A Phase 3 Randomized, Active-comparator-controlled Clinical Study to Evaluate the Efficacy and Safety of Ezetimibe/Atorvastatin Combination Tablet (MK-0653C) as Second Line Lipid Lowering Treatment in Chinese Participants
Phase: PHASE3
Conditions: Hypercholesterolemia
Sponsor: Organon and Co

Official Protocol Title: 
NCT number: 
NCT03768427 
Document Date: 
05-Nov-2018
A Phase 3 Randomized, Active-Comparator-Controlled Clinical 
Study to Evaluate the Efficacy and Safety of Ezetimibe/Atorvastatin 
Combination Tablet (MK-0653C) as Second Line Lipid Lowing 
Treatment in Chinese Participants

PRODUCT: MK-0653C 
1
PROTOCOL/AMENDMENT NO.: 439-00
MK-0653C-439-00 FINAL PROTOCOL
05-NOV-2018
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase 3 randomized, active-comparator-controlled clinical study to 
evaluate the efficacy and safety of Ezetimibe/Atorvastatin combination tablet (MK-0653C) 
as second line lipid lowing treatment in Chinese participants 
Protocol Number: 439-00
Compound Number: MK-0653C
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
Approval Date: 05-November-2018
 
 
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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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Table of Contents
1
PROTOCOL SUMMARY ............................................................................................10
1.1
Synopsis.................................................................................................................10
1.2
Schema ..................................................................................................................14
1.3
Schedule of Activities (SoA) ................................................................................15
2
INTRODUCTION..........................................................................................................19
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................20
2.2.1
Pharmaceutical and Therapeutic Background .............................................20
2.2.2
Clinical Studies............................................................................................22
2.3
Benefit/Risk Assessment......................................................................................22
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ................................................23
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design ......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................27
4.2.1
Rationale for Endpoints ...............................................................................27
4.2.1.1
Efficacy Endpoints.............................................................................27
4.2.1.2
Safety Endpoints ................................................................................28
4.2.2
Rationale for the Use of Comparator/Placebo .............................................28
4.3
Justification for Dose ...........................................................................................29
4.4
Beginning and End of Study Definition .............................................................29
4.4.1
Clinical Criteria for Early Study Termination .............................................29
5
STUDY POPULATION ................................................................................................29
5.1
Inclusion Criteria.................................................................................................30
5.2
Exclusion Criteria ................................................................................................31
5.3
Lifestyle Considerations ......................................................................................34
5.3.1
Meals and Dietary Restrictions....................................................................34
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................35
5.3.3
Activity Restrictions ....................................................................................35
5.4
Screen Failures.....................................................................................................35
5.5
Run-in Failure......................................................................................................36
5.6
Participant Replacement Strategy......................................................................36
6
STUDY INTERVENTION............................................................................................36
6.1
Study Intervention(s) Administered...................................................................36
6.2
Preparation/Handling/Storage/Accountability .................................................40
6.2.1
Dose Preparation..........................................................................................40
6.2.2
Handling, Storage, and Accountability........................................................40
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding..............................41
6.3.1
Intervention Assignment..............................................................................41
6.3.2
Stratification.................................................................................................41
6.3.3
Blinding........................................................................................................41
6.4
Study Intervention Compliance..........................................................................41
6.5
Concomitant Therapy..........................................................................................42
6.5.1
Rescue Medications and Supportive Care ...................................................43
6.6
Dose Modification (Escalation/Titration/Other)...............................................43
6.7
Intervention After the End of the Study............................................................43
6.8
Clinical Supplies Disclosure................................................................................43
6.9
Standard Policies..................................................................................................44
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................44
7.1
Discontinuation of Study Intervention...............................................................44
7.2
Participant Withdrawal From the Study...........................................................45
7.3
Lost to Follow-up .................................................................................................45
8
STUDY ASSESSMENTS AND PROCEDURES........................................................46
8.1
Administrative and General Procedures ...........................................................47
8.1.1
Informed Consent.........................................................................................47
8.1.1.1
General Informed Consent.................................................................47
8.1.2
Inclusion/Exclusion Criteria ........................................................................47
8.1.3
Participant Identification Card.....................................................................47
8.1.4
Medical History ...........................................................................................48
8.1.5
Prior and Concomitant Medications Review ...............................................48
8.1.5.1
Prior Medications...............................................................................48
8.1.5.2
Concomitant Medications ..................................................................48
8.1.6
Assignment of Screening Number...............................................................48
8.1.7
Assignment of Treatment/Randomization Number .....................................48
8.1.8
Study Intervention Administration ..............................................................49
8.1.8.1
Timing of Dose Administration.........................................................49
8.1.9
Trial Compliance (Medication/Diet/Activity/Other) ...................................49
8.1.10
Discontinuation and Withdrawal .................................................................49
8.1.11
Participant Blinding/Unblinding..................................................................50
8.1.12
Calibration of Equipment.............................................................................51
8.2
Efficacy Assessments ...........................................................................................51
8.2.1
Clinical Efficacy Laboratory Assessments ..................................................51
8.3
Safety Assessments...............................................................................................51
8.3.1
Physical Examinations.................................................................................52
 
 
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8.3.2
Vital Signs....................................................................................................52
8.3.3
Electrocardiograms ......................................................................................52
8.3.4
Clinical Safety Laboratory Assessments .....................................................53
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................53
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................54
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......55
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...56
8.4.4
Regulatory Reporting Requirements for SAE .............................................56
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................56
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................56
8.4.7
Events of Clinical Interest (ECIs) ................................................................57
8.5
Treatment of Overdose........................................................................................57
8.6
Pharmacokinetics.................................................................................................57
8.7
Pharmacodynamics..............................................................................................57
8.8
Future Biomedical Research Sample Collection...............................................57
8.9
Planned Genetic Analysis Sample Collection ....................................................58
8.10
Biomarkers ...........................................................................................................58
8.11
Visit Requirements...............................................................................................58
8.11.1
Screening (Visit 1) .......................................................................................58
8.11.2
Run-In (Visit 2 and Visit 3) .........................................................................58
8.11.3
Treatment Period (Visit 4-Visit 6)...............................................................59
8.11.4
Discontinued Participants Continuing to be Monitored in the Study ..........59
8.11.5
Poststudy (follow-up visit)...........................................................................59
9
STATISTICAL ANALYSIS PLAN .............................................................................59
9.1
Statistical Analysis Plan Summary.....................................................................60
9.2
Responsibility for Analyses/In-house Blinding .................................................60
9.3
Hypotheses/Estimation ........................................................................................61
9.4
Analysis Endpoints...............................................................................................61
9.4.1
Efficacy Endpoints.......................................................................................61
9.4.2
Safety Endpoints ..........................................................................................61
9.5
Analysis Populations............................................................................................61
9.5.1
Efficacy Analysis Populations .....................................................................61
9.5.2
Safety Analysis Populations ........................................................................62
9.6
Statistical Methods...............................................................................................62
9.6.1
Statistical Methods for Efficacy Analyses ...................................................62
 
 
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9.6.2
Statistical Methods for Safety Analyses ......................................................64
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................66
9.7
Interim Analyses ..................................................................................................67
9.8
Multiplicity ...........................................................................................................67
9.9
Sample Size and Power Calculations .................................................................67
9.10
Subgroup Analyses...............................................................................................68
9.11
Compliance (Medication Adherence).................................................................68
9.12
Extent of Exposure...............................................................................................69
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................70
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........70
10.1.1
Code of Conduct for Clinical Trials.............................................................70
10.1.2
Financial Disclosure.....................................................................................72
10.1.3
Data Protection.............................................................................................72
10.1.3.1
Confidentiality of Data ......................................................................73
10.1.3.2
Confidentiality of Participant Records...............................................73
10.1.3.3
Confidentiality of IRB/IEC Information............................................73
10.1.4
Committees Structure...................................................................................73
10.1.5
Publication Policy........................................................................................73
10.1.6
Compliance with Study Registration and Results Posting Requirements ...74
10.1.7
Compliance with Law, Audit, and Debarment ............................................74
10.1.8
Data Quality Assurance ...............................................................................75
10.1.9
Source Documents .......................................................................................76
10.1.10
Study and Site Closure.................................................................................76
10.2
Appendix 2: Clinical Laboratory Tests..............................................................77
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................79
10.3.1
Definition of AE ..........................................................................................79
10.3.2
Definition of SAE ........................................................................................80
10.3.3
Additional Events Reported.........................................................................81
10.3.4
Recording AE and SAE ...............................................................................81
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................85
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................87
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................88
10.5.1
Definitions....................................................................................................88
10.5.2
Contraception Requirements........................................................................89
 
 
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10.5.3
Pregnancy Testing........................................................................................89
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................90
10.7
Appendix 7: Country-specific Requirements ....................................................91
10.8
Appendix 8: Abbreviations ...............................................................................135
11
REFERENCES.............................................................................................................137
 
 
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LIST OF TABLES
Table 1
Alcohol Consumption Quantities.....................................................................35
Table 2
Study Interventions ..........................................................................................37
Table 3
Dose of Atorvastatin and Other Equivalent Statin...........................................41
Table 4
Prohibited Medications ....................................................................................42
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................54
Table 6
Analysis Strategy for Key Efficacy Variables.................................................64
Table 7
Analysis Strategy for Safety Parameters..........................................................66
Table 8
Safety Power Calculation.................................................................................68
Table 9
Protocol-required Laboratory Assessments .....................................................77
Table 10
The Characteristics and Functions of Lipoproteins .........................................97
Table 11
The Appropriate Levels and Abnormal Stratified Standards of Blood 
Lipids for the Primary Prevention Population of ASCVD in China 
[mmol/L (mg/dL)]..........................................................................................102
Table 12
Clinical Classification of Dyslipidemia .........................................................104
Table 13
The Goal Attainment Values of LDL-C and non-HDL-C Treatments 
Across Different ASCVD Risk Populations [mmol/L (mg/dL)] ...................109
Table 14
Basic Lifestyle Change Elements ..................................................................112
Table 15
The Cholesterol Reduction Intensity of Stains ..............................................115
 
 
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................14
Figure 2
The Risk Assessment Flow Chart..............................................................26
Figure 3
The Risk Assessment Flow Chart of ASCVD .........................................106
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 randomized, active-comparator-controlled clinical study to 
evaluate the efficacy and safety of Ezetimibe/Atorvastatin combination tablet (MK-0653C) 
as second line lipid lowing treatment in Chinese participants 
Short Title: MK-0653C vs. atorvastatin in Chinese hypercholesterolemic participants
Acronym: MK0653C-439
Hypotheses, Objectives, and Endpoints:
All objectives and hypotheses will be evaluated in Chinese participants with 
hypercholesterolemia, inadequately controlled with 10 mg or 20 mg atorvastatin 
monotherapy.
Objectives
Endpoints
Primary
•
Objective: To evaluate the percent 
change in LDL-C from baseline to Week 
12 of MK-0653C 10/10 mg compared to 
atorvastatin 20 mg (Cohort A).
Hypothesis: MK-0653C 10/10 mg is 
superior to atorvastatin 20 mg (Cohort A) 
in percent change from baseline in LDL-
C to 12 weeks after treatment.
•
Objective: To evaluate the percent 
change in LDL-C from baseline to Week 
12 of MK-0653C 10/20 mg compared to 
atorvastatin 40 mg (Cohort B).
Hypothesis: MK-0653C 10/20 mg is 
superior to atorvastatin 40 mg (Cohort B) 
in percent change from baseline in LDL-
C to 12 weeks after treatment.
Overall success is determined by a success 
on at least one hypothesis.
•
Low-Density Lipoprotein – Cholesterol 
(LDL-C) level
 
 
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Objectives
Endpoints
Secondary
•
Objective: To evaluate the safety and 
tolerability of administrated MK-0653C 
10/10 mg and MK-0653C 10/20 mg once 
daily dosing through 12 weeks.
•
Adverse events
•
Laboratory parameters and vital signs
•
Study drug discontinuation 
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Hypercholesterolemia
Population
Chinese participants with hypercholesterolemia
inadequately controlled by 10 mg or 20 mg atorvastatin.
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
Masking
Participant or Subject
Investigator
Monitor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 1.5 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
 
 
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Number of Participants:
Approximately 450 participants will be randomized across two cohorts defined by statin dose 
at the screening visit. In Cohort A (atorvastatin ≤10 mg or equivalent), 180 participants will 
be randomized, and in Cohort B (atorvastatin 20 mg or equivalent), 270 participants will be 
randomized.
Intervention Groups and Duration:
Intervention 
Groups
During double-blinded treatment period:
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
A1
MK-0653C 
FDC (ezetimibe
10 mg + 
atorvastatin 
10 mg)
10 mg/ 
10 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Study
treatment 
Placebo 
atorvastatin
0 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Dummy 
with study 
treatment
A2
atorvastatin
20 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Active 
control
Placebo of MK-
0653C FDC 
(ezetimibe 
10 mg + 
atorvastatin 
10 mg)
0 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Dummy 
with active 
control
B1
MK-0653C 
FDC (ezetimibe 
10 mg + 
atorvastatin 
20 mg)
10 mg/ 
20 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Study
treatment 
Placebo of 
atorvastatin
0 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Dummy 
with study 
treatment
B2
atorvastatin
20 mg x 
2
QD
Oral
Randomization 
treatment: 12 
weeks
Active 
control
Placebo of MK-
0653C FDC 
(ezetimibe 
10 mg+
atorvastatin 
20 mg)
0 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Dummy 
with active 
control
 
 
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Total 
Number
4
Duration of 
Participation
Each participant will participate in the study for approximately 21 weeks, from 
the time the participant signs the Informed Consent Form (ICF) through the 
final contact. After a screening phase of 2 weeks followed by an atorvastatin 
treatment period of approximately 5 weeks, each participant who has not met 
treatment target criteria will receive assigned intervention for approximately 12
weeks. After the end of treatment each participant will be followed for 14 days.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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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 (SoA)
Study Period
Screening
Active
run-in period
(5 weeks)
Treatment (12 weeks)
Follow-
up
(14 days 
post last 
dose)
Notes
Visit Number/Title
Visit 1/
Screening
Visit 
2
Visit 
3
Visit 4/ 
baseline
Visit 5
Visit 6/ 
Discontinuation
Phone 
call
Scheduled Hour, Day, Week,
etc., and Window:
Week -7/-6
Week 
-5 
(±7 
days)
Week 
-1 
(+3 
days)
Week 0 
(±3 days)
Week 6 
(±7 days)
Week 12 (±7 
days)
±3 days
The dates of Visit 3 and Visit 4 
will be decided based on the 
date of Visit 2, while the dates 
of Visit 5 & Visit 6 will be 
decided based on the date of 
Visit 4.
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Participant Identification 
Card
X
The card will be updated once 
randomized.
Medical History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
Assignment of Screening 
Number
X
LDL-C treatment target 
evaluation based on Cardiac 
Risk assessment
X
Based on Chinese Guidelines 
on Prevention and Treatment of 
Dyslipidemia in Adults (2016
Edition).
Monitor Dietary/Exercise 
Compliance
X
X
X
X
X
X
Monitor Medication 
Compliance
X
X
X
X
Assignment of 
Treatment/Randomization
number
X
 
 
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Study Period
Screening
Active
run-in period
(5 weeks)
Treatment (12 weeks)
Follow-
up
(14 days 
post last 
dose)
Notes
Visit Number/Title
Visit 1/
Screening
Visit 
2
Visit 
3
Visit 4/ 
baseline
Visit 5
Visit 6/ 
Discontinuation
Phone 
call
Scheduled Hour, Day, Week,
etc., and Window:
Week -7/-6
Week 
-5 
(±7 
days)
Week 
-1 
(+3 
days)
Week 0 
(±3 days)
Week 6 
(±7 days)
Week 12 (±7 
days)
±3 days
The dates of Visit 3 and Visit 4 
will be decided based on the 
date of Visit 2, while the dates 
of Visit 5 & Visit 6 will be 
decided based on the date of 
Visit 4.
Run-in atorvastatin
administration/dispensing
X
MK-0653C/ Atorvastatin + 
matching placebo 
administration/dispensing
X
X
Efficacy Procedures
Lipid Panel A
X
X
X
X
X
LDL-C, total cholesterol (TC), 
HDL-C, non-HDL-C, and 
Triglyceride (TG).
Blood sample should be drawn 
after at least 10-hour fasting. 
Otherwise the visit need to be 
rescheduled.
Result of local lab within 4 
weeks prior to Visit 1 can be 
used as reference for 
participant screening.
Apo protein (Apo) B
X
X
X
Blood sample should be drawn 
after at least 10-hour fasting. 
Otherwise the visit needs to be 
rescheduled.
Safety Procedures
Full Physical Examination
including height and weight
X
X
X
 
 
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Study Period
Screening
Active
run-in period
(5 weeks)
Treatment (12 weeks)
Follow-
up
(14 days 
post last 
dose)
Notes
Visit Number/Title
Visit 1/
Screening
Visit 
2
Visit 
3
Visit 4/ 
baseline
Visit 5
Visit 6/ 
Discontinuation
Phone 
call
Scheduled Hour, Day, Week,
etc., and Window:
Week -7/-6
Week 
-5 
(±7 
days)
Week 
-1 
(+3 
days)
Week 0 
(±3 days)
Week 6 
(±7 days)
Week 12 (±7 
days)
±3 days
The dates of Visit 3 and Visit 4 
will be decided based on the 
date of Visit 2, while the dates 
of Visit 5 & Visit 6 will be 
decided based on the date of 
Visit 4.
Vital Signs (heart rate, blood 
pressure)
X
X
X
X
X
X
12-lead ECG
X
ECG will performed locally 
and results should be checked 
and confirmed by the 
investigator or qualified
designee.
Urine/ Serum β-Human 
Chorionic Gonadotropin (β-
hCG; WOCBP only)
X
X
X
X
Serum β-hCG test is 
determined by central lab if 
urine pregnancy performed at 
the site is positive.
fT4 and TSH
X
Result of local lab within 4 
weeks prior to Visit 1 can be 
used as reference for 
participant screening.
Hematology
X
X
X
Result of local lab within 4 
weeks prior to Visit 1 can be 
used as reference for 
participant screening.
Urinalysis
X
X
X
Result of local lab within 4 
weeks prior to Visit 1 can be 
used as reference for
participant screening.
 
 
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Study Period
Screening
Active
run-in period
(5 weeks)
Treatment (12 weeks)
Follow-
up
(14 days 
post last 
dose)
Notes
Visit Number/Title
Visit 1/
Screening
Visit 
2
Visit 
3
Visit 4/ 
baseline
Visit 5
Visit 6/ 
Discontinuation
Phone 
call
Scheduled Hour, Day, Week,
etc., and Window:
Week -7/-6
Week 
-5 
(±7 
days)
Week 
-1 
(+3 
days)
Week 0 
(±3 days)
Week 6 
(±7 days)
Week 12 (±7 
days)
±3 days
The dates of Visit 3 and Visit 4 
will be decided based on the 
date of Visit 2, while the dates 
of Visit 5 & Visit 6 will be 
decided based on the date of 
Visit 4.
Chemistry
X
X
X
X
X
Blood sample should be drawn 
after at least 10-hour fasting. 
Otherwise the visit need to be 
rescheduled. 
Result of local lab within 4 
weeks prior to Visit 1 can be 
used as reference for 
participant screening.
AE/SAE Monitoring
X
X-------------------------------------------------------------------------X
The serious adverse events 
occurred within 14 days after 
last study drug administration 
must be reported to Sponsor.
 
 
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2
INTRODUCTION
Atherosclerosis has traditionally been regarded as a disease primarily characterized by the 
progressive fatty debris in the arterial wall followed by progressive stenosis, and 
consequently rupture of this plaque, resulting in occlusive thrombosis and eventually cause
life-threatening heart attack, stroke and so on. Dyslipidemia characterized by the increase of 
low-density lipoprotein cholesterol (LDL-C) or TC is an important risk factor for 
atherosclerotic cardiovascular diseases. Over the last 30 years, the blood lipid level in the 
Chinese population has gradually increased, and the incidence of dyslipidemia has 
significantly increased [Moran, A., et al 2010], accompanied by a significant change in 
disease profile: coronary heart disease became the most predominant heart disease. 
The reduction of LDL-C levels can significantly decrease the development and mortality 
risks of atherosclerotic cardiovascular diseases which were already proved by great lot of 
evidences since landmark 4S trial. The analytic results of the Cholesterol Treatment Trial
indicate that 1 mmol/L LDL-C reduction by statin therapy in populations with different
cardiovascular risk stratifications can produce a 20% the relative risk reduction of major 
cardiovascular events and 10% risk reduction of all-cause mortality, whereas the mortality
caused by non-cardiovascular reasons does not increase. Meta-analyses and epidemiology 
studyies have shown that the reduction in CHD risk is proportional to the absolute change in 
LDL-C, i.e., greater reductions of LDL-C lead to greater cardiovascular risk reductions
[Stamler, J., et al 1986] [Chen, Z., et al 1991] [Szatrowski, T. P., et al 1984] [Gould, A. L., et 
al 1998].
Statin was proved to be a potent LDL-C lowing agent and was widely used in primary 
prevention and secondary prevention of CV event. However, doubling statin dose did not 
correspond to a doubled LDL-C reduction. Introduction of other lipid lowing agents can 
provide greater LDL-C reduction when added to a statin and was recommended by local 
guideline. Ezetimibe provides greater improvements in lipid profile and goal attainment 
when added to a statin compared to a statin monotherapy [Stein, E., et al 2004] [Goldberg, A. 
C., et al 2004] [Pearson, T. A., et al 2005] [US Prescribing Information 2013] [UK Summary 
of Product Characteristics 2013].
Cumulatively, there were approximately 1,038,850 patient-years of treatment with 
ezetimibe/atorvastatin, of which approximately 2875 subjects treated with ezetimibe/
atorvastatin fixed dose combination, and approximately 3,252 subjects treated with 
coadministered ezetimibe (+) atorvastatin in Marketing Authorization Holder-sponsored 
clinical trials. Data from trials and experience of co-administration provide the largest body 
of efficacy and safety data for the FDCs. And 2 definitive bioequivalence studies established 
the comparability between the FDC and the corresponding individual ezetimibe and 
atorvastatin tablets when co-administered [Ballantyne, C. M., et al 2005] [Catapano, A., et al 
2005].
Based on the favorable efficacy and risk profile of co-administration of atorvastatin and 
ezetimibe and the proved bioequivalent of FDC to co-administration of atorvastatin and 
ezetimibe, MK-0653C has been approved in 49 countries by the time of Feb 2018.
 
