Clinical trial NCT02748057
Conditions: Hypercholesterolemia Familial Hypercholesterolemia
Sponsor: Organon and Co
Start date: 2016-05-18; Completion date: 2017-12-11
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will assess the safety and tolerability of Ezetimibe 10 mg+ Rosuvastatin 2.5 mg and Ezetimibe 10 mg+ Rosuvastatin 5.0 mg for up to 52 weeks in Japanese participants with hypercholesterolemia uncontrolled with monotherapy of Ezetimibe 10 mg or Rosuvastatin up to 5 mg.

Detailed description:

Arms: arm 1: 1 Ezetimibe 10 mg tablet and 1 Rosuvastatin 2.5 mg capsule/tablet orally, once daily for 52 weeks. If participant does not achieve low-density lipoprotein- cholesterol (LDL-C) goal after Week 12, dosage of Rosuvastatin may be increased to 5.0 mg arm 2: 1 Ezetimibe 10 mg tablet and 2 Rosuvastatin 2.5 mg capsules/tablets orally, once daily for 52 weeks.
Interventions: intervention 1: Ezetimibe intervention 2: Rosuvastatin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase III, Open-label, Clinical Trial to assess the Long Term 
Safety and Tolerability of MK-0653H in Japanese Patients with 
Hypercholesterolemia Who Have Inadequate LDL-C Control on 
Ezetimibe or Rosuvastatin monotherapy 
NCT number: 
NCT02748057
Document Date: 
11-Apr-2017


Product:  MK-0653H
1
Protocol/Amendment No.: 833-02
MK-0653H-833-02 Final Protocol
11-Apr-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP 
& DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE 
STATION, NJ, U.S.A
This protocol amendment is applicable only to Japan.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder
(or equivalent).
TITLE:
A Phase III, Open-label, Clinical Trial to assess the Long Term Safety and Tolerability of MK-
0653H in Japanese Patients with Hypercholesterolemia Who Have Inadequate LDL-C Control 
on Ezetimibe or Rosuvastatin monotherapy
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES.........................................................................................................9
1.0
TRIAL SUMMARY.........................................................................................................12
2.0
TRIAL DESIGN...............................................................................................................13
2.1
Trial Design ..................................................................................................................13
2.2
Trial Diagram...............................................................................................................14
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).........................................................................14
3.1
Primary Objective(s) & Hypothesis(es).....................................................................14
3.2
Secondary Objective(s) & Hypothesis(es)..................................................................14
3.3
Exploratory Objective(s).............................................................................................15
4.0
BACKGROUND & RATIONALE.................................................................................15
4.1
Background ..................................................................................................................15
4.1.1
Pharmaceutical and Therapeutic Background ...........................................................15
4.1.1.1
Pathophysiology and Epidemiology...................................................................15
4.1.1.2
Significance of the Development of Fixed Dose Combination Tablet 
(FDC) for Therapy of Hyper-LDL-cholesterolemia...........................................16
4.1.2
Pre-clinical and Clinical Trials ..................................................................................17
4.1.3
Ongoing Clinical Trials..............................................................................................18
4.2
Rationale.......................................................................................................................18
4.2.1
Rationale for the Trial and Selected Subject Population ...........................................18
4.2.2
Rationale for Dose Selection/Regimen/Modification................................................18
4.2.3
Rationale for Endpoints .............................................................................................19
4.2.3.1
Safety Endpoints.................................................................................................19
4.2.3.2
Efficacy Endpoints..............................................................................................20
4.3
Benefit/Risk ..................................................................................................................20
5.0
METHODOLOGY ..........................................................................................................20
5.1
Entry Criteria...............................................................................................................20
5.1.1
Diagnosis/Condition for Entry into the Trial.............................................................20
5.1.2
Subject Inclusion Criteria...........................................................................................20
5.1.3
Subject Exclusion Criteria .........................................................................................22
 
 
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5.2
Trial Treatment(s) .......................................................................................................25
5.2.1
Dose Selection/Modification .....................................................................................26
5.2.1.1
Dose Selection (Preparation) ..............................................................................26
5.2.1.2
Dose Modification (Escalation/Titration/Other).................................................26
5.2.2
Timing of Dose Administration.................................................................................27
5.2.3
Trial Blinding.............................................................................................................27
5.3
Randomization or Treatment Allocation...................................................................27
5.4
Stratification.................................................................................................................27
5.5
Concomitant Medications/Vaccinations ....................................................................27
5.6
Rescue Medications & Supportive Care....................................................................27
5.7
Diet/Activity/Other Considerations............................................................................27
5.7.1
Diet.............................................................................................................................27
5.7.2
Activity ......................................................................................................................28
5.7.3
Alcohol Intake............................................................................................................28
5.7.4
Contraception.............................................................................................................28
5.8
Subject Withdrawal/Discontinuation Criteria..........................................................28
5.9
Subject Replacement Strategy....................................................................................30
5.10
Beginning and End of the Trial ..................................................................................30
5.11
Clinical Criteria for Early Trial Termination ..........................................................30
6.0
TRIAL FLOW CHART ..................................................................................................31
7.0
TRIAL PROCEDURES ..................................................................................................33
7.1
Trial Procedures ..........................................................................................................33
7.1.1
Administrative Procedures.........................................................................................33
7.1.1.1
Informed Consent................................................................................................33
7.1.1.1.1
General Informed Consent...........................................................................33
7.1.1.2
Inclusion/Exclusion Criteria ...............................................................................33
7.1.1.3
Subject Identification Card .................................................................................34
7.1.1.4
Medical History ..................................................................................................34
7.1.1.5
Prior and Concomitant Medications Review......................................................34
7.1.1.5.1
Prior Medications.........................................................................................34
7.1.1.5.2
Concomitant Medications............................................................................34
7.1.1.6
Assignment of Screening Number......................................................................34
 
 
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7.1.1.7
Assignment of Treatment/Randomization Number............................................34
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)..........................................35
7.1.2
Clinical Procedures/Assessments...............................................................................35
7.1.2.1
Physical examination ..........................................................................................35
7.1.2.2
Vital sign.............................................................................................................35
7.1.2.2.1
Height...........................................................................................................35
7.1.2.2.2
Weight..........................................................................................................35
7.1.2.2.3
Sitting blood pressure and pulse..................................................................35
7.1.2.2.4
ECG .............................................................................................................36
7.1.2.3
Monitor Medication compliance.........................................................................36
7.1.3
Laboratory Procedures/Assessments .........................................................................36
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .........36
7.1.4
Other Procedures........................................................................................................37
7.1.4.1
Withdrawal/Discontinuation...............................................................................37
7.1.4.2
Blinding/Unblinding ...........................................................................................37
7.1.4.3
Calibration of Critical Equipment.......................................................................37
7.1.5
Visit Requirements.....................................................................................................38
7.1.5.1
Screening (Visit 1)..............................................................................................38
7.1.5.2
Treatment Period (Visit 2 to 9)...........................................................................38
7.1.5.3
Discontinuation...................................................................................................39
7.1.5.4
Post-Trial.............................................................................................................39
7.2
Assessing and Recording Adverse Events .................................................................39
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor ............................................................................................................40
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor ..............................................41
7.2.3
Immediate Reporting of Adverse Events to the Sponsor...........................................41
7.2.3.1
Serious Adverse Events ......................................................................................41
7.2.3.2
Events of Clinical Interest...................................................................................42
7.2.4
Evaluating Adverse Events........................................................................................43
7.2.5
Sponsor Responsibility for Reporting Adverse Events .............................................46
7.3
TRIAL GOVERNANCE AND OVERSIGHT..........................................................46
7.3.1
Scientific Advisory Committee..................................................................................46
 
 
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8.0
STATISTICAL ANALYSIS PLAN ...............................................................................46
8.1
Statistical Analysis Plan Summary ............................................................................46
8.2
Responsibility for Analyses/In-House Blinding ........................................................47
8.3
Hypotheses/Estimation ................................................................................................47
8.4
Analysis Endpoints ......................................................................................................47
8.4.1
Safety Endpoints ........................................................................................................47
8.4.2
Efficacy Endpoints.....................................................................................................47
8.5
Analysis Populations....................................................................................................48
8.5.1
Safety Analysis Populations ......................................................................................48
8.5.2
Efficacy Analysis Populations ...................................................................................48
8.6
Statistical Methods.......................................................................................................48
8.6.1
Statistical Methods for Safety Analyses ....................................................................48
8.6.2
Statistical Methods for Efficacy Analyses.................................................................48
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses...........48
8.7
Interim Analyses ..........................................................................................................49
8.8
Multiplicity ...................................................................................................................49
8.9
Sample Size and Power Calculations .........................................................................49
8.10
Subgroup Analyses and Effect of Baseline Factors ..................................................49
8.11
Compliance (Medication Adherence).........................................................................49
8.12
Extent of Exposure.......................................................................................................49
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ........................................................................................................................50
9.1
Investigational Product ...............................................................................................50
9.2
Packaging and Labeling Information ........................................................................50
9.3
Clinical Supplies Disclosure........................................................................................50
9.4
Storage and Handling Requirements.........................................................................50
9.5
Discard/Destruction/Returns and Reconciliation .....................................................50
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..............................................51
10.1
Confidentiality..............................................................................................................51
10.1.1 Confidentiality of Data ..............................................................................................51
10.1.2 Confidentiality of Subject Records............................................................................51
10.1.3 Confidentiality of Investigator Information...............................................................51
 
 
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10.1.4 Confidentiality of IRB/IEC Information....................................................................52
10.2
Compliance with Financial Disclosure Requirements..............................................52
10.3
Compliance with Law, Audit and Debarment ..........................................................52
10.4
Compliance with Trial Registration and Results Posting Requirements...............54
10.5
Quality Management System......................................................................................54
10.6
Data Management........................................................................................................54
10.7
Publications ..................................................................................................................54
11.0
LIST OF REFERENCES................................................................................................56
12.0
APPENDICES..................................................................................................................57
12.1
Merck Code of Conduct for Clinical Trials...............................................................57
12.2
List of Abbreviations ...................................................................................................59
12.3
Category Assessment for Each Patient......................................................................60
12.4
Lipid Management Goals Based on Risk Assessment..............................................62
12.5
Diet/Alcohol ..................................................................................................................63
12.6
Standard Operating Procedure for Liver and Muscle Enzyme Evaluations.........64
12.7
Clinical Study Conduct System ..................................................................................66
13.0
SIGNATURES..................................................................................................................67
13.1
Sponsor's Representative ............................................................................................67
13.2
Investigator...................................................................................................................67
 
