤40 mg/dL or triglycerides
are ≥400 mg/dL, or calculated LDL C is missing then LDL C will be directly measured using beta quantification. 
PK and PD Sample Collection
PK and PD samples will be collected at the timepoints shown in Table 8.
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Table 8
PK and PD Sample Collection Times
Visit
Number/Title:
Visit 2 (Day 1)
Visit 4 (Week 4)1
Visit 5 (Week 8) or 
SI Discon Visit1, 2, 3
Time:
Predose
~1.5 hours 
post-dose
Predose
~1.5 hours post-
dose
Unspecified Time1
PK samples
X
X
X
X
Free PCSK9
samples
X
X
X
X
X
Total PCSK9
samples
X
X
X
PCSK9=protein convertase subtilisin/kexin type 9, PD=pharmacodynamic, PK=pharmacokinetic, 
SI Discon=study intervention discontinuation
1 When possible, Visit 4 (Week 4) and Visit 5 (Week 8) (or SI Discon Visit) should be scheduled at a time that 
facilitates trough PK sample collection.
2 Do not collect PK, free PCSK9, or total PCSK9 samples at the Study Intervention Discontinuation Visit if this 
visit occurs >48 hours after the last dose of study intervention.
3 For participants who prematurely discontinue study intervention, do not collect PK, free PCSK9, or total
PCSK9 samples after the Study Intervention Discontinuation Visit.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
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, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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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 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
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•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
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-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not Applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc
•
IUSd
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,e
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,e
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods).
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect use failure rates (ie, when used consistently and correctly).
c   If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to those which 
inhibit ovulation. 
d   IUS is a progestin releasing IUD.
e   Country specific contraception requirements are in Appendix 7.
Note: The following are not acceptable methods of contraception:
  Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
 Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways with which drugs/vaccines may interact
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not 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 Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid 45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Requirements for Japan:
Section 5.1
To be eligible for the study, participants in Japan must meet the criteria for Inclusion #1, and 
must require additional LDL-C reduction according to JAS guideline recommendations
[Kinoshita, M., et al 2018].
Sections 5.2, 7.1 and Appendix 2
A 3-variable equation (Equation 4 in [Matsuo, S., et al 2009]) will be used to calculate eGFR 
for participants in Japan.
Section 6.1
The classification of IMP and NIMP in Section 6.1 is based upon guidance issued by the 
European Commission and applies to countries in the EEA.
10.7.2
Country-specific Requirements for Germany:
Sections 1.1, 4.4, 5.2, 7.1, 7.2, 8.1.1, 8.1.1.1, 8.1.1.2
In order for a participant to be eligible to participate in Germany, they must be capable of 
providing documented informed consent; therefore, all references to a participant’s “legally 
acceptable representative” in the protocol are not applicable for participants in Germany.
Section 1.3 Schedule of Activities
For participants in Germany, Visit 7 is an in-person visit and all activities listed in the global 
SoA for Visit 7 apply.
Additional activities at Visit 7 for participants in Germany are: 

Directed physical examination

Vital signs (blood pressure, pulse rate)

Weight

12-lead ECG (local)

Hematology

Chemistry (including CK)

A1C (only for participants with history of diabetes mellitus)

Urine or serum hCG (WOCBP only, per local requirements)
Note: For Visit 7, laboratory samples may be done non-fasting.
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Section 5.2
For participants in Germany, the following changes to the global exclusion criteria apply:

Exclusion criterion # 14: Has moderate or greater renal insufficiency defined as eGFR 
<60 mL/min/1.73 m2 at Visit 1 (Screening); eGFR will be calculated according to 
Appendix 2.

Exclusion criterion #22 (new): Has uncontrolled hypertension defined as sitting SBP 
≥180 mm Hg or DBP ≥110 mm Hg at Visit 1 (Screening).

