A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of MK-0616 Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia
Phase: PHASE3
Conditions: Hypercholesterolemia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:                NCT06450366
Document Date:            17-Jul-2024
A Phase 3, Randomized, Double-Blind Study to 
Evaluate the Efficacy and Safety of MK-0616 Compared 
With Ezetimibe or Bempedoic Acid or Ezetimibe and 
Bempedoic Acid in Adults With Hypercholesterolemia 

PRODUCT: MK-0616
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and 
Safety of MK-0616 Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and 
Bempedoic Acid in Adults With Hypercholesterolemia 
Protocol Number: 018-02
Compound Number: MK-0616
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Pending
EU CT
2023-504920-25
EudraCT
Not Applicable
JRCT
Not Applicable
WHO
Not Applicable
UTN
U1111-1290-3888
IND
152853
Approval Date: 17 July 2024
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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 2
EEA-specific
amendment
17-JUL-2024
The purpose of this amendment is to provide
country-specific requirements for participants in
countries in the European Economic Area
Amendment 1 United 
Kingdom-specific 
amendment
16-JUL-2024
The purpose of this amendment is to provide
country-specific requirements for participants in
the United Kingdom.
Original Protocol
06-DEC-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
The purpose of this amendment is to provide country-specific requirements for participants in 
countries in the European Economic Area.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 10.7, 
Countries in the 
European 
Economic Area
New section created for participating EEA 
countries.
To address Health Authority/Agency 
feedback.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.1, 
Synopsis, 
Estimated 
Duration of the 
Study
Added a cross-reference notation to 
Appendix 7, Country-specific Requirements.
To notify the reader that there are 
country-specific requirements in Appendix 7.
Section 4.4, 
Beginning and 
End-of-Study 
Definition
Added a cross-reference notation to 
Appendix 7, Country-specific Requirements.
Refer to Section 1.1 rationale. 
Section 5, Study 
Population
(and applicable 
subsections)
Added a cross-reference notation to
Appendix 7, Country-specific Requirements.
Refer to Section 1.1 rationale. 
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Section Number 
and Name
Description of Change
Brief Rationale
Section 6.5, 
Concomitant 
Therapy
Added a table summarizing the list of 
prohibited concomitant therapies.
Refer to Section 10.7 rationale.
Section 7,
Discontinuation 
of Study 
Intervention and 
Participant 
Withdrawal 
(and applicable 
subsections)
Added a cross-reference notation to 
Appendix 7, Country-specific Requirements.
Refer to Section 1.1 rationale. 
Section 8, Study 
Assessments and 
Procedures
(and applicable 
subsections)
Added a cross-reference notation to 
Appendix 7, Country-specific Requirements.
Refer to Section 1.1 rationale. 
Section 10.1.3, 
Data Protection
Added EU-specific data protection measures.
Refer to Section 10.7 rationale.
Throughout
document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation 
of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.3
Benefit/Risk Assessment......................................................................................25
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Planned Exploratory Biomarker Research.........................................32
4.2.1.3.1
Planned 
Analysis ........................................................32
4.2.1.4
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparators .........................................................33
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End-of-Study Definition ............................................................35
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.2
Exclusion Criteria................................................................................................38
5.3
Lifestyle Considerations......................................................................................41
5.3.1
Meals and Dietary Restrictions....................................................................41
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................42
5.4
Screen Failures.....................................................................................................42
5.5
Participant Replacement Strategy......................................................................42
6
STUDY INTERVENTION............................................................................................43
6.1
Study Intervention(s) Administered...................................................................43
6.2
Preparation/Handling/Storage/Accountability .................................................46
6.2.1
Dose Preparation..........................................................................................46
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6.2.2
Handling, Storage, and Accountability........................................................46
6.3
Measures to Minimize Bias: Randomization and Blinding..............................47
6.3.1
Intervention Assignment..............................................................................47
6.3.2
Stratification.................................................................................................47
6.3.3
Blinding........................................................................................................47
6.4
Study Intervention Compliance..........................................................................47
6.4.1
Background Lipid-Lowering Therapy Review............................................48
6.4.2
Fasting Compliance .....................................................................................48
6.5
Concomitant Therapy..........................................................................................48
6.5.1
Rescue Medications and Supportive Care ...................................................49
6.6
Dose Modification ................................................................................................49
6.7
Intervention After the End of the Study............................................................50
6.8
Clinical Supplies Disclosure................................................................................50
6.9
Standard Policies..................................................................................................50
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................51
7.1
Discontinuation of Study Intervention...............................................................51
7.2
Participant Withdrawal From the Study...........................................................52
7.3
Lost to Follow-up .................................................................................................53
8
STUDY ASSESSMENTS AND PROCEDURES........................................................54
8.1
Administrative and General Procedures ...........................................................54
8.1.1
Informed Consent.........................................................................................54
8.1.1.1
Full Informed Consent .......................................................................55
8.1.1.2
Consent for Limited Screening..........................................................55
8.1.1.3
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................55
8.1.2
Inclusion/Exclusion Criteria ........................................................................56
8.1.3
Participant Identification Card.....................................................................56
8.1.4
Medical History ...........................................................................................56
8.1.5
Prior and Concomitant Medications Review...............................................56
8.1.5.1
Prior Medications...............................................................................56
8.1.5.2
Concomitant Medications..................................................................56
8.1.6
Dietary Counseling ......................................................................................57
8.1.7
Assignment of Screening Number...............................................................57
8.1.8
Assignment of Treatment/Randomization Number.....................................57
8.1.9
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing....................................................................................................57
8.1.10
Study Intervention Administration ..............................................................57
8.1.10.1
Timing of Dose Administration.........................................................58
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8.1.11
Study Intervention Accountability...............................................................58
8.1.12
Background Lipid-Lowering Therapy Review............................................58
8.1.13
Fasting Accountability.................................................................................58
8.1.14
Discontinuation and Withdrawal .................................................................59
8.1.14.1
Withdrawal From Future Biomedical Research ................................59
8.1.15
Participant Blinding/Unblinding..................................................................59
8.1.16
Calibration of Equipment.............................................................................60
8.2
Efficacy Assessments ...........................................................................................60
8.2.1
Lipid Assessments .......................................................................................60
8.3
Safety Assessments...............................................................................................61
8.3.1
Physical Examinations.................................................................................61
8.3.2
Height and Weight .......................................................................................61
8.3.3
Vital Signs....................................................................................................61
8.3.4
Electrocardiograms ......................................................................................62
8.3.5
Clinical Safety Laboratory Assessments .....................................................62
8.3.6
Pregnancy Testing........................................................................................62
8.3.6.1
Pretreatment Confirmation of Postmenopausal State ........................63
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................63
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................63
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......66
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...66
8.4.4
Regulatory Reporting Requirements for SAE .............................................66
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................67
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................67
8.4.7
Events of Clinical Interest............................................................................67
8.5
Treatment of Overdose........................................................................................68
8.6
Pharmacokinetics.................................................................................................69
8.6.1
Blood Collection for Plasma MK-0616 .......................................................69
8.7
Pharmacodynamics..............................................................................................69
8.8
Biomarkers ...........................................................................................................69
8.8.1
Planned Genetic Analysis Sample Collection..............................................69
8.9
Future Biomedical Research Sample Collection...............................................69
8.10
Health Economics or Medical Resource Utilization and Health Economics..70
8.11
Visit Requirements...............................................................................................70
8.11.1
Visit Reminders ...........................................................................................70
8.11.2
Screening Procedures...................................................................................70
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8.11.2.1
Optional Limited Screening Visit......................................................70
8.11.2.2
Screening............................................................................................71
8.11.2.2.1
Rescreening..............................................................................71
8.11.3
Treatment Period..........................................................................................71
8.11.4
Unscheduled Visits ......................................................................................71
8.11.5
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................72
8.11.6
Posttreatment................................................................................................72
9
KEY STATISTICAL CONSIDERATIONS ...............................................................73
9.1
Responsibility for Analyses/In-house Blinding .................................................73
9.2
Hypotheses/Estimation ........................................................................................73
9.3
Analysis Endpoints...............................................................................................73
9.3.1
Efficacy Endpoints.......................................................................................73
9.3.2
Safety Endpoints..........................................................................................74
9.4
Analysis Populations............................................................................................74
9.4.1
Efficacy Analysis Populations.....................................................................74
9.4.2
Safety Analysis Populations ........................................................................74
9.5
Statistical Methods...............................................................................................75
9.5.1
Estimand(s) ..................................................................................................75
9.5.2
Statistical Methods for Efficacy Analyses...................................................76
9.5.3
Statistical Methods for Safety Analyses ......................................................80
9.5.3.1
Overall Safety Assessment ................................................................80
9.5.3.2
Assessment of Safety Topics of Special Interest ...............................80
9.6
Interim Analyses ..................................................................................................81
9.7
Multiplicity ...........................................................................................................81
9.8
Sample Size and Power Calculations .................................................................82
9.8.1
Sample Size and Power for Safety Analyses ...............................................83
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................85
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........85
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................85
10.1.2
Financial Disclosure.....................................................................................88
10.1.3
Data Protection.............................................................................................89