 
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LIST OF TABLES
    
Table 1
Trial Treatment (Till 30-June-2017†) ........................................................................... 25
Table 2
Trial Treatment (From 1-July-2017‡) ........................................................................... 26
Table 3
Discontinuation Scenarios ............................................................................................ 29
Table 4
Laboratory Tests ........................................................................................................... 37
Table 5
Evaluating Adverse Events........................................................................................... 44
Table 6
Product Descriptions..................................................................................................... 50
 
 
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LIST OF FIGURES
          
Figure 1
Study Design............................................................................................................. 14
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
TRIAL SUMMARY
(Treatment Groups)
NOTE: MK-0653H (EZ 10mg + Ros 2.5mg) is 
co-administration with a tablet of Ezetimibe 10 
mg and a capsule/tablet of Rosuvastatin 2.5 mg. 
MK-0653H (EZ 10 mg + Ros 5 mg) is co-
administration with a tablet of Ezetmibe 10 mg 
and 2 capsules/tablets of Rosuvastatin 2.5 mg . 
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
4.2.2
Rationale for Dose 
Selection/Regimen/Modification
Subject will receive Ezetimibe 10 mg one tablet 
and Rosuvastatin 2.5 mg one capsule/tablet or two 
capsules/tablets in this trial, because BE study of 
MK-0653H FDC has not been completed at the 
start of this study.  
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
5.2
Trial Treatment(s)
Table 1  Trial Treatment (Till 30-
June-2017†)
Table 2 Trial Treatment (From 
1-July-2017‡ )
The treatment(s) to be used in this trial is  outlined 
below in Table 1 and 2.
† According to reevaluation date of rosutastatin 
described in COSC or CFG BRC (Certificate of 
Study Composition / Clinical Finish Goods Batch 
Release Certificate), date will be changed.
Treatment group
PTP sheet
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
‡ According to delivering timing of new 
rosuvastatin, it is allowable to provide the new 
rosuvastatin before 1-July-2017.
MK-0653H
（EZ 10 mg + Ros 2.5 mg）
Rosuvastatin
2.5 mg tablet 
1 tablet
MK-0653H
（EZ 10 mg + Ros 5 mg）
Rosuvastatin
2.5 mg tablet
2 tablets
7.1.5.2
Treatment Period (Visit 2 to 9) 
Week 0 (Visit 2)
Subject who is assigned MK-0653H (EZ 10 mg + 
Ros 2.5 mg) will be instructed to take one tablet 
from a bottle and 1 capsule from blister card or 1 
tablet from PTP sheet, subject who is assigned 
MK-0653H (EZ 10 mg + Ros 5 mg) will be 
instructed to take one tablet from a bottle and 2 
capsules from blister card or 2 tablets from PTP 
sheet and record medication compliance in a 
patient diary by following instruction. All subjects 
will be asked to bring the bottle, blister card(s) or 
PTP sheet(s) and patient diary to their next
scheduled clinic visit for compliance assessment.
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.2.1
Definition of an Overdose for 
This Protocol and Reporting of 
Overdose to the Sponsor
In this trial, an overdose is any dose higher than 
allocated: 1 tablet/capsule from either bottle or
blister card /PTP sheet during a day for MK-
0653H (EZ 10 mg+Ros 2.5 mg), 1 tablet from 
bottle and 2 capsules/tablets from blister cards or 
PTP sheet, respectively during a day for MK-
0653H (EZ 10 mg+Ros 5 mg).
Note: For subject who received Ros PTP sheets as 
study drug and rosuvastatin is up-titrated after 
Week 20 (Visit 5) by investigator, even if he/she 
took Ros above 5 mg including up-titrated dose 
from PTP sheet provided as study drug, this is not 
considered as overdose if the total daily dose is 
not over the instructed dose.
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
9.1
Investigational Product  
Table 6 Product Descriptions
Product Name & Potency
Dosage 
Form
Ezetimibe 10 mg
Tablet
Rosuvastatin Calcium 2.5 mg
Capsule 
or
Tablet
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
9.2
Packaging and Labeling 
Information
Subjects will receive sufficient supplies of open 
label bottle of Ezetimibe 10 mg and open labeled 
blister card or PTP sheet of Rosuvastatin Calcium 
2.5 mg to support a period between visits.
New information for 
change of dosage 
form on trial 
treatment
(Rosuvastatin)
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-0653H Phase III Long-term Safety Study
Sponsor Product Identifiers
MK-0653H
Trial Phase
III
Clinical Indication
Hypercholesterolemia, Familial Hypercholesterolemia
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-0653H (EZ 10 mg+Ros 2.5 mg), MK-0653H (EZ 10 mg+Ros 
5 mg)
NOTE: MK-0653H (EZ 10mg + Ros 2.5mg) is co-administration with 
a tablet of Ezetimibe 10 mg and a capsule/tablet of Rosuvastatin 2.5 
mg. MK-0653H (EZ 10 mg + Ros 5 mg) is co-administration with a 
tablet of Ezetmibe 10 mg and 2 capsules/tablets of Rosuvastatin 2.5 
mg.
Number of trial subjects
Approximately 134 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 19 
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 58 weeks 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of up to 4 weeks,
each subject will be receiving MK-0653H for approximately 52
weeks.  After the end of treatment each subject will be followed for 14 
days.
A list of abbreviations used in this document can be found in Appendix 12.2.
Randomization Ratio
 
 
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2.0 TRIAL DESIGN
2.1
Trial Design
This is a nonrandomized, multi- site, open-label trial of MK-0653H in subjects with 
hypercholesterolemia who don’t achieve LDL-cholesterol (LDL-C) target goal on Ezetimibe
(EZ) or Rosuvastatin calcium (hereafter Rosuvastatin or Ros) monotherapy to be conducted in 
conformance with Good Clinical Practices.
Subjects who have been treated with monotherapy with Ezetimibe 10 mg or Rosuvastatin 2.5 mg 
or 5 mg more than 8 weeks prior to Week 0(Visit 2) and who meet the all criteria will proceed to 
52 weeks of treatment period.  In case, subject received Ezetimibe 10 mg or Rosuvastatin 2.5 mg 
during screening period, dose is assigned MK-0653H (EZ 10 mg+Ros 2.5 mg). If subject 
received Rosuvastatin 5 mg during screening period, MK-0653H (EZ 10 mg+Ros 5 mg) will be 
assigned.  One hundred and thirty-four subjects will be allocated to ensure one hundred 
completers.
In principle, the dose of study drug should be maintained during 52 weeks. 
For MK-0653H(EZ10mg+Ros2.5mg):  If patients who do not attain their LDL-C goal on the 
EZ10mg+Ros2.5mg dose, can be titrated to Ros 5 mg after Week 20(Visit 5).  If they do not 
obtain their goal on EZ10mg+Ros5 mg, the dose of Ros can be increased at intervals not less 
than 12 weeks to Ros 10 and then 20 mg/day or another non-statin drug can be added to the 
patient’s regimen at the next visit. 
For MK-0653H(EZ10mg+Ros5mg): If patients do not obtain their goal on treatment with 
EZ10mg+Ros5mg, the dose of Ros can be increased at intervals not less 12 weeks to 10 and then 
20 mg/day or another non-statin drug can be added to the patients regimen at the next visit. To 
confirm the safety of subjects who changed the study drug or added another lipid lowering agent, 
they will be monitored by the investigator at his discretion schedule visits outside those specified 
by the protocol.
Interim results up to Week 24(Visit 6) will be summarized for filing purpose.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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2.2
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Study Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
Objective:  
To assess the safety and tolerability of MK-0653H (EZ 10 mg+Ros 2.5 mg) and MK-0653H
(EZ 10 mg+Ros 5
mg) through up to 52 weeks in Japanese patients with 
hypercholesterolemia uncontrolled with monotherapy of Ezetimibe 10 mg or Rosuvastatin up 
to 5 mg.
Hypothesis:
There are no hypotheses to test.
3.2
Secondary Objective(s) & Hypothesis(es)
Objective: 
To evaluate the percent change from baseline in LDL-C through 52 weeks of treatment with 
MK-0653H (EZ 10 mg+Ros 2.5 mg) and MK-0653H (EZ 10 mg+Ros 5 mg) in Japanese 
patients with hypercholesterolemia uncontrolled with monotherapy of Ezetimibe 10 mg or 
Rosuvastatin up to 5 mg.
 
 
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3.3
Exploratory Objective(s)
Objective: 
To evaluate below measurements through 52 weeks of treatment with MK-0653H (EZ 10 
mg+Ros 2.5 mg) and MK-0653H (EZ 10 mg+Ros 5 mg) for the following variables in 
Japanese patients with hypercholesterolemia uncontrolled with monotherapy of Ezetimibe 10 
mg or Rosuvastatin up to 5 mg: 

The percent change from baseline in total cholesterol (TC), HDL-C, non-HDL-C, 
triglyceride (TG), Apoprotein (Apo) B and hs-CRP. 