 
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2.1
Study Rationale
This trial is designed to demonstrate the superiority of MK-0653C (Ezetimibe/Atorvastatin 
combination tablet) 10/10 mg or 10/20 mg compare to a doubling dose of atorvastatin in
LDL-C lowing effect in hypercholesterolemia participants not well controlled by statin 
monotherapy. The data from this trial will support the market authorization in China.
2.2
Background
MK-0653C is a fixed dose combination drug containing ezetimibe, a Niemann-Pick Cl 
Like 1 (NPC1L1) inhibitor, and atorvastatin, a HMG-CoA reductase inhibitor, as active 
ingredients. The active ingredients are ezetimibe 10 mg and atorvastatin 10 mg or 20 mg.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on atorvastatin, ezetimibe and MK-0653C.
2.2.1
Pharmaceutical and Therapeutic Background
Coronary heart disease (CHD), stroke and peripheral arterial disease caused by 
atherosclerosis are quite significant burdens to medical care in developed and developing 
countries [Barquera, S., et al 2015], and these diseases have taken the leading cause of death 
among both urban and rural areas in China [Yang, G., et al 2013]. The number of CHD 
incidence and mortality is rapidly increasing in recent 20 years in China [Zhou, M., et al 
2016]. Considering the rapid aging speed in China, the future medical burden related to CHD 
will be even more critical. Blood cholesterol and the LDL-C are the independent risk factors 
to the CHD and ischemic stroke in Chinese cohort studies [Ren, J., et al 2010] [Li, Q., et al 
2017]. Five large clinical studies: 4S, CARE, LIPID, WOSCOPS, and AFCAPS/TexCAPS 
have strongly established the base for statins to treat and prevent CHD progression by 
lowering TC and LDL-C. The following series studies, AVERT, LIPS, HPS, PROSPER, 
ASCOT, PROVE-IT, TNT, and IDEAL have demonstrated the benefit of statins to even 
acute coronary disease and multiple subgroup risky populations. Lower LDL-C became 
possible and gradually target for high risk and very high risk populations. 
Statins have been introduced to China, and proved their efficacy on lowering LDL-C to 18-
55% among Chinese patients. However, only 6-7% more reduction can be expected when 
doubling the doses if the LDL-C cannot be adequately controlled after initiation of statin 
monotherapy. Moreover, increasing statin dose is less efficacy in lipid control while adverse 
events of myopathy and liver function abnormality increased with dosing, especially in 
Chinese patients. In order to achieve the treatment goal and to further reduce the CHD risk, 
new medicines are introduced to China, within whom, ezetimibe is recommended to be 
selected as combined medicine with statins in clinical setting in China to enhance the 
efficacy while no more safety or tolerability issues [IMS Health 2006] [Grundy, S. M., et al 
2004]. Combination of 10 mg ezetimibe with 10 mg atorvastatin or simvastatin may increase 
the rate of target achievement from around 18% to 72%, and the efficacy of combination use 
is similar to high dose (80 mg) of atorvastatin or simvastatin [Ballantyne, C. M., et al 2003] 
[Davidson, M. H., et al 2002] [Mikhailidis, D. P., et al 2009]. Therefore, China guideline 
 
 
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highly recommends using ezetimibe with low dose of atorvastatin to gain the similar effect. It 
also stated that there would be no additional risks of liver toxicity, myopathy or 
rhabdomyolysis when combining ezetimibe with statins compared to statin alone [Ballantyne, 
C. M., et al 2003] [Davidson, M. H., et al 2002] [Mikhailidis, D. P., et al 2009].
Significance of the Development of Fixed Dose Combination (FDC) Tablet for Therapy 
of Hyper-LDL-cholesterolemia

Mode of action
Ezetimibe inhibits the intestinal absorption of cholesterol and structurally-related 
phytosterols by blocking their passage across the intestinal wall. The molecular target of 
ezetimibe action has been identified as the putative cholesterol transporter NPC1L1. This 
blockade results in decreased absorption of dietary and biliary cholesterol without effects on 
the absorption of other lipids (e.g., triglyceride), lipid derivatives (e.g., bile acids) or 
lipidsoluble nutrients or vitamins. 
Atorvastatin is a synthetic HMG-CoA reductase inhibitor. Atorvastatin and its metabolites, 
which show a similar level of activity, inhibit hepatic synthesis of cholesterol by selectively 
and competitively inhibiting HMG-CoA reductase in the liver, one of the main organs, that 
regulates the amount of cholesterol in the blood. As a result, atorvastatin increases the 
number of hepatic LDL receptors and inhibits lipoprotein secretion, thereby reducing the 
amount of lipids in blood [Haque, T. 2010].
Ezetimibe reduces hepatic cholesterol stores by inhibiting the absorption of cholesterol in the 
small intestine, but compensatory increased cholesterol biosynthesis occurs in the liver.
Coadministration of ezetimibe and an HMG-CoA reductase inhibitor which inhibits 
cholesterol biosynthesis was shown to complementarily lower cholesterol in studies in dogs 
and in hypercholesterolemic patients [Van Heek, M. and Davis, H. 2002] [Toth, P. P., et al 
2010] [Grigore, L., et al 2008].

Adherence
In a recent survey on adherence to statin treatment revealed a decrease in adherence with 
time; thus, statin treatment adherence is estimated to be about 50% in long-term therapy 
[Shroufi, A. 2010]. In addition, data on other diseases show that the treatment compliance 
rate is correlated with the number of tablets (capsules) prescribed [Ingersoll, K. S. and
Cohen, J. 2008] [Cheong, C., et al 2008]. Therefore, a combination drug with a good 
tolerability profile in combination therapy for hyper-LDL-cholesterolemia may well be an 
important alternative as a treatment drug that can improve patients’ treatment adherence and 
may be anticipated to display more reliable therapeutic efficacy. Consequently, concomitant 
administration of ezetimibe and statin is assumed to more effectively improve hyper-LDL-
cholesterolaemia based on their different mechanisms of actions.
 
 
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2.2.2
Clinical Studies
IMPROVE-IT Study
The IMPROVE-IT [Cannon, C. P., et al 2015] (Improved Reduction of Outcomes: Vytorin 
Efficacy International Trial) study was a multicenter, randomized, double-blind study, 
designed to establish the incremental clinical benefit and safety of ezetimibe (administered as 
part of ezetimibe/simvastatin Combination 10/40 mg tablet, a single tablet containing 
ezetimibe 10 mg and simvastatin 40 mg, if a participant had 2 consecutive LDL-C 
measurements >79 mg/dL, then that participant was to have his/her simvastatin dose 
increased to 80 mg.) compared with simvastatin monotherapy in high-risk coronary artery 
disease participants and aims to address the question of whether the incremental reductions 
of LDL-C will translate into a clinical benefit. The study enrolled 18,144 high-risk 
participants with established coronary artery disease. At seven years, 32.7 percent of patients 
taking ezetimibe/Simvastatin experienced a primary endpoint event compared to 34.7 percent 
of patients taking simvastatin alone (hazard ratio of 0.936, p=0.016). Based on the LDL-C 
range compared in the study’s treatment arms (at one year, a mean LDL-C of 53 mg/dL 
versus 70 mg/dL, respectively), the 6.4 percent relative risk reduction observed in the 
ezetimibe/simvastatin arm in IMPROVE-IT was consistent with the treatment effect that had 
been projected based on prior studies of statins. 
With regard to safety, there were no significant differences between treatment groups in 
adverse events of special interest in the trial, which included myopathy and rhabdomyolysis, 
gallbladder adverse events, liver enzyme elevations greater than or equal to three times the 
upper limit of normal, and cancer. These safety findings from IMPROVE-IT were generally 
consistent with current labeling for ezetimibe.
MK-0653C Studies
Currently there are no clinical data available of combination administration of ezetimibe and 
atorvastatin in Chinese. However, there are clinical data globally on combination 
administration of ezetimibe and atorvastatin. The completed studies demonstrated the 
combination of ezetimibe and atorvastatin has superior LDL-C lower effect compare to the 
monotherapy of ezetimibe or atorvastatin. Especially in two add-on studies in patients whose 
LDL-C were not well controlled by atorvastatin treatment alone, adding ezetimibe 10 mg 
achieved bigger LDL-C level reduction compare to titrating up statin dose [Conard, Scott E., 
et al 2008] [Leiter, Lawrence A., et al 2008]. The safety of co-administration of ezetimibe 
and atorvastatin is comparable to ezetimibe or atorvastatin monotherapy. FDC has been 
shown to be bioequivalent to co-administration of ezetimibe and atorvastatin. Please refer to 
IB for the details.
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.
 
 
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This is an active control study, and the study interventions have evidenced benefits for study 
predefined participants regardless of the randomization allocation. In addition, the study 
procedure, including dose selection and exclusion criteria, was well designed based on robust 
evidence in terms of safety profile of each component of study interventions from previous 
studies. And also study will be conducted according to GCP guidelines and highest 
regulatory requirement in order to ensure the wellbeing of all participants.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
All objectives and hypotheses will be evaluated in Chinese participants with 
hypercholesterolemia, inadequately controlled with 10 mg or 20 mg atorvastatin
monotherapy.
Objectives
Endpoints
Primary
•
Objective: To evaluate the percent change 
in LDL-C from baseline to Week 12 of 
MK-0653C 10/10 mg compared to 
atorvastatin 20 mg (Cohort A).
Hypothesis: MK-0653C 10/10 mg is 
superior to atorvastatin 20 mg (Cohort A) 
in percent change from baseline in LDL-
C to 12 weeks after treatment.
•
Objective: To evaluate the percent change 
in LDL-C from baseline to Week 12 of 
MK-0653C 10/20 mg compared to 
atorvastatin 40 mg (Cohort B).
Hypothesis: MK-0653C 10/20 mg is 
superior to atorvastatin 40 mg (Cohort B) 
in percent change from baseline in LDL-
C to 12 weeks after treatment.
Overall success is determined by a success on 
at least one hypothesis.
•
Low-Density Lipoprotein – Cholesterol 
(LDL-C) level
 
 
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Objectives
Endpoints
Secondary
•
Objective: To evaluate the safety and 
tolerability of administrated MK-0653C 
10/10 mg and MK-0653C 10/20 mg once 
daily dosing through 12 weeks.
•
Adverse events
•
Laboratory parameters and vital signs 
•
Study drug discontinuation
Exploratory
•
Objective: To evaluate the percentage of 
participants meeting their LDL-C goals* 
with administration of MK-0653C 10/10
mg compared to atorvastatin 20 mg
(Cohort A), and MK-0653C 10/ 20 mg 
compared to atorvastatin 40 mg (Cohort 
B) at Week 12.
•
Objective: To evaluate the percent change 
in LDL-C from baseline to Week 6 with 
MK-0653C 10/10 mg compared to 
atorvastatin 20 mg (Cohort A), and MK-
0653C 10/ 20 mg compared to 
atorvastatin 40 mg (Cohort B).
•
Objective: To evaluate the percent change 
in total cholesterol (TC), high-density 
lipoprotein cholesterol (HDL-C), non-
HDL-C, triglyceride (TG) and 
Apoprotein (Apo) B from baseline to 
Week 6 and Week 12 with MK-0653C 
10/10 mg compared to atorvastatin 20 mg
(Cohort A), and MK-0653C 10/ 20 mg 
compared to atorvastatin 40 mg (Cohort 
B).
•
Meeting LDL-C goal (yes, no)
•
LDL-C level
•
The level of total cholesterol (TC), HDL-
C, non- HDL-C, triglyceride (TG) and 
Apo protein (Apo) B 
* The goal attainment values of LDL-C treatments across different ASCVD riskpopulations, 
detailed information can be found in Table 13 of Appendix 7: 2016 Chinese guidelines for 
the management of dyslipidemia in adults.
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel-group, multi-site, double-blind study of 
MK-0653C in Chinese participants with hypercholesterolemia in order to support the 
marketing authorization in China.
This trial consists of a screening period, an atorvastatin active run-in period, a treatment 
period and a follow-up period, and the total duration for each participant will be 
approximately 21 weeks. Participants will enter the run-in period based on their use of statin 
at the time of screening. After run-in period, 180 participants for Cohort A and 270 
participants for Cohort B will be enrolled for randomization.
Participant’s eligibility will be assessed based on this risk category and randomization will be 
stratified according to the risk category as well. Participants diagnosed with elevated LDL-C
who are currently treated with low to moderate dose of statins only and not at their target 
LDL-C goal will be screened up to 2 weeks for the eligibility. Demographic, medical history, 
lab test review and concomitant medication review or washout if necessary will be 
conducted. LDL-C treatment goal (Table 13 in Appendix 7) is determined on the basis of the 
CV risk assessment result (Figure 2) which is evaluated based on the demographic 
characteristics, medical history and lipid profile according to current Dyslipidemia 
Management Guidelines in China: 2016 Edition.   
 
 
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*Including smoking, low HDL-C, and men ≥45 years of age or women ≥55 years of age. The risk assessment and 
treatment of patients with chronic kidney disease refer to the treatment of dyslipidemia in special populations.
ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CM: chylomicron; HDL-C: high-density 
lipoprotein cholesterol; IDL: intermediate-density lipoprotein; LDL-C: low-density lipoprotein cholesterol; TC: total 
cholesterol; TG: triglyceride; VLDL:very-low-density lipoprotein cholesterol.
Figure 2
The Risk Assessment Flow Chart
(adopted from Dyslipidemia Management Guidelines in China: 2016 Edition, referring to Appendix 7 for more 
details)
Participants who meet all eligibility criteria will be enrolled in a 5-week active run-in period
after they discontinue the current statins with appropriate wash-out interval. Current statin is 
used to determine the allocation of different cohort: the participants who are currently treated 
at stable daily dose of 10 mg atorvastatin or other statin equivalent to or less than atorvastatin 
10 mg will be assigned to Cohort A and will receive 10 mg atorvastatin during the run-in 
period; and the participants who are currently treated by atorvastatin at stable 20 mg or other 
statins equivalent to atorvastatin 20 mg will be assign to cohort B and will receive 20 mg 
 
 
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atorvastatin during the run-in phase. The dose of other statins equivalent to atorvastatin can 
be found in Table 3.
After the run-in period, the participants within either cohort who have not met their treatment 
goals for LDL-C according to their risk levels will be randomized into 2 cohorts to receive 
either MK-0653C or atorvastatin monotherapy (at twice the atorvastatin dose contained in 
MK-0653C) during a 12 weeks double-blind treatment period:

Cohort A: Participants will be randomized to receive either MK-0653C 10/10 mg 
(containing ezetimibe 10 mg + atorvastatin 10 mg) or atorvastatin 20 mg in a 1:1 
ratio;

Cohort B: Participants will be randomized to receive either MK-0653C 10/20 mg 
(containing ezetimibe 10 mg + atorvastatin 20 mg) or atorvastatin 40 mg in a 1:1 
ratio.
Participants who completed the trial or administered at least one dose of study intervention 
but prematurely discontinued will be followed by phone call 14 days after the last dose to 
assess serious adverse events (SAEs) and information will be documented on the follow-up 
visit page.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Since the dosage and administration of this FDC is expected to be a second-line therapy in 
China, MK-0653C will be administered when participants are not well controlled with 
monotherapy of atorvastatin. The target population of this trial is participants with 
hypercholesterolemia in whom the lipid management target value of LDL-C as per their 
CAD-risk category based on Chinese Guidelines on Prevention and Treatment of 
Dyslipidemia in Adults has not been achieved, judging from the results of laboratory tests 
after atorvastatin run-in period and the presence/absence of CAD history.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary objective of this trial is to demonstrate superiority of lipid-modifying efficacy of 
MK-0653C 10/10 mg or 10/20 mg as compared to of atorvastatin monotherapy at twice the 
atorvastatin dose contained in MK-0653C monotherapy in hypercholesterolemia participants 
who are not well controlled by the atorvastatin monotherapy. In this trial, the percent change 
in LDL-C at week 12 from baseline will be used as the primary efficacy endpoint considering 
the maximum efficacy will be reached at that time point; the percentage of participants 
achieving their LDL-C goals will be used as the exploratory efficacy endpoint.
 
 
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LDL-C lowering therapy especially with statin has been proved to be effective for the 
primary and secondary prevention of Coronary Artery Disease [Stamler, J., et al 1986] 
[Kannel, W. B., et al 1979] [Castelli, W. P., et al 1983] [Okamura, T., et al 2007]. LDL-C is 
positioned as a valid biomarker for lipid management, and is used as an important variable 
for the development of lipid-improving drugs in China, as well as in other countries outside 
China. In statin studies, the relationship between LDL-C level and the prevention of 
arteriosclerotic diseases has been well established. The efficacy evaluation based on the 
percent change in LDL-C as the primary variable has been commonly used in the previous 
clinical studies of ezetimibe and statins.
4.2.1.2
Safety Endpoints
The safety will be evaluated with clinical and laboratory safety assessments conducted 
throughout the trial. Centralized liver function test and other biochemistry test will be done at 
Visit 3, Visit 5 and Visit 6 to detect potential hepatic adverse events and muscle adverse 
events which were defined as AE of interest. The rational of arrangement is based on the 
facts as follow. Atorvastatin and Ezetimibe, as the active ingredients, have been authorized
and widely used in China as well as worldwide for many years with well-established safety 
profile. A consistent safety profile is expected of this FDC. According to the label of 
atorvastatin, the majority of liver function abnormality occurs in first 3 months post the 1st
dose, liver function test is suggested to be performed prior to initiation and at 3 month as a 
standard recommendation according to the label. Atorvastatin, like other statins, occasionally
provoke myopathy and rabdomyolysis, especially concomitant use with cyclosporine or 
potent CYP3A4 inhibitors like clarithorommycin. However, surveillance of creatine kinase
(CK) cannot prevent the occurrence of myopathy or rabdomyolysis. Regular surveillance of 
CK is only recommended when those drugs mentioned above are prescribed for concomitant 
use as recommended in the label. Ezetimibe was generally well tolerated and when given as 
concomitant use with statin physicians should refer to the directions for use of statin 
according to the ezetimibe label. In addition, unnecessary blood test cause participant’s 
burden and can potentially cause the procedure related adverse event, e.g. injection site 
reaction and negative impact on the willingness of participation.
In addition to the centralized lab test according to the scheduled visits, qualifying local lab 
can be used to evaluate the eligibility during the screening and also to detect the safety signal 
during the trial conduction when needed.
Clinical measurements include monitoring of vital signs/physical examination at each visit 
will be done.Tiered methods will be used for safety endpoints analysis according to severity, 
frequency and relationship with the drug. 
4.2.2
Rationale for the Use of Comparator/Placebo
The Comparator used in this trial is atorvastatin (Lipitor®). Atorvastatin is one of the active 
components of MK-0653C. In order to demonstrate the additional contribution of the 2nd
active component (ezitimibe) in an FDC (MK-0653C), it is commonly required by the 
agency to demonstrate the superior lipid-modifying efficacy of the FDC compared to 
 
 
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continuing atorvastatin monotherapy (same dose or double dose) in hypercholesterolemia 
participants who are not well controlled by prior atorvastatin monotherapy. In this trial, 
atorvastatin 20 mg and 40 mg are being used as the comparators to MK-0653C 10/10 mg and 
10/20 mg separately. Please refer to the approved label of Lipitor® for more information 
about the dose and usage of atorvastatin.
4.3
Justification for Dose
In this trial, MK-0653C 10 (ezetimibe)/10 mg (atorvastatin) and 10 (ezetimibe)/ 20 mg 
(atorvastatin) were selected. The dosage of ezetimibe is 10 mg once daily. Ezetimibe 
(EZETROL®) at dose of 10 mg has been approved in China since 2006; it is the only 
approved dose in China and has an abundance of clinical use experience both as 
monotherapy and combination therapy in Asian patients. 
The brand atorvastatin product, Lipitor® tablets, has been marketed since 1999 in China. The 
usual clinical dosage of atorvastatin is 10 mg once daily and may be increased up to 40 mg 
for patients with hypercholesterolemia. Post-marketing survey of atorvastatin showed that 
Lipitor® at 10 mg or 20 mg are often be co-administered with brand ezetimibe, EZETROL®
10 mg [Teramoto, T., et al 2012]. 
In consideration of the efficacy and safety profiles of atorvastatin, and clinical position of 
MK-0653C, we have found that 10 or 20 mg is an appropriate dose to be combined for 
atorvastatin.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
5
STUDY POPULATION
Male/Female participants between the ages of 18 and 80 years (inclusive) with 
hypercholesterolemia and inadequately controlled by low to median dose of statins only (see 
below) will be enrolled in this study.
 