Exclusion criterion #23 (new): Has QTcF >450 ms based on an ECG performed within 6 
months before Visit 1 (Screening) OR based on the pretreatment ECG at Visit 2 (Day 1) 
if a prior ECG is not available.
10.7.3
Country-specific Requirements for South Korea
Section 5.1
For participants in South Korea, the following applies:
Clarification for inclusion criterion #2, Note 1: 
For participants in South Korea, lipid-lowering therapies include foods, drugs, or 
supplements that can affect the concentration of lipids during the study (eg, statins, fibrates, 
bile acid sequestrants, niacin, anti-obesity drugs, steroids intended for systemic action, fish 
oil, colestine products, fiber-based laxatives, phytosterol margarines, etc) and drugs that 
affect thyroid function (thyroid preparations or thyroxine administration: except for those on 
alternative therapy). 
Section 5.2
For participants in South Korea, the following addition to the global exclusion criteria 
applies:

Exclusion criterion #22 (new): Has uncontrolled hypertension defined as sitting SBP 
≥180 mm Hg and/or DBP ≥110 mm Hg at Visit 1 (Screening).
Sections 5.3.1, 6.5
All participants in South Korea, regardless of lipid-lowering therapy use, should be following 
Total Lifestyle Change, as per local guidelines, for at least 30 days before Visit 1 
(Screening). 
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10.7.4
Country-specific Requirements for the United Kingdom
Sections 1.2, 1.3, 5.3.1, 8, 8.3.7, 8.11.1, and 8.11.7
For participants in the United Kingdom, additional activities by visit are:
Visit 1

12-lead ECG (local)

Full physical examination
Visit 3

12-lead ECG (local)
Visit 4

12-lead ECG (local)
Visit 7
Visit 7 is an in-person visit, and all activities listed in the global SoA for Visit 7 apply.
Additional activities at Visit 7 are: 

Directed physical examination

Vital signs (blood pressure, pulse rate)

Weight

12-lead ECG (local)

Hematology

Chemistry (including CK)

A1C (only for participants with history of diabetes mellitus)

In WOCBP, urine or serum hCG (per local requirements)
Note: For Visit 7, laboratory samples may be done non-fasting.
For participants in the United Kingdom, the following change to the global blood collection 
applies:
The maximum amount of blood collected from each participant at scheduled visits over the 
duration of the study will not exceed approximately 140 mL (see the laboratory 
documentation). This blood volume does not account for unscheduled visits or the Study 
Intervention Discontinuation Visit.
Section 4.3
For participants in the United Kingdom, additional justification for dose is provided below.
The doses for this study were selected to allow identification of the optimal clinical dose. 
CCI
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 This will allow selection of a 
near-maximal efficacy dose for further development in Phase 3 and ensure sufficient 
additional safety experience in a heterogenous population with longer treatment duration 
before the Phase 3 studies. The expected exposures for the doses to be studied are adequately 
covered by the available clinical and nonclinical data for MK-0616.
Sections 5, 5.1, 5.2, 10.2, and 10.5.2
For participants in the United Kingdom, the following changes to the global inclusion and 
exclusion criteria apply:
Inclusion criterion #2: Participants who are treatment naïve can only be enrolled if they do 
not meet NHS guideline criteria for treatment with lipid lowering therapies.
NHS guidelines: https://www.guidelines.co.uk/cardiovascular/nhs-lipid-management-
pathway/456226.article.
Inclusion criterion #4: Highly effective methods of contraception must be used by WOCBP. 
Contraceptive methods that are not considered highly effective are not allowed (see 
Appendix 5).
Exclusion criterion #15: Has laboratory or clinical evidence of clinically significant hepatic 
conditions, including 1 or more of the following:

ALT or AST >2X ULN at Visit 1 (Screening).

A history of hepatitis or liver disease that, in the opinion of the investigator, has been 
active within the 6 months before Visit 1 (Screening) and may increase the risk 
associated with study participation or administration of study intervention.

Total bilirubin ≥1.5X ULN at Visit 1 (Screening), including those with a history of 
Gilbert’s Syndrome.
Sections 7.1, 8.4.7 and 10.7.4.1
For participants in the United Kingdom, the following changes to the global reasons for study 
intervention discontinuation apply:

The participant has an eGFR consistently <35 mL/min/1.73 m2; eGFR will be calculated 
according to Appendix 2.
Note 1: For eGFR, a consistent value is defined as a repeat measurement performed 
within 7 days of notification from the central laboratory.
Note 2: Not applicable for participants in the United Kingdom where the participant must 
be discontinued from study intervention if the eGFR value continues to meet 
CCI
CCI
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discontinuation criterion even if it demonstrates stability or improvement relative to the 
prior result.