The proportion of patients who achieve LDL-cholesterol goal (refer to Apendix 12.4)
4.0 BACKGROUND & RATIONALE
4.1
Background
MK-0653H is a fixed dose combination drug containing Ezetimibe, a Niemann-Pick C1 Like1 
(NCP1L1) inhibitor and Rosuvastatin, a HMG-CoA reductase inhibitor as active ingredients. The 
active ingredients are Ezetimibe 10 mg and Rosuvastatin 2.5 mg or 5 mg.
Refer to the Investigator’s Brochure (IB)/approved labeling of Zetia® or Crestor® for detailed 
background information on Ezetimibe, Rosuvastatin or MK-0653H.
4.1.1
Pharmaceutical and Therapeutic Background
4.1.1.1
Pathophysiology and Epidemiology
Atherosclerosis and coronary heart disease (CHD), stroke and peripheral arterial disease caused 
by atherosclerosis are quite significant burdens to medical care in advanced countries. 
Approximately 0.4 million and 75,000 people die of CHD each year in the United States[1] and 
Japan[2], respectively. This number is expected to grow further in the next quarter of a century 
with increases in the morbidity of obesity and diabetes mellitus as well as the rapid aging of the 
population in Japan unequaled anywhere in the world.
Based on the results of many epidemiological surveys including the Framingham study, a 
correlation between serum lipid levels and the CHD risk has been well known[3], [4], [5]. 
Epidemiological surveys in Japan such as the NIPPON DATA 80 have also demonstrated that 
serum lipid levels correlate with the CHD risk[6]. Main large-scale clinical interventional studies 
of statins on serum lipid levels have shown that decreases in LDL-C levels are effective for the 
prevention of cardiovascular events, and statins are recommended to be first line therapy for the 
treatment of hyper-LDL-cholesterolaemia (2012 Japan Atherosclerosis Society Guidelines for 
Prevention of Atherosclerotic Cardiovascular Diseases [JAS2012][7]). Nonetheless, statin can 
decrease the relative risk of cardiovascular events only by approximately 20 to 40% so that the 
majority (approximately 70%) of cardiovascular events including myocardial infarction, 
coronary death, coronary revascularization and stroke are not actually prevented[8], [9]. Ezetimibe 
is recommended to be added-on to statin high risk hyper-LDL-cholesterolemia in patient who is 
uncontrolled with statin in the JAS2012[7]. Furthermore, a combination of statin monotherapy 
 
 
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and another lipid-lowering drug to sufficiently lower LDL-C levels is suggested to be an 
approach for reducing the risk of cardiovascular events.
4.1.1.2
Significance of the Development of Fixed Dose Combination Tablet (FDC) 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 lipid-soluble nutrients or vitamins.
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting 
enzyme of cholesterol synthesis taken into liver actively, and the biosynthesis of cholesterol is 
restrained strongly. As a result, cholesterol level in liver decrease so that the expression of LDL-
receptor is induced to support this decrease. Through LDL receptor, promote the synthesis of 
LDL receptors and decrease serum LDL-C. Rosuvastatin is mainly taken into liver via active 
transportation system. Because lipid affinity is relatively low, Rosuvastatin is not taken into 
other organs which don’t have active transportation system. Therefore Rosuvastatin is a liver-
specific HMG-CoA reductase.[10]
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 non-
Japanese hypercholesterolemic patients.[11]
2012 Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular 
Diseases (JAS2012)[7]
For drug therapy for patients with hyper-LDL-cholesterolemia, statin treatment is recommended. 
If the therapeutic target goal for dyslipidemia are not achieved with statin monotherapy, then 
increasing the dose or combination therapy with other class anti-hyperlipidemia drugs can be 
considered. Combination therapies that have been proven to be effective in improving serum 
lipid profiles in Japanese populations include the administration of statins in combination with 
Ezetimibe or resins is theoretically the most effective means of decreasing the LDL-C level. 
Furthermore, statin and Ezetimibe exerts TG-lowering and HDL-C increasing effect.
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[12]. In addition, 
data on other diseases show that the treatment compliance rate is correlated with the number of 
tablets (capsules) prescribed[13], [14]. 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.
 
 
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Consequently, concomitant administration of Ezetimibe and statin is assumed to more effectively 
improve hyper-LDL-cholesterolaemia based on their different mechanisms of actions.
4.1.2
Pre-clinical and Clinical Trials
Assessment of a Multiple-Dose Drug Interaction Between Ezetimibe and Rosuvastatin in 
Healthy Hypercholesterolemic Subjects (P03317)
A randomized, investigator/evaluator blind, placebo-controlled, single-center, multi-dose, 
parallel-group study in healthy hypercholesterolemic subjects (N=39 completers; for PK N=12 
Ezetimibe+Rosuvastatin , N=11 Rosuvastatin alone, N=8 Ezetimibe alone and N=8 placebo) for 
14 days. The data on metabolism of Ezetimibe and Rosuvastatin are also consistent with the lack 
of pharmacokinetic interaction between Ezetimibe and Rosuvastatin in this study. The findings 
of the study demonstrate that the co-administration of Ezetimibe and Rosuvastatin was well 
tolerated, with no evidence of increased incidence of adverse events or increases in clinical 
laboratory tests indicative of liver or skeletal muscle toxicity.
A Multicenter, Randomized, Double-Blind, Titration Study to Evaluate the Efficacy and Safety 
of Ezetimibe Added On to Rosuvastatin Versus Up Titration of Rosuvastatin in Patients with 
Hypercholesterolemia at Risk for Coronary Heart Disease (P139)
440 subjects at moderately high/high risk of coronary heart disease with LDL cholesterol levels 
failing to reach their LDL C goal (100 mg/dL [<2.6 mmol/L] or 70 mg/dL [<1.8 mmol/L] 
depending on baseline characteristics) were stratified to treatment with Rosuvastatin 5 mg or 10 
mg for 4-5 weeks.  Patients were then randomized to either doubling of their Rosuvastatin dose 
(to 10 mg or 20 mg) or adding Ezetimibe 10 mg to their Rosuvastatin (5 or 10 mg) therapy for 6 
additional weeks.
Patients taking Ezetimibe 10 mg+Rosuvastatin 5 mg or 10 mg achieved significantly greater 
LDL C reductions compared to patients doubling the initial dose of Rosuvastatin (to 10 mg or 20 
mg) (p <0.001).  The LS mean percent change in LDL C from baseline to the study end was 
21.0% when Ezetimibe 10 mg was added to Rosuvastatin and -5.71% when the original 
Rosuvastatin dose was doubled (data pooled across the Rosuvastatin 5 mg and 10 mg strata).  
The LS mean treatment difference was -15.3% with a 95% CI (-19.9, -10.6).
The overall safety profile appeared generally comparable between treatment groups. Pooled 
across strata, there were no clinically relevant differences between Rosuvastatin (5 or 10 mg) + 
Ezetimibe 10 mg and Rosuvastatin (10 or 20 mg) in the proportion of patients with clinical 
adverse experiences, serious adverse experiences, drug-related adverse experiences, serious and 
drug-related adverse experiences, or adverse experiences leading to discontinuation. There was 
no significant difference between Rosuvastatin (5 or 10 mg) + Ezetimibe 10 mg and 
Rosuvastatin (10 or 20 mg) with respect to the percentage of patients with gastrointestinal-
related, allergic events or rash, and hepatitis-related clinical adverse experiences.
 
 
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Post-marketing survey of Ezetimibe (Zetia®) in Japan
Specific drug use survey of Ezetimibe for hyperlipidemia (52 weeks long term treatment) was 
performed from June 2007 to February 2011. The objective is to confirm the safety and efficacy 
of long-term use of Ezetimibe as monotherapy and combination therapy with other lipid 
lowering drugs (statins and non-statins) in the routine clinical practice.Total 1640 patients were 
analyzed and the incidence of drug-related adverse events (AE) were 204 patients (12.44%)[15]. 
168 patients of them were co-administered with Ros and the incidence of drug-related AE were 9 
patients (5.36%). This survey shows that the incidence of drug-related AE of total and co-
administered with Ros group are lower than that of Ezetimibe approved in Japan, 18.85%.
The most commonly reported drug-related AE in total is Blood creatine phosphokinase increased 
(2.26%), Hepatic function abnormal (1.40%), Diarrhoea (0.79%), Gamma-glutamyltransferase 
increased (0.61%).  The most commonly reported drug-related AE in co-administered with Ros 
group is Hepatic function abnormal (1.79%), Alanine aminotransferase increased and Gamma-
glutamyltransferase increased (1.19%).
The incidence of side effects was similar in total and Ros co-administration group and As for the 
effectiveness, LDL-C was reduced both in total and Ros co-administration group (-26.06%) and 
no attenuation of clinical effect was observed in the long term administration.
4.1.3
Ongoing Clinical Trials
A phase III, clinical trial to study the efficacy and safety of MK-0653H in Japanese patients with 
hypercholesterolemia(P832) is ongoing.
4.2
Rationale
4.2.1
Rationale for the Trial and Selected Subject Population
Since the dosage and administration of this FDC is expected second-line therapy, FDC will be 
administered when patients are uncontrolled with monotherapy. Therefore, the target population 
of 
this 
study 
is 
patients 
with 
hypercholesterolemia 
and 
heterozygous
familial 
hypercholesterolemia uncontrolled with Ezetimibe or Rosuvastatin monotherapy in whom the 
lipid management target value of LDL-C as per their Coronary artery disease (CAD)-risk 
category based on JAS2012 has not been achieved.
Considering hypercholesterolemia, MK-0653H will be used for long-term. Based on “The Extent 
of Population Exposure to Assess Clinical Safety of Drugs Intended for Long term Treatment of 
Non life-threatening Conditions” (Notification No. 592; issued May 24, 1995), patients will 
receive study drug for up to 52 weeks.  Because this study is designed to provide information 
about the safety of long-term administration of MK-0653H(EZ 10 mg+Ros 2.5 mg or EZ 10 
mg+Ros 5 mg), this study is open-label.
4.2.2
Rationale for Dose Selection/Regimen/Modification
The dosage of Ezetimibe is 10 mg once daily. The results of the Japanese Phase II study of 
Ezetimibe (JPC-00-335-21) revealed that the LDL-C lowering rate practically reached the 
maximum at a dose of 10 mg and there was no increase in the incidence of adverse events with 
increases in the dose. The dosage of Ezetimibe in foreign countries is 10 mg once daily as in 
 