 
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
Visit 1 and 2 Criteria
Participants should meet these criteria at Visit 1 and Visit 2.
1. Participant with hypercholesterolemia diagnosed by investigator according to Chinese 
Guidelines on Prevention and Treatment of Dyslipidemia in Adults (2016 Edition). 
2. Participant has been stabilized on atorvastatin treatment at 10 mg (other statins with 
LDL-C lowering efficacy equivalent to or less than atorvastatin 10 mg) or 20 mg (or 
other statins with LDL-C lowering efficacy equivalent to 20 mg, refer to Table 3) for at 
least 4 weeks prior to Visit 1.
Demographics
3. Participant is male or female.
4. Participant is from 18 years to 80 years of age inclusive, at the time of signing the 
informed consent.
5. Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
A male participant must agree to use contraception as detailed in Appendix 5 of this protocol 
from the time of providing informed consent through completion of the study and refrain 
from donating sperm during this period.
6. Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
 
 
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
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 from the 
time of providing informed consent through completion of the study.
Informed Consent
7. Participant (or legally acceptable representative if applicable) provides written informed 
consent/assent for the study. 
Additional Categories
8. Participant agree to maintained a stable diet and stable exercise during the study.
Visit 4 Criteria
9. Participant has completed the 5-week atorvastatin run-in period.
10. Participant has ≥75% compliance with study medication during the atorvastatin run-in 
period. 
11. Participant meets any of the following criteria on LDL-C level based on the lipid panel 
test at Visit 3.
a. For medium or low risk participants: ≥130 mg/dL (3.4 mmol/L).
b. For high risk participants: ≥100 mg/dL (2.6 mmol/L) and ≤160 mg/dL (4.1 mmol/L).
c.
For very high risk participants: ≥70 mg/dL (1.8 mmol/L) and ≤160 mg/dL (4.1
mmol/L).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Visit 1 Criteria
Medical Conditions
1. Participant had a uncontrolled hypertriglyceridemia which needs drug intervention or a 
fasting triglyceride (TG) value ≥500 mg/dL (4.52 mmol/L) at Visit 1.
2. Participant is currently treated with statin at dose of equivalent LDL-C lowering effect 
greater than 20 mg atorvastatin.
3. Participants has active liver disease at Visit 1 or lab test evidenced liver transaminases 
(ALT and AST) > 2 X upper limit of normal (ULN) per central laboratory at Visit 1 or 
local lab within 4 weeks prior to the screening visit. 
4. Participant has NYHA (New York Heart Association) Class III or IV symptomatic 
congestive heart failure at Visit 1.
 
 
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5. Participant has uncontrolled cardiac arrhythmias, myocardial infarction (MI), PCI,
CABG, unstable angina, or stroke within 3 months (12 weeks) prior to Visit 1.
6. Participant has homozygous familial hypercholesterolemia or has undergone LDL 
apheresis.
7. Participant has endocrine or metabolic disease known to influence serum lipids or 
lipoproteins (i.e., secondary causes of hyperlipidemia, e.g., hyper or hypothyroidism, 
Cushing’s syndrome) at Visit 1.
8. Participant has an estimated glomerular filtration rate (eGFR) < 30 mL/min /1.73m2 or 
other clinical significant renal disease which needs intensive medical care (e.g. 
systematic use of steroids/immunosuppressant, renal transplant, hemodialysis, etc.) at 
Visit 1. eGFR calculation is based on the below equation:
Male: eGFR [mL/min/1.73m2] =194 x Cr [mg/dL] -1.094 x age [yr] -0.287
Female: eGFR[mL/min/1.73m2]=194 x Cr [mg/dL] -1.094 x age [yr] -0.287 x 0.739
9. Participant has had a gastrointestinal tract bypass, or other significant intestinal 
malabsorption.
10. Participant has a history of cancer within the past 5 years from Visit 1 (except for 
successfully treated dermatological basal cell or squamous cell carcinoma or in situ 
cervical cancer).
11. Participant who is known human immunodeficiency virus (HIV) positive (as assessed by 
medical history).
12. Participant has hypersensitivity or intolerance to ezetimibe, atorvastatin, the 
ezetimibe/atorvastatin combination tablet, or any component of these medications or has 
a condition or situation, which described as contraindication in labeling of EZETROL® or 
Lipitor® or may interfere with participation in the trial in the opinion of the investigator.
13. Participant has disorders of the hematologic, digestive, or central nervous systems 
including cerebrovascular disease and degenerative disease that in the opinion of the 
investigator would limit evaluation or participation.
14. Participant has a history of mental instability, drug/alcohol abuse within the past 5 years, 
or major psychiatric illness not adequately controlled and stable on pharmacotherapy in 
the investigator’s judgement.
15. Participant has a history of myopathy or rhabdomyolysis with ezetimibe or any statin.
16. Participant has a medical condition or personal circumstance which, in the opinion of the 
investigator, places the participant at unnecessary risk through continued participation in 
the trial or does not allow the participant to adhere to the requirements of the protocol.
 
 
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17. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose 
of study intervention. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.
Prior/Concomitant Therapy
18. Participant is currently taking medications that are potent modulators of cytochrome P-
450 3A4 (CYP3A4) including:

Cyclosporine

Systemically administered azole antifungals such as ketoconazole, fluconazole, and 
itraconazole

Macrolide antibiotics (e.g., clarithromycin, and erythromycin)

Protease inhibitors (e.g., ritonavir, saquinavir, and lopinavir)

Grapefruit or juice of grapefruit (200 ml/day for more than 3 times per week).
19. Participant is taking any cyclical hormones (e.g., cyclical oral contraceptives, cyclical 
hormone replacement), including the combination of ethinyl estradiol and norethisterone, 
or non-cyclical hormones, including non-cyclical hormone replacement therapy (HRT) or 
any estrogen antagonist/agonist within 8 weeks.
Note: If participant has been treated with a stable regimen of non-cyclical HRT for > 8 
weeks and agree to continue this regimen for the duration of the trial, concomitant 
therapy is acceptable.
20. Participant is receiving treatment with systemic corticosteroids (intravenous, 
intramuscular and oral steroids).
21. Participant is treated with psyllium, other fiber-based laxatives, phytosterol margarine, 
and herbal medicine and/or over the counter (OTC) therapies that are known to affect 
serum lipids.
Note: If participant has been treated with a stable regimen for > 8 weeks and agree to 
continue this regimen for the duration of the trial, concomitant therapy is acceptable.
22. Participant is treated with an anti-obesity drug (e.g. mazindol) within 12 weeks prior to 
Visit 1.
23. Participant is treated with warfarin or warfarin-like anticoagulants and has not been on a 
stable dose with a stable International Normalized Ratio (INR) for at least 6 weeks.
 
 
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24. Participant has taken lipid-lowering agents (except probucol) including, Cholestin™, bile 
acid sequestrants, ezetimibe, fibrates or niacin (>200 mg/day), PCSK9 inhibitors within 6 
weeks prior to Visit 1. Participant has taken probucol within 10 weeks prior to Visit 1.
Prior/Concurrent Clinical Study Experience
25. Participant who has been treated with any other investigational drug within 30 days of 
Visit 1.
Diagnostic Assessments
Not applicable.
Other Exclusions
26. Participant who currently follows an excessive weight reduction diet in the opinion of the 
investigator.
27. Participant currently engages in a vigorous exercise regimen (e.g.; marathon training, 
body building training) or intends to starts training during the trial.
28. 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.
Visit 4 Criteria
29. Participant reaches the treatment goal with mono-statin therapy [per central lab].
30. Participant has creatine kinase (CK) levels > 3 X ULN [per central laboratory reference 
ranges].
31. Participant has developed a new medical condition, suffered a change in status of an 
established medical condition or required a new treatment or medication, which meets 
any, previously described trial exclusion criteria.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should be instructed for diet or a similar diet according to China 2016 Guideline 
at Visit 1. Participants also should keep exclusion criteria 24 (Participant consumes less than 
0.2 L of grape fruit juice per day.) during trial period.
At each subsequent trial visit, the dietary compliance will be monitored and sites should 
reinstruct participants who are not compliant. This monitoring is particularly important in an 
effort to minimize any diet-related lipid changes.
 
 
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Participants should fast (no food or drink except water) for at least 10 hours prior to all 
scheduled trial visits. Permitted concomitant therapies can be taken during the fasting period.
Note: If the participant reports to the visit without having fasted, the sample should not be 
drawn, and the participant should be asked to return for another appointment.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
Participants will be suggested not consume more than the 25 g alcohol per day.
Participants will not be permitted in the trial if they consistently consume excessive amounts 
of alcohol. Participants should be encouraged not to make major changes in their alcohol 
consumption for the duration of the trial. Please refer to Table 1 for reference volume of 
alcohol.
Table 1
Alcohol Consumption Quantities
Alcohol
25 g/day
Beer
1 bottle (633 ml/bottle)
Sake
180 ml
Whiskey/ Brandy
2.5 glasses (single)
Distilled spirit
90 ml
Wine
2 glasses
Participants should refrain from smoking during the trial.
5.3.3
Activity Restrictions
Participants should continue any activity he/she was accustomed to prior to entering the trial, 
but should refrain from engaging in a vigorous exercise regimen during the trial. Participants 
should be instructed the activity by investigator based on Chinese Guidelines on Prevention 
and Treatment of Dyslipidemia in Adults. Participant also should keep Exclusion Criterion 
27 and 28 (Participant does not follow excessive weight reduction diet from trial duration, 
and does not engage in a vigorous exercise regimen or start training) during the trial.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently enter the run-in epoch in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
 
 
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screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Run-in Failure
For participants successfully screened but discontinued during the treatment run-in period 
must be carefully documented with the reason in the appropriate CRF, and these participants 
are considered treatment run-in failures. 
No re-screening of participants that are discontinued from the run-in period will be allowed.
5.6
Participant Replacement Strategy
A participant who discontinues from study intervention will not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies [study intervention(s) provided by the Sponsor] will be packaged to support 
enrollment . Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
Each assigned study interventions will be administered orally once daily. As there is no 
recommended dosing time, the participant should take their treatment at a consistent time 
each day and participants are suggested to avoid taking the study intervention with other 
concomitant medications at the same time. On the visit day, the participant should take the 
medication after all procedures are completed.
 
 
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Table 2
Study Interventions
During active run-in period:
Cohort 
Name
Cohort 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/N
IMP
Sourcing
A
Active 
Compara
tor
atorvastatin
Drug
Tablet
10 mg
10 mg 
QD
Oral
Run-in period/ 
5 weeks
Active 
treatment to 
select 
uncontrolled 
participants
NIMP
Provided 
centrally 
by the 
Sponsor
B
Active 
Compara
tor
atorvastatin
Drug
Tablet
20 mg
20 mg 
QD
Oral
Run-in period/ 
5 weeks
Active 
treatment to 
select 
uncontrolled 
participants
NIMP
Provided
centrally 
by the 
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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During double-blinded treatment period:
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
A1
Experi-
mental
MK-0653C 
FDC 
(ezetimibe 10 
mg + 
atorvastatin 
10 mg)
Drug
Tablet
10 mg / 10 
mg
10 mg / 
10 mg
QD
Oral
Randomization 
treatment: 12 
weeks
Experimental
IMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo 
atorvastatin
Drug
Tablet
0 mg
0 mg QD Oral
Randomization 
treatment: 12 
weeks
Dummy with 
study 
treatment
NIMP
Provided 
centrally 
by the
Sponsor
A2
Active 
Comparator
atorvastatin
Drug
Tablet
20 mg
20 mg 
QD
Oral
Randomization 
treatment: 12 
weeks
Active control
NIMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo of 
MK-0653C 
FDC 
(ezetimibe 10 
mg + 
atorvastatin 
10 mg)
Drug
Tablet
0 mg
0 mg QD Oral
Randomization 
treatment: 12 
weeks
Dummy with 
study 
treatment
NIMP
Provided 
centrally 
by the 
Sponsor
B1
Experi-
mental
MK-0653C 
FDC 
(ezetimibe 10 
mg + 
atorvastatin 
20 mg)
Drug
Tablet
10 mg / 20 
mg
10 mg / 
20 mg
QD
Oral
Randomization 
treatment: 12
weeks
Experimental
IMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo of 
atorvastatin
Drug
Tablet
0 mg
0 mg QD Oral
Randomization 
treatment: 12 
weeks
Dummy with 
study 
treatment
NIMP
Provided 
centrally 
by the 
Sponsor
 
 
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Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
B2
Active 
Comparator
atorvastatin
Drug
Tablet
20 mg
40 mg 
QD
Oral
Randomization 
treatment: 12 
weeks
Active control
NIMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo of 
MK-0653C 
FDC 
(ezetimibe 10 
mg+atorvasta
tin 20 mg)
Drug
Tablet
0 mg
0 mg QD Oral
Randomization 
treatment: 12 
weeks
Dummy with 
study 
treatment
NIMP
Provided 
centrally 
by the 
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
The first dose of trial treatment will be administered at the trial site at Visit 4. Subsequent dosing will be performed once daily by the participant (i.e.,
unsupervised at his/her home) at approximately the same time each day.
 
 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (e.g., not applicable in 
the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided 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 allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 cohorts with 2 study intervention arms in each cohort. 
Algorithm of participant’s allocation is based on current statin dose prior to the screening (a 
stable dose is required at least 4 weeks prior to Visit 1). For participants who is currently 
treated with atorvastatin 10 mg or equivalent or equivalents less than 10 mg atorvastatin will 
be assigned to cohort A; while other participants who is currently under treatment of 20 mg 
atorvastatin or equivalents will be assigned to cohort B (atorvastatin and other equivalent 
statin can be found in Table 3). Within each cohort, participants will be assigned randomly in 
a 1:1 ratio to receive MK-0653C or atorvastatin treatment, respectively.
Table 3
Dose of Atorvastatin and Other Equivalent Statin
Cohort
Atorvastatin 
(mg)
Simvastatin 
(mg)
Lovastatin 
(mg)
Pravastatin 
(mg)
Fluvastatin 
(mg)
A
-
10
20
20
40
A
10
20
40
40
80
B
20
40
80
-
-
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:

Cohort (i.e., Cohort A – atorvastatin ≤10 mg or equivalent and Cohort B – atorvastatin 
20 mg or equivalent).

Disease risk category (low, moderate, high, and very high risk, referred to Section 4.1).
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. A double-dummy design is 
used because the identity of MK-0653C and comparator (atorvastatin) cannot be disguised 
due to different appearance. 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 needs to be documented, for those 
interruption >=25% from the treatment plan will require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
 
 
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medications or vaccinations
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 or vaccination 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.
Specific restrictions are listed in Table 4 for concomitant therapy or vaccination:
Table 4
Prohibited Medications
Exclu-
sion 
Class
Details
Prohibi-
tion Start
Note
18
CYP3A4 
modulators
Cyclosporine;
Systemically administered azole 
antifungals such as ketoconazole, 
fluconazole, and itraconazole;
Macrolide antibiotics (e.g., 
clarithromycin, erythromycin);
Protease inhibitors (e.g., ritonavir, 
saquinavir, lopinavir );
Grapefruit or juice of grapefruit (the 
amount should not be over 200 ml/day, 
and should not be consumed 3 
consecutive days or longer).
V1
19
Cyclical 
hormones and
Non-cyclical 
hormones
Cyclical hormones (cyclical oral 
contraceptives, cyclical hormone 
replacement) including the 
combination of ethinyl estradiol, 
norehisterone;
Non-cyclical hormone therapy 
(including non-cyclical hormone 
replacement therapy or any estrogen 
antagonist/agonist).
V1
If the participant takes cyclical 
hormones (e.g., cyclical oral 
contraceptives, cyclical hormone 
replacement), including the 
combination of ethinyl estradiol 
and norethisterone, or non-
cyclical hormones, including 
non-cyclical hormone 
replacement therapy or any 
estrogen antagonist/agonist, these 
treatment should be stably taken 
more than 8 weeks and supposed 
to be taken at the same dosage
20
Corticosteroids Systemic corticosteroids (intravenous, 
intramuscular and oral steroids)
V1
Topical, intra-articular, nasal, 
inhaled and ophthalmic steroid 
therapies are allowed.
21
Agents 
potentially 
affect serum 
lipids
psyllium, other fiber-based laxatives, 
phytosterol margarine, herbal medicine
and/or over the counter (OTC) 
therapies
8 weeks 
prior to 
V1
If the participant has been treated 
with a stable regimen for > 8 
weeks prior to Visit 1 and agree 
to continue this regimen for the 
duration of the trial, concomitant 
therapy is acceptable.
 
 
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Exclu-
sion 
Class
Details
Prohibi-
tion Start
Note
22
Anti-obesity 
drug
Mazindol
12 weeks 
prior to 
V1
23
warfarin
Warfarin or warfarin-like 
anticoagulants and has not been on a 
stable dose with a stable INR.
V1
Warfarin or warfarin-like 
anticoagulants therapy is 
acceptable, if the participant must 
be on a stable dose with a stable 
INR for 6 weeks prior to Visit 1.
24
Lipid lowering 
agents
Cholestin TM, bile acid sequestrants, 
Ezetimibe, fibrates or niacin (>200 
mg/day)
6 weeks 
prior to 
V1
Probucol
10 weeks 
prior to 
V1
Statin other than atorvastatin, 
Ezetimibe other than the ezetimibe 
component of MK-0653C
V1
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modifications are planned for this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity . The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.11). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/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.
Each study site will be supplied by Sponsor with the investigational treatment.
 
 
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6.9
Standard Policies
Trial site personnel will have access to a central electronic treatment 
allocation/randomization system (IRT system) to allocate participants, to assign treatment to 
participants and to manage the distribution of clinical supplies. Each person accessing the 
IRT system must be assigned an individual unique participant identification number (PIN). 
They must use only their assigned PIN to access the system, and they must not share their 
assigned PIN with anyone.
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 prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.4.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Consecutive (2 or more measurements within 1 week) elevations in ALT or AST ≥3 x 
ULN.
 
 
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•
Consecutive(2 or more measurements within 1 week) elevations in CK ≥10 x ULN with 
or without muscle symptoms.
•
Consecutive (2 or more measurements within 1 week) elevations in CK ≥5 to <10 x ULN 
with muscle symptoms.
•
The participant is requiring any treatment with telaprevir or fibrates.
•
The participants are requiring any treatment with a potent inhibitor of cytochrome P450 
3A4 (CYP3A4) such as, itraconazole, ketoconazole, erythromycin, clarithromycin or 
HIV protease inhibitors for their emerging medical conditions.
•
Moved (or relocated): When the participant has either moved or relocated and is no 
longer able to participate in the trial.
•
Participant developed a new condition which needs more intensive statin treatment or 
LDL-C lowing treatment.
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.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.10. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
 
 
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•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
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 sample collection from each participant over the study is served to prove the efficacy 
and safety of the study intervention and will be described in laboratory manual. 
Local laboratory use is allowed for the purpose of close monitoring of safety signals and 
should follow the site’s clinical practice.
 
 
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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study. 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
 
 
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the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 12 weeks before the Visit 1. Please note that the prior medications for the treatment of 
hypercholesterolemia must be documented in eCRF.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Randomization number will be allocated at Week 0 (Visit 4) via IVRS/IWRS.
 
 
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8.1.8
Study Intervention Administration
Administration of first study dosing during randomization phase will be witnessed by the 
investigator and/or study staff at study site. Subsequent dosing will be performed once daily 
by the participant (i.e., unsupervised at his/her home).Since MK-0653C and atorvastatin 
differ in appearance thus corresponding matching placebos will be provided to ensure the 
efficient blinding. Participants who successfully pass the eligibility check at Visit 4 will be 
randomized within each cohort and will receive one bottle (20 mg atorvastatin or matching 
placebo) and one blister (MK-0653C or matching placebo) of study treatments during the 
double-blinded treatment period. Participants should be instructed to take 1 (for Cohort A) or 
2 (for Cohort B) tablets from bottle and 1 tablet from blister every day during the study (i.e., 
Cohort A: either 1 tablet of MK-0653C 10/10 mg and 1 tablet of placebo matched to 20 mg 
atorvastatin OR 1 tablet of atorvastatin 20 mg and 1 tablet of placebo matched to 10/10 mg 
MK-0653C; Cohort B: either 1 tablet of MK-0653C 10/20 mg and 2 tablets of placebo 
matched to 20 mg atorvastatin OR 2 tablets of atorvastatin 20 mg and 1 tablet of placebo 
matched to 10/20 mg MK-0653C). 
Participants will be provided with enough study treatment to last between study site visits.
8.1.8.1
Timing of Dose Administration
Administration of study medication will be performed once daily at approximately the same 
time each day for 12 weeks during the double-blinded treatment period, without regard to the 
time of meals.
8.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Adherence to study treatment will be assessed by tablet countat Visit 4-6. Participants with 
≥75% compliance during run-in period will be eligible for study entry.
Every effort must be made to maintain adherence to study treatment dosing per protocol as 
close to 100% as possible. Interruptions from the protocol specified treatment plan for 
compliance<75% require consultation between investigator and Sponsor. 
Paicipant will be instructed for prohibited medication according to the protocol exclusion 
criteria. And also participant will be instructed for diet, or a similar diet and life style
according to China 2016 Guideline at Visit 1. Investigator will check any changes at each 
visit regarding concomitant medication, diet and life style, and document the changes on 
eCRF dedicated page.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the predefined 
treatment period for any reason at any time can restart the study intervention. However, 
participants are expected to rechallenge the study intervention at the earliest time upon 
decision of the investigator, and all premature discontinued participants should be 
encouraged to continue to be followed for all remaining study visits , regardless of the 
rechallenge, as outlined in the SoA and Section 8.11.3.
 
 
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the end of study visit should be performed (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 and 8.11.
8.1.11
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. Prior to 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 chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that 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 that is 
part of the study design has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants will remain blind to the identity of the treatment from Visit 4 until database lock, 
using the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will 
not be accessible by anyone involved in the study;

The identity of the treatment will be concealed by using the identical packaging, labeling, 
appearance, taste and color. And a double-dummy design is used because differences 
between investigational treatment and comparator cannot be disguised due to their 
different appearance;

Lipid panel test after randomization will be done centrally and the result will not reveal
to the participants or study team until end of the study. No attempts could be made to 
have local evaluation of the lipid levels once the participant successfully entered the 
double blind treatment phase.
 