10.1.3.1
Confidentiality of Data ......................................................................89
10.1.3.2
Confidentiality of Participant Records...............................................89
10.1.3.3
Confidentiality of IRB/IEC Information............................................90
10.1.4
Committees Structure...................................................................................90
10.1.4.1
Executive Oversight Committee........................................................90
10.1.4.2
External Data Monitoring Committee ...............................................90
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10.1.4.3
National Leader Committee...............................................................90
10.1.5
Publication Policy........................................................................................91
10.1.6
Compliance with Study Registration and Results Posting Requirements ...91
10.1.7
Compliance with Law, Audit, and Debarment ............................................91
10.1.8
Data Quality Assurance ...............................................................................92
10.1.9
Source Documents .......................................................................................93
10.1.10
Study and Site Closure.................................................................................93
10.2
Appendix 2: Clinical Laboratory Tests..............................................................94
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................96
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................96
10.3.2
Definition of AE ..........................................................................................96
10.3.3
Definition of SAE ........................................................................................97
10.3.4
Additional Events Reported.........................................................................98
10.3.5
Recording AE and SAE ...............................................................................98
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................102
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................103
10.5
Appendix 5: Contraceptive Guidance..............................................................104
10.5.1
Definitions..................................................................................................104
10.5.2
Contraceptive Requirements......................................................................105
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................106
10.7
Appendix 7: Country-specific Requirements..................................................110
10.8
Appendix 8: Statin Intensity Chart Based on Total Daily Dose....................111
10.9
Appendix 9: Abbreviations ...............................................................................112
11
REFERENCES.............................................................................................................117
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................44
Table 2
Examples of Lipid Lowering Therapy.............................................................48
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................65
Table 4
Analysis Strategy for Key Efficacy Variables.................................................79
Table 5
Analysis Strategy for Safety Parameters..........................................................81
Table 6
Power for the Primary and Key Secondary Efficacy Endpoints......................83
Table 7
Examples of AE Incidences for Which 95% CI for the Difference Would 
Exclude Zero....................................................................................................84
Table 8
Protocol-required Safety Laboratory Assessments..........................................94
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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 3, Randomized, Double-Blind Study to Evaluate the Efficacy and 
Safety of MK-0616 Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and 
Bempedoic Acid in Adults With Hypercholesterolemia 
Short Title: MK-0616-018 Versus Comparators Study in Hypercholesterolemia
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table. The order of 
the listed hypotheses does not represent the order of hypotheses testing.
In adults with hypercholesterolemia: 
Primary Objectives
Primary Endpoints
To compare the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid,
and ezetimibe + bempedoic acid on mean 
percent change from baseline in LDL-C at 
Day 56. 
Hypothesis (H1): MK-0616 is superior to 
bempedoic acid on mean percent change 
from baseline in LDL-C at Day 56.
Hypothesis (H2): MK-0616 is superior to 
ezetimibe on mean percent change from 
baseline in LDL-C at Day 56.
Hypothesis (H3): MK-0616 is superior to 
ezetimibe + bempedoic acid on mean percent 
change from baseline in LDL-C at Day 56.
LDL-C
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Secondary Objectives
Secondary Endpoints
To compare the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on mean 
percent change from baseline in ApoB at 
Day 56. 
Hypothesis (H4): MK-0616 is superior to 
bempedoic acid on mean percent change 
from baseline in ApoB at Day 56.
Hypothesis (H5): MK-0616 is superior to 
ezetimibe on mean percent change from 
baseline in ApoB at Day 56. 
Hypothesis (H8): MK-0616 is superior to 
ezetimibe + bempedoic acid on mean percent 
change from baseline in ApoB at Day 56.
ApoB
To compare the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid,
and ezetimibe + bempedoic acid on mean 
percent change from baseline in Non-HDL-C 
at Day 56.
Hypothesis (H6): MK-0616 is superior to 
bempedoic acid on mean percent change 
from baseline in Non-HDL-C at Day 56.
Hypothesis (H7): MK-0616 is superior to 
ezetimibe on mean percent change from 
baseline in Non-HDL-C at Day 56.
Hypothesis (H9): MK-0616 is superior to 
ezetimibe + bempedoic on mean percent 
change from baseline in Non-HDL-C at Day 
56.
Non-HDL-C
To evaluate the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on percent 
change from baseline in Lp(a) at Day 56.
Lp(a)
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To evaluate the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on the 
proportion of participants who at Day 56 
have an LDL-C <70 mg/dL and ≥50% 
reduction from baseline.
LDL-C
To evaluate the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on the 
proportion of participants who at Day 56
have an LDL-C<55 mg/dL and ≥50% 
reduction from baseline.
LDL-C
To evaluate the safety and tolerability of 
MK-0616
Adverse Events
Discontinuation of study intervention due 
to adverse events
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Hypercholesterolaemia
Population
Participants ≥18 years of age with 
hypercholesterolemia 
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Sponsor
Investigator
Participants or Subjects
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 15 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.
Refer to Appendix 7 for country-specific 
requirements.
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Number of Participants:
Approximately 300 participants will be randomized.
Intervention Groups and Duration:
Arm 
Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
Group 1
MK-0616
20 mg
20 mg QD
Oral
56 days
Test Product
Group 1
Placebo for 
ezetimibe 
0 mg
0 mg QD
Oral
56 days
Placebo
Group 1
Placebo for 
bempedoic acid
0 mg
0 mg QD
Oral
56 days
Placebo
Group 2
Ezetimibe
10 mg
10 mg QD
Oral
56 days
Comparator
Group 2
Placebo for 
MK-0616
0 mg
0 mg QD
Oral
56 days
Placebo
Group 2
Placebo for 
bempedoic acid
0 mg
0 mg QD
Oral
56 days
Placebo
Group 3
Bempedoic 
Acid
180 mg
180 mg QD Oral
56 days
Comparator
Group 3
Placebo for 
ezetimibe
0 mg
0 mg QD
Oral
56 days
Placebo
Group 3
Placebo for 
MK-0616
0 mg
0 mg QD
Oral
56 days
Placebo
Group 4
Ezetimibe
10 mg
10 mg QD
Oral
56 days
Comparator
Group 4
Bempedoic 
Acid
180 mg
180 mg QD Oral
56 days
Comparator
Group 4
Placebo for 
MK-0616
0 mg
0 mg QD
Oral
56 days
Placebo
Note: MK-0616 is formulated with 
 of sodium caprate, a permeation enhancer. The placebo formulation does not 
contain a permeation enhancer. Bempedoic acid will be encapsulated to maintain blinding.
Total Number of Intervention 
Groups/Arms
4 (2:1:1:2, MK-0616: Ezetimibe: Bempedoic 
acid: Ezetimibe and Bempedoic Acid) 
Duration of Participation
Each participant will participate in the study 
for approximately 140 days (20 weeks) from 
the time the participant provides documented 
informed consent through the final contact. 
After a screening phase of up to 30 days, 
each participant will receive assigned 
intervention for approximately 56 days (8 
weeks). After the end-of-treatment each 
participant will be followed for 56 days or 
will be offered the opportunity to participate 
in a separate open-label extension study. 
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
With IRB/IEC approval and participant consent, this study allows specified screening procedures to be performed under limited 
screening consent. See Sections 8.1.1.2 and 8.11.2.1.
Study Period:
Optional
Limited 
Screening 
Screening
Intervention
Follow
-up 
SI Discon Notes
Visit Number/Title:
1
2
3 
4
5
6
7
Visit 7 not required for 
participants who enroll in the 
OLE protocol. Participants 
who discontinue study 
intervention before 
completion of the treatment 
period should continue to be 
monitored in the study and 
encouraged to participate in 
the study visits and procedures
(Section 8.11.5).
Week/Day/
Visit Type
Up to 60 
days prior to 
Day 1
Up to 30 
days
Day 
1
Day 14
TC
Day 
21
Day 
42
Day 
56
Day
112
TC
N/A
The follow-up call should 
occur 56 days (8 weeks) after 
the last dose of study 
intervention.
Visit Windows (Days):
N/A
N/A
N/A
±3
±3
±3
±5
+7
N/A
Administrative Procedures
Informed Consent (Optional Limited 
Screening)
X
Participants who undergo 
Optional Limited Screening 
must provide documented 
consent for a blood draw 
before the Screening Visit
(Section 8.11.2.1)
Informed Consent
X
Informed Consent for FBR
X
Participants remain eligible 
for the main study if they opt 
out of FBR
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Study Period:
Optional
Limited 
Screening 
Screening
Intervention
Follow
-up 
SI Discon Notes
Visit Number/Title:
1
2
3 
4
5
6
7
Visit 7 not required for 
participants who enroll in the 
OLE protocol. Participants 
who discontinue study 
intervention before 
completion of the treatment 
period should continue to be 
monitored in the study and 
encouraged to participate in 
the study visits and procedures
(Section 8.11.5).
Week/Day/
Visit Type
Up to 60 
days prior to 
Day 1
Up to 30 
days
Day 
1
Day 14
TC
Day 
21
Day 
42
Day 
56
Day
112
TC
N/A
The follow-up call should 
occur 56 days (8 weeks) after 
the last dose of study 
intervention.
Visit Windows (Days):
N/A
N/A
N/A
±3
±3
±3
±5
+7
N/A
Inclusion/Exclusion Criteria
X
X
Participant Identification Card
X
X
X
Add randomization number at 
Visit 2/Day 1.
Medical History
X
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Dietary Counseling
X
Participants will receive 
counseling from a qualified 
health care professional on a 
diet consistent with local 
guidelines. See Section 5.3.1.
for details.
IRT Visit Registration
X
X
X
X
X
X
X
Refer to IRT manual for 
details
Intervention Randomization
X
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Study Period:
Optional
Limited 
Screening 
Screening
Intervention
Follow
-up 
SI Discon Notes
Visit Number/Title:
1
2
3 
4
5
6
7
Visit 7 not required for 
participants who enroll in the 
OLE protocol. Participants 
who discontinue study 
intervention before 
completion of the treatment 
period should continue to be 
monitored in the study and 
encouraged to participate in 
the study visits and procedures
(Section 8.11.5).
Week/Day/
Visit Type
Up to 60 
days prior to 
Day 1
Up to 30 
days
Day 
1
Day 14
TC
Day 
21
Day 
42
Day 
56
Day
112
TC
N/A
The follow-up call should 
occur 56 days (8 weeks) after 
the last dose of study 
intervention.
Visit Windows (Days):
N/A
N/A
N/A
±3
±3
±3
±5
+7
N/A
Study Intervention Dispensing
X
X
X
Study Intervention Compliance
X
X
X
X
X
Compliance with study 
intervention will be assessed 
by counting returned tablets 
and capsules, corroborated 
with participant reporting. See 
Section 6.4 for details.
Background Lipid-lowering Therapy 
Review
X
X
X
X
X
X
X
See Section 6.4.1 for details.
Fasting Accountability
X
X
X
X
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:
Optional
Limited 
Screening 
Screening
Intervention
Follow
-up 
SI Discon Notes
Visit Number/Title:
1
2
3 
4
5
6
7
Visit 7 not required for 
participants who enroll in the 
OLE protocol. Participants 
who discontinue study 
intervention before 
completion of the treatment 
period should continue to be 
monitored in the study and 
encouraged to participate in 
the study visits and procedures
(Section 8.11.5).
Week/Day/
Visit Type
Up to 60 
days prior to 
Day 1
Up to 30 
days
Day 
1
Day 14
TC
Day 
21
Day 
42
Day 
56
Day
112
TC
N/A
The follow-up call should 
occur 56 days (8 weeks) after 
the last dose of study 
intervention.
Visit Windows (Days):
N/A
N/A
N/A
±3
±3
±3
±5
+7
N/A
Efficacy Procedures
Lipid Panel
X
X
X
X
X
Lipid panel parameters are 
listed in Appendix 2. The 
values for the lipid panel will 
be masked after Visit 2.
LDL-C
X
Please refer to the “notes” 
column for “Informed Consent 
(Optional Limited 
Screening).” Specimen may 
be processed by local or 
central laboratory. See 
Appendix 2 for details
ApoB, Lp(a)
X
X
X
X
Safety Procedures
Full Physical Examination
X
X
X
Height
X
Weight
X
X
X
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Study Period:
Optional
Limited 
Screening 
Screening
Intervention
Follow
-up 
SI Discon Notes
Visit Number/Title:
1
2
3 
4
5
6
7
Visit 7 not required for 
participants who enroll in the 
OLE protocol. Participants 
who discontinue study 
intervention before 
completion of the treatment 
period should continue to be 
monitored in the study and 
encouraged to participate in 
the study visits and procedures
(Section 8.11.5).
Week/Day/
Visit Type
Up to 60 
days prior to 
Day 1
Up to 30 
days
Day 
1
Day 14
TC
Day 
21
Day 
42
Day 
56
Day
112
TC
N/A
The follow-up call should 
occur 56 days (8 weeks) after 
the last dose of study 
intervention.
Visit Windows (Days):
N/A
N/A
N/A
±3
±3
±3
±5
+7
N/A
Vital Signs (pulse rate, BP)
X
X
X
X
X
12-lead ECG
X
Chemistry
X
X
X
X
X
TSH
X
A1C
X
Hematology
X
X
X
X
Urine or Serum (hCG; POCBP)
X
X
X
X
X
X
POCBP will perform a urine 
pregnancy test approximately 
4 weeks after the last dose of 
study intervention prior to 
Day 112 (TC)a. A serum test 
will be performed if a urine 
test is not acceptable per local 
regulations (Section 8.3.6). 
Serum hCG will be performed 
when a pregnancy is 
suspected.
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Study Period:
Optional
Limited 
Screening 
Screening
Intervention
Follow
-up 
SI Discon Notes
Visit Number/Title:
1
2
3 
4
5
6
7
Visit 7 not required for 
participants who enroll in the 
OLE protocol. Participants 
who discontinue study 
intervention before 
completion of the treatment 
period should continue to be 
monitored in the study and 
encouraged to participate in 
the study visits and procedures
(Section 8.11.5).
Week/Day/
Visit Type
Up to 60 
days prior to 
Day 1
Up to 30 
days
Day 
1
Day 14
TC
Day 
21
Day 
42
Day 
56
Day
112
TC
N/A
The follow-up call should 
occur 56 days (8 weeks) after 
the last dose of study 
intervention.
Visit Windows (Days):
N/A
N/A
N/A
±3
±3
±3
±5
+7
N/A
FSH
X
FSH only to be performed to 
confirm postmenopausal state 
(Appendix 5). Testing 
requirements for FSH are in 
Section 8.3.6.1.
AE/SAE Review
X
X
X
X
X
X
X
X
X
Biomarkers
X
Collect
 