 
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Japan, and the Ezetimibe dose combined in its combination drug with simvastatin approved in 
foreign countries is 10 mg. In Japan, Ezetimibe at a dose of 10 mg has been approved since 
2007; thus, it has an abundance of clinical use experience both as monotherapy and combination 
therapy in Japanese patients. Consequently, we have chosen to examine Ezetimibe to be 
combined in MK-0653H at 10 mg.
The starting dose of Rosuvastatin in Japanese patients is 2.5 mg once a day, which can be titrated 
to 10 mg and 20 mg (where available). Furthermore, according to the survey of Japan Medical 
Data Center (JMDC) prescription receipt data from January 2013 out of the subjects who were 
coadministered Rosuvastatin and Ezetimibe (estimated number of patients is 0.2 million 
including familial cholesterolemia), the ratio of subjects who were administered the daily dose of 
Rosuvastatin 2.5mg and 5 mg were 54.5% and 35.3%, respectively, and these two doses 
accounted for 90% of the total subjects.[16]
In consideration of the efficacy and safety profiles of Rosuvastatin, the prescription status of 
Rosuvastatin, and the clinical position of MK-0653H, we have found that 2.5 mg or 5 mg is an 
appropriate dose to be combined for Rosuvastatin.
Subject will receive Ezetimibe 10 mg one tablet and Rosuvastatin 2.5 mg one capsule/tablet or 
two capsules/tablets in this trial, because BE study of MK-0653H FDC has not been completed
at the start of this study. MK-0653H demonstrated bioequivalence of the coadministration of 
Japan-sourced Ezetimibe and Rosvastatin tablets.
4.2.3
Rationale for Endpoints
4.2.3.1
Safety Endpoints
In this study, the safety and tolerability of MK-0653H for up to 52 weeks will be used as the 
primary variable.
The safety will be evaluated with clinical and laboratory safety assessments conducted 
throughout the study.
Clinical measurements to assess the safety and tolerability of MK-0653H include monitoring of 
AEs and clinical evaluation (including vital signs and physical examination).
Laboratory safety assessments include chemistry, hematology and urinalysis, performed at 
specific study visits. All determinations will be performed by the central laboratory.
Gastrointestinal related AEs, gallbladder-related AEs, allergic reaction or rash AEs, hepatitis-
related AEs, consecutive elevations in ALT and/or AST ≥3xULN, ALT and/or AST elevation 
≥5xULN, ALT and/or AST elevation ≥10xULN, Potential Hy's Law Condition (defined as ALT 
or AST elevations >3xULN, with alkaline phosphatase <2xULN and total bilirubin (TBL) 
≥2xULN), elevations in CK ≥10xULN, elevations in CK ≥10xULN with muscle symptoms, and 
elevations in CK ≥10xULN with muscle symptoms that are considered drug-related are 
determined as safety events of special interest and will be evaluated.
 
 
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4.2.3.2
Efficacy Endpoints
In this study, the efficacy of MK-0653H in below parameters will be used as the secondary
variable.
The percent change in LDL-C from baseline, in other lipid parameters (TC, TG, HDL-C, non 
HDL-C and Apo B), hs-CRP and the proportion of patients who achieve LDL-cholesterol goal 
after 52 weeks will be used as secondary variable.
4.3
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment during 
participation, as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Because this study is open-label study, all enrolled subjects is able to receive active MK-0653H
(EZ 10 mg+Ros 2.5 mg) or MK-0653H (EZ 10 mg+Ros 5 mg). And if subject is not achieved 
goal, it is allow to uptitrate to MK-0653H (EZ 10 mg+Ros 5 mg) or add another lipid lowering 
agent (i.e., total up to 20 mg of Rosuvastatin, NOTE: to add another statin except with 
Rosuvastatin is not allowed.) after 12 weeks or beyond treatment. However, concomitant 
medications concerned drug interaction with EZ or Ros is limited during study period.
Additional details regarding specific benefits and risks for subjects participating in this clinical 
trial may be found in the accompanying Investigators Brochure (IB) and Informed Consent 
documents.
5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with hypercholesterolemia between the ages of 20 and 80 years (inclusive)
will be enrolled in this trial.
Subjects with screening one value/finding outside the range described in the inclusion or 
exclusion criteria may, at the discretion of the investigator, have one repeat determination 
performed and if the repeat value satisfies the criterion, they may continue in the screening 
process. Only one specific out of range value/finding should be repeated (not entire panel).
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
<Visit 1: Screening, Week -4>
1. Japanese male or female and between ≥ 20 and ≤ 80 years of age on the day of signing 
informed consent.
 
 
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2. Subject understands the study procedures alternative treatments available, and risks 
involved with the study, and voluntarily agrees to participate by giving written informed 
consent.
3. Outpatient with hypercholesterolemia.
4. Subject is a male or female subject who is of reproductive potential agrees about 
contraception, or a female subject who is not of reproductive potential.
Female subject who is of reproductive potential has to agree to remain abstinent or use 
(or partner use) two acceptable methods of birth control from date of signed informed 
consent to the 14 days after the last dose of study drug. Acceptable methods of birth 
control are: intrauterine device (IUD), diaphragm with spermicide, condom, and
vasectomy.
A female subject who is not of reproductive potential is eligible without requiring the use 
of contraception.  A female subject who is not of reproductive potential is defined as:  
one who has either 1) reached natural menopause defined as age 46 or older with 12 
months of spontaneous amenorrhea, 2) 6 weeks post surgical bilateral oophorectomy or 
hysterectomy, or 3) bilateral tubal ligation.
5. Subject will maintain a stable diet that is consistent with the Japan Atherosclerosis 
Society Guideline 2012 (JAS 2012) for prevention of atherosclerotic cardiovascular 
diseases for the duration of the study.
6. Subject who has been treated with a stable regimen of Ezetimibe monotherapy at 10 mg 
or Rosuvastatin monotherapy at 2.5 mg or 5 mg more than 4 weeks.
<Visit 2: Week 0>
7. Subject meets any of the following criteria.
Category will be assessed based on Section 12.3 . (JAS2012).
LDL-C value will be calculated by Friedewald method at Visit 1. 
Friedewald method: LDL-C = Total cholesterol – HDL-cho – TG/5.
(1) Subject is categorized “Category I” and has LDL-C value ≥160 mg/dL
(2) Subject is categorized “Category II” and has LDL-C value ≥140 mg/dL
(3) Subject is categorized “Category III” and has LDL-C value ≥120 mg/dL
(4) Subject is categorized History of Coronary Artery Disease (CAD) group because 
of history of CAD and has LDL-C value ≥ 100 mg/dL
(5) For the subject with heterozygous familial hypercholesterolemia (HeFH), subject
whose LDL-C value ≥ 100 mg/dL can be enrolled.
Note: HeFH is
Subject is diagnosed as HeFH using genetic testing.
Or 
 
 
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Subject meets two or more of the below criteria based on JAS2012.
-
Hyper LDL-cholesterolemia (an untreated LDL-C level of ≥180mg/dL)
-
Tendon xanthoma (tendon xanthoma on the backs of the hands, elbows, 
knees, etc. or Achilles tendon hypertrophy) or xanthoma tuberosum
-
Family history of FH or premature CAD (within the subject’s second-degree 
relatives)
8. Subject has TG value < 400 mg/dL at Visit 1.
9. Subject has CK (CPK) value ≤ 3 x upper limit of normal (ULN) [per central laboratory 
reference ranges] at Visit 1.
10. Subject has ALT and AST value ≤ 2 x ULN [per central laboratory reference ranges] at 
Visit 1.
11. Subject is greater than 75% compliant with Ezetimibe monotherapy at 10 mg or 
Rosuvastatin monotherapy at up to 5 mg administered between Visit 1 and Visit 2.
5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
<Visit 1: Screening, Week -4>
Prohibited Medical Conditions
1. Subject has uncontrolled hypertension (treated or untreated) systolic blood pressure >160 
mmHg or diastolic >100 mmHg at Visit 1.
2. Subject has uncontrolled type 1 or type 2 diabetes mellitus (treated or untreated, HbA1c 
≥8.0% at Visit 1 or newly diagnosed within 3 months).
3. Subject has chronic heart failure defined by New York Heart Association (NYHA) 
Classes III or IV.
4. Subject has uncontrolled cardiac arrhythmias or recent significant abnormality in the 
subject's electrocardiogram as takes within 6 months prior to Visit 1, by investigator's 
opinion.
5. Subject has the following history within 3 month prior to Visit 1.
a.
Acute coronary syndrome (e.g., myocardial infarction, or unstable angina).
b. Coronary 
revascularization 
procedures 
(coronary 
bypass, 
percutaneous 
transluminal coronary angioplasty, or similar procedure).
c.
Acute stroke
6. Subject has homozygous familial hypercholesterolemia or has undergone LDL apheresis.
7. Subject has uncontrolled 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).
 
 
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Note: Definitions of hyper- and hypothyroidism are as follows:

Hyperthyroidism: TSH below the central laboratory's LLN.