 
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is 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
Clinical Efficacy Laboratory Assessments
Fasting blood samples (obtained at least 10 hours after intake of last meal/food/beverage 
other than water) will be drawn as outlined in the SoA. The central laboratory will perform 
all laboratory test determinations from Visit 3 till Visit 6 (Appendix 2). LDL-C will be 
calculated using the Friedewald method when TG 400 mg/dL and beta quantification 
ultracentrifugation when TG>400 mg/dL. All Lipid Panel A and Apo B data will be blinded 
once the participant is centrally randomized. Once a participant is randomized (Visit 4), no 
attempts should be made on the part of the investigator or participant to have a local 
evaluation of the participant’s lipid values (Lipid Panel A and Apo B). 
8.3
Safety Assessments
The assessment of safety will be based primarily on the frequency of AEs, SAEs, and
laboratory abnormalities. Other safety data will be summarized as appropriate. 
1.
Laboratory evaluations (performed at baseline and at the end of the study)
2.
Adverse events and serious adverse events, adverse events of interest including muscular 
event and hepatic events (performed throughout full study)
3.
Discontinuation due to AEs (performed throughout full study)
4.
Physical Exam (performed throughout full study)
5.
Vital signs (performed throughout full study)
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 Section 8.
Planned time points for all safety assessments are provided in the SoA.
 
 
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard at screening and 
scheduled timepoint. 
Height and weight will also be measured and recorded. Body height and weight will be 
obtained with the participants shoes off, jacket or coat removed, using a standardized scale.
The investigator will determine if the results are clinically significant prior to Week 0 (Visit 
4), any physical examination abnormalities will be recorded as part of the participant's 
medical history. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.3.2
Vital Signs
•
Heart rate and blood pressure will be assessed.
•
Blood pressure and pulse measurements will be assessed in sitting position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
•
Vital signs (to be taken before blood collection for laboratory tests, or at least 5 minutes 
afterwards) will consist of 1 pulse and 3 blood pressure measurements (after the 
participant has been sitting for 5 minutes, 3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). 
•
Any clinically significant change from baseline for vital sign measurement (not 
associated with another adverse event) will be recorded.
8.3.3
Electrocardiograms
•
12-lead electrocardiogram (ECG) will be obtained and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) as outlined in the SoA 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. 
•
The investigator will determine if the results are clinically significant and they meet the
eligibility criteria. Any ECG abnormalities at screening visit will be recorded as part of 
the participant's medical history.
 
 
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8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
 
 
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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 consent form is signed 
but before intervention allocation/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.
From the time of intervention allocation/randomization through 14 days following 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 of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (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
 
 
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Serious Adverse Event 
(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:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (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
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
 
 
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth 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 suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of 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
Refer to Appendix 3.
 
 
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8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon 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).
2. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
3. Myopathy, rhabdomyolysis, or if the CK criterion necessitating study medication 
discontinuation is met, the event should be reported as ECI because of their association 
with lipid-lowering treatments. 
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the amount of study treatment taken
outside the treatment assignment.
Sponsor does not recommend specific treatment for an overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
 
 
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8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Biomarkers
Biomarkers 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
Screening (Visit 1)
Approximately 6-7 weeks prior to intervention allocation/randomization, potential 
participants will be evaluated up to 2 weeks, to determine that they fulfill the entry 
requirements as set forth in Section 5. Screening procedures may be repeated after 
consultation with the Sponsor. A participant may be re-screened up to two times. The 
participant must provide new written informed consent before each time they are re-screened.
A participant who enters screening but is determined not to be eligible to enter the treatment 
run-in epoch will be considered a screen failure. The investigator may consider re-screening 
the participant at a later time if he/she believes that the participant’s condition has changed 
and they may potentially be eligible. In this case, a new participant number will be allocated 
to the participant and he/she will need to re-perform all Visit 1 procedures.
8.11.2
Run-In (Visit 2 and Visit 3)
Visit 2 will be performed approximately 5 weeks prior to randomization (Visit 4).
Dispense run-in intervention to a participant if he/she is eligible for study participation. 
Participants will be instructed to take 1 tablet from the bottle. 
After initiating administration, participant who is determined to be not appropriate by the 
investigator will be excluded the study as screen failed. If a participant is not eligible for 
study participation, the investigator should contact with the participant, stop dosing study 
drug and performing the end of study visit immediately, and a safety follow-up visit by 
phone-call as appropriate.
NOTE: it is not necessary for screen failed participant who did not start the study 
intervention to perform follow-up visit after the end of study visit.
Approximately 4 weeks after Visit 2, participants will be scheduled to return for Visit 3.
Blood lipid levels (e.g. LDL-C values) and biochemistry test measured at Visit 3 (Week -1) 
will be used to determine participant’s eligibility for intervention allocation/randomization at 
Visit 4 (Day 1/Week 0).
 
 
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Participant will be instructed on Chinese Guidelines on Prevention and Treatment of 
Dyslipidemia in Adults (2016 Edition), and will agree to maintain the diet/exercise regimen 
throughout the study.
No rescreening will be allowed of participants who discontinue during the run-in phase or 
fail to be eligible after the run-in phase. 
8.11.3
Treatment Period (Visit 4-Visit 6)
After 5-week run-in treatment, participants who archive ≥75% compliance with the run-in 
medication and have not met their treatment goals for LDL-C according to their risk levels 
will be eligible for study entry. The site will perform all procedures for Visit 4 and the 
participant will be randomized. After the all procedures have been completed, the study 
drugs will be dispensed and the participants should take the treatment at a consistent time 
each day to promote compliance.
The following visits will be scheduled every 6 weeks for participants to return to perform the 
study procedures required as per Section 1.3 – SoA.
8.11.4
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment prior to completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits.
8.11.5
Poststudy (follow-up visit)
Participants will be followed-up by phone approximately 14 days after the last dose of study 
intervention to determine if any AEs have occurred since the last clinic visit.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the trial. If, after the 
trial has begun, but prior to any unblinding, changes are made to the study 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 non-confirmatory analyses made 
after the protocol has been finalized, but prior to unblinding, will be documented in a 
supplemental SAP (sSAP) and referenced in the Clinical Study Report (CSR) for the trial. 
Post hoc exploratory analyses will be clearly identified in the CSR.
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design 
Overview
A Phase III, Randomized, Double-blind Clinical Trial to Study the Efficacy and
Safety of MK-0653C in Chinese participants with Hypercholesterolemia
Treatment Assignment
A double-blind/masking technique will be used. After the run-in period, 180 
participants will be randomized in a ratio of 1:1 into the arms of MK-0653C 10/10
mg and atorvastatin 20 mg in Cohort A and 270 participants will be randomized in a 
ratio of 1:1 into the arms of MK-0653C 10/20 mg and atorvastatin 40 mg in Cohort 
B. Randomization will be stratified by disease risk category (low, moderate, high, 
very high) as defined in Section 4.1.
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
Primary Endpoint
Percent change from baseline in LDL-C at Week 12
Secondary Endpoints
1.
Percentage of participants with adverse events.
2.
Change from baseline in laboratory parameters and vital signs at each visit
3.
Percentage of participants discontinued from study medication
Statistical Methods for 
Key Efficacy Analyses
The primary hypothesis for each cohort will be evaluated by comparing MK-0653C 
to atorvastatin on the percent change from baseline in LDL-C using a constrained 
longitudinal data analysis (cLDA) model. 
Statistical Methods for 
Key Safety Analyses
Counts and percentages of AEs will be provided. P-values and confidence intervals 
for the incidence of AEs of clinical interest will be estimated using the Miettinen and 
Nurminen method [Miettinen, Olli and Nurminen, Markku 1985].
Interim Analyses
No interim analyses are planned for this trial.
Multiplicity
The Type-I error rate over the multiple treatment comparisons will be controlled by 
the Hochberg testing procedure.  
Sample Size and 
Power
A total of approximately 450 participants (180 in Cohort A, 270 in Cohort B) will be 
randomized.The sample in Cohort A has 93% power to demonstrate the superiority 
of MK-0653C 10/10 mg over atorvastatin 20 mg at a one-sided 2.5% alpha-level. 
Similarly, the sample in Cohort B has 95% power to demonstrate the superiority of 
MK-0653C 10/20 mg over atorvastatin 40 mg at a one-sided 2.5% alpha-level. The 
overall power to succeed on at least one hypothesis is 99% at a 2.5% alpha-level 
with 88% power to succeed for both hypotheses.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial will be conducted as a double-blind trial under in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
 
 
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an interactive voice 
response system/integrated web response system (IVRS/IWRS).
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for between-treatment differences are 
listed below.
9.4.1
Efficacy Endpoints
1. Percent change from baseline in LDL-C at Week12.
2. Percentage of participants meeting the LDL-C treatment goal (see Table 13 in 
Appendix 7) at Week 12.
3. Percent change from baseline in LDL-C at Week 6.
4. Percent change from baseline in total cholesterol (TC), HDL-C, non-HDL-C, 
triglyceride (TG), Apo protein (Apo) B at Weeks 6 and 12.
9.4.2
Safety Endpoints
1. Percentage of participants with adverse events.
2. Change from baseline in laboratory parameters and vital signs at each visit.
3. Percentage of participants discontinued from study medication.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this trial. The FAS population for any given endpoint consists of all 
randomized participants who took at least one dose of study treatment, and have at least one 
observation of the respective endpoint (baseline or post-baseline) during the treatment period.
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population. Details on the approach to handling 
missing data are provided in Section 9.6 Statistical Methods.
 
 
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9.5.2
Safety Analysis Populations
Analyses of safety data will be performed in the All Participants as Treated (APaT) 
population, consisting of all randomized participants who received at least one dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population. 
This will be the treatment group to which they are randomized for all participants except for 
those who take incorrect study treatment for the entire treatment period. Such participants 
will be included in the treatment group corresponding to the study treatment actually 
received. At least one laboratory measurement or vital sign obtained subsequent to at least 
one dose of study treatment is required for inclusion in the analysis of each specific 
parameter. To assess change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
9.6 Statistical Methods.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Nominal p-
values may be computed for other efficacy analyses, but should be interpreted with caution 
due to potential issues of multiplicity, sample size, etc. Unless otherwise stated, all statistical 
tests will be conducted at α=0.05 (2-sided) level.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  
The study’s estimand is a hypothetical estimand that seeks to estimate efficacy as if all 
participants were to take study medication for 12 weeks. 
The estimand consists of the following elements:
•
Target population: Participants with hypercholesterolemia (age 18 to 80 years, inclusive), 
consistent with the study’s inclusion/exclusion criteria.
•
Variable: Percent change from baseline in LDL-C at Week 12.
•
Intercurrent event: Data obtained after discontinuation of treatment are not relevant to 
this estimand.
•
Population level-summary: Difference in variable means comparing randomized 
treatments (within each cohort).
Analyses will thus exclude measurements collected more than 5 days after the last dose of 
study treatment.
 
 
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For the analyses of percent change from baseline in LDL-C at Week 12 in both cohorts, a 
constrained longitudinal data analysis (cLDA) method proposed by Liang and Zeger will be 
used [Liang, Kung-Yee and Zeger, Scott L. 2000]. Within each baseline disease risk category
(i.e., stratum), this model assumes a common mean across treatment groups at baseline and a 
different mean for each treatment at each of the post-baseline time points. In this model, the 
response vector consists of baseline and the values (percent change) observed at each post-
baseline time point. Time is treated as a categorical variable so that no restriction is imposed 
on the trajectory of the means over time. The analysis model will adjust for time and the 
interaction of time by treatment, and time by baseline disease risk category given in Section 
4.1. The treatment difference in terms of mean change from baseline to Week 12 will be 
estimated and tested from this model. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the stratum-specific baseline means are constrained to be the same for 
different treatment groups. Of note, in the event that there are no missing data, the estimated 
treatment difference from the above cLDA model will be identical to that from a traditional 
longitudinal ANCOVA model which uses the baseline value as a covariate. However, unlike 
longitudinal ANCOVA, the cLDA model accounts for variability in the baseline values, thus 
providing more accurate standard errors and confidence intervals for individual treatment 
effects. Moreover, this model allows the inclusion of participants who are missing either the 
baseline or post-baseline measurements, thereby increasing efficiency. Details of the model 
specification, assumptions, and SAS implementation codes will be provided in the sSAP.
The cLDA method assumes that the mechanism for missing data is missing at random 
(MAR). Sensitivity analyses will be performed to assess the robustness of the conclusions 
from the cLDA analyses to departures from MAR. The details will be described in sSAP.
The percentage of participants reaching the LDL-C goals will be analyzed via a logistic 
regression model with LDL-C goal achievement rate as response variable and treatment and 
baseline disease risk category given in Section 4.1 as explanatory variables. Odds ratio 
estimate derived from the logistic regression model and 95% CI will be used to quantify the 
treatment effect. Imputation of missing data will be based on the marginal univariate normal 
distributions with means equal to the predicted values and variances equal to the squared 
standard errors for the predicted values from the cLDA model. Ten sets of imputations of 
each missing value will be constructed from the cLDA model. Odds ratio estimate derived 
from the logistic regression model and 95% confidence interval will be used to quantify the 
treatment effect. Other exploratory endpoints will be evaluated using the same cLDA model, 
but TG will be transformed by the natural logarithm on account of the non-normality of this 
endpoint. Geometric mean percent changes from baseline in TG will be calculated based on 
back-transformation via exponentiation of the model-based LS means and expressed as 
(geometric mean – 1) multiplied by 100. The treatment differences in geometric mean 
percent changes from baseline will be calculated based on the difference in the back 
transformed model-based LS means and 95% confidence intervals (CIs) for the differences 
will be calculated using the delta method [Wong, P., et al 1999]. Key efficacy analysis is 
summarized in Table 6.
 
 
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Table 6
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Hypotheses
Percent change from baseline in LDL-C at 
Week 12
cLDA†
FAS
Model-based
†
Constrained LDA model with terms for treatment, time, the interaction of time by treatment and time by 
baseline disease risk category.
9.6.2
Statistical Methods for Safety Analyses
All safety summaries and analyses will consider the cohorts separately (i.e., treatment groups 
will not be pooled across cohorts).  
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests and vital signs.
The analysis of safety results will follow a tiered approach (Table 7). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse events of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be participant 
to inferential testing for statistical significance with p values and 95% confidence intervals 
provided for between-group comparisons. Nominal p-values will be provided without any 
adjustments to account for multiple comparisons. Other safety parameters will be considered 
Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters.
Adverse events (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory test and vital signs parameters that are not pre-specified as Tier-1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of 
events observed. Membership in Tier 2 requires that at least 4 participants in any treatment 
group exhibit the event; all other adverse events and predefined limits of change will belong 
to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse events and 
predefined limits of change.
 
 
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Continuous measures such as changes from baseline in laboratory test and vital signs 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters. 
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.  
For this protocol, the specific Tier 1 adverse events are listed in Table 7. In addition, 
summary measures of AEs consisting of the percentage of participants with any AE, a drug 
related AE, a serious AE, an AE which is both drug-related and serious, and who 
discontinued due to an AE, who discontinued due to a drug-related AE, who discontinued 
due to a serious AE and who discontinued due to a drug-related and serious AE will be
considered Tier 2 endpoints. P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and 
Tier 2) will be provided for between-treatment differences in the percentage of participants 
with events; these analyses will be performed using the Miettinen and Nurminen method 
(1985), an unconditional, asymptotic method [Miettinen, Olli and Nurminen, Markku 1985].
 
 
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Table 7
Analysis Strategy for Safety Parameters
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant characteristic will be assessed 
observationally; no statistical hypothesis tests will be performed on these characteristics. The 
number and percentage of participants screened, the primary reasons for screening failure,
and the primary reason for discontinuation will be displayed. Demographic variables and 
baseline characteristics will be summarized by treatment group either by descriptive statistics
or categorical tables.
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Hepatitis-related AEs 
X
X
X
Consecutive elevations in ALT ≥3xULN 
X
X
X
Consecutive elevations in AST ≥3xULN 
X
X
X
Consecutive elevations in ALT ≥3xULN or
X
X
X
consecutive elevations in AST≥3xULN
ALT elevation ≥5xULN 
X
X
X
AST elevation ≥5xULN 
X
X
X
ALT elevation ≥5xULN or AST elevation
≥5xULN
X
X
X
Potential Hy's Law Condition (ALT or AST 
elevations >3xULN, with ALP <2xULN and 
TBL ≥2xULN)
X
X
X
Elevations in CK ≥5xULN with muscle 
symptoms
X
X
X
Elevations in CK ≥10xULN 
X
X
X
Elevations in CK ≥10xULN with muscle 
symptoms
X
X
X
Elevations in CK ≥10xULN with muscle
symptoms that are considered drug-related
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
Discontinuation due to drug-related AE 
X
X
X
X
Discontinuation due to serious AE 
X
X
Discontinuation due to serious and drug-related
X
X
Specific AEs, SOCs (incidence ≥4 of 
participants in all of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of 
participants in all of the treatment groups)
X
Change from baseline in laboratory tests and
vital signs
X
SOC=System Organ Class; X = results will be provided.
 
 
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9.7
Interim Analyses
No interim analyses are planned for this trial.
9.8
Multiplicity
The Type-I error rate over the two primary hypotheses will be controlled by the Hochberg 
procedure [Benjamini, Y. and Hochberg, Y. 1995]. The overall success is determined by a 
success of at least one hypothesis.
If the one-sided p-values for both primary hypothesis tests are < 0.025, then both tests will be 
declared successful. Otherwise, if the smaller of the p-values is <0.0125, then only the 
hypothesis test associated with the smaller p-value will be declared successful.
9.9
Sample Size and Power Calculations
A total of approximately 450 participants (180 in Cohort A, 270 in Cohort B) will be 
randomized. The power computation has been performed conservatively based on the 
number of participants expected to have LDL-C data at Week 12. Assuming a drop-out rate 
of 10%, 162 participants (81 per arm) in Cohort A and 242 participants (121 per arm) in 
Cohort B will be available for the power calculation. The sample in Cohort A has a 93% 
power to demonstrate the superiority of MK-0653C 10/10 mg over atorvastatin 20 mg at a 
one-sided 2.5% alpha-level. The half-width of the 95% confidence interval for the between-
treatment difference is expected to be 7.0%. Similarly, the sample in Cohort B has a 95% 
power to demonstrate the superiority of MK-0653C 10/20 mg over atorvastatin 40 mg at a 
one-sided 2.5% alpha-level. The half-width of the 95% confidence interval for the between-
treatment difference is is expected to be 5.7%. The overall power to success on at least one 
hypothesis is 99% at a 2.5% alpha-level with 88% power to succeed for both hypotheses. If 
only one hypothesis is successful according to Hochberg procedure, the sample in Cohort A 
will result in a power of 88% and the sample in Cohort B will result in a power of 91% at 
1.25% alpha-level. The power and sample sizes are based on the following assumptions: the 
treatment difference in percent changes from baseline in LDL-C at Week 12 are 12.3% and 
10.5%, and unconditional standard deviations are 22% and 23% for Cohorts A and B, 
respectively, according to P162 results from the ANCOVA model.  
The safety power table displays a range of AE rates and the possible difference that can be 
detected with the sample size of the study at 90% and 80% power is shown in Table 8. All 
calculations are based on 2-sided α=0.05 significance level.
 
 
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Table 8
Safety Power Calculation
AE rate in 
Atorvastatin 20 
mg or 40 mg 
Group
Percentage Point Difference in Cohort A
(MK-0653C 10/10 mg- Atorvastatin 20 mg)
Power of 80% (90%)
Percentage Point Difference in Cohort B
(MK-0653C 10/20 mg- Atorvastatin 40 mg)
Power of 80% (90%)
1%
10.3 (12.2)
8.2 (10.0)
2%
11.4 (13.5)
9.2 (11.1)
3%
12.3 (14.6)
9.9 (11.9)
AE = adverse event
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated within each category of the following classification variables:
•
Age category (< 65, ≥65 years)
•
Gender (male, female)
•
Baseline LDL-C (≤ or > median)
•
Disease risk Category based on LDL-C (as in Section 4.1)
9.11
Compliance (Medication Adherence)
As part of the routine recording of the amount of study treatment taken by each participant, 
the number of tablets remaining in trial packaging will be counted, reviewed, and recorded at 
regular intervals. These results will be used to calculate participant compliance.
A day within the trial will be considered an “On-Therapy” day if the participant in Cohort A 
takes two tablets OR the participant in Cohort B takes three tablets every day: 1 (for Cohort 
A) or 2 (for Cohort B) tablets from the bottle and 1 tablet from the blister, as described in 
Section 8.1.8.
For each participant, percent compliance will then be calculated using the following formula:
Compliance (%) =
Number of days on therapy
x100.
Number of days in the double-blind treatment period
 
 
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The “Number of days in the double-blind treatment period” is the total number of days from 
the first dose of study medication to the last dose of study medication.
Summary statistics will be provided on percent compliance by treatment group for the FAS 
population.
9.12
Extent of Exposure
The Extent of Exposure to study treatment will be evaluated by summary statistics for the 
“Number of Days on Therapy” by treatment group.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) 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 (eg, 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 (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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 to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
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 fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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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 (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly 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
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.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to 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
Not applicable for this study.
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.
 
 
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 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 Studies.
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. 
 
 
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Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, 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.
 