The participant has an ALT or AST result ≥3X ULN, a total bilirubin result ≥2X ULN, 
and, at the same time, an alkaline phosphatase result <2X ULN (guidance on follow-up 
of participants with laboratory values meeting this criterion is in Section 10.7.4.1 and in 
the Investigator Study File Binder, or equivalent).
10.7.4.1
DILI Site Guidance Document for Assessment and Follow-up
10.7.4.1.1
Purpose
The purpose of this document is to provide guidance to enable the investigator/study 
coordinator to provide clinical follow-up and systematically gather and report data on 
potential DILI. The data collected will be used by the Sponsor to create narratives for 
regulatory agency reporting.
10.7.4.1.2
Introduction
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver 
function (Navarro and Senior 2006). Drug-induced hepatotoxicity is one of the most common 
causes of termination of drug development, a major reason for refusal of market 
authorization and for restricted use, and the single most important cause of the withdrawal of 
market authorization for products (Björnsson 2006). Thus, drug-induced hepatotoxicity is a 
major concern during the discovery, development to post-authorization phases of the product 
life cycle (excerpted from Premarket Evaluation of Hepatotoxicity of Health Products, 
Ministry of Public Health, Canada, April 2012).
As stated in the United States Food and Drug Administration (FDA) “Guidance for Industry -
Drug-Induced Liver Injury: Premarketing Clinical Evaluation”; hepatocellular injury (usually 
detected by serum aminotransferase elevations [AT]) can be caused by drugs that rarely, if 
ever, cause severe DILI (e.g., aspirin, tacrine, statins, and heparin), as well as by drugs that 
do cause such injury. The frequency of serum AT elevations also is not a good indicator of a 
potential for severe DILI because drugs such as tacrine (not a cause of severe DILI) can 
cause AT elevations in as many as 50 percent of patients. Very high levels of observed ATs 
may be a somewhat better indicator of potential for severe DILI, but the most specific 
indicator is evidence of altered liver function accompanying or promptly following evidence 
of hepatocellular injury.
The single clearest (most specific) predictor found to date of a drug’s potential for severe 
hepatotoxicity, is the occurrence of hepatocellular injury (AT elevation) accompanied by 
increased serum total bilirubin (TBL) not explained by any other cause, such as viral 
hepatitis or exposure to other hepatotoxins, and without evidence of cholestasis, together 
with an increased incidence of AT elevations in the overall trial population compared to 
control. Increased plasma prothrombin time, or its international normalized ratio (INR), a 
consequence of reduced hepatic production of Vitamin K-dependent clotting factors, is 
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another potentially useful measure of liver function that might suggest the potential for 
severe liver injury.
Recognition of the importance of altered liver function, in addition to liver injury, began with 
Hyman Zimmerman’s observation that drug-induced hepatocellular injury (i.e., AT 
elevation) accompanied by jaundice (i.e., TBL elevation) had a poor prognosis, with a 10 to 
50 percent mortality from acute liver failure (in pretransplantation days) (Zimmerman 1978, 
1999). This became known as "Hy's Law". This document describes the recommended 
process for monitoring and evaluation of subjects meeting the laboratory criteria for potential 
DILI defined as:

an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that 
is greater than or equal to three times (3X) the upper limit of normal (ULN) and 

an elevated TBL lab value that is greater than or equal to two times (2X) ULN and

at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
as a result of within-protocol-specific testing or unscheduled testing. 
The protocol identifies these laboratory criteria for potential DILI as ECIs. ECIs are selected 
adverse experiences that must be reported to the Sponsor within 24 hours. The Principal 
Investigator should record these ECIs on the Adverse Experience Case Report Forms (CRFs) 
and complete pertinent adverse experience fields as outlined in the Data Entry Guidelines 
(DEGs).
10.7.4.1.3
Close Observation Recommendations
The following steps should be taken when a subject is observed to have an elevated AST or 
ALT lab value that is greater than or equal to 3X ULN and an elevated TBL lab value that is 
greater than or equal to 2X ULN and, at the same time, an ALP lab value that is less than 2X 
ULN, as a result of within-protocol-specific testing or unscheduled testing. 
Initiate close observation, defined below, and continue performing follow-up to resolution.
Close observation is defined as follows: 

Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
study drug has been discontinued and the subject is asymptomatic.

Obtain a more detailed history of symptoms and prior or concurrent diseases. (See 
Section 10.7.4.1.5).

Obtain a history of concomitant medication use (including prescription and 
nonprescription medications, herbal and other dietary supplements), alcohol use, 
recreational drug use and special diets. (See Section 10.7.4.1.5 for details).
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
Obtain a history of exposure to chemical agents or other environmental toxins. 