Hypothyroidism: TSH >20% above the ULN.
For subjects receiving thyroid hormone, there is no lower TSH threshold for entry 
(Visit 1) and the subject must be on a stable dose for ≥6 weeks before the allocation
visit (Visit 2). One redraw will be allowed if the original TSH value is less than 40% 
above or below the reference range, but the subject must meet the criterion upon 
redraw.
8. Subject has estimated glomerular filtration rate (eGFR) < 30 mL/min/ 1.73 m2 based on 
the below equation, nephrotic syndrome or other clinically significant renal disease at 
Visit 1. 
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. Subject
has had a gastrointestinal tract
bypass, or other significant intestinal 
melabsorption.
10. Subject 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. Subject who is known HIV positive (as assessed by medical history).
12. Subject has a history of drug/ alcohol abuse within the past 5 years from Visit 1, or 
psychiatric illness no adequately controlled and stable on pharmacotherapy.
13. Subject has a condition or situation, which described as contraindication in labeling of 
Zetia® or Crestor® (i.e ., Patients with diminished liver metabolism capacity due to the 
following conditions: Acute hepatitis, acute exacerbation of chronic hepatitis, hepatic 
cirrhosis, liver cancer, or jaundice.) or may interfere with participation in the study in the 
opinion of the investigator.
Prohibited therapies
14. Subject is currently taking medications restricted co-administration by labeling as 
followings; 

Cyclosporine

Systemically administered azole antifungals (i.e., ketoconazole, itraconazole and 
fluconazole)

Macrolide antibiotics (e.g., clarithromycin, erythromycin and telithromycin)

Antacid (e.g., aluminum hydroxide/magnesium hydroxide)

Protease inhibitors (e.g., Lopinavir/Ritonavir, Atazanavir+Ritonavir, Darunavir 
+Ritonavir, concomitant use with elbasvir and grazoprevir)

Simeprevir

Eltrombopag
 
 
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15. Subject is receiving treatment with systemic corticosteroids. (intravenous, intramuscular 
and oral steroids)
Note1: If subject has been treated with a stable regimen of oral corticosteroids used as 
replacement therapy for pituitary/adrenal disease as well as inhaled steroid therapy for ≥
4 weeks prior to Visit 1 and agree to continue this regimen for the duration of the trial, 
concomitant therapy is acceptable. 
NOTE2: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are 
acceptable.
16. Subject is taking any cyclical hormones (e.g., cyclical oral contraceptives, cyclical 
hormone replacement), including the combination of ethinyl estradiol and norethisterone.
Note: If subject has been treated with a stable regimen for ≥ 4 weeks prior to Visit 1 and 
agree to continue this regimen for the duration of the trial, concomitant therapy is 
acceptable.
17. Subject is receiving non-cyclical hormone therapy (including non-cyclical hormone 
replacement therapy or any estrogen antagonist/agonist).
Note: If subject has been treated with a stable regimen for ≥4 weeks prior to Visit 1 and 
agree to continue this regimen for the duration of the trial, concomitant therapy is 
acceptable. 
18. Subject is treated with psyllium, other fiber-based laxatives, phytosterol margarine, 
herbal medicine and/or over the counter (OTC) therapies.
Note: If subject has been treated with a stable regimen for ≥4 weeks prior to Visit 1 and 
agree to continue this regimen for the duration of the trial, concomitant therapy is 
acceptable.
19. Subject is treated with an anti-obesity drug (e.g. mazindol) within 3 months (12 weeks) 
prior to Visit 1.
20. Subject is newly treated with warfarin and/or warfarin-like anticoagulants at Visit 1, or 
subject has not been on a stable dose with a stable International Normalized Ratio (INR) 
for at least 6 weeks prior to Visit 1.
General 
21. Subject consumes more than 25 g of alcohol per day. (refer to Appendix 12.5)
22. Subject who currently follows an excessive weight reduction diet in the opinion of the 
investigator.
23. Subject currently engages in a vigorous exercise regimen (e.g.; marathon training, body 
building training etc.) or intends to start training during the study.
24. Subject has hypersensitivity or intolerance to Ezetimibe or Rosuvastatin.
25. Subject has a history of myopathy or rhabdomyolysis with Ezetimibe or any statin.
26. Subject is currently pregnant or lactating.
 
 
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27. Subject is taking any other investigational drugs and/or has taken any investigational 
drugs within 30 days prior to the day of signing informed consent, unless 
pharmacokinetics necessitates a longer washout.
<Visit 2: Week 0>
28. Subject has taken lipid-lowering agents including fish oils, Cholestin™, bile acid 
sequestrants, statins other than Rosuvastatin, fibrates or niacin (>200 mg/day) except for 
pretreatment Ezetimibe or Rosuvastatin in screening period (from 8 weeks prior to Visit 
2). OR Subject has taken probucol or protein convertase subtilisin/kexin type 9 (PCSK 9) 
inhibitor within 12 weeks prior to Visit 2.
<Visit 1~2>
29. The subject who is considered inappropriate for participation in the study by the 
investigator for any other reason.
30. Subject 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 study exclusion criteria.
31. Subject Is or has an immediate family member (e.g., spouse, parent/legal guardian, 
sibling or child) who is investigational site or sponsor staff directly involved with this 
trial.
5.2
Trial Treatment(s)
The treatment(s) to be used in this trial is outlined below in Table 1 and Table 2.
Table 1
Trial Treatment (Till 30-June-2017†)
Treatment group
Bottle
Blister card A
Blister card B
MK-0653H
(EZ 10 mg +
Ros 2.5 mg)
Ezetimibe 10 mg 
tablet 
Rosuvastatin 2.5 mg 
capsule
NA
MK-0653H
(EZ 10 mg + Ros 5 
mg)
Ezetimibe 10 mg 
tablet 
Rosuvastatin 2.5 mg 
capsule 
Rosuvastatin 2.5 mg 
capsule 
† According to reevaluation date of rosutastatin described in COSC or CFG BRC (Certificate of Study 
Composition / Clinical Finish Goods Batch Release Certificate), date will be changed. 
 
 
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Table 2
Trial Treatment (From 1-July-2017‡)
Treatment group
Bottle
PTP sheet
MK-0653H
(EZ 10 mg + Ros 2.5 mg)
Ezetimibe 10 mg tablet 
Rosuvastatin 2.5 mg tablet 
1 tablet
MK-0653H
(EZ 10 mg + Ros 5 mg)
Ezetimibe 10 mg tablet 
Rosuvastatin 2.5 mg tablet 
2 tablets 
‡ According to delivering timing of new rosuvastatin, it is allowable to provide the new rosuvastatin 
before 1-July-2017.
The first dose of trial treatment will be administered at the trial site at Visit 2.  Subsequent 
dosing will be performed once daily by the subject (i.e., unsupervised at his/her home) at 
approximately the same time each day.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
5.2.1
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
Dose of MK-0653H is assigned according to pretreatment within 8 weeks prior to Visit2. In case, 
subject received Ezetimibe 10 mg or Rosuvastatin 2.5 mg during screening period, dose is 
assigned MK-0653H (EZ 10 mg+Ros 2.5 mg). If subject received Rosuvastatin 5 mg during 
screening period, MK-0653H (EZ 10 mg+Ros 5 mg) must be assigned.
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
At any point after Week 12 (Visit 4), if the subject's LDL-C value does not achieve the lipid
management goals and investigator consider it is clinically safe and tolerable, the dosage for the 
subject treated with MK-0653H (EZ 10 mg+Ros 2.5 mg) may be increased to MK-0653H (EZ 
10 mg+Ros 5 mg) at next scheduled visit.
The dosage should be maintained at least 12 weeks after dose changing.
If subject treated with MK-0653C (EZ 10 mg + Ros 5 mg) more than 12 weeks but does not 
achieve the lipid management goal, adding another lipid lowering agent (i.e., total up to 20 mg of 
Rosuvastatin. NOTE:, to add another statin except with Rosuvastatin is not allowed.) may be 
allowed from next scheduled visit at the discretion of the investigator.
 
 
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5.2.2
Timing of Dose Administration
Study drug will be administered orally once daily after a meal. As there is no recommended time 
for the dosage, subject should take their treatment at a consistent time each day to promote 
compliance. On the visit day, subject should take medication after all procedure is completed.
The scheduled last study drug is a day before Visit9.
5.2.3
Trial Blinding
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
Subjects will be assigned randomly according to a computer-generated allocation schedule.
Subjects participating in this trial will be allocated by non-random assignment.
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 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 subject's primary physician.  However, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the investigator, the Sponsor 
and the subject.
Concurrent antihypertensive, and antihyperglycemic medications are permitted. If doses of these 
medications change, details must be reported to SPONSOR.
5.6
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
5.7
Diet/Activity/Other Considerations
5.7.1
Diet 
Subjects should be instructed on JAS2012 diet or a similar diet at Visit 1. Please refer to Section 
12.5 for details on the diet regimen.
At each subsequent study visit, the dietary compliance will be monitored and sites should 
reinstruct subjects who are not compliant. This monitoring is particularly important in an effort 
to minimize any diet-related lipid changes.
 
 
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5.7.2
Activity 
Subjects should continue any activity (including smoking) he/she was accustomed to prior to 
entering the study, but should refrain from engaging in a vigorous exercise regimen and initiating 
smoking during the study. Subjects should be instructed the activity by investigator based on 
JAS2012. Subject also should keep exclusion criterion #22 and #23. (Subject does not follow 
excessive weight reduction diet and does not engage in a vigorous exercise regimen or start 
training) during the study.
5.7.3
Alcohol Intake
Subjects should not consume more than the 25 g alcohol per day, and should not have any 
alcohol within 24 hours prior to scheduled visit.
Subjects will not be permitted in the study if they consistently consume excessive amounts of 
alcohol. Subjects should be encouraged not to make major changes in their alcohol consumption 
for the duration of the study. Please refer to Section 12.5 for reference volume of alcohol.
5.7.4
Contraception
Women of reproductive potential can be entered in the study (see inclusion criteria #4) and must 
agree to use 2 acceptable methods of contraception during sexual activity with a male partner. 
These contraceptive methods must be used throughout the study. Acceptable methods of 
contraception are either 2 barrier methods to prevent pregnancy. The following are considered 
acceptable barrier methods of contraception: intrauterine device (IUD), diaphragm with 
spermicides, condoms, partner or vasectomy. Contraception medications are prohibited by
exclusion criteria #16 and #17.
5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other Procedures.
Table 3 provides reasons why a subject must be discontinued from treatment but may continue to 
be monitored in the trial, as well as reasons why a subject must be discontinued from treatment 
and the trial.
 