 
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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 will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests with marker of * listed in Table 9 will be performed by the local laboratory at 
Visit 1.
•
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 9
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology*
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry*
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
elevated above the upper 
limit of normal)
Albumin
CK (CPK)
Chloride
eGFR
Creatinine
Sodium
Calcium
Potassium
Phosphorous
Bicarbonate
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (fasting)
Uric acid
Alkaline 
phosphatase (ALP)
γ-glutamyl transferase
Lipid Panel A*
LDL-C
HDL-C
non-HDL-C
total cholesterol 
(TC)
Triglyceride (TG)
Routine 
Urinalysis*
Specific gravity
pH, glucose, protein, blood, ketones, 
[bilirubin, urobilinogen, nitrite, 
leukocyte esterase] by dipstick
Microscopic examination (if 
blood or protein is 
abnormal)
Apolipoprotein 
Evaluations
•
Apolipoprotein B (Apo B)
Pregnancy test
•
Urine pregnancy test (urine hCG) will be determined at the site (as needed for 
WOCBP).
•
Serum β-hCG test will be required if urine pregnancy result is positive.
Other 
Laboratory
Tests
•
Follicle-stimulating hormone (FSH): only applicable for perimenopausal women.
•
Thyroid stimulating hormone (TSH), fT4
 
 
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Laboratory 
Assessments
Parameters
NOTES:
* Laboratory tests results received within 4 weeks prior to screening visit is acceptable as screening test to 
check the eligibility.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
All lipid evaluations results will be blinded to participants and to study team once the 
participant is centrally randomized. No attempts could be made to have local evaluation of 
the participant’s lipid levels once they have successfully entered the double blind treatment 
phase. The investigator will not be blinded to laboratory safety results. Emergency treatment 
code breaks should only be undertaken when it is essential to treat the participant safely and 
efficaciously. Most often, study drug discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study participant who presents with an 
emergency condition. In case that emergency unblinding is required, investigator should start 
the processed after consultation and discussion with sponsor.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
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.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
 
 
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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
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
•
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
 
 
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
 
 
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ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
 
 
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(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).
 
 
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the 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
Contraception Requirements
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
Intrauterine hormone-releasing system (IUS)c,d
•
Intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
1.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
2.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation.
a)
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, sympothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. This test should be repeated a maximum of 
24 hours before the first dose.
Following initiation of treatment, pregnancy testing will be performed at scheduled visits
during the treatment period, and as required locally.
Additional pregnancy testing will be performed whenever an expected menstrual cycle is 
missed or when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
 
 
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10.7
Appendix 7: Country-specific Requirements
2016 Chinese guidelines for the management of dyslipidemia in adults
Joint committee for guideline revision
National Expert Committee on Cardiovascular Diseases, National Center for Cardiovascular Diseases
Chinese Society of Cardiology, Chinese Medical Association
Chinese Diabetes Society, Chinese Medical Association
Chinese Society of Endocrinology, Chinese Medical Association
Chinese Society of laboratory Medicine, Chinese Medical Association
Writing group members
Group leader: 
Main authors: 
Members: Listed in Supplement 3
Academic secretary: 
J Geriatr Cardiol 2018; 15: 1-29. doi:10.11909/j.issn.1671-5411.2018.01.011
Keywords: Adults; Chinese guidelines; Dyslipidemia
Abbreviations
ACS: acute coronary syndrome
IDL: intermediate-density lipoprotein
ALT: alanine aminotransferase
LDL-C: low-density lipoprotein 
cholesterol
Apo: apolipoprotein
LP: lipoprotein
ASCVD: atherosclerotic cardiovascular disease
Lp (a): lipoprotein(a)
LPL: lipoprotein lipase
AST: aspartate aminotransferase
Ox-LDL: oxidized low-density 
lipoprotein
BMI: body mass index
PCI: percutaneous coronary intervention
CKD: chronic kidney disease
CM: chylomicron
PCSK: proprotein convertase 
subtilisin/Kexin
ESDR: end-stage renal disease
FDA: Food and Drug Administration
PPARα: peroxisome proliferator 
activated receptor α
FH: familial hypercholesterolemia
sLDL: small and low density lipoprotein
GFR: glomerular filtration rate
TC: total cholesterol
HDL-C: high-density lipoprotein cholesterol
TG: triglyceride
 
 
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HeFH: heterozygous familial 
hypercholesterolemia
TIA: transient ischemic attack
TLC: therapeutic lifestyle changes
HMG-CoA: 3-hydroxy-3-methylglutaryl-
coenzyme A
VLDL-C: very-low-density lipoprotein 
cholesterol
HoFH: homozygous familial 
hypercholesterolemia
Table of contents
1 Introduction
9.3 Quit smoking
2 Blood lipids and lipoproteins
9.4 Limit drinking
2.1 Chylomicrons
10 Lipid-lowering drug treatments
2.2 VLDL
10.1 Major cholesterol-lowering drugs
2.3 LDL-C
10.2 Major triglyceride-lowering drugs
2.4 HDL-C
10.3 New types of lipid-lowering drugs
2.5 Lp (a)
10.4 Combined application of lipid-
2.6 Non-high-density lipoprotein-cholesterol
lowering drugs
3 Blood lipid test items
11 Other measures for dyslipidemia 
3.1 TC
treatment
3.2 TG
11.1 Lipoprotein-plasma exchange
3.3 LDL-C
11.2 Liver transplantation and other 
3.4 HDL-C
surgical treatments
3.5 Apo A1
12 Management of dyslipidemia in 
4 Appropriate levels and abnormal cutoff points
special populations
5 Classification of dyslipidemia
12.1 Diabetes
5.1 Etiological classification of dyslipidemia
12.2 Hypertension
5.2 Clinical classification of dyslipidemia
12.3 Metabolic syndrome
6 Screening of dyslipidemia
12.4 Chronic kidney diseases
7 Overall cardiovascular risk assessment
12.5 Familial hypercholesterolemia
8 Principles of treatment of dyslipidemia
12.6 Stroke
8.1 Lipid-lowering therapy targets
12.7 Elderly people
8.2 Setting lipid-lowering target values
References
8.3 Standard lipid-lowering values
Supplements
 
 
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8.4 Goal attainment strategies for lipid-
Supplement 1 Recommendations for 
lowering
clinical determination of 
8.5 Other interventions for dyslipidemia
blood lipids.
8.6 Lifestyle intervention
Supplement 2 The color figure of risk 
8.7 Monitoring treatment process
stratification of
9 Therapeutic lifestyle changes
atherosclerotic
9.1 Body weight control
cardiovascular disease.
9.2 Physical activity
Supplement 3 Writing group members
1
Introduction
Over the last 30 years, the blood lipid level in the Chinese population has gradually 
increased, and the incidence of dyslipidemia has significantly increased. A nationwide survey 
in 2012 showed that the average serum total cholesterol (TC) value in adults was 4.50 
mmol/L and that the prevalence of hypercholesterolemia was 4.9%; the average value of 
triglyceride (TG) was 1.38 mmol/L, and the prevalence of hypertriglyceridemia was 13.1%; 
the average value of high-density lipoprotein cholesterol (HDL-C) was 1.19 mmol/L, and the 
prevalence of HDL-C hypolipidemia was 33.9%.[1] The overall prevalence of dyslipidemia 
among Chinese adults reached 40.4%, which has substantially increased since 2002. The 
increase of serum cholesterol level in the population will increase by approximately 9.2 
million cases of cardiovascular events in China between 2010 and 2030.[2] The prevalence of 
hypercholesterolemia among Chinese children and adolescents is also significantly 
increasing,[3] suggesting that the development of dyslipidemia and the relevant disease 
burdens in Chinese adults will continue to increase.
Dyslipidemia characterized by the increase of low-density lipoprotein cholesterol (LDL-C) or 
TC is an important risk factor for atherosclerotic cardiovascular diseases. The reduction of 
LDL-C levels can significantly decrease the development and mortality risks of 
atherosclerotic cardiovascular diseases.[4] Other types of dyslipidemia (e.g., increases of TG 
or decreases of HDL-C) are also correlated with the increase of developing atherosclerotic 
cardiovascular diseases.[5–7]
The effective control of dyslipidemia has important significance for the management of 
atherosclerotic cardiovascular diseases in China. Encouraging people to adopt a healthy 
lifestyle is the basic strategy for managing dyslipidemia and atherosclerotic cardiovascular 
diseases. The focus of dyslipidemia management is to increase the awareness, treatment, and 
control rates of dyslipidemia. Although the awareness and treatment rates of Chinese adult 
dyslipidemia patients have increased over recent years,[8] they remain at low levels. 
Therefore, the management work of dyslipidemia urgently needs to be strengthened.
 
 
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In 2007, a joint committee of multidisciplinary experts together formulated the “Chinese 
Guidelines for the Management of Dyslipidemia in Adults” (referred to as "Guidelines" 
hereafter). Based on the full adoption of epidemiological and clinical study results from the 
Chinese population and combined with international study results and guideline 
recommendations, the “Guidelines” proposed recommendations that were more appropriate 
for the management of dyslipidemia in the Chinese population. These recommendations had 
important guiding functions for the management of dyslipidemia in China. [9]
Since 2007, more clinical study results have further validated the effectiveness and safety of 
cholesterol-lowering treatments on the primary and secondary prevention of atherosclerotic 
cardiovascular diseases. Many international academic institutions successively updated or 
formulated new management guidelines for dyslipidemia. During this period, studies in the 
clinical blood lipid field in China made significant progress. Prospective cohort studies on 
the Chinese population obtained new 20-year follow-up data. Based on the 10-year overall 
risk assessment program recommended by the 2007 Guidelines, the lifetime risk assessment 
program was proposed.[10]
In November 2013, supported by the Department of Diseases Control of the National Health 
and Family Planning Commission of the People’s Republic of China (NHFPC), the National 
Expert Committee on Cardiovascular Diseases of the National Center for Cardiovascular 
Diseases, the Chinese Society of Cardiology of Chinese Medical Association, the Chinese 
Diabetes Society of the Chinese Medical Association, the Chinese Society of Endocrinology 
of the Chinese Medical Association, and the Chinese Society of Laboratory Medicine of the 
Chinese Medical Association formed a joint committee to revise the blood lipid guidelines. 
These committee members extensively collected core issues to be addressed by the new 
guidelines. After discussion, 17 core issues across 4 aspects (the overall principle of 
guideline revisions, the overall cardiovascular risk assessment, the goals of lipid-lowering 
treatment, and lipidlowering treatments for special populations) were eventually confirmed. 
The guideline-revision working group targeted these core issues to formulate specific 
literature retrieval and evaluation strategies as well as comprehensively evaluate and screen 
the relevant literature. The literature retrieval databases included the Chinese Biomedicine 
Literature Database (CBM), Wanfang Data Knowledge Service Platform, China National 
Knowledge Infrastructure (CKNI), the American Biomedical Literature Database (PubMed), 
and the Dutch Excerpta Medica database (EMBASE). In addition, new data from long-term 
cohort studies in China were used to conduct targeted analyses. The recommendations and 
suggestions proposed by the revised guidelines were developed after repeated discussion 
among multidisciplinary experts based on a systemic assessment. When the expert opinions 
disagreed, the consensus of the majority of experts was accepted based on a full 
consideration of the different opinions.
The guideline revision referenced the standard procedures developed by the World Health 
Organization (WHO) and the Chinese Medical Association’s clinical guidelines.[11] During 
the process of guideline revision, the National Center for Cardiovascular Diseases raised 
funds to avoid conflicts of interest with vendors.
 
 
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The definitions of the recommendation classifications in the “Guidelines” reference the 
definitions in the relevant European and American blood lipid guidelines.[12,13] The specific 
descriptions are shown below:
Class I: Manipulations or treatments that have been confirmed confirmed/unanimously 
recognized as beneficial, useful, and effective are recommended.
Class II: Manipulations or treatments that still have contradictions or different opinions 
according to useful/effective evidence.
Class IIa: Relevant evidence/opinions tend to be useful/effective. The application of these 
manipulations or treatments is reasonable.
Class IIb: Relevant evidence/opinions cannot be fully confirmed as useful/effective. Its 
application can be considered.
Class III: It has been confirmed/consistently recognized as useless/ineffective and 
manipulations or treatments might be harmful in some cases. Its application is not 
recommended.
The definitions of the level of evidence in the “Guidelines” are described below:
Evidence level A: Evidence based on many randomized clinical trials or meta-analyses.
Evidence level B: Evidence based on single randomized clinical trials or many non-
randomized controlled studies.
Evidence level C: Only expert consensus opinion or based on the results of small-scale 
studies, retrospective studies, or registry studies.
2
Blood lipids and lipoproteins
Highlights: Blood lipids are the collective term for cholesterol, TG, and lipoids (e.g., 
phospholipids) in the serum. Blood lipids that have a close clinical association are primarily 
cholesterol and TG. Cholesterol in the human body primarily exists in the forms of free 
cholesterol and cholesteryl ester. TG is formed by the fatty acid esterification of the three 
hydroxyl groups in the glycerol molecule. Blood lipids are insoluble in water, and they can 
be dissolved in water after binding to special proteins, lipoproteins (Apo), to form 
lipoproteins that are transferred to tissues to be metabolized. Lipoproteins are classified as 
CM, VLDL, IDL, LDL, HDL, and Lp (a).
Blood lipids are the collective term for cholesterol, TG, and lipoids (e.g., phospholipids) in 
serum. Blood lipids that have close clinical association are primarily cholesterol and TG. The 
blood lipids that have a close clinical association are primarily cholesterol and TG. 
Cholesterol in the human body primarily exists in the forms of free cholesterol and 
cholesteryl ester. TG is formed by the fatty acid esterification of the three hydroxyl groups in 
the glycerol molecule. Blood lipids are insoluble in water, but they can be dissolved in water 
 
 
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after binding to special proteins, apolipoproteins (Apo), to form lipoproteins that are 
transferred to tissues to be metabolized.
Lipoproteins are classified as chylomicrons (CM), verylow-density lipoprotein (VLDL), 
intermediate-density lipoprotein (IDL), LDL-C, and HDL-C. One type of lipoprotein is 
known as lipoprotein (a) (Lp[a]). The physical properties, main components, sources, and 
functions of lipoproteins are listed in Table 10.[14,15]
 
 
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Table 10
The Characteristics and Functions of Lipoproteins
Classifi
-cation
Hydration 
density, g/mL
Particle 
diameter, 
nm
Main 
component
Major 
apolipoproteins
Sources
Functions
CM
< 0.950
80-500
TG
B48, A1, A2
Synthesis 
in small 
intestine
Transfers TG and 
cholesterol in food from 
small intestine to other 
tissues
VLDL
0.950-1.006
30-80
TG
B100, E, Cs
Synthesis 
in liver
Transfers endogenous 
TG to the peripheral 
tissues to release free 
fatty acids after lipase 
hydrolysis
IDL
1.006-1.019
27-30
TG, 
cholesterol
B100, E
Formed 
after lipase 
hydrolysis 
of TG in 
VLDL
Belongs to the LDL-C 
precursor; some are 
metabolized in liver
LDL-C
1.019-1.063
20-27
Cholesterol
B100
Formed 
after lipase 
hydrolysis 
of TG in 
VLDL and 
IDL
The major carrier of 
cholesterol, taken-up 
(mediated by LDL-C 
receptors) and used by 
the peripheral tissues. 
Directly associated with 
ASCVD
HDL-C
1.063-1.210
8-10
Phospho-
lipid, 
cholesterol
A1, A2, Cs
Primarily 
synthesized 
by liver 
and small 
intestine
Promotes the removal 
of cholesterol from the 
peripheral tissues. 
Transfers cholesterol to 
liver or other tissues for 
re-distribution. HDL-C 
is negatively correlated 
with ASCVD
Lp(a)
1.055-1.085
26
Cholesterol
B100, (a)
Complex 
formed by 
lipoprotein 
(a) and 
LDL-C 
through
disulfide 
bonds in 
liver
Might be associated 
with ASCVD
ASCVD: atherosclerotic cardiovascular disease; CM: chylomicron; HDL-C: high-density lipoprotein 
cholesterol; IDL: intermediate-density lipoprotein; LDL-C: low-density lipoprotein cholesterol; Lp (a): 
lipoprotein(a); TG: triglyceride; VLDL: very-low-density lipoprotein cholesterol.
 
 
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2.1 CM
CM is the largest lipoprotein particle in the blood. The major component is TG, which 
accounts for approximately 90% of CM. The density is low. Blood collected after healthy 
individuals fast for 12 h shows that no CM exists in serum. After a meal or under certain 
pathological conditions when the blood contains a large amount of CM, the appearance of the 
blood shows a white turbidity. When the serum tube is stored at 4°C overnight, CM will float 
to the upper layer of the serum to aggregate, and the shape is like butter. This simple method 
is used to examine the presence of CM.
2.2 VLDL
VLDL is synthesized by the liver. Its TG content accounts for approximately 55% of its 
mass. VLDL and CM are collectively termed as “TG-rich lipoproteins”. In serum without the
presence of CM, the TG concentration can reflect the amount of VLDL. Because the VLDL 
molecule is smaller than CM, the serum after fasting for 12 h is clear and transparent. When 
the TG level in fasting serum is > 3.4 mmol/L (300 mg/dL), the serum will exhibit emulsion 
luster until it becomes turbid.
2.3 LDL-C
LDL-C is converted from VLDL and IDL (of which TG forms LDL-C after lipase 
hydrolysis). The LDL-C particle contains approximately 50% cholesterol, and it is the 
lipoprotein in blood with the highest cholesterol content; therefore, it is called a “cholesterol-
rich” lipoprotein. In simple hypercholesterolemia, the increase of the cholesterol 
concentration parallels the serum LDL-C level. Because LDL-C particles are small even 
when the concentration of LDL-C is high, the serum will not become turbid. More than 95% 
of the Apo in LDL-C is Apo B100. Based on particle size and different density levels, LDL-
C can be divided into different sub-components. LDL-C transfers cholesterol to the 
peripheral tissues. Most LDL-C is catabolized by hepatocytes and extrahepatic LDL-C 
receptors.
2.4 HDL-C
HDL-C is primarily synthesized by the liver and small intestine. HDL-C is the smallest 
particle lipoprotein. Lipid and protein portions almost account for half of the mass. The Apo 
in HDL-C is primarily Apo A1. HDL-C represents a group of heterogeneous lipoprotein 
because the quantity and quality of lipids, Apo, enzymes, and lipid transfer proteins in HDL-
C particles are different. Using different separation methods, HDL-C can be divided into 
different sub-components. These HDL-C sub-components have different shapes, densities, 
particle sizes, electric charges, and anti-atherosclerotic characteristics. HDL-C transfers 
cholesterol from the peripheral tissues (including atherosclerotic plaques) to the liver for 
recycling or excretion in the form of cholic acid. This process is called “reverse cholesterol 
transport”.
 
 
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2.5 Lp (a)
Lp (a) represents a group of special lipoprotein discovered using immunization methods. The 
lipid components of Lp (a) are similar to those of LDL-C. In addition to one molecule of Apo 
B100, however, its Apo fraction also contains one molecule of Apo (a). Little is known about 
the exact mechanisms of Lp (a) synthesis and catabolism.
2.6 Non-HDL-C
Non-HDL-C refers to the sum of cholesterol in other lipoproteins except for HDL-C. The 
calculation formula is non-HDL-C = TC - HDL-C. As a secondary target of lipidlowering 
treatment during the management of atherosclerotic cardiovascular disease (ASCVD) and the 
high-risk population, non-HDL-C is applicable for individuals with LDL-C levels that are not 
high or have already reached the treatment goal when the TG level is 2.3-5.6 mmol/L (200-
500 mg/dL). International blood lipid guidelines recommend using non-HDL-C as the marker 
for the primary and secondary prevention of ASCVD.[16]
3
Blood lipid examination
Highlights: The basic items in clinical blood lipid examination are TC, TG, LDL-C, and 
HDL-C. The clinical application values of other blood lipid items (e.g., Apo A1, Apo B, and 
Lp [a]) have also received increasing attention.
The basic items in clinical blood lipid detection are TC, TG, LDL-C, and HDL-C. The 
clinical application values of other blood lipid items (e.g., Apo A1, Apo B, and Lp [a]) have 
also received increasing attention.[17]
3.1 TC
TC refers to the total amount of cholesterol in the various lipids in the blood. The major 
factors affecting the TC level include the following:
(1) Age and gender. TC levels usually increase with age; however, it no longer increases or 
decreases after 70 years old. The level of TC in young and middle-aged women is lower than 
that in men. The TC level in women after menopause is higher than that in age-matched men.
(2) Eating habits. Long-term high cholesterol and highsaturated fatty acid intake can increase 
TC.
(3) Genetic factors. Mutations in lipoprotein metabolismrelated enzymes or receptor genes 
are the major causes of significant increases in TC.
The risk assessment and prediction values of TC on ASCVD are not as accurate as those of 
LDL-C. The calculation of non-HDL-C and VLDL-C should detect TC.
 