 See Section 
8.8.1.
A1C=glycosylated hemoglobin, AE=adverse event, ApoB=apolipoprotein B, BP=blood pressure, ECG=electrocardiogram, FBR=future biomedical research, FSH=follicle stimulating hormone, 
hCG=human chorionic gonadotropin, IRT=interactive response technology, LDL-C=low-density lipoprotein cholesterol, Lp(a)=lipoprotein (a), N/A=not applicable, OLE=open-label extension, 
PK=pharmacokinetic, POCBP=participants of childbearing potential, SAE=serious adverse event, SI Discon=study intervention discontinuation, TC=telephone call (includes other virtual forms 
of contacting the participant), TSH=thyroid-stimulating hormone.
aIn case of pregnancy, participants are required to contact the site.
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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, injectable PCSK9i), a substantial proportion of patients with 
hypercholesterolemia are not at guideline recommended LDL-C targets [Fox, K. M., et al 
2018] [Cannon, C. P., et al 2021]. 
Use of ezetimibe, a cholesterol absorption inhibitor, leads to additional LDL-C reduction, 
when added to statin therapy, without raising significant safety concerns. A number of 
clinical trials have demonstrated additional benefits of ezetimibe add-on therapy. Among 
them, a large, randomized study, “Improved Reduction of Outcomes: Vytorin Efficacy 
International Trial (IMPROVE-IT),” reported that adding ezetimibe to statins decreased 
LDL-C by an additional 24% and reduced cardiovascular events in patients with acute 
coronary syndrome [Cannon, C. P., et al 2015]. However, there is still a residual risk of 
recurrent ASCVD.
Bempedoic acid is a novel nonstatin drug that inhibits cholesterol biosynthesis in the same 
pathway as statins. It is administered as a prodrug and is converted to active drug in the liver 
but not in muscle. Phase 2 and 3 clinical trials have demonstrated promising results regarding 
its safety and efficacy either as monotherapy or in combination with statins or ezetimibe 
among different patient profiles including patients with statin intolerance [Nissen, S. E., et al 
2023] [Ballantyne, C. M., et al 2020].
Bempedoic acid is currently FDA approved as an adjunct to diet and maximally tolerated 
statin therapy for the treatment of adults with HeFH or established ASCVD who require 
additional lowering of LDL-C. Use of bempedoic acid in the trial for participants with 
hyperlipidemia (including participants without history of major ASCVD events) is based on 
current publications and expert consensus decision pathways, where bempedoic acid is listed 
as a treatment option for hypercholesterolemia for both groups of patients with and without 
history, but at high risk of, major ASCVD events [Ballantyne, C. M., et al 2020] [Nissen, S. 
E., et al 2023].
 
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 
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increases steady state levels of cell surface hepatic LDL receptors, which enhances LDL-C 
clearance and lowers circulating levels of LDL-C. 
Several injectable PCSK9i’s have shown large reductions in LDL-C and received regulatory 
approval for the treatment of hypercholesterolemia. Unlike these injectable therapies, 
MK-0616 is an orally administered PCSK9i for the treatment of hypercholesterolemia. An 
oral PCSK9i that can achieve similar LDL-C-lowering as the injectable PCSK9i and offers 
potential advantages in simplicity of dosing, patient preference, and access.
The principal objectives of this Phase 3 study are to evaluate the LDL-C-lowering efficacy of 
MK-0616 compared to ezetimibe or bempedoic acid, or ezetimibe and bempedoic acid in 
participants with hypercholesterolemia.
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 macrocyclic 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.
MK-0616 is formulated with sodium caprate to enhance intestinal absorption and oral 
bioavailability. Refer to the IB for additional information.
Refer to Section 4.2.2 for detailed information on ezetimibe, bempedoic acid, and ezetimibe 
and bempedoic combination therapy.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
PCSK9 is a well-validated target for lowering LDL-C, with strong human genetics
implicating an important role for PCSK9 in regulating LDL-C, a key risk factor for ASCVD 
events. Additionally, cardiovascular outcomes studies have demonstrated that treatment with 
anti-PCSK9 mAbs reduces the risk of cardiovascular events such as myocardial infarction 
and ischemic stroke [Sabatine, M. S., et al 2017] [Schwartz, G. G., et al 2018].
In the preclinical development program, no clinically relevant safety findings associated with 
MK-0616, or its permeation enhancer (sodium caprate), have been observed in any species 
studied. Additionally, robust LDL-C lowering was observed following single-dose 
administration of MK-0616 in monkeys. 
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In Phase 1 studies, multiple dose administration of MK-0616 was associated with reduction 
in LDL-C similar to that observed with injectable PCSK9i (~65% reduction of LDL-C from 
baseline following 14 days of once-daily dosing). 
In the Phase 2b study, results showed that the reduction in LDL-C at Week 8 was both 
statistically significant and clinically meaningful for all doses of MK-0616 (6 mg, 12 mg, 
18 mg, and 30 mg) versus placebo ranging from 41.2% to 60.9%, respectively.
MK-0616 has been generally well tolerated in clinical studies to date. In Phase 1 studies in 
both healthy participants and in those on statins for hypercholesterolemia,
 
 The 
Phase 2b study in participants with hypercholesterolemia collected safety data over 16 weeks 
in approximately 300 participants assigned to 1 of 4 MK-0616 dose levels (6 mg, 12 mg, 
18 mg, or 30 mg). In these clinical studies, AEs were generally of mild to moderate intensity 
and there were no clinically meaningful trends as a function of study intervention on AEs, 
laboratory parameters, vital signs, or ECGs.
Based on the available preclinical and clinical data, the benefit/risk assessment for MK-0616 
is considered favorable.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
Furthermore, based on the available clinical data, the benefit/risk assessment for ezetimibe, 
bempedoic acid and the combination of ezetimibe and bempedoic acid is considered 
favorable. Refer to Section 4.2.2 for details.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table. The order of 
the listed hypotheses does not represent the order of hypotheses testing.
In adults with hypercholesterolemia: 
Primary Objectives
Primary Endpoints
To compare the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid,
and ezetimibe + bempedoic acid on mean 
percent change from baseline in LDL-C at 
Day 56. 
Hypothesis (H1): MK-0616 is superior to 
bempedoic acid on mean percent change 
from baseline in LDL-C at Day 56.
Hypothesis (H2): MK-0616 is superior to 
ezetimibe on mean percent change from 
baseline in LDL-C at Day 56.
Hypothesis (H3): MK-0616 is superior to 
ezetimibe + bempedoic acid on mean percent 
change from baseline in LDL-C at Day 56.
LDL-C
Secondary Objectives
Secondary Endpoints
To compare the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on mean 
percent change from baseline in ApoB at 
Day 56. 
Hypothesis (H4): MK-0616 is superior to 
bempedoic acid on mean percent change 
from baseline in ApoB at Day 56.
Hypothesis (H5): MK-0616 is superior to 
ezetimibe on mean percent change from 
baseline in ApoB at Day 56. 
Hypothesis (H8): MK-0616 is superior to 
ezetimibe + bempedoic acid on mean percent 
change from baseline in ApoB at Day 56.
ApoB
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To compare the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid,
and ezetimibe + bempedoic acid on mean 
percent change from baseline in Non-HDL-C 
at Day 56.
Hypothesis (H6): MK-0616 is superior to 
bempedoic acid on mean percent change 
from baseline in Non-HDL-C at Day 56.
Hypothesis (H7): MK-0616 is superior to 
ezetimibe on mean percent change from 
baseline in Non-HDL-C at Day 56.
Hypothesis (H9): MK-0616 is superior to 
ezetimibe + bempedoic on mean percent 
change from baseline in Non-HDL-C at Day 
56.
Non-HDL-C
To evaluate the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on percent 
change from baseline in Lp(a) at Day 56.
Lp(a)
To evaluate the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on the 
proportion of participants who at Day 56
have an LDL-C <70 mg/dL and ≥50% 
reduction from baseline.
LDL-C
To evaluate the efficacy of MK-0616 against 
3 comparators: ezetimibe, bempedoic acid, 
and ezetimibe + bempedoic acid on the 
proportion of participants who at Day 56
have an LDL-C<55 mg/dL and ≥50% 
reduction from baseline.
LDL-C
To evaluate the safety and tolerability of 
MK-0616
Adverse Events
Discontinuation of study intervention due 
to adverse events
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel-group, multisite, double-blind study of 
MK-0616 versus ezetimibe or bempedoic acid or ezetimibe and bempedoic acid in 
participants with hypercholesterolemia. Participants with a history of a major ASCVD event 
and those at intermediate to high risk for first major ASCVD event are eligible for the study, 
including those with and without HeFH. Participants should be receiving optimized treatment 
(per local guidelines and investigator judgment) with a low, moderate, or high intensity statin 
(± non-statin LLT) at a stable dose. To ensure that the majority of enrolled participants with 
clinical ASCVD or HeFH are receiving at least moderate intensity statin therapy, a 
 
Participants previously treated with ezetimibe or bempedoic acid or combination of 
ezetimibe plus bempedoic acid are eligible for the study if they discontinued the medication
at least 30 days prior to Visit 1 (Screening). LLTs should be stable for ≥30 days before 
screening and are expected to be unchanged for the duration of the study. 
Participants with homozygous FH and those on treatment with a PCSK9i are not eligible for 
the study.
This study consists of an up-to 30-day screening period (Visit 1 [Screening] to Visit 2 [Day
1]), 56 days (8-week) treatment period (Visit 2 [Day 1] to Visit 6 [Day 56]), and either 
56 days post treatment follow-up period by telephone contact (Visit 6 [Day 56] to Visit 7
[Day 112]) for safety assessment or participants will be offered the opportunity to enter the 
separate OLE study. Participants who discontinue study intervention prematurely should be 
encouraged to continue in the study off-treatment and to complete all remaining visits as 
outlined in the SoA.
A single optional Limited Screening Visit may be performed to assess potential eligibility for 
participants who do not have a recent (within 3 months) historical assessment of LDL-C 
level. After providing documented consent for this Limited Screening Visit, participants will 
be assigned a screening number and undergo a blood draw. If, based on LDL-C values, the 
decision to proceed to Visit 1 (Screening) is made, documented consent for the full study will 
be obtained and the mandatory Screening Visit will be conducted.
After completing the Screening Period, approximately 300 participants meeting eligibility 
criteria will be randomized in a 2:1:1:2 fashion to treatment with MK-0616, ezetimibe,
bempedoic acid, or ezetimibe and bempedoic acid. Randomized participants will take 1 tablet 
of MK-0616/placebo, and 1 tablet of ezetimibe/placebo, and 1 capsule of bempedoic 
acid/placebo (Table 1) daily in the fasted state according to the guidelines provided in 
Section 5.3.1.
 