Obtain additional history and complete Stage 1 work-up to attempt to rule out other 
potential causes of the transaminase elevation, including but not limited to the following: 
acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-
alcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and biliary tract 
disease (See Section 10.7.4.1.5.5 for details.)

Consider gastroenterology or hepatology consultation.
In general, treatment with study therapy should be stopped if the laboratory criteria for 
potential DILI are met. Please refer to the specific discontinuation criteria in the 
protocol as appropriate.
10.7.4.1.4
Hepatic Assessment Flow Chart
10.7.4.1.5
Factors to Consider in Assessing Potential DILI
When there is a potential DILI, it is important to thoroughly assess the subject’s history, 
hepatic risk factors, clinical condition and hepatic function until resolution (normal or 
baseline levels). 
Answers to the following questions should be recorded in source documents and in 
appropriate CRFs as outlined in the DEGs.
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10.7.4.1.5.1
Study Medication
Considerations should include the following: What was the time interval between 
administration of study medication and the laboratory abnormality(ies)? What is the status of 
study medication use- Continuing? Interrupted? Discontinued? Was the subject re-challenged 
with study medication?
10.7.4.1.5.2
Treatment
Record any concomitant treatments.
10.7.4.1.5.3
Signs and Symptoms (Associated With the Potential DILI Event)
Does the subject have a concomitant illness?  Does the subject currently exhibit signs or 
symptoms of hepatitis/DILI?  What are the subject’s signs and symptoms (see examples 
below)?  What are the pertinent findings from medical history, physical/laboratory 
examination (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia > 5%, hepatomegaly, splenomegaly, etc.) that could suggest DILI?
Category
Examples of Signs and Symptoms
Blood/lymphatic
Eosinophilia, coagulopathy, susceptibility to bleeding/bruising
Circulatory
Varicose veins, edema
Constitutional
Fever, fatigue, malaise, weight gain, other (identify).
Digestive/hepatic
Anorexia, diarrhea, bloody or black stool, light-colored stools, 
nausea, vomiting, hematemesis, upper quadrant abdominal pain, 
upper quadrant tenderness, hepatomegaly, jaundice, splenomegaly, 
ascites, cholestasis
Endocrine/reproductive
Loss of libido
Integumentary
Rash, pruritus
Muscular
Myalgia
Nervous
Changes in mental status or level of consciousness
Urinary
Dark urine
10.7.4.1.5.4
Confounding Variables
What are the relevant medical history and findings?  What is the differential diagnosis? What 
risk factors does the subject have for hepatic injury? (See examples below.) Provide onset of 
risk factor and duration.
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Category
Examples of Confounding Variables
Subject medical history
Autoimmune disorder, cancer, Gilbert’s syndrome, obesity, Wilson’s 
disease
Substance use/abuse
Alcohol, illegal drugs, illegal intravenous (IV) drugs 
Prior & Concomitant Medications:  
Review all non-study medications 
and therapies, including: over-the-
counter (OTC), as well as 
prescription.  Ask the subject to bring 
products/packaging to site and 
review contents.
History of recent concomitant acetaminophen (APAP)/paracetamol 
use, excessive nonsteroidal anti-inflammatory drug (NSAID) intake, 
use of non-study drug or therapy that can cause liver damage or 
idiosyncratic adverse drug reactions
Herbal and nutritional supplements
Herbal, complementary therapies, and nutritional supplements
Adulteration of products
History of previous exposure to the product or a similar product, and 
information on potential contamination or adulteration of products
Chemical exposure
Occupational or in other situations
Potential exposure to infectious 
agents 
Infectious hepatitis, transfusion, travel, tattoos, sexually transmitted 
diseases, new sexual partner, shared needles
Special Diet
Special diet started since randomization
Other
Recent physical trauma, excessive exercise, or other prolonged 
physical exertion
Family history 
Autoimmune disorder, cancer, Gilbert’s syndrome, Wilson’s disease
10.7.4.1.5.5
Evaluation Algorithm for Potential DILI if There are no Other Clinical 
Reasons
Note: If clear etiology for the laboratory abnormalities has been confirmed, Stage 1 and 2 
testing may not be required. In this case, consultation with the Sponsor is recommended.
Stage 1 work-up should be performed within 48-72 hours: 

ALT

AST

Bilirubin: total, direct, indirect

Alkaline phosphatase (ALP) 

Prothrombin Time (PT)/international normalized ratio (INR) 

Creatine phosphokinase (CPK)

Manual eosinophil count (if automated count was elevated) 
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
Toxicology screen for drugs of abuse (including ethanol) and for 
acetaminophen/paracetamol level should also be sent. Investigators may order additional 
toxicology tests as clinically indicated.