 
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3.2 TG
TG level is affected by the effects of genetic and environmental factors and is associated with 
race, age, gender, and living habits (e.g., diet and exercise). Unlike TC, TG shows large 
variations within and between individuals. The TG level in the same individual is influenced 
by factors such as diet and different time points. Therefore, when the same individual 
receives multiple detections, the TG values might have significant differences. The serum TG 
levels in the population show an obvious positive skew.
Mild-to-moderate increases in TG usually reflect increases in VLDL and its remnant particles 
(VLDL with smaller particles). These remnant lipoproteins might directly cause 
atherosclerosis because the particles become smaller. However, most studies suggest that the 
increase of TG causes atherosclerosis through the influence of the structures of LDL-C or 
HDL-C. Survey data indicate that people with mild-to-moderate increases in serum TG levels 
are at increased risk for the development of coronary heart disease.[18] Severely increased TG 
is usually accompanied by acute pancreatitis.
3.3 LDL-C
Cholesterol accounts for approximately 50% of LDL-C. Therefore, the LDL-C concentration 
basically reflects the total amount of LDL-C in the blood. The factors that affect TC can also 
affect the LDL-C level. The increase of LDL-C is a major risk factor for the initiation and 
progression of atherosclerosis.[12,16] LDL-C enters into the vascular wall through the vascular 
endothelia. LDL-C retained in the subcutaneous layer is modified into oxidized-LDL (Ox-
LDL). After being phagocytized by macrophages, Ox-LDL forms a foam cell; the latter 
continues to increase and fuse to become the lipid core of atherosclerotic plaques. Although 
the pathology of atherosclerosis exhibits chronic inflammatory reaction features, LDL-C 
might be the basic element for the initiation and maintenance of this chronic inflammatory 
reaction. Under general conditions, LDL-C parallels TC; however, the TC level is also 
influenced by the HDL-C level. Therefore, it is better to use LDL-C as the assessment 
indicator for the risk of ASCVD.
3.4 HDL-C
HDL-C can transport cholesterol in peripheral tissues such as the vascular wall to the liver 
for catabolism (i.e., reverse cholesterol transport). HDL-C can reduce cholesterol deposition 
in the vascular wall to as an anti-atherosclerosis function. Because the cholesterol content in 
HDL-C is stable, its current cholesterol content is primarily measured to indirectly 
understand HDL-C levels in the blood.
Genetic factors also significantly influence the level of HDL-C. With the significant 
reduction of serum TC, people with severe malnutrition have decreased HDL-C. The HDL-C
levels of obese people are also lower. Smoking can reduce HDL-C. Diseases such as 
diabetes, hepatitis, and cirrhosis can be accompanied by low HDL-C; however, exercise and 
a small amount of alcohol increase HDL-C. Much epidemiological data indicate that serum 
HDL-C levels are negatively correlated with the incidence of ASCVD.[19]
 
 
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3.5 Apo A1
The Apo A1 levels in the normal population are primarilywithin the range of 1.2-1.6 g/L. The 
levels in women are slightly higher than those in men. The protein component of HDL-C 
particles (i.e., apolipoprotein) accounts for approximately
50% of its mass. In proteins, Apo A1 accounts for approximately 65%-75%, whereas little 
Apo A1 is present in other lipoproteins. Therefore, serum Apo A1 reflects the HDL-C level. 
It is positively correlated with HDL-C levels and has a similar clinical significance.
3.6 Apo B
The Apo B levels in the healthy population are primarily within the range of 0.8-1.1 g/L. 
Under normal conditions, LDL-C, IDL, VLDL, and Lp (a) particles have one molecule of 
Apo B. Because LDL-C particles account for the majority of these molecules, approximately 
90% Apo B is distributed in LDL-C. There are two types of Apo B: Apo B48 and Apo B100. 
The former is primarily present in CM, whereas the latter is primarily present in LDL-C. 
Except for special instances, the Apo B routinely measured in clinics usually refers to Apo 
B100.
Serum Apo B primarily reflects the LDL-C level and is positively correlated with the serum 
LDL-C level. These two types have a similar clinical significance. In a few cases, Apo B 
hyperlipidemia and normal LDL-C concentrations can occur, suggesting the presence of 
increased small and dense LDL (sLDL) in the blood. During hypertriglyceridemia (high 
VLDL), sLDL (LDL pattern B) increases. However, compared with large and light LDL 
(LDL pattern A), sLDL particles have a high Apo B content and less cholesterol; therefore, 
this condition when LDL-C is not high but serum Apo B increases is called “Apo B 
hyperlipidemia”. This situation reflects the increase of LDL pattern B. Therefore, the 
measurement of ApoB and LDL-C together can help clinical diagnoses.
3.7 Lp (a)
Serum Lp (a) concentration is primarily associated with genetics. Gender, age, body weight, 
and most cholesterollowering drugs do not often affect this concentration. The Lp (a) level in 
the healthy population shows an obvious skew. Although the level in individuals can reach 
above 1,000 mg/L, the level in 80% healthy individuals is less than 200 mg/L. Usually, 300 
mg/L is used as the cutoff point. People with levels higher than this cutoff are at a 
significantly increased risk for coronary heart disease, suggesting that Lp (a) causes 
atherosclerosis. However, clinical evidence is lacking.[20] Furthermore, an increase of Lp (a) 
can also be observed during various acute phase responses, nephrotic syndrome, diabetic 
nephropathy, pregnancy, and the administration of growth hormone. After all types of stress 
increase are excluded, Lp (a) is considered as an independent risk factor for ASCVD.
The expression unit of the values of all blood lipid measurement items is mmol/L according 
to the national standard of China. Some other countries use mg/dL. The conversion 
coefficients are: TC, HDL-C, LDL-C: 1 mg/dL = 0.0259 mmol/L; and TG: 1 mg/dL = 0.0113 
mmol/L.
 
 
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4
Appropriate levels and abnormal cutoff points
Highlights: The appropriate levels and abnormal cutoff points of blood lipids are primarily 
applicable for the target population regarding the primary prevention of ASCVD.
The major hazard of dyslipidemia is the increase of the risk for developing ASCVD. The 
“Guidelines” recommend the appropriate levels and abnormal cutoff points for the blood 
lipid components in the Chinese population (Table 11) based on the results of many long-
term observatory studies concerning the risk of developing ASCVD in Chinese populations 
with different blood lipid levels, including the independent influence of different blood lipid 
levels with regard to the cumulative risk for developing ASCVD in the study populations in 
10 and 20 years. In addition, the recommendations and the references for the appropriate 
levels of blood lipid components in the many blood-lipid-related guidelines worldwide are 
referenced.[12,16,21,22] Importantly, these appropriate levels and abnormal cutoff points of 
blood lipids are primarily applicable for the target population regarding the primary 
prevention of ASCVD.
Table 11
The Appropriate Levels and Abnormal Stratified Standards of Blood Lipids for 
the Primary Prevention Population of ASCVD in China [mmol/L (mg/dL)]
TC
LDL-C
HDL-C
Non-HDL
TG
Ideal level
< 2.6 (100)
< 3.4 (130)
Appropriate level
< 5.2 (200 )
< 3.4 (130)
< 4.1 (160)
< 1.7 (150)
Marginal increase
≥5.2 (200) and < 
6.2 (240)
≥3.4 (130) and 
< 4.1 (160)
≥4.1 (160) and < 
4.9 (190)
≥1.7(150) and < 
2.3 (200)
Increase
≥6.2 (240)
≥4.1 (160)
≥4.9 (190)
≥2.3 (200)
Decrease
< 1.0 (40)
ASCVD: atherosclerotic cardiovascular disease; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-
density lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride.
5
Classification of dyslipidemia
Highlights: The classification of dyslipidemia is complicated. The simplest methods include 
etiological classification and clinical classification, and the latter is the most practical.
Dyslipidemia usually refers to increases in cholesterol, TG, or both levels in serum. This 
condition is generally called hyperlipidemia. In fact, dyslipidemia also extensively refers to 
various blood lipid abnormalities, including HDL-C hypolipidemia. The classification is 
complicated. The simplest classifications include the etiological classification and clinical 
classification, and the latter is the most practical.[16,23,24]
 
 
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5.1 Etiological classification of dyslipidemia
5.1.1
Secondary hyperlipidemia
Secondary hyperlipidemia refers to dyslipidemia caused by other diseases. The diseases that 
can induce dyslipidemia primarily include obesity, diabetes, nephrotic syndrome, 
hypothyroidism, renal failure, liver disease, systemic lupus erythematosus, glycogen storage 
disease, myeloma, lipoatrophy, acute porphyria, and polycystic ovary syndrome. In addition, 
some drugs such as diuretics, non-cardiac selective β-blockers, and glucocorticoids can also 
induce secondary dyslipidemia.
5.1.2
Primary hyperlipidemia
In addition to the association between unhealthy lifestyles (e.g., high energy, high fat, and 
high sugar diet; excessive drinking; and others) and dyslipidemia, most cases of primary 
hyperlipidemia are caused by mutations on a single gene or multiple genes. Because 
hyperlipidemia caused by gene mutations has a family aggregation feature and an obvious 
genetic tendency (especially in people with a single gene mutation), this condition is usually 
called familial hyperlipidemia in the clinic.
For example, loss-of-function mutations on the gene encoding the LDL-C receptor, 
mutations on the gene encoding the Apo B that interacts with the LDL-C receptor, gain-
offunction mutations on the gene encoding proprotein convertases subtilisin/kexin type 9 
(PCSK9) that degrades the LDL-C receptor, and mutations on the gene encoding the LDL-C 
receptor modulator that modulates the LDL-C receptor to the surface of the plasma cell 
membrane can cause familial hypercholesterolemia (FH). In more than 80% of patients, FH 
is caused by a single gene mutation; however, hypercholesterolemia is associated with 
multiple gene mutations. Loss-of-function mutations on the LDL-C receptor gene are the 
major cause of FH. The incidence of homozygous familial hypercholesterolemia (HoFH) is 
approximately 1/300,000-1/160,000, whereas the incidence of heterozygous familial 
hypercholesterolemia (HeFH) is approximately 1/500-1/200.
Familial hypertriglyceridemia is caused by a single gene mutation. This condition is usually 
caused by a gene mutation to the lipoprotein lipases that are involved in TG metabolism, on 
the Apo C2 gene, or on the Apo A5 gene. It presents as severe hypertriglyceridemia (TG >10 
mmol/L), and the incidence rate is 1/1000,000. Mild and moderate hypertriglyceridemia are 
usually associated with multiple gene mutations.[25,26]
 
 
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5.2 Clinical classification of dyslipidemia
In practice, dyslipidemia can be stratified based on a simple clinical classification (Table 12).
Table 12
Clinical Classification of Dyslipidemia
Type
TC
TG
HDL-C
Equal to WHO phenotype
Hypercholesterolemia
Increase
IIa
Hypertriglyceridemia
Increase
IV, I
Mixed hyperlipidemia
Increase
Increase
IIb, III, IV, V
HDL-C hypolipidemia
Decrease
LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride; WHO: 
world health organization.
6
Dyslipidemia screening
Highlights: Regular blood lipid examinations are an important measure for managing blood 
lipid levels and cardiovascular disease.
The early detection of individuals with dyslipidemia and the monitoring of their blood lipid 
level changes are important for the effective implementation of management measures for 
ASCVD. All MAST institutions in China have the ability to determine blood lipid levels. The 
detection and monitoring work for patients with dyslipidemia is primarily implemented 
through routine blood lipid examination in the populations who visit medical institutions. 
These populations include those who already have ASCVD as well as those who have not 
developed ASCVD. Health examinations are also an important route to detect dyslipidemia. 
For the early detection of dyslipidemia, adults between 20-40 years old should receive at 
least one blood lipid measurement (including TC, LDL-C, HDL-C, and TG) every 5 years. 
Men older than 40 years of age and postmenopausal women should receive blood lipid 
measurements every year. Patients with ASCVD and high-risk populations should receive 
one blood lipid measurement every 36 months. Patients who are admitted into hospitals 
because of ASCVD should receive blood lipid measurements at admission or within 24 h of 
admission.
The key participants for blood lipid examination are (1) people with a history of ASCVD; (2) 
populations with multiple ASCVD risk factors (e.g., hypertension, diabetes, obesity, and 
smoking); (3) people with a family history of early-onset cardiovascular diseases (i.e., 
immediate male family members younger than 55 years old or immediate female family 
members younger than 65 years old who develop ischemic cardiovascular disease) or patients 
with familial hyperlipidemia; and (4) people with skin or tendon xanthomas and Achilles 
tendon thickening. Many factors influence blood lipid detection results. Implementing blood 
lipid detection should work according to the requirements of the clinical recommendations 
for determining blood lipids (Supplement 1).
 
 
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7
Overall cardiovascular risk assessment
Highlights: Using different intensities of intervention measures based on the risk of 
developing ASCVD is the core strategy for the management of dyslipidemia. Overall 
cardiovascular risk assessment is the basis of dyslipidemia treatment decisions. Overall 
cardiovascular risk assessment should be performed according to recommended procedures. 
For people younger than 55 years old, a lifetime risk for cardiovascular disease should be 
considered.
LDL-C or TC levels are independent predictors of the risk of developing ASCVD in 
individuals and populations.[27–29] However, the risk levels of developing ASCVD in 
individuals are determined not only by the level of cholesterol but also by the number and 
levels of comorbid risk factors of ASCVD.[29–31] Individuals with the same LDL-C level 
might have significantly different overall risks regarding the development of ASCVD 
because of the different numbers and levels of other risk factors. More importantly, the 
overall ASCVD risk is not simply an addition of the cholesterol level and the independent 
functions of other risk factors; rather, it is the result of the complicated interaction between 
the cholesterol level and many combined risk factors. Therefore, the same cholesterol level 
can cause greater harm because of the presence of other risk factors. The comprehensive 
assessment of the overall risk of ASCVD is a necessary prerequisite for the management of 
dyslipidemia. The assessment of the overall risk of ASCVD can not only help to confirm the 
decision of lipid-lowering treatment for patients dyslipidemia but also help clinical 
physicians make personalized comprehensive treatment decisions targeting multiple risk 
factors, thereby reducing the overall risk of ASCVD in patients to the greatest degree. 
Currently, the core content of the dyslipidemia management guidelines released by China 
and other countries include the assessment methods and risk stratification standards for the 
overall risk of developing ASCVD.[9,12,13,16,22,32–35] The 2007 blood lipid guidelines proposed 
using the risk of development of “ischemic cardiovascular disease” (i.e., coronary heart 
disease and ischemic stroke) to reflect the comprehensive pathogenic risk of the major risk 
factors of dyslipidemia and other cardiovascular diseases. For people at moderate risk of 
developing ASCVD in 10 years who are < 55 years old, this edition of the “Guidelines” add 
recommendations for the assessment of the lifetime risk of ASCVD for the early recognition 
of individuals with a high lifetime risk of ASCVD to perform active interventions.[10]
During risk assessment, people who have been diagnosed with ASCVD are directly listed as 
a high-risk population. People who meet one of the following conditions are directly listed as 
a high-risk population: (1) LDL-C ≥4.9 mmol/L (190 mg/dL); (2) 1.8 mmol/L (70 mg/dL) ≤
LDL-C <4.9 mmol/L (190 mg/dL), and diabetes patients older than 40 years of age. The very 
high-risk and high-risk populations who meet the above conditions do not need to receive an 
ASCVD risk stratification based on their number of risk factors.
When considering whether a lipid-lowering treatment is required, individuals who do not 
meet the above three conditions should receive an assessment of the overall risk of 
developing ASCVD over the following 10 years according to the procedures shown in Figure 
1. The risk assessment revised in the “Guidelines” has 21 combinations according to the level 
of LDL-C or TC, the presence of hypertension, and the number of other ASCVD risk factors. 
In addition, according to the average 10-year incidence risk of ASCVD across different 
 
 
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combinations, these levels are defined as low-risk, medium-risk, and high-risk: < 5%, 5%-
9%, and ≥ 10%, respectively. This revision continues the risk-stratification program 
published in the 2007 Blood Lipid Guidelines to use hypertension as an important parameter 
in risk stratification (Figure 3). This version of the “Guidelines” provides a more quantitative 
color figure of the risk stratification of ASCVD development as the reference for risk 
stratification (Supplement 2).
*Including smoking, low HDL-C, and men ≥45 years of age or women ≥55 years of age. The risk assessment 
and treatment of patients with chronic kidney disease refer to the treatment of dyslipidemia in special 
populations.
ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CM: chylomicron; HDL-C: high-
density lipoprotein cholesterol; IDL: intermediate-density lipoprotein; LDL-C: low-density lipoprotein 
cholesterol; TC: total cholesterol; TG: triglyceride; VLDL:very-low-density lipoprotein cholesterol.
Figure 3
The Risk Assessment Flow Chart of ASCVD
 
 
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Because studies in China and other countries have already discovered the effect of the risk 
factor levels on the lifetime risk of people younger than 55 years old, [10,31,36,37] this revision of 
the “Guidelines” recommends assessing the lifetime risk of ASCVD in people who have 
medium 10-year incidence risk for ASCVD to identify middle-aged and young individuals 
who have high lifetime risks for developing ASCVD in 10 years to perform early 
interventions on certain risk factors including blood lipids. If people with medium 10-year 
incidence risk of ASCVD have any two or more of the following risk factors, then their 
lifetime risk of ASCVD is high: (1) systolic pressure ≥160 mmHg or diastolic pressure ≥100 
mmHg; (2) non-HDL-C ≥5.2 mmol/L (200 mg/dL); (3) HDL-C <1.0 mmol/L (40 mg/dL); 
(4) body mass index (BMI) ≥28 kg/m2; and (5) smoking.
8
Principles of dyslipidemia treatment
Highlights: Very high-risk, LDL-C <1.8 mmol/L; high-risk, LDL-C <2.6 mmol/L; medium-
risk and low-risk, LDL-C <3.4 mmol/L. 
People who cannot achieve the target value because the baseline value of LDL-C is higher 
should reduce LDL-C values by at least 50%. Very-high-risk people who have LDL-C 
baseline values within the target still should reduce LDL-C levels by approximately 30%.
For clinical lipid-lowering goal attainment, statin lipid-lowering drugs are preferred. At the 
beginning of treatment, medium-intensity statins should be applied. Doses should be properly 
adjusted according to individual lipid-lowering efficacy and tolerance conditions. If the 
cholesterol level cannot reach the goal, then other lipid-lowering drugs can be used in 
combination.
Dyslipidemia treatment seeks to manage ASCVD and reduce the incidence risk of clinical 
cardiovascular events, such as myocardial infarction, and ischemic strike, and coronary heart 
disease mortality. Because of the differences in genetic background and living environments, 
the risk levels of the development of ASCVD among individuals significantly differ. Lipid-
lowering treatment can benefit patients with ASCVD and high-risk populations. Whether the 
lipid-lowering drug treatment should be initiated should be based on the risk levels of 
ASCVD in individuals in the clinic (Class I recommendation, Level A evidence).
8.1 Lipid-lowering treatment targets
Dyslipidemia, especially an increase in LDL-C, is the key factor that causes the initiation and 
progression of ASCVD. Many clinical studies have repeatedly confirmed that regardless of 
the drugs or measures adopted, as long as the serum LDL-C level can be reduced, 
atherosclerotic lesions can be stably delayed or regressed, and the incidence, morbidity, and 
mortality of ASCVD can be significantly reduced. All of the guidelines for the management 
of dyslipidemia in China and other countries emphasize that LDL-C plays a core role in 
developing ASCVD, and they advocate reducing serum LDL-C levels to manage ASCVD 
risk.[9,12,35,38] Therefore, the use of LDL-C as the preferred intervention target is 
recommended (Class I recommendation, Level A evidence).
 
 
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Non-HDL-C can be used as the secondary intervention target (Class IIa recommendation, 
Level B evidence). Given that patients with hypertriglyceridemia have increased remnant 
lipoproteins in their bodies that might cause atherosclerosis, non-HDL-C is used as the 
secondary intervention target.
8.2 Setting up lipid-lowering target values
Clinical physicians are familiar with establishing target values of lipid-lowering treatments 
and have experience applying such measures. However, certain newly published 
dyslipidemia diagnoses and treatment guidelines in other countries do not recommend 
establishing lipid-lowering target values,[12,35] because no evidence from randomized 
controlled studies support the specific target values of blood lipid treatment, and it is not 
known what type of blood lipid target values engender the largest degree of reduction of the 
risks of ASCVD. However, if lipid-lowering target values are eliminated, then the 
compliance of patients who take lipid-lowering drugs will be severely affected. Regarding 
the benefits of lipid-lowering treatment, a long-term adherence to treatment is important. 
Only when lipid-lowering target values are established can physicians more accurately 
evaluate the effectiveness of treatment methods, effectively communicate with patients, and 
increase the compliance of patients regarding lipid-lowering drugs. Furthermore, no evidence 
or reasons exists to eliminate lipid-lowering target values in China.[38,39] Therefore, target 
values should be established in a lipid-lowering treatment (Class I recommendation, Level C 
evidence).
8.3 Lipid-lowering goal attainment values
The basic target value of cholesterol to be achieved in lipid-lowering treatment should be 
confirmed according to the different risk levels of ASCVD. The recommendation for the 
reduction of LDL-C to a certain cutoff point (i.e., target value) is primarily based on risk-
benefit analysis; when the risk for developing a cardiovascular event in the future is high, the 
benefit is larger. Although LDL-C might be reduced to a lower level, more clinical 
cardiovascular benefits exist, and the drug-related adverse reactions will also significantly 
increase. In addition, health economics are also important factors that affect making 
treatment decisions and should be considered.
Patients who are diagnosed with ASCVD [including acute coronary syndrome (ACS)], stable 
coronary heart disease, post revascularization, ischemic cardiomyopathy, ischemic stroke, 
transient ischemic attack (TIA), and peripheral atherosclerosis in the clinic all belong to the 
very high-risk population.[13,35] In the non-ASCVD population, risk assessment is performed 
according to cholesterol level, its severity, and the number of risk factors. These patients are 
divided into high-risk, medium-risk, and low-risk groups. The target value for reducing LDL-
C is determined based on the risk of developing ASCVD among individuals. The LDL-C and 
non-HDL-C target values that must be achieved by populations with different risks show 
large differences (Table 13, Class I recommendation, Level B evidence).
 