All central lipid panel results and efficacy assessments will be masked after Visit 2 (Day 1) 
through study completion. Investigators should not evaluate lipid levels at a local laboratory 
during the study. 
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Participants who 1) are compliant with taking study intervention; and 2) complete the study 
(Visit 6, Day 56) while on study intervention will be offered the opportunity to participate in 
a separate OLE study where all participants receive MK-0616 daily.
All participants who opt not to enter the OLE study, who are not eligible for the OLE or who 
continue in the study after discontinuation of study intervention will have a follow-up contact 
~56 days after last study intervention dose for AE monitoring. An independent, external 
DMC will monitor data for safety.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The goals of this Phase 3 study are to assess whether MK-0616 is superior to ezetimibe or 
bempedoic acid or ezetimibe and bempedoic acid in reducing LDL-C in participants with 
hypercholesterolemia, and to evaluate its safety and tolerability. To do so, this study will use 
a double-blind, parallel-group design in the assessment of MK-0616 versus ezetimibe or
bempedoic acid, or ezetimibe and bempedoic acid (details on the rationale for use of 
comparators are in Section 4.2.2). Eligibility criteria for this study will support enrollment of 
participants with history of a major ASCVD event or those with intermediate or high risk for 
first major ASCVD event who require LDL-C reduction despite background therapies. 
Since
 
 those with eGFR <30 mL/min/1.73 m2 or ESKD on dialysis are not 
eligible to participate. Additionally, stratification by 
 
 
Fifty-six days (8-week) treatment period was selected to provide adequate efficacy and safety 
data for MK-0616. A sample size of 300 was chosen to allow for sufficient power to detect 
clinically significant treatment effects in primary and secondary endpoints as well as safety 
signals.
 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
LDL-C is causally associated with ASCVD, the most common condition leading to mortality 
in the world (Section 2.1). Therefore, the efficacy of MK-0616, like that of LLTs, will be 
determined by its effect on LDL-C relative to ezetimibe or bempedoic acid or ezetimibe and 
bempedoic acid, with the primary endpoint of mean percent change from baseline in LDL-C 
at Day 56. Secondary endpoints include proportions of participants with LDL-C <70 mg/dL 
and ≥50% reduction from baseline and <55 mg/dL and ≥50% reduction from baseline at 
Day 56.
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At Visit 2, LDL-C will be calculated based on the Martin/Hopkins calculation and directly 
measured using beta-quantification. At all other timepoints, LDL-C will be calculated based 
on the Martin/Hopkins calculation and 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.
Like LDL-C, non-HDL-C, ApoB, and Lp(a) are predictors of ASCVD risk. Therefore, the 
efficacy of MK-0616 compared with ezetimibe or bempedoic acid or ezetimibe and 
bempedoic acid on mean percent change from baseline in ApoB, non-HDL-C, and percent 
change from baseline in Lp(a) at Day 56 will be evaluated as secondary endpoints. 
 
4.2.1.2
Safety Endpoints
AEs (new, abnormal physical examination findings would be reported as AE), vital signs, 
and laboratory safety tests (chemistry and hematology) will be assessed to provide a 
comprehensive safety evaluation of MK-0616 relative to ezetimibe or bempedoic acid, or
ezetimibe and bempedoic acid in participants with hypercholesterolemia. Potential DILI 
events will be captured as ECIs per the standard requirement of Sponsor studies. 
 
Section 8.4.7). AEs will be evaluated and assessed according to 
the guidelines in Section 8.4 and Appendix 3. Participants may be asked to return for 
unscheduled visits to perform additional safety monitoring.
4.2.1.3
Planned Exploratory Biomarker Research
4.2.1.3.1
Planned 
 Analysis
 variation may impact a participant’s response to therapy, susceptibility to, severity, 
 
 
 
 
 
 
 
 
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4.2.1.4
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include 
 
 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.
4.2.2
Rationale for the Use of Comparators
Ezetimibe is a non-statin lipid-lowering medication that inhibits absorption of dietary 
cholesterol by blocking the NPC1L1. It has a half-life of approximately 22 hours due to 
enterohepatic circulation. Ezetimibe is metabolized in the small intestine and the liver – not 
via the cytochrome P450 system – and excreted back in bile as means of elimination [Al 
Danaf, J., et al 2016].
Multiple studies in patients at a high risk or with underlying cardiovascular disease have 
shown significant decrease in mean LDL-C levels with the combination therapy of ezetimibe 
and statin versus statin monotherapy [Morrone, D., et al 2012]. The addition of ezetimibe 10 
mg to a statin therapy is recommended by guidelines and represents the first step in the 
combination therapy aiming at reducing LDL-C plasma levels in patients who do not achieve 
the LDL-C goal or cannot tolerate a high-dose statin, but it only reduces LDL-C by 15% to 
25% when added to statins.
In IMPROVE-IT, a Phase 3, double-blind, randomized study, addition of ezetimibe to statin 
therapy lowered LDL-C by approximately 24% and improved cardiovascular outcomes in 
participants hospitalized within the preceding 10 days for an acute coronary syndrome
[Cannon, C. P., et al 2015]. Furthermore, in combination with a mild-to-moderate statin 
intensity, ezetimibe is used in situations of statin-associated adverse effects such as myalgia 
and the combination therapy is relatively safer. mAb of proprotein convertase subtilisin/kexin 
type 9 (PCSK9), alirocumab, and evolocumab, have been approved to lower LDL cholesterol 
level. While there are drawbacks to the use of PCSK9 inhibitors, including high cost and 
adverse events such as injection site reaction, they significantly decrease serum LDL 
cholesterol levels and thereby ASCVD risks when added to maximally tolerated statin 
therapy[Stoekenbroek, R. M., et al 2018].
Bempedoic acid is a new class of nonstatin LDL-C lowering therapy. It is an ACL inhibitor 
that reduces LDL-C levels and is associated with a low incidence of muscle-related AEs
[Brandts, J. 2023]. Bempedoic acid inhibits an early step in the cholesterol biosynthetic 
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pathway by modulating the activity of ACL, an enzyme located upstream of 3-hydroxy-3-
methyl-glutaryl-CoA reductase (HMG-CoAR, the target of statins), resulting in the 
upregulation of hepatic LDLR and a reduction of circulating LDL-C levels [Pirillo, A. 
2022].Unlike statins, bempedoic acid is administered as a prodrug and is converted to active 
coenzyme A form by enzymes found only in the liver and not in muscles. The half-life of 
bempedoic acid ranges between 15 and 24 hours.
In Phase 2 trials, bempedoic acid 120 mg demonstrated efficacy in lowering LDL-C up to 
23% as monotherapy. 
In a Phase 3, CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting 
Regimen) Serenity study, treatment with bempedoic acid significantly reduced LDL-C 
compared with placebo at Week 12 (placebo-corrected change from baseline, -21.4% [95% 
CI -25.1% to -17.7%]; p<0.001), in participants with hypercholesterolemia and a history of 
intolerance to at least 2 statins (1 at the lowest available dose) [Laufs, U., et al 2019].
Additional Phase 2 trials have assessed the combination of bempedoic acid with other lipid-
lowering medications, in particular statins and ezetimibe [Ballantyne, C. M., et al 2016].
When compared to ezetimibe monotherapy, Thompson et al. reported that bempedoic acid 
monotherapy at a dose of 180 mg daily reduced LDL-C by 30% at 12 weeks compared to 
21% LDL-C reduction for ezetimibe alone. A combination of bempedoic acid and ezetimibe 
resulted in 48% LDL-C reduction at 12 weeks [Thompson, P. D., et al 2016].
Finally, a Phase 3 trial of a fixed-dose combination of bempedoic acid 180 mg and ezetimibe 
10 mg in high-risk patients with ASCVD, HeFH, or multiple cardiovascular risk factors and 
hypercholesterolemia on maximally tolerated statin therapy was performed. In this trial, 
301 participants were randomized to either a fixed-dose combination therapy or 180 mg 
bempedoic acid or 10 mg ezetimibe or placebo. At 12 weeks, the fixed-dose combination led 
to a 38% LDL-C lowering compared to placebo [Ballantyne, C. M., et al 2020].
Ezetimibe, bempedoic acid, and the combination of ezetimibe and the bempedoic acid will 
serve as the active control in this study to aid interpretation of the study results. 
4.3
Justification for Dose
The 20 mg dose of MK-0616 was chosen for evaluation in this study based on the popPK 
analysis of data from Phase 1 and 2 studies, exposure-response and dose-response analyses of 
data from the Phase 2 study, and results from a relative bioavailability study. 
 
 
 
 
 
 
 