 
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Table 3
Discontinuation Scenarios
Reason for Discontinuation Scenario
Action
The subject or legal representative (such 
as a parent or legal guardian) withdraws 
consent.
Discontinuation from Treatment and Trial
Consecutive (2 or more measurements) 
elevations in ALT and/or AST ≥3 x ULN.
Discontinuation from Treatment and Trial 
Consecutive elevations in CK ≥10 x ULN 
with or without muscle symptoms.
Discontinuation from Treatment and Trial 
Consecutive elevations in CK ≥5 to <10 x 
ULN with muscle symptoms.
Discontinuation from Treatment and Trial 
Subject requiring any treatment with 
cyclosporine or fibrates.
Discontinuation from Treatment and Trial 
Adverse experiences: Subject may be 
withdrawn from the study in the event that 
the 
investigator 
assesses 
that 
administration of the study drug should be 
discontinued due to the occurrence of 
adverse experiences which would interfere 
with study continuation.
Discontinuation from Treatment and Trial 
Serious deviation from the protocol: It 
becomes inappropriate to continue study 
treatment as a result of a significant 
protocol deviation.
Discontinuation from Treatment and Trial
Insufficient responses: When subject is 
judged by the investigator it interferes 
with study continuation.
Discontinuation from Treatment and Trial 
Lost to follow up: When a subject stops 
visiting a site after initiation study drug, 
he/she will be contacted via a letter or 
telephone call to confirm the reason for 
missed visits, dosing of study drug and the 
subsequent courses as much as possible.
Discontinuation from Treatment and Trial
Moved (or relocated): When subject has 
either moved or relocated and is no longer 
able to participate in the study.
Discontinuation from Treatment and Trial
 
 
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Reason for Discontinuation Scenario
Action
Positive serum pregnancy test (Positive 
serum pregnancy test): A positive urine 
pregnancy 
test 
requires 
immediate 
interruption of study drug while awaiting 
results of serum pregnancy (β-hCG) test.
Discontinuation from Treatment and Trial 
The subject has a medical condition or 
personal circumstance which, in the 
opinion of the investigator and/or Sponsor, 
places the subject at unnecessary risk 
through continued participation in the trial 
or does not allow the subject to adhere to 
the requirements of the protocol.
Discontinuation from Treatment and Trial 
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall not 
be allowed to restart treatment.
5.9
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall trial 
ends when the last subject completes the last study-related phone-call or visit, discontinues from 
the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
5.11 Clinical Criteria for Early Trial Termination
The clinical trial 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 trial population as a whole is 
unacceptable.  In addition, further recruitment in the trial or at (a) particular trial site(s) may be 
stopped due to insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for administrative 
reasons is too high.
 
 
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1.
Visit window at Visit 2 are relative to Visit 1. Visit windows at Visits 3 to 9 are relative to the Visit 2. NOTE: Visit apart 
between 5 and 6 must be set within 35-day.
2.
Informed consent must be obtained before any protocol-related study procedures are performed. It is allowable to obtain 
informed consent before Visit 1. After obtaining informed consent, subject will be given a unique screening number (refer to
7.1.1.6) and a subject identification card (refer to 7.1.1.3).
3.
Subject’s risk category assessment is determined at Visit 2 according to the Japan Atherosclerosis Society (JAS) Guideline
2012 based on the results obtained at Visit 1 (refer to Appendix 12.3).
4.
Auscultation and palpation and interview of condition will be conducted for physical examination.
5.
Height will be measured only at Visit 1. 
6.
All laboratory draws for the study will be conducted after at least 10-hour fast
7.
Lipid panel A: LDL-C, total cholesterol (TC), HDL-C, non-HDL-C, and TG
8.
Lipid panel B: hs-CRP and Apo B
9.
Chemistry: Glucose, ALT, AST, ALP, uric acid, total bilirubin, BUN, CK (CPK), creatinine, Cl, potassium, sodium,
γ-glutamyltransferaze
10. Hematology: hemoglobin, platelet count, red blood cell count, white blood cell count, hematocrit
11. Subjects who have diagnosed with diabetes only may have their sample collected.
12. Urinalysis: pH, glucose (qualitative), protein (qualitative)
13. Only in female subjects who have reproductive potential as specified in inclusion criteria #4. Urine pregnancy test (urine hCG) 
will be determined locally, serum β-hCG test is determined by central lab if urine pregnancy performed at the site is positive.
14. Visit day’s dose of study drug should be taken on the day of the visit; last dose between each visit should be taken on the day 
before the next scheduled visit.
15. Medical compliance from Visit 1 to 2 should be recorded to patient diary.
16. Considering subject’s LDL-C at any point after Week 12 (Visit 4) and conditions, investigator determines it is necessary to 
change the dosage of study drug, it is allows to change the dosage at next scheduled visit after Week 20 (Visit 5). When study 
drug is changed or the dose of Ros is increased at intervals not less than 12 weeks to Ros 10 and then 20 mg/day or another 
non-statin drug is added to the patient’s regimen, it must be reported to SPONSOR and Patient Registration Center 
immediately.
17. Poststudy phone call will be conducted 14 days after administration of the last dose of study drug.
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical trial.
If there are changes to the subject’s status during the trial (e.g., health or age of majority 
requirements), the investigator or qualified designee must ensure the appropriate consent is in 
place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’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 subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  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 subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.
 
 
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7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee will 
provide the subject with a Subject Identification Card immediately after the subject provides 
written informed consent. At the time of treatment allocation/randomization, site personnel will 
add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency unblinding 
call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 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 subject within 8 weeks 
before Week 0 (Visit 2). 
Target is subjects who treated with Rosvastatin as prior medication will be enrolled at least 40% 
of total enrolled subjects.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to randomization or treatment allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is screened multiple times will retain the original screening number assigned at 
the initial screening visit.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject for 
all procedures occurring after treatment allocation/randomization.  Randomization number will 
be allocated at Week 0 (Visit 2).
Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
 
 
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7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Adherence to study medication will be assessed by subject report by patient diary recorded by 
subject every day.
Interruptions from the protocol specified compliance <= 75% at each visit require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Administration of trial medication at Visit 2 will be witnessed by the investigator and/or trial 
staff.
7.1.2
Clinical Procedures/Assessments
In order to minimize variability, it is preferred that the same individual perform the same 
procedure (s)/ evaluation (s) for all subjects at each trial site. All procedures will be performed at 
Visits outlined in the study flow chart (Section 6.0).
7.1.2.1
Physical examination
Physical examination (auscultation, palpation, and interview of condition) will be performed by 
investigator. The investigator will determine if the results are clinically significant prior to Week 
0 (Visit 2), any physical examination abnormalities will be recorded as part of the subject's 
medical history.
7.1.2.2
Vital sign
7.1.2.2.1 Height 
Standing height will be assessed through maximum vertical stature for persons who can stand 
unassisted. Hair ornaments, barrettes, braids, jewelry, or cornrows should be moved or removed 
from the top of the head before the measurement is taken.
7.1.2.2.2 Weight
Weight must be measured after at least 10 hours of fasting after voiding, with shoes and socks 
off, wearing only underwear, or a clinic vest or light clothing to reduce variability and to 
maintain consistency. Subjects should not be weighed while wearing sweaters, coats, or other 
heavy clothing.
7.1.2.2.3 Sitting blood pressure and pulse
Sitting blood pressure (SiDBP) and pulse will be measured by automated sphygmomanometer 
provided by the SPONSOR. Throughout the study, the measurement should be conducted with a 
consistent arm for a given person.
1.
The subject will remain in the sitting position for at least 10 minutes before any blood 
pressure readings are recorded. 
2.
Situate the individual in a quiet environment with the arm resting at heart level.
3.
Select the appropriately sized cuff.  
 
 
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4.
Systolic and diastolic blood pressures will be determined by averaging 2 replicate 
measurements obtained 1 to 2 minutes apart.  
5.
The mean BP value is calculated from 2 readings by omitting the figures below the first 
decimal place 
6.
None of the 2 consecutive SiDBP readings can be >5 mm Hg from the calculated average of 
the 2 readings.  Additional readings must be done until this is achieved.
7.
Assessment should be used average of 2 readings.
NOTE: Pulse rate will be 2 consecutive readings measured simultaneously with blood pressure, 
and assessment should be used average of 2 readings.
7.1.2.2.4 ECG
12-lead ECG will be performed at the respective study sites and recorded. The investigator or 
sub-investigator will determine if the results are clinically significant and they meet the 
eligibility criteria.  Any ECG abnormalities will be recorded as part of the subject's medical 
history. ECG readings reported to Sponsor will be diagnosed by the investigator or sub-
investigator.
7.1.2.3
Monitor Medication compliance
Subjects should be instructed to record date and the number of tablet that administered the study 
drug at home to the provided patient diary during treatment period. The site staff should confirm 
and collect the diary at each visit.
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 4.
 
 
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Table 4
Laboratory Tests
Category
Test
Lipid Panel A
LDL-C, total cholesterol (TC), HDL-C, non-HDL-C, and TG
Lipid Panel B
Apo B, hs-CRP
Blood 
Chemistry
Glucose, ALT, AST, ALP, uric acid, total bilirubin, BUN, CK 
(CPK), creatinine, Cl, potassium, sodium, γ-glutamyltransferaze
Hematorogy
hemoglobin, platelet count, red blood cell count, white blood cell 
count, hematocrit
TSH
HbA1C
NOTE: Subjects who have diagnosed with diabetes only
Urinalysis test
pH, glucose (qualitative), protein (qualitative)
Pregnancy test
Urine pregnancy test (urine hCG) will be determined at the site.
Serum β-hCG test is determined by central lab if urine pregnancy 
performed is positive.
NOTE: female subjects who have reproductive potential Only
Laboratory safety tests will be performed after at least a 10-hour fast. 
Fasting blood samples will be drawn as outlined in the Study Flow Chart. The central laboratory 
will perform all laboratory test determinations. LDL-C will be calculated using the Friedewald 
method when TG≤400 mg/dL and beta quantification ultracentrifugation when TG>400 mg/dL.
7.1.4
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit (Visit9) should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device or 
instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or reproducible.  
Documentation of equipment calibration must be retained as source documentation at the trial 
site.
Critical Equipment for this trial includes:

Auto sphygmomanometer
 
 
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7.1.5
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening (Visit 1)
Potential subjects will be evaluated to determine that they fulfill the entry requirements as set 
forth in Section 5.1. A signed informed consent will be obtained prior to performing any protocol 
study procedures.
Screening procedures may be repeated after consultation with the Sponsor. In case of re-
screening, all procedure listed at screening visit including informed consent should be performed.
Visit 1 will be performed approximately 4 weeks prior to Visit 2. Subject must discontinue the 
prior medication for hypercholesterolemia [fish oils, Cholestin™, bile acid sequestrants, statins, 
fibrates or niacin (>200 mg/day)] except with Ezetimibe 10 mg, Rosvastatin 2.5 mg or 5 mg at 
least 8 weeks prior to Visit 2. If subject has taken probucol, probucol must be discontinued from 
12 weeks prior to Visit 2. If a subject is eligible for study participation, a 10 hour fasting blood 
sample will be drawn. Subject should not take prior medication (Ezetimibe 10 mg or Rosvastatin 
2.5 mg or 5 mg) before screening procedure and take prior medication after all test completed. 
Subject should be instructed diet therapy according to JAS2012 and must continue throughout 
the study.
If a subject is not eligible for study participation before Visit 2, the investigator should contact 
with the subject, stop performing the study immediately. NOTE: it is not necessary for screen 
failed subject to perform examination at discontinuation visit.
Subject will record the compliance of ezetimibe or rosuvastatin to patient diary following 
instruction. All subjects will be asked to bring patient diary to their next scheduled clinic visit for 
compliance assessment.
7.1.5.2
Treatment Period (Visit 2 to 9)
Week 0 (Visit 2)
If the subject meets all inclusion criteria and does not meet any of the exclusion criteria, the site 
will perform all procedures for Visit 2 and the subject will be allocated. Blood sample will be 
obtained after at least 10 hour fasting and prior to administrating the study medication.
The first dose of trial treatment will be administered at the trial site after all procedures of Visit 2.
Subject who is assigned MK-0653H (EZ 10 mg + Ros 2.5 mg) will be instructed to take one
tablet from a bottle and 1 capsule from blister card or 1 tablet from PTP sheet, subject who is 
assigned MK-0653H (EZ 10 mg + Ros 5 mg) will be instructed to take one tablet from a bottle
and 2 capsules from blister card or 2 tablets from PTP sheet and record medication compliance in 
a patient diary by following instruction. All subjects will be asked to bring the bottle, blister
card(s) or PTP sheet(s) and patient diary to their next scheduled clinic visit for compliance 
assessment.
 
 
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From Week 20 (Visit 5) to Week 40 (Visit 8)
If the subject's LDL-C value does not achieve the lipid management goals at any point after 
Week 12 (Visit 4) and it is clinically safe and tolerable to continue the study, below is acceptable.
Subject who treated with MK-0653H (EZ 10 mg + Ros 2.5 mg) from Week 0 (Visit 2) : Patients 
who do not attain their LDL-C goal on the EZ10mg+Ros2.5mg dose, can be titrated to MK-
0653H (EZ 10 mg+Ros 5 mg) as study drug.  If they do not obtain their goal on EZ10mg+Ros5 
mg, the dose of Ros can be increased at intervals not less than 12 weeks to Ros 10 and then 20 
mg/day or another non-statin drug can be added to the patient’s regimen at the next visit.
Subject who treated with MK-0653H (EZ 10 mg + Ros 5 mg) : If patients do not obtain their 
goal on treatment with EZ10 mg+Ros5 mg, the dose of Ros can be increased at intervals not less 
12 weeks to 10 and then 20 mg/day or another non-statin drug can be added to the patients 
regimen at the next visit. NOTE: to add another statin except with Rosuvastatin is not allowed.
In case Ros is increased above 5 mg, study drug of Ros should not be provided. If dosage of 
study drug is changed or another lipid lowering agent is added, site staff must report it to the 
SPONSOR and Patient Registration Center immediately.
To confirm the safety of subjects who increased/decreased the dose of study drug or added 
another lipid lowering agent will be monitored by the investigator, who may at his discretion 
schedule visits outside those specified by the protocol. Unscheduled visit will be allowed all 
procedures planned for scheduled visit (i.e., laboratory test, vital sign and ECG) at the discretion 
of the investigator and all data should be reported to the SPONSOR.
Week 24 (Visit 6)
Because interim results will be summarized for filing, all continuing subjects must be performed 
the examination listed in Section 6.0 and all data should be entered to the eCRF immediately.
Week 52 (Visit 9)
All continuing subjects must take the examination listed in Section 6.0. 
7.1.5.3
Discontinuation
Once subject receive the study drug, subject who is determined to be not appropriate to continue 
the study by the investigator will be discontinued from the study. The investigator should contact 
with the subject to perform the examination listed at Visit 9 (Week 52/Discon) immediately, and 
be discontinued from the study.
7.1.5.4
Post-Trial
14 days after the last dose of study drug and thereafter, a follow up contact will be conducted via 
telephone to collect all adverse events that might have occurred within the 14 days.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
 
 
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symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The reporting 
timeframe for adverse events meeting any serious criteria is described in Section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than allocated: 1 tablet/capsule from either bottle, 
blister card or PTP sheet during a day for MK-0653H (EZ 10 mg+Ros 2.5 mg), 1 tablet from 
bottle and 2 capsules/ tablets from blister cards or PTP sheet, respectively during a day for MK-
0653H (EZ 10 mg+Ros 5 mg). Note: For subject who received Ros PTP sheets as study drug
and rosuvastatin is up-titrated after Week 20 (Visit 5) by investigator, even if he/she took Ros
above 5 mg including up-titrated dose from PTP sheet provided as study drug, this is not 
considered as overdose if the total daily dose is not over the instructed dose.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
 
 
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reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the investigator 
within 24 hours to the Sponsor either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 14 days following cessation of Sponsor’s product must be reported by the investigator.  
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.
Such events must be reported within 24 hours to the Sponsor either by electronic media or paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
7.2.3
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
 
 
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Refer to Table 5 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours to 
the Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days following 
cessation of treatment, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, whether or not related to the Sponsor's product, must be 
reported within 24 hours to the Sponsor either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the investigator 
at any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days following 
cessation of treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s 
product, must be reported within 24 hours to the Sponsor, either by electronic media or paper.  
Electronic reporting procedures can be found in the EDC data entry guidelines.  Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results. 
2. 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.*
 
 
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*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 trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent).
3. Myopathy or Rhabdomyolysis are to be reported as ECI because of their association with 
lipid-lowering treatments. If a subject is reported as having myopathy, rhabdomyolysis, or if 
the CPK criterion necessitating study medication discontinuation is met, this constitutes an 
ECI. ECIs will be recorded in the database, monitored by the SPONSOR and reported in the 
clinical study report.
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to the 
elements outlined in Table 5. The investigator’s assessment of causality is required for each 
adverse event.  Refer to Table 5 for instructions in evaluating adverse events.
 
 
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Table 5
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event 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 drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject 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 trials 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
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
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 trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      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 trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 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 SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
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.
Record one of the following:
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
Subject 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 subject with overdose without 
an associated AE.)
 
 
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7.2.5
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
7.3.1
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with respect 
to trial design, interpretation of trial results and subsequent peer-reviewed scientific publications.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to the 
analyses made after the protocol has been finalized will be documented in a supplemental SAP 
(sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
8.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Sections 8.2-8.12.
Study Design Overview
MK-0653H Phase III Long-term Safety Study
Treatment Assignment
All subjects enrolled in the study will receive MK-0653H 
(EZ 10 mg + Ros 2.5 mg) or MK-0653H (EZ 10 mg + Ros 5 
mg). The subjects who started with MK-0653H (EZ 10 mg + 
Ros 2.5 mg) may be titrated to MK-0653H (EZ 10 mg + Ros 
5 mg) at Visit 5 or later.
Analysis Populations
Safety
All Subject as Treated (ASaT) population, defined as all 
subjects who received at least one dose of study treatment for 
the open-label treatment period.
Efficacy
Full Analysis Set (FAS) population, defined as all subjects 
who:

received at least one dose of study treatment for the 
open-label treatment period

have baseline or post-baseline data

have baseline data for those analyses that require 
baseline data
Primary Endpoint
AEs, as well as change from baseline in laboratory tests, vital 
signs and ECG at respective timepoints.
Secondary Endpoint
Percent change from baseline in LDL-C
 
 
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Statistical Methods for Key 
Safety Analyses
AEs will be summarized by the number and percentage of 
the subjects who experienced respective events. Change from 
baseline in laboratory tests, vital signs and ECG at respective 
timepoints will be summarized by descriptive statistics.
Statistical Methods for Key 
Efficacy Analyses
Percent change from baseline in LDL-C at respective 
timepoints will be summarized by descriptive statistics and 
95% confidence intervals (CIs).
Interim Analyses
All safety and efficacy analyses will be performed based on 
the data up to Week 24 after all subjects remaining in the trial 
have completed Week 24.
Multiplicity
No adjustment for multiplicity is planned.
Sample Size and Power
A total of 134 subjects will be enrolled. Assuming a 
discontinuation rate of approximately 25%, 100 subjects are 
expected to complete 52 weeks of treatment, in accordance 
with the ICH guideline of "The extent of population exposure 
to assess clinical safety for drugs intended for long-term 
treatment of non-life-threatening conditions (E1)".
8.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. This trial will be conducted as an open-label 
study, i.e., subjects, investigators, and SPONSOR personnel will be aware of patient treatment 
assignments after each patient is enrolled and treatment is assigned.
8.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
8.4
Analysis Endpoints
Safety and efficacy endpoints that will be evaluated for within-treatment differences are listed 
below. For both safety and efficacy parameters, the baseline value is defined as the last available 
measurement prior to enrollment, which typically corresponds to the measurement obtained at 
Visit 2.
8.4.1
Safety Endpoints
Refer to Section 4.2.3.1 for a list of safety endpoints.
8.4.2
Efficacy Endpoints
Refer to Section 4.2.3.2 for a list of efficacy endpoints.
 