 
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Table 13
The Goal Attainment Values of LDL-C and non-HDL-C Treatments Across 
Different ASCVD Risk Populations [mmol/L (mg/dL)]
Risk level
LDL-C
Non-HDL-C
Low/medium risk
< 3.4 (130)
< 4.1 (160)
High risk
< 2.6 (100)
< 3.4 (130)
Very high risk
< 1.8 (70)
< 2.6 (100)
HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density 
lipoprotein cholesterol.
All clinical study results of enhanced statin therapy show that several increased doses of 
statins can reduce the risk of developing ASCVD events; however, the absolute values of 
these benefits are small, and the all-cause mortality is not decreased.[40] Studies of statins 
combined with ezetimibe treatment have also obtained similar results.[41] Reduction of LDL-
C from 1.8 mmol/L to 1.4 mmol/L can further reduce the absolute risk of cardiovascular 
events by 2% and the relative risk by 6.4%; however, the risks of cardiovascular mortality 
and all-cause mortality are not reduced. These results suggest that although a clinical benefit 
exists after LDL-C is reduced, the absolute benefits are already decreased.
If the baseline value of LDL-C is high, then LDL-C is difficult to reduce to the basic target 
value after treatment with the existing standard lipid-lowering treatment for 3 months. Thus, 
the alternative goal of at least 50% reduction of LDL-C should be considered (Class IIa 
recommendation, Level B evidence). In the clinic, the LDL-C baseline values of certain very-
high-risk patients are already within the basic target values. At this time, LDL-C can be 
reduced by approximately 30% from the baseline value (Class I recommendation, Level A 
evidence).
The target value of non-HDL-C is higher than that of LDL-C by 0.8 mmol/L (30 mg/dl). The 
target values of non-HDL-C treatment in populations at different risks are shown in Table 13
(Class I recommendation, Level B evidence).
8.4 Lipid-lowering goal attainment strategy
Over the last 20 years, the results of many large-scale clinical trials consistently show that 
statins can significantly reduce the risk of cardiovascular events (including myocardial 
infarction, coronary heart disease mortality, ischemic stroke, and others) with regard to the 
primary and secondary prevention of ASCVD. Statins have already become the most 
important drugs in the management of this group of diseases. Therefore, to lower lipids, 
statins should be a first-line treatment chosen in clinical practice (Class I recommendation, 
Level A evidence).
However, how to reasonably and effectively use statins remains controversial. Recent 
guidelines in other countries recommend using high-intensity (equivalent to the maximum 
maximum allowable dose) statins at the beginning of clinical practice. However, the 
increased benefits and safety of the maximum allowable dose of statins in the Chinese 
population have not been confirmed.[42] The HPS2-THRIVE study indicates that the Chinese 
population can achieve lower LDL-C levels than their European counterparts when the exact 
 
 
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same statin drug and dose are used.[43] The DYSISCHINA study showed that an increase of 
statin doses does not increase the goal attainment rate of LDL-C.[44] The CHILLAS study did 
not show that Chinese patients with ACS obtain more benefits from high-intensity statins.[45]
In the Chinese population, safety must be considered during the use of high-intensity statins. 
More studies have indicated that high-intensity statin therapy is accompanied by high risks of 
myopathy and increases in the liver enzymes that are more prominent in the Chinese 
population. The HPS2-THRIVE study indicated that the incidence of adverse liver reactions 
was significantly higher in Chinese patients than in European patients during treatment with 
medium-intensity statins. The rate of increase in liver enzymes (> 3 times of the upper limit 
of the normal value) was more than 10 times higher than that among European patients, and 
the risk of myopathy was also 10 times higher. Currently, no safety data exist regarding high-
intensity statin therapy in the Chinese population.
One feature of the efficacy of lipid-lowering statin drugs is that the initial dose of every statin 
has excellent lipidlowering efficacy. When the dose is doubled, LDL-C is further reduced by 
6% (the statin efficacy “rule of six”). When the statin dose is doubled, the drug cost 
proportionally increases, whereas the increase of the efficacy for LDL-C reduction is relative 
small. Therefore, the use of medium-intensity statins is recommended for initial treatment. 
The dose is properly adjusted according to individual lipid-lowering efficacy and tolerance 
conditions. If the cholesterol level does not reach the target, then other lipidlowering drugs 
(e.g., ezetimibe) can be used in combination to obtain safe and effective lipid-lowering 
effects (Class I recommendation, Level B evidence).
8.5 Other dyslipidemia interventions
In addition to active cholesterol interventions, whether other dyslipidemia conditions also 
require treatment lacks the evidence of relevant clinical trial benefits. The appropriate level 
of serum TG is < 1.7 mmol/L (150 mg/dL). When serum TG is ≥1.7 mmol/L (150 mg/dL), 
non-drug intervention measurement is first applied including therapeutic diet, reduction of 
body weight, and abstinence from alcohol. If the TG level only shows a mild-to-moderate 
increase [i.e., 2.3-5.6 mmol/L (200-500 mg/dL)] to manage the risk of ASCVD, then 
although the reduction of the LDL-C level is the major goal, non-HDL-C should also reach 
the target value. If non-HDL-C cannot reach the target value even after statin therapy, then 
fibrates and high purity fish oil preparations should be used additionally with statins. For 
patients with severe hypertriglyceridemia and fasting TG levels of ≥5.7 mmol/L (500 
mg/dL), drugs that reduce TG and VLDL-C should be considered first (e.g., fibrates, high 
purity fish oil preparations, or niacin).
For people with HDL-C < 1.0 mmol/L (40 mg/dL), diet should be controlled and lifestyle 
should be improved. Currently, not enough evidence exists for drug interventions.
8.6 Lifestyle interventions
Diet and lifestyle typically and significantly influence dyslipidemia. Dietary treatment and 
lifestyle improvements are the basic measures of dyslipidemia treatment. Whether a drug 
lipid-lowering therapy is performed, diet control and lifestyle improvement must be assured 
(Class I recommendation, Level A evidence). Excellent lifestyle habits include adhering to a 
 
 
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heart-healthy diet and regular exercise, avoiding tobacco, and maintaining an ideal body 
weight. Lifestyle intervention is the therapeutic measure with the best cost-benefit and risk-
benefit ratios.
For low- and medium-risk patients, if LDL-C fails to reach the goal after 6 months of 
lifestyle intervention, then a low/medium intensity statin therapy is initiated. For highand 
very-high-risk patients, a medium-intensity statin drug treatment is initiated immediately 
combined with a lifestyle intervention.
8.7 Treatment process monitoring
Patients with dietary and non-drug treatment should test their blood lipid levels again in the 
first 3-6 months. If blood lipid control reaches the recommended target, then the non-drug 
treatment should continue and re-examinations should be performed every 6 months to 1 
year. People who have attained long-term goals should receive a re-examination once every 
year. People who take lipid-lowering drugs require closer blood-lipid monitoring. People 
who take lipidlowering drugs for the first time should receive re-examinations for blood 
lipids, transaminases, and creatine kinase within 6 weeks of drug administration. If their 
blood lipids reach the target value and no adverse drug reaction exists, then re-examination 
should be gradually changed to once every 6-12 months. If blood lipid levels do not reach the 
goal and no adverse drug reaction occurs, then monitoring should be performed once every 3 
months. If blood lipids do not reach the target value even after 3-6 months of treatment, the 
dose and type of lipid-lowering drugs should be adjusted, or the treatment should be 
combined with lipidlowering drugs with different action mechanisms. After each adjustment 
of the type or dose of lipid-lowering drugs, re-examination should be performed within 6 
weeks of treatment. Therapeutic lifestyle change (TLC) and lipidlowering drug treatment 
must be continued over the long term to obtain excellent clinical benefits.
9
Therapeutic lifestyle changes
Highlights: Total energy is controlled by fulfilling the requirement of daily essential 
nutrition. The percentage of composition of all nutritional elements should be selected 
reasonably. People should control body weight, quit smoking, limit drinking, and adhere to 
regular medium-intensity metabolic exercise.
Dyslipidemia is closely associated with diet and lifestyle. Dietary therapy and lifestyle 
improvement are the basic measures of dyslipidemia treatment.[46] Whether the lipidlowering 
drug treatment is chosen, control of diet and improvement of lifestyle should be maintained 
(Table 14). Daily essential nutrition and total energy requirements should be met when the 
total amount of saturated fatty acid and trans-fat uptake exceeds the upper limit; these 
compounds should be replaced with unsaturated fatty acids. The recommended daily 
cholesterol intake is <300 mg; lipid intake should not be >20%-30% total energy, especially 
for high-risk people for ASCVD and other similar conditions. Saturated fatty acid intake 
should be <10% total energy for the general population. For patients with 
hypercholesterolemia, the amount of saturated fatty acid intake should be <7% total energy, 
and the amount of trans-fat intake should be <1% total energy. Patients with 
hypertriglyceridemia should reduce their total amount of daily fat intake as low as possible, 
 
 
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and their daily consumption of cooking oil should be < 30 g. Regarding lipid intake, food 
that is rich in omega-3 polyunsaturated fatty acids should be selected first (e.g., deep-sea fish, 
fish oil, and vegetable oil).
Table 14
Basic Lifestyle Change Elements
Element
Recommendation
Limiting dietary ingredients that can increase LDL-C
Saturated fatty acid
< 7% of total energy
Dietary cholesterol
< 300 mg/dL
Increasing dietary ingredients to reduce LDL-C
Plant sterols
2-3 g/dL
Water soluble dietary fiber
10-25 g/dL
Total energy
Adjusting to the level that can maintain ideal 
body weight or reduce body weight
Physical activity
Maintaining medium-intensity exercise and 
consuming at least 200 kcal
LDL-C: low-density lipoprotein cholesterol.
The recommended daily carbohydrate intake accounts for 50%-65% of total energy. 
Carbohydrates rich in dietary fibers and low in glycemic index should be chosen to replace 
saturated fatty acids. Daily diets should include 25-40 g of dietary fiber (7-13 g of water-
soluble dietary fiber). The carbohydrate intake should be primarily cereals, tubers, and whole 
grains. The intake of added sugar should not be over 10% total energy (this percentage is 
lower for people with obesity or hypertriglyceridemia). Food additives such as plant 
sterols/alkanols (2-3 g/dL) and soluble/viscous dietary fibers (10-25 g/dL) can help with 
blood lipid control; however, their safety requires long-term monitoring.
9.1 Controlling body weight
Obesity is an important risk factor for dyslipidemia. Overweight or obese people with 
dyslipidemia should uptake less energy than the body energy consumed to gradually reduce 
body weight to the ideal status. Reducing the total energy from daily food (by 300-500 kcal 
daily), improving dietary structure, and increasing physical activity can reduce more than 
10% body weight in overweight and obese people. The maintenance of a health body weight 
(BMI: 20.0-23.9 kg/m2) is conducive to blood lipid control.
9.2 Physical activity
Medium-intensity metabolic exercise is recommended for 5–7 days every week, 30 min each 
time. Patients with ASCVD should first perform an exercise load test; after the safety of this 
exercise has been fully evaluated, physical activity is then performed.
9.3 Quit smoking
Patients should completely quit smoking and effectively avoid the inhalation of secondhand 
smoke to prevent ASCVD and to increase HDL-C levels. Smoking cessation treatments, 
smoking cessation hotline consultation, and medicines can be used to help quit smoking.
 
 
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9.4 Limit drinking
A moderate amount of drinking (20-30 g of alcohol daily for men and 10-20 g of alcohol 
daily for women) can increase HDL-C levels. Even a small amount of drinking can further 
increase TG levels in patients with hypertriglyceridemia. No exact evidence exists regarding 
the influence of drinking on cardiovascular events. Restricted drinking is advocated.
10 Lipid-lowering drug treatments
Highlights: Whether the lipid-lowering drug treatment should be initiated should be based 
on the risk levels of ASCVD in individuals in the clinic.
The reduction of LDL-C levels should be used as the preferred intervention target in the 
management of ASCVD risks. Non-HDL-C can be used as the secondary intervention target. 
Lipid-lowering treatment should establish very high-risk, LDL-C < 1.8 mmol/L; high-risk, 
LDL-C < 2.6 mmol/L; medium-risk and low-risk, LDL-C < 3.4 mmol/L. 
People who cannot achieve the target value because the baseline value of LDL-C is higher
should reduce LDL-C values by at least 50%. Very-high-risk people who have LDL-C 
baseline values within the target still should reduce LDL-C levels by approximately 30%.
For clinical lipid-lowering goal attainment, statin lipid-lowering drugs are preferred. At the 
beginning of treatment, medium-intensity statins should be applied. Doses should be properly 
adjusted according to individual lipid-lowering efficacy and tolerance conditions. If the 
cholesterol level cannot reach the goal, then other lipid-lowering drugs can be used in 
combination.
The blood lipid metabolic pathway in the human body is complicated. Many enzymes, 
receptors, and transport proteins are involved. Many types of lipid-lowering drugs can be 
chosen in clinical practice. Generally, these drugs can be divided into two large groups: (1) 
drugs that primarily reduce cholesterol; and (2) drugs that primarily reduce TG. Some lipid-
lowering drugs can reduce both cholesterol and TG. Severe hyperlipidemia usually requires 
the combined application of many lipid-lowering drugs to obtain excellent efficacy.
10.1
Drugs that primarily reduce cholesterol
The major action mechanisms of this group of drugs inhibit cholesterol synthesis in 
hepatocytes, accelerate LDL-C catabolism, or reduce cholesterol absorption in the intestinal 
tract. This group of drugs includes statins, cholesterol absorption inhibitors, probucol, bile 
acid sequestrants, and other lipid-lowering drugs (e.g., Zhibitai and policosanol).
10.1.1 Statins
Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase 
inhibitors, can inhibit the rate-limiting enzyme of cholesterol synthesis (HMG-CoA 
reductase) to reduce cholesterol synthesis and further upregulate the LDL-C receptor on the 
cell surface and accelerate serum LDL-C catabolism. In addition, statins can also inhibit 
 
 
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VLDL synthesis. Therefore, statins can significantly reduce serum TC, LDL-C, and Apo B 
levels as well as reduce serum TG levels and mildly increase HDL-C levels.
The advent of statins was a milestone in the history of human ASCVD management. The 4S 
clinical trial first confirmed that statins reduce coronary heart disease mortality and overall 
patient mortality.[47] The subsequent CARE,[48] LIPID,[49] and LIPS[50] studies also confirmed 
the important functions of this group of drugs with regard to the secondary prevention of 
coronary heart disease. The HPS study indicated that statin therapy benefits the high-risk 
population when their baseline cholesterol is not high.[51] The clinical trials regarding 
enhanced statin therapy primarily included PROVE-IT,[52] A to Z,[53] TNT,[54] MIRACL,[55]
and IDEAL.[56] Compared with the routine dose of statins, enhanced statin therapy for 
patients with coronary heart disease further reduces the likelihood of cardiovascular 
events;[52,54] however, the reduction level is not high,[53,56] and total mortality is not 
reduced.[57] The ASTEROID study confirmed that statin therapy reverses coronary 
atherosclerosis.[58] The WOSCOPS,[59] AFCAPS/TexCAPS,[60] CARDS,[61] JUPITER,[62] and 
HPS[51] studies expanded the application of statins from patients with ASCVD to primary 
prevention and more extensive populations. Currently, the function of statins with regard to 
the primary prevention of cardiovascular disease among high-risk populations has been 
affirmed. However, the application effect in people at low risk of cardiovascular disease 
awaits further study. Many studies have targeted special populations for investigation. The 
SPARCL,[63] PROSPER,[64] CARDS,[61] ALLHAT-LLT,[65] and ASCOT-LLA[66] studies 
individually showed that statins have clinical benefits in the elderly as well as patients with 
stroke, diabetes, or hypertension. Furthermore, evidence from Chinese clinical studies does 
not support the cardiovascular benefits of shortterm enhanced statin therapy before 
percutaneous coronary intervention (PCI) among patients with ACS. Moreover, the newest 
guidelines in other countries do not recommend short-term enhanced statin intervention 
strategies during the perioperative period of PCI.
Statins are applicable for patients with hypercholesterolemia, mixed hyperlipidemia, or 
ASCVD. Currently, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, 
rosuvastatin, and pitavastatin are used in clinical practice in China. The cholesterol reduction 
levels have large differences depending on the different types and doses of statins. However, 
when any statin does is doubled, the continued reduction of LDL-C is only 6% (i.e., the so-
called “rule of six of statin efficacy”). Statins can reduce TG levels by 7%-30% and increase 
HDL-C levels by 5%-15%.
Statins can be administered once per day at any time. However, the administration of LDL-C 
at night might be associated with higher levels of LDL-C reduction. After the expected 
efficacy of statin administration is obtained, the long-term administration should be 
continued. If patients can tolerate this treatment, then drug withdrawal should be avoided. 
Previous studies have suggested that statin withdrawal might increase the development of 
cardiovascular events.[67] If adverse reactions occur after statin administration,then this 
treatment should be replaced with another type of statin, the dose should be reduced, and 
drug administration should be performed every other day;[68] otherwise, other non-statin lipid 
lowering drugs should be used.
 
 
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The analytic results of the Cholesterol Treatment Trials' (CTT) collaboration indicate that 
when LDL-C is reduced by 1 mmol/L after statin therapy in populations with different 
cardiovascular risk stratifications, the relative risk of major cardiovascular events is reduced 
by 20%, and allcause mortality is reduced by 10%, whereas the mortality caused by non-
cardiovascular reasons does not increase.[57,69] Current studies have repeatedly confirmed that 
the level of clinical reduction benefits of ASCVD by statins is linearly and positively 
correlated with the level of LDL-C reduction. The clinical benefits produced by statin 
therapy originate from the effect of LDL-C reduction. The levels of LDL-C reduction via 
different types and doses of statins are shown in Table 15.[35]
Table 15
The Cholesterol Reduction Intensity of Stains
High intensity (daily dose can 
reduce LDL-C by ≥ 50%)
Medium intensity (daily dose 
can reduce LDL-C by 25%-
50%)
Atorvastatin 40-80 mg*
Atorvastatin 10-20 mg
Rosuvastatin 20 mg
Rosuvastatin 5-10 mg
Fluvastatin 80 mg
Lovastatin 40 mg
Pitavastatin 2-4 mg
Pravastatin 40 mg
Simvastatin 20-40 mg
Xuezhikang 1.2 g
*Studies of atorvastatin (80 mg) among the Chinese population are 
limited; please use with caution. LDL-C: low-density lipoprotein 
cholesterol.
Although Xuezhikang capsules are classified as a lipidlowering Chinese medicine, their 
lipid-lowering mechanism is similar to that of statins. These capsules are refined via the 
biological fermentation of a special monascus added to rice using the modern GMP standard 
manufacturing process. The main ingredients of these capsules include 13 types of natural 
statin compounds, including lovastatin without a crystal structure and its homologs. The 
commonly used dose is 0.6 g twice per day. The China Coronary Secondary Prevention 
Study (CCSPS) and other clinical studies confirmed that Xuezhikang capsules reduce 
cholesterol and significantly reduce the overall mortality of patients with coronary heart 
disease, the incidence of cardiovascular events, and number of side effects.[70-73]
Most people show excellent tolerance to statins. Adverse reactions are primarily observed in 
patients who receive large doses of statin therapy. The most common manifestations are 
discussed below.
(1) Abnormal liver function.[74,75] The main presentation of this condition is the increase of 
transaminases. The incidence is approximately 0.5%-3%, and it shows dose dependence. 
Patients with an increase of serum alanine aminotransferase (A), aspartate aminotransferase 
(AST) higher than three times the upper limit of normal values, and the combined increase of 
total bilirubin should reduce or discontinue drug use. Patients with an increase of 
transaminases within three times of the upper limit of normal values can be observed based 
on the original doses or reduced doses. Some patients can restore normal transaminases after 
 
 
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this treatment. The application contraindications of statins are decompensated cirrhosis and 
acute liver failure.
(2) Statin-related adverse muscle reactions include myalgia, myositis, and 
rhabdomyolysis.[76,77] When patients have muscle discomfort, weakness, or both and 
continuous creatine kinase detection shows progressive increases, statins doses should be 
reduced or the drugs should be discontinued.
(3) The long-term administration of statins might increase the risk of new-onset diabetes.[78]
The incidence is approximately 10%-12%, and it is classified as a statin effect. The overall 
benefits of statins on cardiovascular diseases are more significant than the risk of new-onset 
diabetes. Patients with diabetes or those at high risk for diabetes who have statin therapy 
indications should adhere to the administration of this group of drugs.
(4) Statin therapy can cause cognitive dysfunction.[79] However, this dysfunction is transient, 
and its incidence is not high. The results of a meta-analysis showed that statins do not have 
adverse effects on renal function.[80] The adverse reactions of statins also include headache, 
insomnia, and depression as well as digestive tract symptoms such as indigestion, diarrhea, 
abdominal pain, and nausea.
10.1.2 Cholesterol absorption inhibitors
Ezetimibe can effectively inhibit cholesterol absorption in the intestinal tract. The 
IMPROVE-IT study indicated that the administration of ezetimibe based on simvastatin 
further reduces the likelihood of cardiovascular events in patients with ACS.[41] The SHARP 
study showed that a combined treatment with ezetimibe and simvastatin improves 
cardiovascular disease prognosis in patients with CKD[81]. The recommended dose of 
ezetimibe is 10 mg/d. This drug shows excellent safety and tolerance, and the adverse 
reactions are mild and mostly transient. The major presentations are headache and digestive 
tract symptoms.
When combined with statins, ezetimibe can produce adverse reactions such as transaminase 
increases and myalgia. Ezetimibe is prohibited during pregnancy and lactation.
10.1.3 Probucol
Probucol influences lipoprotein metabolism through an incorporation into the core of LDL-C 
particles; thus, LDL-C is easily cleared through the non-receptor pathway. The commonly 
used dose of probucol is 0.5 g twice per day. This drug is primarily applicable for patients 
with hyperlipidemia, especially those with HoFH or xanthoma. Probucol relieves skin 
xanthomas.[82,83] Its common adverse reactions are gastrointestinal in nature. Probucol can 
also induce dizziness, headache, insomnia, and skin rash. Rare but severe adverse reactions 
include QT interval prolongation. Probucol is prohibited for patients with ventricular 
arrhythmia, QT interval prolongation, or hypokalemia.
 