 
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MK-0616 will be administered after an overnight fast (≥8 hours) and at least 30 minutes 
before the first food or beverage of the day in order to maintain optimal MK-0616 
concentrations.
This study will use the currently approved dose of ezetimibe 10 mg qd administered orally.
Bempedoic acid will be administered 180 mg orally qd (currently approved dose).
Combination of bempedoic acid and ezetimibe will be administered orally qd as a capsule 
and a tablet (180 mg bempedoic acid and 10 mg ezetimibe).
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last. Refer to Appendix 7 for country-specific requirements.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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 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 as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Participants with an exclusionary laboratory value, blood pressure measurement and/or ECG 
findings (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 tests/procedures not meeting entry criteria should be 
repeated. The last laboratory draw/result should be used to assess eligibility.
5.1
Inclusion Criteria
Refer to Appendix 7 for country-specific requirements.
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has either:
a.
History of a major ASCVD event  
Note: history of a major ASCVD event is defined as having a history of 1 or more of the 
following: acute coronary syndrome, myocardial infarction, coronary revascularization, 
cerebrovascular arterial revascularization, ischemic stroke, or peripheral arterial disease with 
a history of acute limb ischemia, peripheral arterial revascularization, or major amputation.
OR
b. If no history of a major ASCVD event, has intermediate to high risk for development 
of a first major ASCVD event. 
Note: Intermediate to high risk for ASCVD event is defined as history of one or more of the 
following: 
◦
Possible or definite diagnosis of HeFH based on a locally accepted diagnostic 
algorithm (eg, AHA algorithm, US MEDPED, Simon Broome, Dutch Lipid 
Network, or Japanese Atherosclerosis Society Guidelines) [Gidding, S. S., et al 
2015] [McGowan, M. P., et al 2019] [Kinoshita, M., et al 2018].
◦
Diabetes mellitus 
◦
Stable angina pectoris
◦
Transient ischemic attack
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◦
Symptomatic peripheral arterial disease without a history of acute limb ischemia, 
peripheral arterial revascularization, or major amputation.
◦
Age ≥40 years with ASCVD risk score ≥7.5% based on the Pooled Cohort 
Equation or equivalent 
◦
Coronary artery calcium score ≥100 Agatston units (performed within 3 year of 
Visit 1)
2. Has fasted lipid values (evaluated by the central laboratory) at Visit 1 (Screening) as 
follows: 
a.
History of a major ASCVD event with LDL-C ≥55 mg/dL (≥1.42 mmol/L) 
OR
b. No history of a major ASCVD event with LDL-C ≥70 mg/dL (≥1.81 mmol/L)
3. At Visit 1 (Screening) is either treated with a low, moderate, or high intensity statin (± 
non-statin LLT) (See Appendix 8). 
4. Doses of LLTs (including statin [Table 2]) should be stable for ≥30 days before screening 
with no planned medication or dose change during the participation in the study.
Demographics
5. Is an individual of any sex/gender, from 18 years of age inclusive, at the time of 
providing the informed consent.
Male Participants
Note: No contraceptive measures are required for male participants. 
Female Participants
6. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses an acceptable contraceptive method, or is abstinent from penile-vaginal 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 56 days after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
POCBPs should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. If the contraception 
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requirements in the local label for any of the study interventions are more stringent 
than the requirements above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the 
first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive. 
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.6.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
8. 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.
5.2
Exclusion Criteria
Refer to Appendix 7 for country-specific requirements.
An individual must be excluded from the study if the individual 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], compound HeFH, or double HeFH.
Cardiac Conditions
2. Has New York Heart Association class IV heart failure, or last known left ventricular 
ejection fraction ≤25% by any imaging method, or had a heart failure hospitalization 
within 3 months before Visit 1 (Screening).
3. Has recurrent ventricular tachycardia within 3 months prior to randomization that is not 
controlled by medication or ablation.
4. Has QTc ≥500 ms (in the absence of intraventricular conduction delay and/or a bundle 
branch block) based on an ECG performed at Visit 1 (Screening).
5. Has uncontrolled hypertension defined as sitting SBP >160 mm Hg or DBP >100 mm Hg 
at Visit 2 (Randomization) despite stable antihypertensive treatment.
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6. Has unstable angina, a myocardial infarction, coronary artery bypass graft, percutaneous 
transluminal coronary angioplasty, transient ischemic attack, or stroke within 3 months 
before Visit 1 (Screening).
7. Has a planned arterial revascularization procedure within 8 weeks after randomization.
Non-Cardiac Conditions
8. Has a history of nephrotic syndrome.
9. Has any clinically significant malabsorption condition based on principal investigator 
assessment (eg, recurrent vomiting, inflammatory bowel disease with ongoing symptoms, 
chronic intestinal disease accompanied by a disturbance in digestion and absorption, or a 
history of extensive resection of the upper GI tract).
10. Has poorly controlled diabetes mellitus, defined as A1C ≥9.0%, at Visit 1 (Screening).
11. Has laboratory or clinical evidence of clinically significant hepatic conditions, including 
1 or more of the following: 
•
ALT or AST ≥3 x ULN at Visit 1 (Screening)
•
Direct bilirubin >2 x 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.
12. Participants with a history of tendon disorder or tendon rupture.
13. Participants with a history of gout.
14. Has an abnormal TSH (defined as TSH < LLN or >1.5 x ULN) at Visit 1 (Screening). 
Participants with a history of hypothyroidism must be on a stable treatment for this 
condition for ≥3 months before Visit 1 (Screening).
15. Has a known allergy or intolerance to any of the ingredients in the study intervention.
16. Is actively receiving chemotherapy for malignancy or 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).
17. Has a life expectancy of <2 years based on investigator judgment.
Prior/Concomitant Therapy
18. Is undergoing or previously underwent an LDL-C apheresis program within 3 months 
before Visit 1 (Screening) or plans to initiate an LDL-C apheresis program.
19. Meets 1 or more of the following criteria:
•
Is on treatment with ezetimibe or bempedoic acid within 30 days before Visit 1 
(Screening).
•
Is on treatment with simvastatin >20 mg or pravastatin >40 mg within 30 days before 
Visit 1 (Screening). 
•
Is on treatment with fibrates other than fenofibrates within 30 days before Visit 1 
(Screening).
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•
Is on fenofibrates and have cholelithiasis.
•
Is on cholestyramine.
•
Is on cyclosporine.
•
Is on treatment with a PCSK9i (siRNA or mAb), an ANGPTL3 inhibitor, or an MTP 
inhibitor (eg, lomitapide) at Visit 1 (Screening) or such treatment planned.
•
Was previously treated with an siRNA PCSK9i within 18 months before Visit 1 
(Screening).
•
Was previously treated with a mAb PCSK9i within 3 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
20. 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
21. Has severe renal insufficiency defined as eGFR <30 mL/min/1.73 m2 at Visit 1 
(Screening); or has ESKD on dialysis (eGFR will be calculated according to 
Appendix 2).
22. Has elevated CK >3 x ULN at Visit 1 (Screening).
23. Has a fasting triglyceride value ≥400 mg/dL (≥4.52 mmol/L) at Visit 1 (Screening).
Other Exclusions
24. Routinely consumes >3 alcoholic drinks per day. One standard drink is defined as any 
beverage containing 14 g of pure alcohol (ie, 12 oz [355 ml] of beer, 8 to 9 oz [237 to 
266 ml] of malt liquor, 5 oz [148 ml] of wine, 1.5 oz [44 ml] of distilled spirits).
25. Has a recent history of drug abuse (within the last year) or is a current user of illicit drugs 
at the time of Visit 1 (Screening).
26. Has a medical disorder, condition, or history thereof that in the opinion of the investigator 
would impair the participant’s ability to participate in or complete the study.
27. 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.
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5.3
Lifestyle Considerations
Participants should be encouraged to follow a low cholesterol diet and a medically 
appropriate and consistent exercise regimen per local guidelines if applicable.
5.3.1
Meals and Dietary Restrictions
Fasting Guidance for Clinic Visits
To ensure laboratory parameters are collected in the fasted state, it is recommended to 
contact participants approximately 3 days before each clinic visit and instruct them 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.
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:
•
Take the dose of study intervention, tablet and capsule (with small amounts of water) at 
the same time first thing in the morning, following an overnight fast (≥8 hours); note that 
other dosing times may be considered based on investigator judgment provided 
participant can follow fasting instructions.
AND
•
Withhold food and beverages (except small amounts of water) until 30 minutes after 
administration of study intervention.
•
For convenience, tablets and capsule will be taken together in the morning at the same 
time.
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.
Note: Nonstudy medications should be taken as prescribed.
Dietary Counseling
Participants will receive counseling from a qualified health care professional on a diet 
consistent with local guidelines. At designated subsequent visits, participants will be asked 
about their diet and exercise, and further counseling should be provided, as appropriate. 
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Detailed dietary information will not be captured in the database but recorded in the source 
documents.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
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.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (MK-0616, ezetimibe, bempedoic, and their matching placebos) 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 a fasted state 
(Section 5.3.1) and are outlined in Table 1.
For convenience, tablet and capsule will be taken together in the morning at the same time.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Interven
tion 
Type
Dose 
Formula
tion
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra
tion
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Group 1 Experimental
MK-0616
Drug
Tablet
20 mg
20 mg 
QD
Oral
56 days
Test 
Product
IMP
Central
Group 1 Other
Placebo for 
ezetimibe 
Drug
Tablet
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
Group 1 Other
Placebo for 
bempedoic 
acid
Drug
Capsule
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
Group 2 Active 
Comparator
Ezetimibe
Drug
Tablet
10 mg
10 mg 
QD
Oral
56 days
Comparator IMP
Central
Group 2 Other
Placebo for 
MK-0616
Drug
Tablet
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
Group 2 Other
Placebo for 
bempedoic 
acid
Drug
Capsule
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
Group 3 Active 
Comparator
Bempedoic 
Acid
Drug
Capsule
180 mg
180 mg 
QD
Oral
56 days
Comparator IMP
Central
Group 3 Other
Placebo for 
ezetimibe
Drug
Tablet
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
Group 3 Other
Placebo for 
MK-0616
Drug
Tablet
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
Group 4 Active 
Comparator
Ezetimibe
Drug
Tablet
10 mg
10 mg
QD
Oral
56 days
Comparator IMP
Central
Group 4 Active 
Comparator
Bempedoic 
Acid
Drug
Capsule
180 mg
180 mg 
QD
Oral
56 days
Comparator IMP
Central
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Arm 
Name
Arm Type
Intervention 
Name
Interven
tion 
Type
Dose 
Formula
tion
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra
tion
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Group 4 Other
Placebo for 
MK-0616
Drug
Tablet
0 mg
0 mg QD Oral
56 days
Placebo
IMP
Central
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; QD=once daily
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
To maintain blinding each group will receive placebo tablet or placebo capsule depending on the group assignment.
Note: MK-0616 is formulated with 
 of sodium caprate, a permeation enhancer. The placebo formulation does not contain a permeation enhancer. Bempedoic acid will be 
encapsulated to maintain blinding. 
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.10 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 4 study 
intervention arms. Participants will be assigned randomly in a 2:1:1:2 fashion to MK-0616 or 
ezetimibe or bempedoic acid or ezetimibe and bempedoic acid study interventions, 
respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the
 