Evaluate subject for the following signs and symptoms: fatigue, nausea, vomiting, right 
upper quadrant abdominal pain or tenderness, fever, rash.

Obtain the following additional history and assessment for associated risk/confounding 
factors:
-
More detailed history of symptoms and prior or concurrent illness
-
Aminotransferase values obtained prior to the study or administration of study 
medication
-
Alcohol consumption (recent and historical)
-
Acetaminophen (APAP)/paracetamol use 
-
New prescription, concomitant, or non-prescription (including herbal and other 
dietary supplements) medications
-
Unusual foods (e.g. mushrooms) or special diets. Consumption of seasonal foods.
-
Recreational drug use
-
Prior history of liver injury or disease, including but not limited to Gilbert's 
syndrome, autoimmune disorders, cancer, Wilson's disease, NASH, alcoholic or 
infectious hepatitis, biliary tract disease, hypoxic/ischaemic hepatopathy
-
Obesity/abdominal adiposity (record weight, height, and waist circumference)
-
Occupational history and history of exposure to chemical agents or other 
environmental toxins
-
Recent travel (last three [3] years)
-
Transfusion history

Perform the following laboratory tests: 
-
Albumin
-
Eosinophils (percentage and absolute; obtain manual count if automated count is 
elevated)
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-
Viral hepatitis serologies (obtain appropriate consent prior to testing, if required 
locally)
◦
A (IgG, IgM)
◦
B (HepBs Ag, Hep Bs Ab, Hep Bc Ab, Hep Be Ag)
◦
C (RNA)
◦
D (requires concomitant hepatitis B infection)
-
Human Immunodeficiency Virus (HIV) testing (obtain appropriate consent prior to 
testing, if required locally)
-
Evaluation for autoimmune hepatitis: 
◦
Serum gamma globulin levels/ serum protein electrophoresis  
◦
Antinuclear antibody (ANA) 
◦
Anti-mitochondrial antibody (if ALP or TBL >ULN)
-
If AST/ALT ratio is greater than one (1) with suspicions of increased alcohol intake, 
perform the following:
◦
Gamma-glutamyl transferase (GGT)

Obtain a right upper quadrant ultrasound
Stage 2 work-up tests should be drawn within one (1) week of receiving the Stage 1 
work-up results and the results of Stage 1 evaluation are negative.
Note: A specific test may be performed earlier if the investigator determines that the 
clinical presentation leads to a certain diagnosis.
Stage 2 work-up:

Perform the following laboratory tests:
-
Genetic test for Gilbert's disease if there is a suspicious history. Ensure appropriate 
subject consent is obtained for this test.
-
Viral hepatitis E (IgG and IgM, obtain appropriate consent prior to testing, if required 
locally) 
-
Anti-smooth muscle antibody 
-
Anti-liver-kidney microsomal antibody 
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-
Anti-soluble liver antigen
-
Serologies for the following:
◦
Cytomegalovirus (CMV) (IgG, IgM)
◦
Epstein-Barr Virus (EBV) (IgG, IgM)
◦
Herpes simplex
◦
Toxoplasmosis
◦
Varicella
◦
Parvovirus
-
Ceruloplasmin
-
Serum alpha-1 anti trypsin
-
Genetic test for hemochromatosis. Ensure appropriate subject consent is obtained for 
this test 
-
Iron Studies: 
◦
serum ferritin, 
◦
serum iron,  
◦
total iron binding capacity

Consider referral to hepatologist/gastroenterologist

Consider screen for celiac disease and cystic fibrosis if clinically indicated 

If laboratory tests or ultrasound evidence of biliary tract obstruction, consider obtaining 
Endoscopic Retrograde Cholangiopancreatography (ERCP) or Magnetic Resonance 
Cholangiopancreatography (MRCP)
If applicable, request copies of hospital discharge summaries, consultation reports, pathology 
reports, special studies (e.g. imaging or biopsy), etc.
10.7.4.1.5.6
Potential Diagnosis
What diagnosis do the history, clinical course, and laboratory tests suggest?
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10.7.4.1.5.7
Overall Clinical Impression
What are the investigator’s overall clinical impressions (e.g., differential diagnosis, potential 
alternative causes)?
10.7.4.1.5.8
Treatment Plan
What is the plan for treatment and follow-up?
10.7.4.1.6
Preapproved Tests
For the blood volume requirements, please refer to the trial laboratory manual. The following 
tests have been pre-approved by the Sponsor:  