 
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10.1.4
Bile acid sequestrants
Bile acid sequestrants are basic anion exchange resins. They can block the reabsorption of 
cholesterol in the bile acid in the intestinal tract.[84] The clinical dosage of cholestyramine is 5 
g three times per day, 5 g of colestipol three times per day, and 1.875 g of colesevelam twice 
per day. When combined with statins, these drugs can significantly increase lipid-lowering 
efficacy. The most common adverse reactions include gastrointestinal discomfort and 
constipation; furthermore, they can influence the absorption of certain drugs. The absolute 
contraindications of this group of drugs are abnormal dysbetalipoproteinemia and serum TG 
>4.5 mmol/L (400 mg/day).
10.1.5 Other lipid-lowering drugs
Zhibitai is a compound preparation of monascus and traditional Chinese medicine (i.e., 
hawthorn, alisma, and atractylodes). The most commonly used dose is 0.24-0.48 g twice per 
day. This compound has mild-to-moderate cholesterol-reducing functions.[85,86] This drug has 
few adverse reactions.
Policosanol is a mixture containing 8 types of advanced aliphatic alcohol purified from 
sugarcane wax. The most commonly used dose is 10-20 mg/day. Its lipid-lowering effect is 
slow, and rare but adverse reactions are known.[87,88]
10.2
Major TG-lowering drugs
Three major TG-lowering drugs exist: fibrates, niacin, and high-purity fish oil preparations.
10.2.1 Fibrates
Fibrates reduce serum TG levels and increase HDL-C levels through the activation of 
peroxisome proliferator activated receptor-α (PPARα) and lipoprotein lipase (LPL).[89–93] The 
most commonly used fibrates include fenofibrate tablets 0.1 g three times per day, 
micronized fenofibrate 0.2 g once per day, gemfibrozil 0.6 g twice per day, and bezafibrate 
0.2 g three times per day. The most common adverse reactions are similar to those of statins, 
including liver, muscle, and kidney toxicities. The incidence rates of increased serum 
creatine kinase and ALT levels are both < 1%. Meta-analyses of clinical trial results have 
shown that fibrates can reduce the risk of cardiovascular events in people with high TG 
combined with low HDL-C by approximately 10%. These drugs primarily reduce nonfatal 
myocardial infarction and coronary revascularization, but they do not significant affect 
cardiovascular mortality, fatal myocardial infarction, or stroke.[90-92]
10.2.2 Niacin
Niacin, also known as vitamin B3, is an essential vitamin in the human body. Niacin can 
decrease TC, LDL-C, and TG as well as increase HDL-C in large doses. Its lipid- lowering 
function is associated with the inhibition of hormone-sensitive lipase activities in adipose 
tissue, the reduction of free fatty acid entry into the liver, and the decease of VLDL secretion. 
Niacin has two formulation types: general and sustained-releasing. The sustained-releasing 
 
 
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formulation is more commonly used. The most commonly used dose of sustained-releasing 
tablets is 1-2 g once per day. Starting with a small dose (0.375-0.5 g/day) before going to bed 
is recommended. After four weeks, the dose gradually increases to the commonly used 
maximum dose. The most common adverse reaction is facial flushing. Other reactions 
include liver damage, hyperuricemia, hyperglycemia, acanthosis, and gastrointestinal 
discomfort. Niacin is prohibited for patients with chronic active liver disease, active peptic 
ulcer, or severe gout. The results of a meta-analysis of early clinical trials showed that 
whether used alone or as a combined application with other lipid-lowering drugs, niacin 
improves cardiovascular prognosis, reduces the risk of cardiovascular events by 30%, and 
reduce the risk of coronary events by 25%.[94] Because clinical studies concerning the 
combination of niacin based on statins suggest that no cardiovascular protective function 
exists compared with using statins alone,[95,96] niacin is being phased out of the lipid-
lowering drug market in many European and American countries.
10.2.3 High-purity fish preparations
The main ingredient of fish oil is n-3 fatty acid (i.e., ω-3 fatty acids). The common dose is 
0.5-1.0 g three times per day. Fish oil is primarily used to treat hypertriglyceridemia 
hypertriglyceridemia.[97–99] Adverse reactions such as digestive tract symptoms are rare, and 
their incidence is approximately 2%-3%. A few patients have mild increases of 
transaminases or creatine kinase; a bleeding tendency is sometimes observed. An early 
clinical study showed that high-purity fish oil preparations reduce the risk of cardiovascular 
events;[100] however, subsequent clinical trials did not confirm this result.[101,102]
10.3
New types of lipid-lowering drugs
Three new types of lipid-lowering drugs have recently been approved for clinical 
applications in other countries.
10.3.1 Microsomal triglyceride transfer protein inhibitors
Lomitapide (brand name, Juxtapid) was approved for the market by the US Food and Drug 
Administration (FDA) in 2012. It is primarily used to treat HoFH. Lomitapide can reduce 
LDL-C by approximately 40%. This drug has higher adverse reaction rates, and the major 
presentations are an increase of transaminases or fatty liver.[103,104]
10.3.2 Apolipoprotein B100 synthesis inhibitors
Mipomersen is a second-generation anti-sense oligonucleotide. In 2013, the FDA approved it 
for use alone or combined with other lipid-lowering drugs to treat HoFH. The action 
mechanism is an anti-sense oligonucleotide that targets the transcription of Apo B messenger 
ribonucleic acid (mRNA) to reduce VLDL synthesis and secretion and LDL-C levels. This 
drug can reduce LDL-C levels by 25%. The most common adverse reaction is an injection 
site reaction including local rash, swelling, itching, and pain. Most adverse reactions are mild 
to moderate.[105]
 
 
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10.3.3 PCSK9 inhibitor
PCSK9 is a secretory serine protease synthesized by the liver that can bind to the LDL-C 
receptor to cause its degradation, thereby reducing the clearance of serum LDL-C via the 
LDL-C receptor. Through the inhibition of PCSK9, LDL-C receptor degradation can be 
blocked to promote LDL-C clearance. Among PCSL09 inhibitors, the development PCSK9 
monoclonal antibodies is the most rapid, and additional studies exist on alirocumab, 
evolocumab, and bococizumab. These study results show that whether used alone or 
combined with statins, PCSK9 inhibitors significantly reduce serum LDL-C levels and 
improve other blood lipid indicators including HDL-C and Lp (a). The European Medicines 
Agency and the US FDA have already approved two injection-type PCKS9 inhibitors 
(evolocumab and alirocumab) for the market. Preliminary clinical study results indicate that 
PCSK9 inhibitors can reduce LDL-C and cardiovascular events by 40%-70%.[106,107]
Currently, no reports regarding severe or life-threatening adverse effects have been 
published.[108] This drug is still in the clinical trial stage in China.
10.4
Combined application of lipid-lowering drugs
The combined application of lipid-lowering drugs represents a trend of intervention measures 
for dyslipidemia. The advantage of a combined application is to increase the goal attainment 
rate of blood lipid control and simultaneously reduce the incidence of adverse reactions. 
Statin functions have been recognized; few adverse reactions are known that can reduce 
overall mortality. The combined lipid-lowering programs are primarily composed of statins 
and other types of lipid-lowering drugs with different action mechanisms. Different programs 
exist for the application of drug combinations targeting the different action mechanisms of 
lipidlowering drugs.
10.4.1 Combined application of statins and ezetimibe
Two types of drugs can individually influence cholesterol synthesis and absorption to 
produce excellent synergistic effects. Combined treatment can reduce serum LDL-C based on 
statin therapy by approximately 18%, but it does not increase the adverse reactions of 
statins.[109–111] Many clinical trials have observed that ezetimibe combined with different 
types of statins shows excellent lipid-lowering effects.[110,112,113] The IMPROVE-IT and 
SHARP studies independently showed that the administration of combined statins and 
ezetimibe in people with high-risk ASCVD and patients with CKD reduces the risk of 
cardiovascular events.[41,81] People whose cholesterol levels do not reach the target after a 
medium-intensity statin therapy or who show intolerance should consider medium-to-low 
intensity statins combined with ezetimibe therapy (Class I recommendation (Level B 
evidence). 
10.4.2 Combined application of statins and fibrates
The combination of these two drugs effectively reduces LDL-C and TG levels, increases 
HDL-C levels, and reduces sLDL-C. Fibrates include fenofibrate, gemfibrozil, and 
bezafibrate; of these compounds, fenofibrate has been the most studied and is associated with 
the most sufficient evidence.[114] Previous studies have suggested that the combined 
 
 
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application of statins and fenofibrate increases cardiovascular benefits among patients with 
high TG combined with low HDL-C.[115] Fenofibrate is applicable for patients with severe 
hypertriglyceridemia with or without mixed hyperlipidemia of low HDL-C levels, especially 
for those with accompanied dyslipidemia, diabetes, and metabolic syndrome and high-risk 
cardiovascular patients who show poor control of their TG or HDL-C levels after statin 
therapy. Because the metabolic pathways of statins and fibrates are similar, they both have 
the possibility of damaging the liver function and risk myositis and myopathy. The chances 
of an adverse reaction during combined application can increase. Therefore, the safety of the 
combined application of statins and fibrates should be highly focused. Gemfibrozil combined 
with statins show relatively higher risks of myopathy. In the beginning of a combined 
application, small doses should be used via the administration of fibrates in the morning and 
the administration of statins at night to avoid significant increases in the blood drug 
concentration. In addition, muscle enzymes and liver enzymes should be monitored closely. 
If adverse reactions occur, then the dose of statins can be gradually increased.
10.4.3 Combined application of statins and PCSK9 inhibitors
Although PCSK9 inhibitors are still not on the Chinese market, the combined application of 
statins and PCSK9 inhibitors has already become a method for treating patients with severe 
dyslipidemia, especially those with FH, in Europe and America. This treatment can cause 
greater reductions in LDL-C levels and increase goal attainment rates compared with other 
single drug treatments. Patients with FH, especially those with HoFH, treated with the largest 
dose of lipid-lowering drugs (e.g., statins+ezetimibe) and lifestyle modification as well as 
patients with ASCVD and LDL-C levels > 2.6 mmol/L can also use PCSK9 inhibitors, 
constituting the combined application of three lipid-lowering drugs with different action 
mechanisms.
10.4.4 Combined application of statins and n-3 fatty acids
The combined application of statins and fish oil preparation n-3 fatty acids can be used to 
treat mixed hyperlipidemia without increasing adverse reactions. Because taking larger doses 
of n-3 polyunsaturated fatty acids has a bleeding risk and increases calorie intake in obese 
patients with diabetes, long-term application is not appropriate. Whether this combination 
can reduce cardiovascular events is currently under investigation.
11 Other measures for dyslipidemia treatment
Highlights: Lipoprotein-plasma exchange, liver transplantation, partial ileal bypass surgery, 
and portacaval shunt are used as adjuvant treatment measures for patients with FH. The 
effect of lipoprotein-plasma exchange has been recognized.
11.1
Lipoprotein-plasma exchange
Lipoprotein-plasma exchange is an important adjuvant treatment measure for patients with 
FH,[116] especially for those with HoFH. This treatment can reduce LDL-C levels by 55%-
70%. Long-term treatment can cause a reduction of skin xanthomas. The best treatment 
frequency is once each week. Currently, however, treatments are typically performed once 
 
 
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every two weeks. Lipoprotein-plasma exchange can be persistently performed during 
pregnancy. This treatment measure is expensive, time-consuming, and risks infection. 
Adverse reactions include hypotension, abdominal pain, nausea, hypocalcemia, iron-
deficiency anemia, and allergic reaction. However, with the development of science, 
technology, and materials, the incidence of relevant adverse reactions has already decreased.
11.2
Liver transplantation and other surgical treatments
Liver transplantation can significantly improve LDL-C levels. Although simple liver 
transplantation or liver transplantation combined with heart transplantation is a successful 
treatment strategy, many problems exist including many post-transplantation complications, 
high mortality rates, a lack of donors, and the lifetime administration of immunosuppressive 
agents. Therefore, this treatment is rarely performed in clinical practice. Although partial 
ileal bypass surgery and portacaval shunt are not recommended, they should be considered 
when more effective treatment is lacking for patients with severe HoFH.[116]
12 Management of dyslipidemia in special populations
12.1
Diabetes
The major presentations of diabetes combined with dyslipidemia are increased TG, decreased 
HDL-C, and increased or normal LDL-C.[117] Lipid-lowering treatment can significantly 
reduce the risk of developing cardiovascular events in patients with diabetes.[61] The target 
level of LDL-C should be confirmed based on the severity of cardiovascular risks.[118]
Patients with diabetes aged 40 years or older should control their serum LDL-C levels below 
2.6 mmol/L (100 mg/dL) and maintain their target values of HDL-C above 1.0 mmol/L (40 
mg/dL). The principle of dyslipidemia treatment in patients with diabetes follows the 
ASCVD risk assessment flow chart (Figure 3) for intervention management. According to 
the features of dyslipidemia, the preferred choice is statin therapy. If patients have combined 
high TG levels or do not have combined low HDL-C levels, a combination application of 
statins and fibrates can be used.
12.2
Hypertension
For patients with hypertension and dyslipidemia, lipidlowering treatments should be applied 
to determine lipidlowering target values according to different risk levels (Figure 3). Lipid-
lowering treatments enable most patients with hypertension to obtain adequate benefits. The 
results are often more prominent with regard to the reduction of coronary heart disease 
events.[66] Therefore, the hypertension guidelines recommend that patients with hypertension
and medium risk should initiate statin therapy. The newly released HOPE-3 study results 
suggest that statin therapy significantly reduces cardiovascular events for people at medium 
risk.[119,120] For the subgroup population with systolic pressure >143.5 mmHg, the combined 
application of statins and antihypertensive drugs reduces cardiovascular risks more 
significantly.
 
 
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12.3
Metabolic syndrome
Metabolic syndrome is a group of clinical conditions that combine the development of 
obesity, high blood glucose (sugar regulation impairment or diabetes), hypertension, and 
dyslipidemia (hypertriglyceridemia, HDL-C hypolipidemia, or both). One feature is the 
combination of interrelated risk factors in the body metabolism of the same individual. These 
factors directly promote ASCVD development and increase the risk of developing type 2 
diabetes. Some evidence indicates that patients with metabolic syndrome are most likely to 
develop cardiovascular disease. Compared with people without metabolic syndrome, their 
risks for developing cardiovascular disease and type 2 diabetes are significantly increased.
[121]
The current cutoff points for determining the hyperglycemia, hypertension, and dyslipidemia 
aspects of metabolic syndrome were reached via a worldwide consensus. However, the core 
indicator of metabolic syndrome, obesity (especially central obesity), has different diagnostic 
criteria. The diagnostic criteria of metabolic syndrome formulated based on study evidence 
taken from the Chinese population should include three or more of the following items: (1) 
Central obesity/abdominal obesity: a waist circumference for men of ≥90 cm and that for 
women of ≥85 cm; (2) Hyperglycemia: fasting blood glucose ≥6.10 mmol/L (110 mg/dL) or 
2-h blood glucose after glycemic load ≥7.80 mmol/L (140 mg/dL) or patients with 
confirmed diabetes who have received treatment; (3) Hypertension: blood pressure ≥130/85 
mmHg or patients with hypertension who have received treatment; (4) Fasting TG ≥1.7 
mmol/L (150 mg/dL); and (5) Fasting HDL-C < 1.0 mmol/L (40 mg/dL).
The major goal of metabolic syndrome management is toprevent ASCVD and type 2 
diabetes. Patients who already have ASCVD should seek to prevent cardiovascular events. 
Active and sustained lifestyle interventions are important measures to achieve these 
treatment goals. In principle, lifestyle treatments should be initiated first. If these goals 
cannot be achieved, then corresponding drug treatments should be adopted to target each 
component. The treatment goals for dyslipidemia in metabolic syndrome are LDL-C < 2.6 
mmol/L (100 mg/dL), TG < 1.7 mmol/L (150 mg/dL), and HDL-C ≥1.0 mmol/L (40 
mg/dL).
12.4
CKD
CKD is usually accompanied by dyslipidemia and can promote the development of ASCVD. 
No clinical study has investigated the LDL-C treatment goal of patients with CKD. Under the 
premise of tolerance, patients with CKD are advised to receive statin therapy. The treatment 
goals for patients with mild-to-moderate CKD are LDL-C < 2.6 mmol/L and non-HDL-C < 
3.4 mmol/L; those for patients with severe CKD and CKD combined with hypertension or 
patients with diabetes are LDL-C < 1.8 mmol/L and non-HDL-C < 2.6 mmol/L. Medium-
intensity statin therapy is recommended. When necessary, cholesterol absorption inhibitors 
are combined. For patients with end-stage renal disease (ESRD) and those receiving 
hemodialysis, the risks and benefits of cholesterol-lowering treatments should be assessed 
carefully. Drug selection and the setting of the LDL-C goal should be personalized.
 
 
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Patients with CKD represent a population at high risk for statin-induced myopathy, 
especially when renal function has shown a progressive decline or the glomerular filtration 
rate (GFR) is < 30 mL/min per 1.73 m2. In addition, the risk of disease development is 
closely associated with the statin dosage; therefore, the administration of large doses should 
be avoided. When LDL-C cannot reach the target level after treatment with medium-intensity 
statins, combination therapy with ezetimibe is recommended.[81] Fibrate drugs can increase 
creatinine levels; when combined with statins among patients with moderate-to-severe CKD, 
the risk of myopathy might be increased.
12.5
FH
FH is an autosomal dominant hereditary cholesterol metabolism disorder. The pathogenic 
mechanism of FH is the functional genetic mutations on the LDL-C receptor, and a small 
number of cases are caused by functional mutations on Apo B or PCSK9. The newly 
discovered mutations on the LDL-C receptor modulator gene also explain the development of
FH. The prominent clinical manifestations are the significant increase of serum LDL-C levels 
and early-onset coronary heart disease (myocardial infarction or angina pectoris). According 
to dominant genetic characteristics, the clinical phenotypes of FH are divided into the 
homozygous type (HoFH) and the heterozygous type (HeFH). Cholesterol level screening 
shows that the serum TC level of HeFH is usually > 8.5 mmol/L (328 mg/dl), and the serum
TC level of HoFH is usually >13.5 mmol/L (521 mg/dl). Left untreated, HeFH patients 
usually develop cardiovascular disease after 40 years (men) or 50 years (women) of age.
HoFH patients typically develop severe cardiovascular disease during childhood, and the 
mortality rate from cardiovascular diseases in early adulthood is 100 times higher than that 
among non-FH patients.
The ultimate goal of FH treatment is to reduce the risk of ASCVD and decrease the 
development of fatal and disabling cardiovascular diseases.[116] One focus of treatment is that 
all patients with FH (including HoFH and HeFH patients) should make enhanced therapeutic 
lifestyle changes to their diets (i.e., reduce lipid and cholesterol intake and consume a 
comprehensive balanced diet), exercise, and behavioral habits (i.e., quit smoking and reduce 
body weight). In addition, the management of other risk factors (e.g., hypertension and 
diabetes) should be emphasized. Next, patients with FH should adhere to long-term statin 
therapy beginning in adolescence to significantly reduce the risk of ASCVD. The target level 
of lipid-lowering treatment is the same as that for people at high cardiovascular risk. LDL-C 
is reduced by 25% in people with low LDL-C receptors after receiving statin therapy but 
only by 15% in people without LDL-C receptors. In fact, patients with FH usually require 
combined treatment with two or more types of lipid-lowering drugs. Patients at very high 
cardiovascular risk whose cholesterol levels still do not reach target levels after a combined 
lipid-lowering treatment, especially those with disease in progress, should consider receiving 
lipoprotein-plasma exchange as an adjuvant therapy.
12.6
Stroke
Whether other evidence of combined treatments with atherosclerosis exists, the use of long-
term statin therapy for patients with non-cardiogenic ischemic stroke or TIA is recommended 
to reduce the risk of stroke and cardiovascular events (Class I recommendation, Level A 
 
 
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evidence).[63] If the baseline LDL-C level of patients is ≥2.6 mmol/L (100 mg/dL), then 
evidence of the treatment effect of statins is clear; if the baseline level of LDL-C is < 2.6 
mmol/L (100 mg/dl), then clinical evidence is lacking. For patients with ischemic stroke 
resulting from intracranial large atherosclerotic stenosis (stenosis rate: 70%-99%) or patients 
with TIA, the recommended target value is LDL-C <1.8 mmol/L (70 mg/dL; Class I 
recommendation, Level B evidence). The long-term administration of statin therapy is safe in 
general. For patients with non-cardiogenic ischemic stroke and a history of cerebral 
hemorrhage or patients with TIA, statins can be reasonably used after weighing the risks and 
benefits.
12.7
Elderly people
Elderly people ≥80 years old usually have many types of chronic diseases and take various 
types of drugs. Attention should be paid to the interaction among drugs and their adverse 
reactions. Most elderly patients have different degrees of liver and kidney dysfunction; 
therefore, the selection of doses of lipid-lowering drugs should be individualized. The initial 
dose should not be too high, and the doses of lipid-lowering drugs should be adjusted based 
on treatment effects; in addition, liver and kidney function and creatine kinase should be 
closely monitored. Because no randomized controlled studies regarding the target goals of 
statin therapy have been conducted among elderly patients, there are no special 
recommendations concerning these patients. Current studies indicate that elderly patients 
with hypercholesterolemia combined with cardiovascular disease or diabetes benefit from 
lipid-lowering therapy.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ALT
alanine transaminase
APaT
All Participants as Treated
ASCVD
atherosclerotic cardiovascular disease
AST
aspartate transaminase
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
CABG
coronary artery bypass graft
CAC
Clinical Adjudication Committee
CHD
coronary heart disease
CK
creatine kinase
CKD
chronic kidney disease
CRF
Case Report Form 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
CYP3A4
cytochrome P-450 3A4
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FAS
Full Analysis Set
FDAAA
Food and Drug Administration Amendments Act
FDC
Fixed Dose Combination
FSH
Follicle stimulating hormone 
fT4
Free thyroxin
GCP
Good Clinical Practice 
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IMPROVE-IT
Improved Reduction of Outcomes: Vytorin Efficacy International Trial
INR
International Normalized Ratio
 
 
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Abbreviation
Expanded Term
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVRS
interactive voice response system
IWRS
integrated web response system
LDL-C
low-density lipoprotein cholesterol
MI
myocardial infarction
NYHA
New York Heart Association
NIMP
Non-Investigational Medicinal Product
NPC1L1
Niemann-Pick Cl Like 1
OTC
over the counter
PCI
percutaneous coronary intervention
PIN
participant identification number
PK
pharmacokinetic
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
statistical analysis plan
SoA
schedule of activities
sSAP
supplemental SAP
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TC
total cholesterol
TG
triglyceride
TSH
thyroid stimulating hormone
ULN
Upper Limit Of Normal
WOCBP
woman/women of childbearing potential 
 
 
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