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-0616 and its placebo 
will be packaged identically. Ezetimibe and its placebo will be packaged identically. 
Bempedoic acid and its placebo will be packaged identically. 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.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan that results <85% compliance with 
study intervention require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
Sponsor consultation and written documentation is not required if the reason for <85% 
compliance is due to an AE.
•
Compliance with study intervention will be assessed by counting returned tablets and 
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.
•
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, will be recorded in 
the eCRF.
•
A record of the number of study intervention tablets and capsules dispensed to and taken 
by each participant must be maintained and reconciled with study intervention and 
compliance records.
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6.4.1
Background Lipid-Lowering Therapy Review
Adherence to LLT (medications and supplements), at Visit 1 (Screening), will be reviewed at 
every visit by direct questioning and will be documented in source documents throughout the 
study. Those who report non-compliance with their LLT during double-blind treatment 
period should receive additional counseling by site staff.
6.4.2
Fasting Compliance
Participants 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 period before each visit will be assessed by direct questioning. Those who report 
non-compliance with fasting during the period before each visit will receive additional 
counseling by site staff.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are discouraged 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 LLTs (medications and/or supplements) the participant was receiving within 30 days 
before Visit 1 (Screening) should be recorded on the concomitant therapy CRF. See Table 2
for examples of LLTs. Participants should be receiving optimized treatment (per local 
guidelines and investigator judgment) and as such, no LLT additions or dose changes are 
expected during the study (Visit 1 [Screening] to Visit 7 [Day 112]), unless clinically 
mandated. 
Acceptable LLTs include, but are not limited to the following:
Table 2
Examples of Lipid Lowering Therapy
Accepted Lipid-Lowering Therapy Examples
Statins except for simvastatin >20 mg and 
Pravastatin > 40 mg
Niacin
ATP citrate lyase inhibitors except for 
bempedoic acid
Omega-3 fatty acids
Bile acid sequestrants except 
cholestyramine
Cholesterol absorption inhibitors except for 
ezetimibe
ATP= adenosine triphosphate
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The following medications are prohibited during the study:
Prohibited Concomitant Therapies
Commercial (non-study) ezetimibe and
bempedoic acid
Cholestyramine
Simvastatin doses >20 mg
Cyclosporine
Pravastatin doses >40 mg
PCSK9i (siRNA or mAb)
Fibrates
Fenofibrate in patients with cholelithiasis
only
PCSK9i= protein convertase subtilisin/kexin type 9 inhibitor; siRNA= small interfering RNA; 
mAb= monoclonal antibody
Treatment with any nonstudy PCSK9i is prohibited during the study (Visit 1 [Screening] to 
Visit 7 [Day 112]). Participants who initiate treatment with commercially available PCSK9i 
must discontinue study intervention and should continue in the study for follow-up 
(Section 7.1). The PCSK9i should be recorded as a concomitant medication. Commercially
available ezetimibe or bempedoic acid or ezetimibe and bempedoic acid are prohibited 
during the study (Visit 1 [Screening] to Visit 7 [Day 112]).
Participants previously treated with ezetimibe or bempedoic acid or ezetimibe and 
bempedoic acid will be eligible for the study only if the last use of these medications was at 
least 30 days prior to Visit 1 (Screening).
If bile acid sequestrants (except cholestyramine, which is prohibited) are prescribed, it should 
be taken ≥2 hours after the administration of study intervention.
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. 
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
No dose modifications are permitted.
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6.7
Intervention After the End of the Study
Participants who are 1) compliant with taking study intervention, and 2) complete the study 
(Visit 6, Day 56) while on study intervention will be offered the opportunity to participate in 
a separate OLE study where all participants receive MK-0616 daily.
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 8.1.15). 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 and Section 8.11.5 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.
•
Tendon rupture.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed 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.
•
The participant has an eGFR consistently (defined as a repeat measurement performed 
within 14 days of notification from the central laboratory) <20 mL/min/1.73 m2; has a 
25% decline in eGFR from baseline and eGFR <30 ml/min/1.73 m2 or develops new 
onset proteinuria (urine protein/creatinine ≥500 mg/g assessed by local laboratory) of 
unknown etiology. eGFR will be calculated according to Appendix 2. 
•
The participant has an ALT or AST result ≥5 x ULN or symptoms of hepatic dysfunction.
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•
Has a potential DILI event defined as an elevated AST or ALT laboratory value that is 
greater than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is 
greater than or equal to 2× the ULN and, at the same time, an alkaline phosphatase 
laboratory value that is less than 2× the ULN, without any other immediately apparent 
cause for the abnormalities.
•
The participant begins treatment with commercially available PCSK9i.
•
Development of gout.
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.
Participants may be allowed to begin study intervention again if deemed medically 
appropriate, after consultation with the Sponsor.
Participants with transient alterations in eGFR or hepatic enzymes may resume study 
intervention once specified discontinuation criteria are no longer met. 
Refer to Appendix 7 for country-specific requirements.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
For participants who have withdrawn consent from further study follow-up, collection of 
vital status data will be completed by review of medical or public records in accordance with 
participant informed consent and local regulations.
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 8.1.14. 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.
Refer to Appendix 7 for country-specific requirements.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed the volume mentioned in the operations/laboratory manual.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The ICF, any subsequent revised ICF, and any written information 
provided to the participant must receive the IRB/IEC’s approval/favorable opinion in 
advance of use.
Informed consent given by the participant (or their legally acceptable representative) must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
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A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
Refer to Appendix 7 for country-specific requirements.
8.1.1.1
Full Informed Consent
Specifics about the study and the study population are to be included in the ICF.
The participant (or their legally acceptable representative) should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the participant’s or the participant’s legally acceptable 
representative’s dated signature.
Refer to Appendix 7 for country-specific requirements.
8.1.1.2
Consent for Limited Screening
If allowed by the IRB/IEC and local regulations, this study allows specified optional 
screening activities to be conducted under limited consent, before the participant has 
provided full consent under the main ICF. A separate ICF will be used for participants who 
consent to limited screening.
The specific screening activities that the Sponsor allows to be conducted under optional 
limited consent are identified in Section 1.3. 
No other study activities can be conducted unless the participant has provided full consent 
under the main ICF. See also Section 8.11.2.2.
8.1.1.3
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.
Refer to Appendix 7 for country-specific requirements.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
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) and Visit 2 (Randomization).
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 LLTs (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 record medication, if any, taken by the participant 
during the study. No LLT additions or dose changes are expected during the study (Visit 1 
[Screening] to Visit 6 [Day 56]). Treatment with any non-study PCSK9i is prohibited during 
the study (Visit 1 [Screening] to Visit 7 [Day 112]).
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8.1.6
Dietary Counseling
Refer to Section 5.3.1 for guidance on dietary counseling.
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 individual who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit (Optional Limited Screening Visit or Visit 1, as 
applicable). Specific details on the screening/rescreening visit requirements are in Section 
8.11.2.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 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.
Study intervention will be dispensed at the clinical site at visits indicated in the SoA 
(Section 1.3) or at unscheduled visits if approved locally. 
8.1.10
Study Intervention Administration
Study intervention could be dispensed at the clinical site at visits indicated in the SoA 
(Section 1.3) or at unscheduled visits if approved locally. Only authorized site staff may 
arrange shipment of study intervention from the site to the participant following Sponsor 
process to ensure temperature control, full traceability, participant data privacy, and that the 
study blind is preserved where applicable.
Study intervention will be administered as oral tablets and capsules. At Visit 2 (Day 1), 
participants will be educated by a trained member of the site staff on appropriate dosing 
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(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 QD at home. Study intervention dosing
will occur first thing in the morning (with water) following an overnight fast (ie, no food or 
beverages, except small amounts of water) of ≥8 hours. Participants will 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) after all visit 
procedures are complete. 
•
Visit 4 (Day 21): Study intervention will be administered (with water) after laboratory 
samples are collected.
•
Visit 5 (Day 42): Study intervention will be administered (with water) after all visit 
procedures are complete.
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
Study Intervention Accountability
Accounting for compliance with study intervention is described in Section 6.4.
8.1.12
Background Lipid-Lowering Therapy Review
Review of background LLT is described in Section 6.4.1.
8.1.13
Fasting Accountability
Accounting for compliance with fasting guidelines relative to administration of study 
intervention is described in Section 6.4.2.
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8.1.14
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 8.11.5.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study 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.
8.1.14.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.15
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.
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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 may be allowed to continue study 
intervention with Sponsor consultation and should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. 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.
8.1.16
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Lipid Assessments
Lipid parameters (LDL-C, HDL-C, non-HDL-C, total cholesterol, triglycerides, ApoB, and 
Lp[a]), will be measured at the visits specified in the SoA. The rationale for efficacy 
endpoints is provided in Section 4.2.1.1. At Visit 2, LDL-C will be calculated based on the 
Martin/Hopkins calculation and directly measured using beta quantification. At other 
timepoints, LDL-C will be calculated based on the Martin/Hopkins calculation and 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. 
Participants must be fasting for ≥8 hours before obtaining lipid panel assessments. 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. Investigators should not evaluate efficacy endpoints 
locally during the study. 
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A full physical examination will be aligned with the local requirements and conducted by an 
investigator or medically qualified designee (consistent with local requirements), per 
institutional standard, at the visits specified in the SoA. A full examination will include 
review of multiple organ systems.
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 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 sweatshirts). The site should follow their local 
procedures to ensure the body weight scale is working properly.
8.3.3
Vital Signs
Vital signs (BP 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).
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•
When performed manually, pulse rate must be measured in the brachial/radial artery for 
at least 30 seconds.
8.3.4
Electrocardiograms
ECG measurements will be performed only at the Screening visit as 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 heart rate and measures PR, QRS, QT, and QTc intervals.
•
ECGs should be performed after the participant has rested quietly for at least 10 minutes.
8.3.5
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 56 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
•
Monitor and assess serum uric acid levels, signs and symptoms of hyperuricemia, 
consider discontinuation from study intervention and initiating treatment with urate-
lowering drugs as appropriate. Refer to Section 7.1 for details.
8.3.6
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
The length of time required to continue pregnancy testing for study intervention is 
4 weeks after the last dose of study intervention prior to Day 112 (TC).
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-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.6.1
Pretreatment Confirmation of Postmenopausal State
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 based on investigator judgment (Section 8.11.2.2.1).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
If the participant undergoes any protocol-specified procedure or intervention under limited 
screening consent, eg, a blood draw, the participant is first required to provide consent to 
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limited screening, and AEs will be captured according to guidelines for standard AE 
reporting.
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.
Participants who do not enter the separate OLE:
From the time of intervention randomization through 56 days after cessation of treatment, all 
AEs, SAEs, and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraphs must be reported immediately to the Sponsor if 
the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
Participants who enter the separate OLE:
From the time of intervention randomization through the last dose of study intervention at 
Visit 6 (Day 56), all AEs, SAEs, and other reportable safety events must be reported by the 
investigator in this protocol (parent study). Laboratory values that meet criteria for reporting 
as AEs performed at Visit 6 (Day 56) will be collected in the parent study.
Note: Once consented to the OLE study, all new AEs, SAEs including those considered 
related to study intervention, and other reportable safety events will be collected in the OLE 
study.
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Table 3
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
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.
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 toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
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Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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.
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Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
In this study, an overdose is any dose that exceeds the prescribed daily dose of study 
interventions in Section 6.1 (ie, >1 tablet of MK-0616 or 1 tablet of ezetimibe or 1 capsule of 
bempedoic acid/ day of study intervention is an overdose).
The Sponsor does not recommend specific treatment for an overdose.
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma MK-0616
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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 
8.8.1
 
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, 
 for FBR if the participant provides documented 
informed consent for FBR. If the 
 is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
The 
 sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for 
 samples will be in the 
Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover samples listed in Section 8.8.
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8.10
Health Economics or Medical Resource Utilization and Health Economics
Health Economics or Medical Resource Utilization and Health Economics are not evaluated 
in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Visit Reminders
Approximately 3 days before scheduled clinic visits, site staff will be encouraged to contact 
participants and remind them to do the following:
•
On the days without clinic visits (applicable after Visit 2 [Day 1]): Take their daily dose 
of study intervention (with small amounts of water) first thing in the morning after an 
overnight fast (≥8 hours), and to withhold food and beverages (except small amounts of 
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.
8.11.2
Screening Procedures
8.11.2.1
Optional Limited Screening Visit
If approved by the IRB/IEC, and the participant consents, a single Optional Limited 
Screening Visit may be performed to assess potential eligibility for participants who do not 
have a recent (within 3 months) historical assessment of LDL-C level. After providing 
documented consent for this limited optional screening, participants will be assigned a 
screening number and undergo a blood draw. If the decision based on the LDL-C value to 
proceed to study screening is made, documented consent for the full study will be obtained 
and Visit 1 (Screening) will be conducted.
Those who qualify for randomization will have Visit 2 (Day 1) within 60 days after the 
Optional Limited Screening Visit. The optional limited screening LDL-C test can be 
performed by either a local or central laboratory.
See Section 1.3 and Section 8.1.1.2 for additional information on consent for limited 
screening.
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8.11.2.2
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 30 days after Visit 1 (Screening). 
Participants with an exclusionary laboratory/procedure 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). Except for pregnancy tests, Screening hematology tests, 
and Optional Limited Screening LDL-C tests, which may be performed locally, the tests 
detailed in Table 8 will be performed by the central laboratory.
Site staff will reinforce participant compliance with background LLT (medications and/or 
supplements), at Visit 1 (Screening) (Section 6.4.1).
8.11.2.2.1
Rescreening
If a participant screen-fails (Section 5.4), the participant may be rescreened once based on 
investigator judgment. Participants who are rescreened will retain the same screening number 
assigned at the initial Screening Visit (Section 8.1.7).
8.11.3
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).
The first dose of study intervention at Visit 2 (Day 1), and the subsequent doses at), Visit 4
(Day 21), and Visit 5 (Day 42) will be administered in the clinic.
Compliance with study intervention (Section 6.4), background LLT (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.
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 30 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, should be 
rescheduled to occur within the allowable visit window (specified in the SoA).
8.11.4
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 LLT (medications and/or supplements), if applicable 
(Section 6.4.1)
•
Review and reinforcement of compliance with study intervention (Section 6.4) and 
fasting guidelines (Section 6.4.2)
8.11.5
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:
•
Study intervention accountability
•
Plasma collection for FBR
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 visits conducted via phone 
(Section 7.1).
8.11.6
Posttreatment
Participants will be contacted approximately 56 days after the last dose of study intervention 
for the poststudy visit. If the posttreatment contact occurs less than 56 days after the last dose 
of study intervention, a subsequent follow-up telephone call should be made at 56 days post 
the last dose of study intervention to determine if any AEs have occurred since the poststudy 
contact.
Participants enrolling into the OLE will not have the 56-day follow up call.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the principal statistical analysis strategy and procedures for the study. 
If, after the study has begun, but prior to any unblinding/final database lock, changes are 
made to primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses then the protocol will be amended (consistent with ICH Guideline E9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to any unblinding/final database lock, will be documented in an amendment of the 
SAP and referenced in the CSR for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR. Other planned analyses (eg, those specific to FBR) are beyond the 
scope of this document or will be documented in separate analysis/operational plans.
9.1
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee/Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The database addressing all study objectives will not be unblinded until medical/scientific 
review has been performed, protocol deviations have been identified, and data have been 
declared final and complete.
The Clinical Biostatistics department of the Sponsor will generate the randomized allocation 
schedule(s) for study treatment assignment, and the randomization will be implemented in 
the IRT.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.3
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment
differences are listed below.
9.3.1
Efficacy Endpoints
Primary Efficacy endpoint

Percent change from baseline in LDL-C at Day 56
Secondary Efficacy Endpoints

Percent change from baseline in ApoB at Day 56

Percent change from baseline in non-HDL-C at Day 56

Percent change from baseline in Lp(a) at Day 56
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
LDL-C < 70 mg/dL and ≥50% reduction from baseline at Day 56