Anti-liver-kidney microsomal antibody

Anti-mitochondrial antibody (if alkaline phosphatase or total bilirubin > ULN)

Antinuclear antibody (ANA)

Anti-smooth muscle antibody

Anti-soluble liver antigen

Ceruloplasmin

Chemistry Panel (as specified in protocol)

Complete blood count (CBC), with manual differential if absolute eosinophil count is > 
ULN

Hepatitis tests:  Hepatitis A IgG AB, Hepatitis A IgM AB, Hepatitis B Core AB, 
Hepatitis Be AG, Hepatitis B surf AB, Hepatitis B surf AG, Hepatitis C AB, Hepatitis C 
Qualitative RNA, Hepatitis D AB, Hepatitis E Ab IgM, Hepatitis E IgG (obtain consent 
prior to testing, if required locally)

HIV antibody (obtain consent prior to testing, if required locally)

Genetic test for hemochromatosis 

Iron studies 
-
Serum ferritin
-
Serum iron
-
Total iron binding capacity
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
Lactic Acid dehydrogenase (LDH)

PT / INR

Serum albumin and total protein

Serum alpha-1 anti trypsin

Serum creatine kinase (CK)

Serum gamma globulin levels/ serum protein electrophoresis

Serum gamma-glutamyl transferase (GGT)

Toxicology screen (including ethanol and acetaminophen/paracetamol level) -  tests not 
on the standard screen may be ordered, if clinically indicated

IgM, IgG for both CMV and EBV-VCA Antibody, herpes simplex IgM, toxoplasma AB 
IgG, IgM, varicella zoster AB IgG, IgM, parvovirus IgM, IgG (if clinically relevant)

Screen for celiac disease and cystic fibrosis (if clinically indicated and appropriate 
consent obtained for cystic fibrosis screen)

UGT1A tests for Gilbert's syndrome (appropriate consent should be obtained)
NOTE: If a test is not listed on the lab requisition form, please contact one of the PPD 
Central Lab MK-0616-008 Project Managers to obtain information regarding test code and 
sample collection. In general, the tests should be sent to the Central Lab for analysis 
whenever possible. However, if tests cannot be performed at the Central Laboratory or in 
case of emergency, tests may be ordered at a local laboratory.
Additional lab tests and/or procedures
The investigator may order additional tests after 
consultation with the Sponsor.
10.7.4.1.7
Contacts
If you have any questions, please refer to your Sponsor contact list for the following 
company personnel:
- Clinical Research Associate or Subsidiary Monitor
- Clinical Monitor 
- Clinical Scientist
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10.7.4.1.8
DILI Site Guidance Document References

Drug-Related Hepatotoxicity, Victor J. Navarro and John R. Senior, N Engl J Med 
2006;354:7314-9

Drug-induced liver injury: Hy’s rule revisited, Einar Björnsson MD, PhD, Clinical 
Pharmacology & Therapeutics, Vol. 79, Issue 6, June 2006.

Premarket Evaluation of Hepatotoxicity of Health Products, Ministry of Public Health, 
Canada, April 2012
https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-
products/applications-submissions/guidance-documents/hepatotoxicity-pre-market-
evaluation.html

FDA Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf 

Zimmerman HJ 1978 Hepatotoxicity, The Adverse Effects of Drugs and Other 
Chemicals on the Liver, Drug-induced liver disease (Appleton-Centry-Crofts, New 
York), pp 351-5.

Zimmerman HJ 1999 Hepatotoxicity, The Adverse Effects of Drugs and Other 
Chemicals on the Liver, Drug-induced liver disease (Lippincott Williams & Wilkins, 
Philadelphia), 2, pp 428-33. 
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10.8
Appendix 8: ASCVD Risk Calculator
The 10-year risk for an ASCVD event should be calculated using the ASCVD Risk Estimator 
Plus (or equivalent).