LDL-C < 55 mg/dL and ≥50% reduction from baseline at Day 56
Analyses of percent change and change from baseline in LDL-C will use results from the 
same method (i.e., either beta-quantification at both baseline and post-baseline or 
Martin/Hopkins calculation at both baseline and post-baseline). If results from both methods 
are available, results from beta-quantification will be used. 
9.3.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory test results, and vital signs. Safety endpoints are further described in Section 
4.2.1.2 of the protocol.
9.4
Analysis Populations
9.4.1
Efficacy Analysis Populations
The FAS population will serve as the population for the analyses 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 baseline data for those analyses that require baseline data
Participants will be included in the intervention group to which they are randomized for the 
analyses of efficacy data using the FAS population.
9.4.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study intervention. Participants will be 
included in the intervention group corresponding to the study intervention they actually 
received for the analyses of safety data. This will be the intervention group to which they are 
randomized except for participants who take incorrect study intervention for the entire 
treatment period; such participants will be included in the intervention group corresponding 
to the study intervention actually received. 
Analyses of laboratory test results and vital signs will include only participants with at least 
one measurement obtained after at least one dose of study intervention. If the analyses will 
assess change from baseline, a baseline measurement is also required.
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9.5
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 SAP.
P-values for efficacy endpoints not controlled for multiplicity may be provided as an 
assessment of strength of evidence without intent to make inferential claims.
For analysis purposes, the baseline assessment is the one closest to, but before or on the day 
of randomization prior to the first dose of study medication (Visit 2 [Day 1]). 
For stratified analyses, the stratification factor used for randomization,
 
 will be applied to the 
analysis. If it is expected that statistical models will not converge on account of small sample 
sizes within the stratum, the stratification factor will be dropped from the models. Any 
decision to drop the stratification factor due to small strata will be based on blinded data and 
documented in the SAP prior to database lock.
9.5.1
Estimand(s)
The primary efficacy estimand following the guidance in ICH E9 (R1) 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, ezetimibe, bempedoic acid, or
ezetimibe and bempedoic acid added to background lipid-lowering therapy (if 
background therapy is applicable).
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 Day 56.
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 any changes to treatment with MK-0616 or other lipid 
lowering therapy). Consistent with the treatment policy approach, no observed data 
will be excluded from analyses on account of intercurrent events.
5. The population-level summary for the endpoint which provides the basis for a 
comparison between treatment conditions: the difference (MK-0616 minus each of 
the active controls) in the mean percent change from baseline in LDL-C at Day 56.
Estimands for the continuous secondary endpoints are analogous to the estimand for the 
primary endpoint.
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9.5.2
Statistical Methods for Efficacy Analyses
For the primary estimand, the intervention group comparison for the LDL-C mean percent 
change from baseline at Day 56 will be done using an ANCOVA model with treatment and
the stratification factor 
as fixed effects and baseline LDL-C as a covariate.
Data permitting (discussed below), missing data will be imputed using a retrieved dropout 
(RD) approach [Wang, S. 2022] which assumes that all missing Day 56 data can be 
represented by the observed Day 56 data for participants in the same intervention group who 
discontinued study treatment but remained in the study.
A “retrieved dropout” value is defined as an observed Day 56 value in a participant who 
discontinued study treatment prior to Day 56 but remained in the study. 
For the RD approach, missing Day 56 values will be imputed as follows:
RD imputation will be done within each intervention group. All Day 56 RD values will be 
used for imputation, regardless of when a participant discontinued from study medication. 
The RD imputation analysis will include only participants with a baseline measurement. The 
RD imputation analysis steps are as follows:
1. Generate 1000 bootstrap samples from the dataset that includes all observed LDL-C 
percent change from baseline values.
2. Within each bootstrap sample, do the following:
a.
Impute missing Day 56 values using a normal distribution where the expected 
percent change from baseline value is set to the estimated mean percent change 
from baseline value from the RD participants in the same intervention group. The 
standard deviation will be the root mean squared error (RMSE) derived from the 
ANCOVA model described above and estimated based on all participants with 
Day 56 data. 
b. Repeat the imputation for a total of 100 imputed datasets, each containing the 
original non-missing data and the imputed data for those with missing Day 56
values.
c.
Analyze each imputed dataset using the ANCOVA model described above to 
generate 100 ANCOVA-based estimates of the treatment difference. 
d. Calculate the average of the 100 ANCOVA-based estimates of the treatment 
difference – this is the bootstrap parameter estimate.
3. Compute the estimate of the treatment difference for the mean percent change from 
baseline as the mean of the 1000 bootstrap parameter estimates, and compute the 
standard error of the treatment difference for the mean percent change from baseline
as the standard error of the 1000 bootstrap parameter estimates from step 2d.
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4. Using the estimate and standard error in step 3, calculate a 95% confidence interval 
and p-values assuming a normal distribution.
The RD analysis may not be feasible due to insufficient observed Day 56 data post 
discontinuation of study treatment. If the number of retrieved dropout participants per group 
is at least 5 participants and at least 50% of participants who discontinued from study 
medication per group, then RD will be the primary approach to impute missing data. If at 
least one group has fewer than 5 RD participants or less than 50% of participants who 
discontinued from study medication, then Washout Imputation (WI) will become primary. If 
the minimum data requirement for the RD method is met, then WI will be implemented as a 
sensitivity approach. The WI analysis assumes participants who prematurely discontinued 
from the study or who have an intermittent missing Day 56 value would have a ‘washout’ of 
any potential effect of the assigned study medication.
For the WI approach, missing Day 56 values will be imputed using data from participants in 
the active control group who have Day 56 data, as follows: 
•
For participants in the MK-0616 group:
1. Fit a regression model as Y56 = β0 + β1*Y0 + γ*X + error, where Y0 and Y56 are the 
observed corresponding active control group LDL-C values at Baseline and Day 56, 
respectively, and X is the fixed covariate (stratification factor).
2. Impute missing Day 56 LDL-C values for MK-0616 using the estimated mean from 
the above model and standard deviation equal to the root mean squared error from the 
model.
•
For participants in the active control group (ezetimibe, bempedoic acid, or ezetimibe and 
bempedoic acid): 
1. Fit models according to the observed LDL-C data pattern from participants in the 
active control group who have both a Baseline and a Day 56 value. Selection of the 
following models will be based on the last available LDL-C value prior to Day 56:
a.
For participants whose last value prior to Day 56 is Baseline: 
Y56 = β0 + β1*Y0 + γ*X + error
b.
For participants whose last value prior to Day 56 is Day 21: 
Y56 = β0 + β1*Y0 + β2*Y21 + γ*X + error
2. Impute missing Day 56 LDL-C values for active control using one of the two models 
above based on the missing data pattern with a mean equal to the mean from the 
regression model and a standard deviation equal to the RMSE from the model.
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The WI analysis will include only participants with a baseline measurement. The WI
imputation analysis steps are:
1. Generate 1000 bootstrap samples from the observed LDL-C change from baseline 
analysis dataset.
2. Within each bootstrap sample, do the following:
a.
Impute Missing Day 56 values using a normal distribution where the expected 
percent change from baseline value and RMSE will be derived from the WI 
regression models described above. The WI regression model parameters will be 
estimated based on all participants with Day 56 data. 
b. Repeat step 2a for a total of 100 imputed datasets, each containing the original 
non-missing data and the imputed data for those with missing Day 56 values.
c.
Analyze the 100 datasets using the ANCOVA model described above to generate 
100 ANCOVA-based estimates of the treatment difference. 
d. Calculate the average of the 100 ANCOVA-based estimates of the treatment 
difference – this is the bootstrap parameter estimate.
3. Compute the estimate of the treatment difference for the mean percent change from 
baseline as the mean of the 1000 bootstrap parameter estimates, and compute the 
standard error of the treatment difference for mean percent change from baseline as
the standard error of the 1000 bootstrap parameter estimates from step 2d.
4. Using the estimate and standard error in step 3, calculate a 95% confidence interval 
and p-value assuming a normal distribution.
For all analyses involving simulated data, a random seed of 616018 will be used.
Mean percent change and change from baseline for the secondary endpoints except Lp(a)
will be analyzed using the methods applied to the primary endpoint. 
The percent change and change from baseline in Lp(a) at Day 56 from baseline will be 
analyzed using the aligned rank stratified Wilcoxon test (ARSW) [Hodges, J. L., Jr. and 
Lehmann, E. L. 1962] [Mehrotra, D. V., et al 2010] with the randomization stratification 
factor as strata. In this test, the endpoint values are first aligned across the randomization 
strata using the stratum-level Hodges-Lehmann location shift estimates, and the aligned 
values are then analyzed using a Wilcoxon rank sum test. The output from this analysis will
be used to provide a Hodges-Lehmann location-shift estimate of the overall treatment 
difference with 95% confidence interval (CI). A boxplot of the change from baseline in Lp(a) 
at Day 56 will be provided for each intervention group. This will be based on the observed 
data.
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For the analysis of percent change from baseline with respect to Lp(a), the following primary 
method will be used if a participant’s Day 56 assessment is missing: For participants who 
missed an assessment multiple imputation will be used to impute missing data.
The MAR assumption will be made to perform standard Multiple Imputation. It has been 
shown [Mogg, R. and Mehrotra, D. V. 2007] that MAR-based imputation under non-MAR 
conditions is unlikely to impact the overall treatment-level mean ranks. For missing data, 
Fully Conditional Specification (FCS) regression [van Buuren, S., et al 2006] [van Buuren, S. 
2007] will be used to fill in the missing data in the order of timepoints using measurements 
calculated at the previous timepoints.
A line plot (Mean ± SEM) of the percent change from baseline in Lp(a) by visit will be 
provided for each intervention group based on observed data.
For the other secondary endpoints of the proportions of participants with LDL-C < 70 mg/dL 
and < 55 mg/dL and ≥50% reduction from baseline at Day 56, 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 intervention groups (MK-0616 minus each of the active 
controls). Any participant who does not have a Day 56 assessment will be considered as not 
being at the LDL-C goal at Day 56. 
The analysis strategy for key efficacy variables is outlined in Table 4.
Table 4
Analysis Strategy for Key Efficacy Variables
Endpoint
Statistical 
Method
Analysis 
Population
Missing 
Data 
Approach
Primary Endpoint
Percent change from baseline in LDL-C at Day 56
ANCOVA
FAS
RD/WI
Secondary Endpoints
Percent change from baseline in ApoB at Day 56
ANCOVA
FAS
RD/WI
Percent change from baseline in non-HDL-C at Day 56
ANCOVA
FAS
RD/WI
Percent change from baseline in Lp(a) at Day 56
ARSW
FAS
Multiple 
Imputation
LDL-C < 70 mg/dL and ≥50% reduction from baseline at Day 
56
M&N
FAS
M=F
LDL-C < 55 mg/dL and ≥50% reduction from baseline at Day 
56
M&N
FAS
M=F
ANCOVA= analysis of covariance; ARSW= aligned rank stratified Wilcoxon test, FAS=full analysis set, RD= 
retrieved dropout, WI= washout imputation, LDL-C=low-density lipoprotein cholesterol, M&N=Miettinen and 
Nurminen, M=F: Missing=Failure.
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9.5.3
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory tests and vital signs. The primary assessment of safety will 
use all data through the efficacy cutoff date including 56 days after last dose of study 
intervention, if available.
9.5.3.1
Overall Safety Assessment 
The overall safety evaluation will include a summary by intervention 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 intervention 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 intervention groups in the percentages of 
participants with specific AEs will be provided for AEs that occur in at least 5% of 
participants in any intervention group.
CIs for between intervention 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 intervention 
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 values and vital 
signs, summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by intervention group.
9.5.3.2
Assessment of Safety Topics of Special Interest
The analysis strategy for safety parameters is in Table 5.
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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
AE that resulted in death
X
Specific AEs (≥5% of 
participants in any intervention 
group)
X
Xa
Xa
SOCs, PDLCs (≥5% of 
participants in any intervention 
group)
X
Xa
Change from Baseline Results 
(Labs, Vital Signs)
X
AE=adverse event; CI=confidence interval; PDLC=predefined limit of change; SOC=system organ class.
a Threshold for incidence will be applied for CI and graphical display.
9.6
Interim Analyses
The DMC will be responsible for periodic interim safety reviews.
9.7
Multiplicity
Testing will be performed in order of the primary and secondary efficacy endpoints with 
hypotheses as below:

H1: MK-0616 is superior to bempedoic acid on mean percent change from baseline in 
LDL-C at Day 56.

H2: MK-0616 is superior to ezetimibe on mean percent change from baseline in LDL-C 
at Day 56.
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
H3: MK-0616 is superior to ezetimibe and bempedoic acid on mean percent change from 
baseline in LDL-C at Day 56.

H4: MK-0616 is superior to bempedoic acid on mean percent change from baseline in 
ApoB at Day 56.

H5: MK-0616 is superior to ezetimibe on mean percent change from baseline in ApoB at 
Day 56.

H6: MK-0616 is superior to bempedoic acid on mean percent change from baseline in 
non-HDL-C at Day 56.

H7: MK-0616 is superior to ezetimibe on mean percent change from baseline in non-
HDL-C at Day 56.

H8: MK-0616 is superior to ezetimibe and bempedoic acid on mean percent change from 
baseline in ApoB at Day 56.

H9: MK-0616 is superior to ezetimibe and bempedoic acid on mean percent change from 
baseline in non-HDL-C at Day 56.
 
.
9.8
Sample Size and Power Calculations
The sample size calculations are based on the primary and secondary efficacy endpoints with 
hypotheses, with the following assumptions based on results from MK-0616-008 and 
previous research [Ballantyne, C. M., et al 2020]:

The treatment difference with respect to mean percent change from baseline in LDL-
C at Day 56 for MK-0616 minus bempedoic acid, MK-0616 minus ezetimibe and 
MK-0616 minus ezetimibe and bempedoic acid is 
 

The treatment difference with respect to mean percent change from baseline in ApoB
at Day 56 for MK-0616 minus bempedoic acid, MK-0616 minus ezetimibe and MK-
0616 minus ezetimibe and bempedoic acid is
.

The treatment difference with respect to mean percent change from baseline in non-
HDL-C at Day 56 for MK-0616 minus bempedoic acid, MK-0616 minus ezetimibe 
and MK-0616 minus ezetimibe and bempedoic acid is 
 
respectively.

 

Percent change from baseline in LDL-C, ApoB and non-HDL-C follows 
approximately normal distribution.
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All FAS participants will be included in analyses with missing Day 56 values imputed using 
RD imputation or WI approach where appropriate. The sample size calculations take account 
of the attenuation in treatment differences due to missing data imputation approach with an 
expected 3% missing rate at or before Day 56. Based on the assumptions above, Table 6
provides individual power for the primary and secondary efficacy endpoints with a 
hypothesis at a one-sided alpha of 0.025 with a sample size of 300 randomized in a 2:1:1:2 
fashion for MK-0616, ezetimibe, bempedoic acid, and ezetimibe and bempedoic acid arm.
Table 6
Power for the Primary and Key Secondary Efficacy Endpoints
Endpoints
MK-0616 vs. 
Bempedoic acid
MK-0616 vs. Ezetimibe
MK-0616 vs. Ezetimibe 
and Bempedoic acid
Percent change in LDL-
C at Day 56
>99%
>99%
91%
Percent change in ApoB 
at Day 56
>99%
>99%
>99%
Percent change in non-
HDL-C at Day 56
>99%
>99%
>99%
The overall probability of being successful and demonstrating superiority of MK-0616 vs 
each of the active controls on all primary and secondary hypotheses is approximately 90%
assuming independence of the three pairwise comparisons on primary and secondary 
endpoints.
The sample size and power calculations are based on nQuery software version 8.4.1.0.
9.8.1
Sample Size and Power for Safety Analyses
Given the sample size of 300 randomized in a 2:1:1:2 fashion (100 for MK-0616 and 
ezetimibe and bempedoic acid, respectively and 50 for ezetimibe and bempedoic acid, 
respectively), Table 7 provides examples of treatment differences in AEs between MK-0616 
and each of the active control that would have a 95% CI that excludes zero.
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Table 7
Examples of AE Incidences for Which 95% CI for the Difference Would 
Exclude Zero
MK-0616
n/N (%)
Bempedoic acid
n/N (%)
8/100 (8%)
0/50 (0%)
18/100 (18%)
3/50 (6%)
24/100 (24%)
5/50 (10%)
MK-0616
n/N (%)
Ezetimibe
n/N (%)
8/100 (8%)
0/50 (0%)
18/100 (18%)
3/50 (6%)
24/100 (24%)
5/50 (10%)
MK-0616
n/N (%)
Ezetimibe and bempedoic acid
n/N (%)
4/100 (4%)
0/100 (0%)
13/100 (13%)
5/100 (5%)
20/100 (20%)
10/100 (10%)
AE= adverse event; CI=confidence interval; n=number of participants with an AE; N=population size.
Based on the M&N method
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
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 
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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 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants and recommend to the 
EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
National Leader Committee
The primary role of the National Leader Committee is to serve as a strong advocate for the 
program in their respective countries, partnering with the local Sponsor study team to 
optimize the conduct of the studies, and to facilitate the progress of the study at the regional 
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level. The National Leader Committee is composed of Country Leads selected by the 
Sponsor with appropriate clinical study experience.
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 trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
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.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
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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.
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, Screening hematology tests, and Optional Limited Screening 
LDL-C tests, which may be performed locally, the tests detailed in Table 8 will be 
performed by the central laboratory.
•
The optional limited screening LDL-C test can be performed by either a local or central 
laboratory.
•
Efficacy results will be masked by the central laboratory after Visit 2 (Day 1) through the 
end of the study (Section 8.2.1). The study team and site will be blinded to the data. 
Investigators should not evaluate efficacy endpoints locally during the study. 
•
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
-MCH
-MCHC
-RDW
-Nucleated RBC
Reticulocytes
WBC count 
RBC Count
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
Fasting 
glucose
Uric acid
Lipid Panel
LDL-C
HDL-C
Non-HDL-C
Total cholesterol
Triglycerides
Other Efficacy 
Parameters
ApoB
Lp(a)
Pregnancy Testing
Highly sensitive serum or urine hCG pregnancy test (POCBP only)
Other Tests

A1C

TSH (screening only)

FSH (screening only, as needed to assess menopausal status)
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Laboratory 
Assessments
Parameters
A1C=hemoglobin A1c, ALT=alanine aminotransferase, 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, hCG=human chorionic gonadotropin, HDL-C=high-
density lipoprotein cholesterol, 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, PK=pharmacokinetic, POCBP=participants of childbearing potential, RBC=red blood 
cell, RDW=red cell distribution width, SGOT=serum glutamic-oxaloacetic transaminase, SGPT=serum glutamic-
pyruvic transaminase, stimulating, TSH=thyroid-stimulating hormone, ULN=upper-limit of normal, WBC=white 
blood cell
Note 1: eGFR will be calculated using CKD-EPI Creatinine.
Note 2: LDL-C will be calculated based on the Martin/Hopkins calculation; 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.
Note 3: A serum pregnancy test should only be performed if the local urine pregnancy test is positive or inconclusive, or 
if a serum pregnancy test is required per local guidelines.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb,c
IUSb,d
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraceptionb,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionb,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
b
Penile/external condoms must be used in addition to the POCBP’s hormonal contraception.
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation.
d
IUS is a progestin-releasing IUD.
Note:
Tubal occlusion includes tubal ligation
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Countries in the European Economic Area
The following requirements apply to all participating EEA countries:
Sections 1.1, 4.4, 5.1, 7.1, 7.2, 8.1.1, 8.1.1.1, and 8.1.1.3
In order to be eligible to participate in the study, individuals in participating EEA countries 
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 
individuals in participating EEA countries. Individuals who cannot provide documented 
informed consent are not eligible to participate in the study.
Section 5.2
The following is an additional Exclusion Criterion for participants in EEA countries:
A participant assigned female sex at birth is not eligible to participate in the trial if pregnant,
breastfeeding, or planning to become pregnant.
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10.8
Appendix 8: 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].
Note: XUEZHIKang, an extract of red yeast rice containing statin, is not considered as statin therapy for this 
trial. XUEZHIKang use is allowed if the participant meets the requirements in Inclusion Criterion 3.
Consult the Sponsor to determine the appropriate statin intensity category for participants whose daily statin 
dose is not shown above.
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
A1C
glycated hemoglobin
ACL
ATP citrate lyase
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AHA
American Heart Association
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANGPTL3
angiopoietin-like 3
APaT
All-Participants-as-Treated
ApoB
apolipoprotein B
ARSW
aligned rank stratified Wilcoxon test
ASCVD
atherosclerotic cardiovascular disease
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AxMP
auxiliary medicinal product
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen,
CI
confidence interval
Cmax
maximum plasma concentration
CLEAR
Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen
CONSORT
Consolidated Standards of Reporting Trials
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
Case Report Form
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group
DBP
diastolic blood pressure
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Abbreviation
Expanded Term
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ESKD
end stage kidney disease
FAS
Full Analysis Set
FBR
future biomedical research
FCS
Fully Conditional Specification
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FH
familial hypercholesterolemia
FSH
follicle-stimulating hormone 
FSR
First Site Ready
GCP
Good Clinical Practice
GI
gastrointestinal
H
hypothesis
hCG
human chorionic gonadotropin
HDL-C
high-density lipoprotein cholesterol
HeFH
heterozygous familial hypercholesterolemia
HMG-CoAR
3-hydroxy-3-methyl-glutaryl-CoA reductase
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
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Abbreviation
Expanded Term
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICH GCP
International Council for Harmonisation Good Clinical Practice
ICMJE
International Committee of Medical Journal Editors
ID
identification
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IMPROVE-IT
IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LDL
low-density lipoprotein
LDL-C
low-density lipoprotein cholesterol
LDLR
low-density lipoprotein receptor
LLN
lower limit of normal
LLT
lipid-lowering therapy
Lp(a)
lipoprotein (a)
mAb
monoclonal antibody
M&N
Miettinen and Nurminen
MAR
missing at random
MCH
mean corpuscular hemoglobin, 
MCV
mean corpuscular volume, 
MCHC
mean corpuscular hemoglobin concentration,
MEDPED
make early decisions prevent early deaths
MPV
mean platelet volume, 
MTP
microsomal triglyceride transfer protein
N/A
not applicable
NIMP
noninvestigational medicinal product
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Abbreviation
Expanded Term
non-HDL-C
non-high-density lipoprotein cholesterol
NPC1L1
Niemann-Pick C1-Like 1 protein
NSAE
nonserious adverse event
OLE
open-label extension
PCSK9
protein convertase subtilisin/kexin type 9
PCSK9i
protein convertase subtilisin/kexin type 9 inhibitor
PDLC
predefined limit of change
PK
pharmacokinetic
POCBP
participant of childbearing potential
popPK
population pharmacokinetic
PR
PR interval
QD
once daily
QRS
QRS complex
QT
QT interval
QTc
heart rate-corrected QT interval
RBC 
red blood cell, 
RD
retrieved dropout
RDW
red cell distribution width,
RMSE
root mean squared error
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SEM
standard error of the mean
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SI Discon
study intervention discontinuation
siRNA
small interfering RNA
SLAB
supplemental laboratory test(s)
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Abbreviation
Expanded Term
SoA
schedule of activities
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TC
telephone call
TSH
thyroid stimulating hormone
ULN
upper limit of normal
USA
United States of America
UTN
Universal Trial Number
V
visit
WBC
white blood cell
WI
Washout Imputation
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11
REFERENCES
[Al Danaf, J., et al 2016]
Al Danaf J, Martin SS, Blumenthal RS. 
Expert Analysis - Ezetimibe: the lower the 
LDL-C, the better (even for total 
cardiovascular events). J Am Coll Cardiol. 
2016 Mar 09.
[08GK9M]
[Ballantyne, C. M., et al 
2016]
Ballantyne CM, McKenney JM, 
MacDougall DE, Margulies JR, Robinson 
PL, Hanselman JC, et al. Effect of ETC-
1002 on serum low-density lipoprotein 
cholesterol in hypercholesterolemic 
patients receiving statin therapy. Am J 
Cardiol. 2016;117:1928-33.
[089BG5]
[Ballantyne, C. M., et al 
2020]
Ballantyne CM, Laufs U, Ray KK, Leiter 
LA, Bays HE, Goldberg AC, et al. 
Bempedoic acid plus ezetimibe fixed-dose 
combination in patients with 
hypercholesterolemia and high CVD risk 
treated with maximally tolerated statin 
therapy. Eur J Prev Cardiol. 
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