ASCVD Risk Estimator Plus
-
https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/
Equivalent calculators/algorithms to determine ASCVD risk include the European 
Association of Preventive Cardiology interactive tool (https://www.heartscore.org), the Suita 
Score [Kinoshita, M., et al 2018], or any other locally acceptable calculator/algorithm to 
determine ASCVD risk.
If a participant’s demographic information is not compatible with a particular risk calculator 
(eg, a participant is 80 years old and the calculator is limited to individuals who are 20 to 79 
years old), a different risk calculator or algorithm should be used.
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10.9
Appendix 9: Statin Intensity Chart Based on Total Daily Dose
High Intensity
Moderate Intensity
Low Intensity
Atorvastatin 40 mg or 80 mg
Rosuvastatin 20 mg or 40 mg
Atorvastatin 10 mg or 20 mg
Rosuvastatin 5 mg or 10 mg
Simvastatin 20 mg to 40 mg
Simvastatin 5 mg or 10 mg
Pravastatin 40 mg or 80 mg
Lovastatin 40 mg or 80 mg
Fluvastatin 80 mg
Pitavastatin 1 mg to 4 mg
Pravastatin 10 mg to 20 mg
Lovastatin 10 mg to 20 mg
Fluvastatin 20 mg to 40 mg
Adapted from Table 3 in [Grundy, S. M., et al 2019].
Consult the Sponsor to determine the appropriate statin intensity category for participants whose daily statin 
dose is not shown above.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
A1C
hemoglobin A1C
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANGPTL3
angiopoietin-like 3
APaT
All-Participants-as-Treated
ApoA1
apolipoprotein A1
ApoB
apolipoprotein B
AR
adverse reaction
ASCVD
atherosclerotic cardiovascular disease
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice-daily
BMI
body mass index
BUN
blood urea nitrogen
C24
concentration at 24 hours
CI
confidence interval
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
cLDA
constrained longitudinal data analysis
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form 
CSR
clinical study report
CTFG
Clinical Trial Facilitation Group 
DBP
diastolic blood pressure
DILI
drug-induced liver injury
Discon
discontinuation
DNA
deoxyribonucleic acid
EC50
half maximal effective concentration
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collector
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
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Abbreviation
Expanded Term
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FH
familial hypercholesterolemia
FSH
follicle stimulating hormone
FT4
free T4 test
GCP
Good Clinical Practice 
hCG
human chorionic gonadotropin
HDL-C
high-density lipoprotein cholesterol
HR
heart rate
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
IB
investigator’s brochure 
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ID
identification
IEC
independent ethics committee
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVRS
interactive voice response system
JAS
Japan Atherosclerosis Society
LAM
lactational amenorrhea method
LDL-C
low-density lipoprotein cholesterol
Lp(a)
lipoprotein (a)
mAb
monoclonal antibody
MAR
missing at random
MCH
mean corpuscular hemoglobin 
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MEDPED
Make Early Diagnosis to Prevent Early Death
M F: 
missing failure
M&N
Miettinen and Nurminen
MPV
mean platelet volume
mRNA
messenger RNA
MTP
microsomal triglyceride transfer protein
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Abbreviation
Expanded Term
N
population size
n
number of participants
N/A
not applicable
NIMP
noninvestigational medicinal product
NSAE
nonserious adverse event
PCSK9
protein convertase subtilisin/kexin type 9
PD
pharmacodynamic
PDLC
predefined limit of change
PK
pharmacokinetic
PP
per-protocol
QD
once-daily
RBC
red blood cell
RDW
red cell distribution width
RNA
ribonucleic acid
SAC
scientific advisory committee
SAE
serious adverse event 
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SGOT
serum glutamic-oxaloacetic transaminase 
SGPT
serum glutamic-pyruvic transaminase
siDMC
standing internal data monitoring committee
siRNA
small interfering ribonucleic acid
SAC
scientific advisory committee
SLAB
supplemental laboratory test
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedures
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TC
telephone call
TSH
thyroid stimulating hormone
ULN
upper-limit of normal
USA
United States of America
V
visit
VLDL-C
very low-density lipoprotein cholesterol
vs
versus
WBC
white blood cell
Wk
week
WOCBP
woman/women of childbearing potential
08BH5D


PRODUCT:  MK 0616  
123
PROTOCOL/AMENDMENT NO.:  008 04  
MK 0616 008 04 FINAL PROTOCOL
24 MAY 2022
11
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08BH5D