 
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8.5
Analysis Populations
8.5.1
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all subjects who received at least one dose of study treatment. At least one 
laboratory, vital sign or ECG measurement 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.
8.5.2
Efficacy Analysis Populations
The FAS population will serve as the population for the analysis of efficacy data in this study. 
The FAS population consists of all subjects who:

received at least one dose of study treatment for the open-label treatment period

have baseline or post-baseline data

have baseline data for those analyses that require baseline data
8.6
Statistical Methods
The results will be provided by initial dose (EZ 10 mg + Ros 2.5 mg, EZ 10 mg + Ros 5 mg). For 
the safety analyses and summary of baseline characteristics, the results for all subjects will also 
be provided. Missing data will not be imputed.
8.6.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs and ECG.
AEs and other safety events will be summarized using the number and percentage of the subjects 
who experienced respective events. Change from baseline in laboratory tests, vital signs and 
ECG at respective timepoints will be summarized using descriptive statistics.
8.6.2
Statistical Methods for Efficacy Analyses
For all continuous efficacy endpoints, means, standard errors and 95% CIs will be provided for 
percent change from baseline at respective timepoints. The proportion and corresponding 95% 
CI of subjects achieving LDL-C goal will be provided by timepoint. These analyses will include 
the data obtained after titration of rosuvastatin. As a sensitivity analysis, the analysis that 
excludes the data obtained after titration of rosuvastatin will also be performed.
The data obtained after administration of any lipid-lowering therapy other than the study drug 
will be excluded from efficacy analyses.
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed. Demographic variables, 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant therapies 
will be summarized either by descriptive statistics or categorical tables.
 
 
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8.7
Interim Analyses
For the purpose of filing, all safety and efficacy analyses will be performed based on the data up 
to Week 24 after all subjects remaining in the trial have completed Week 24.
8.8
Multiplicity
No adjustment for multiplicity is planned for the study.
8.9
Sample Size and Power Calculations
A total of 134 subjects will be enrolled. Assuming a discontinuation rate of approximately 25%,
100 subjects are expected to complete 52 weeks of treatment, in accordance with the ICH 
guideline of "The extent of population exposure to assess clinical safety for drugs intended for 
long-term treatment of non-life-threatening conditions (E1)".
The probability of observing at least one AE in this study depends on the number of subjects
treated and underlying percentage of subjects with an AE in the study population. If the 
underlying incidence of an AE is 2%, there is 87% chance of observing at least one AE among 
100 subjects treated.  If no subjects out of 100 had a specific AE, then upper bound of the 95% 
CI of the underlying incidence rate would be 3.6%.
8.10 Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the within-
treatment percent change from baseline in LDL-C at respective time points will be estimated 
within each category of the following classification variables:

age category (< 65, ≥65 years)

gender (male, female)

prior lipid-lowering agents therapy (EZ 10 mg, Ros 2.5 mg or Ros 5 mg)

diabetes mellitus (yes, no)

hypertension (yes, no)

baseline LDL-C (≤ median, > median)

heterozygous familial hypercholesterolemia (yes, no)
8.11 Compliance (Medication Adherence)
A day within the study will be considered an “On-Therapy” day if the subject takes both EZ 10 
mg and Ros [2.5 or 5 mg (2 x 2.5 mg)]. The“Number of Days Should be on Therapy” is defined 
as the total number of days from Visit 2 to the day before Visit 9 for those subjects who 
completed the study, and from Visit 2 to the date of the last administration of study medication 
for those subjects who discontinued from the study.
Percent compliance for each subject will be calculated using the following formula:
(Number of Days on Therapy / Number of Days Should be on Therapy) x 100.
Summary statistics will be provided on percent compliance for the FAS population.
8.12 Extent of Exposure
The dose level and treatment duration will be summarized for the ASaT population.
 
 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 6.
Table 6
Product Descriptions
Product Name & Potency
Dosage Form
Ezetimibe 10 mg
Tablet
Rosuvastatin Calcium 2.5 mg
Capsule or Tablet
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
Subjects will receive sufficient supplies of open label bottle of Ezetimibe 10 mg and open 
labeled blister card or PTP sheet of Rosuvastatin Calcium 2.5 mg to support a period between 
visits.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received from 
the Sponsor or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. For all trial 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.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
10.1.1 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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
10.1.2 Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject agrees 
to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
10.1.3 Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying information 
with respect to the investigator, and all subinvestigators and trial site personnel, may be used and 
disclosed for trial management purposes, as part of a regulatory submissions, and as required by 
law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  Additionally, 
the investigator’s name and business contact information may be included when reporting certain 
serious adverse events to regulatory authorities or to other investigators.  By signing this 
protocol, the investigator expressly consents to these uses and disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor may 
share an investigator’s name and contact information with other participating investigators upon 
request.
 
 
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10.1.4 Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that reviews 
and approves this trial.  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.
10.2 Compliance with Financial Disclosure Requirements
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.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline 
and other generally accepted standards of good clinical practice); and all applicable federal, state 
and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to all 
trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as required 
by this protocol or as otherwise required pursuant to any agreement with the Sponsor.
 
 
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Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon 
request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation and 
worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the conduct of 
the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, monitor 
visit logs, laboratory reference ranges, laboratory certification or quality control procedures and 
laboratory director curriculum vitae.  By signing this protocol, the investigator agrees that 
documentation shall be retained until at least 2 years after the last approval of a marketing 
application in an ICH region or until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  Because the clinical 
development and marketing application process is variable, it is anticipated that the retention 
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 
the minimum retention period and notify the investigator when documents may be destroyed.  
The Sponsor will determine the minimum retention period and upon request, will provide 
guidance to the investigator when documents no longer need to be retained.  The sponsor also 
recognizes that documents may need to be retained for a longer period if required by local 
regulatory requirements. All trial documents shall be made available if required by relevant 
regulatory authorities. The investigator must consult with and obtain written approval by the 
Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the investigator’s 
knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly 
notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating investigator 
for a multi-center trial (including multinational).  When more than one trial site is open in an EU 
country, Merck, as the Sponsor, will designate, per country, a national principal coordinator 
(Protocol CI), responsible for coordinating the work of the principal investigators at the different 
trial sites in that Member State, according to national regulations.  For a single-center trial, the 
Protocol CI is the principal investigator.  In addition, the Sponsor must designate a principal or 
 
 
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coordinating investigator to review the trial report that summarizes the trial results and confirm 
that, to the best of his/her knowledge, the report accurately describes the conduct and results of 
the trial [Clinical Study Report (CSR) CI].  The Sponsor may consider one or more factors in the 
selection of the individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI 
during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The Protocol 
CI must be a participating trial investigator.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as Sponsor of 
this trial, will review this protocol and submit the information necessary to fulfill these 
requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
10.5 Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining 
a quality management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that trials are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of Good Clinical 
Practice, and all applicable federal, state, and local laws, rules and regulations relating to the 
conduct of the clinical trial.
10.6 Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy of 
subject data.  By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature.  By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be provided 
separately.
10.7 Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some cases 
 
 
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such as vaccine trials.  However, manuscript submission timelines may be extended on OTC 
trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees to delay 
publication of the trial results until the Sponsor notifies the investigator that all relevant 
regulatory authority decisions on the trial drug have been made with regard to pediatric-related 
regulatory filings. Merck will post a synopsis of trial results for approved products on 
www.clinicaltrials.gov by 12 months after the last subject's last visit for the primary outcome, 12 
months after the decision to discontinue development, or product marketing (dispensed, 
administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality agreements 
with other parties.  Authors of the primary results manuscript will be provided the complete 
results from the Clinical Study Report, subject to the confidentiality agreement. When a 
manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include the 
protocol and statistical analysis plan to facilitate the peer and editorial review of the manuscript.  
If the manuscript is subsequently accepted for publication, the Sponsor will allow the journal, if 
it so desires, to post on its website the key sections of the protocol that are relevant to evaluating 
the trial, specifically those sections describing the trial objectives and hypotheses, the subject 
inclusion and exclusion criteria, the trial design and procedures, the efficacy and safety 
measures, the statistical analysis plan, and any amendments relating to those sections.  The 
Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of the 
results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, due to 
statistical concerns.  In rare cases, publication of single trial site data prior to the main paper may 
be of value.  Limitations of single trial site observations in a multicenter trial should always be 
described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors must meet conditions 1, 2 and 3.  Significant contributions to trial execution may also be 
taken into account to determine authorship, provided that contributions have also been made to 
all three of the preceding authorship criteria.  Although publication planning may begin before 
conducting the trial, final decisions on authorship and the order of authors’ names will be made 
based on participation and actual contributions to the trial and writing, as discussed above. The 
first author is responsible for defending the integrity of the data, method(s) of data analysis and 
the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; this 
confidentiality does not include efficacy and safety results. Sponsor review can be expedited to 
meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
[1]
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 
update: a report from the American Heart Association. Circulation. 2015;131:e29-e322.
[2]
Ministry of Health, Labour and Welfare. Summary of Vital Statistics (2013), Table 7. 
http://www.mhlw.go.jp/toukei/saikin/hw/jinkou/kakutei13/index.html
[3]
Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk 
of premature death from coronary heart disease continuous and graded? Findings in 356, 
222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 
1986;256:2823-8.
[4]
Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic 
disease. New perspectives based on the Framingham Study. Ann Intern Med. 
1979;90:85-91.
[5]
Castelli WP, Abbott RD, McNamara PM. Summary estimates of cholesterol used to 
predict coronary heart disease. Circulation. 1983;67:730-4.
[6]
Okamura T, Tanaka H, Miyamatsu N, et al. The relationship between serum total 
cholesterol and all-cause or cause-specific mortality in a 17.3-year study of a Japanese 
cohort. Atherosclerosis. 2007; 190:216-23.
[7]
Japan Atherosclerosis Society. Dyslipidemia medical treatment guide 2012
[8]
Gotto AM Jr. High-density lipoprotein cholesterol and triglycerides as therapeutic 
targets for preventing and treating coronary artery disease. Am Heart J. 2002;144:S33-
42.
[9]
Shah PK, Kaul S, Nilsson J, et al. Exploiting the vascular protective effects of high-
density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, 
part I. Circulation 2001;104:2376-83.
[10]
Crestor®2.5 mg、Crestor®5 mg label (Revised: Jun 2016, version 13).
[11]
Zetia® 10 mg label (Revised:Oct 2010, version 5).
[12]
Shroufi A, Powles JW. Adherence and chemoprevention in major cardiovascular 
disease: a simulation study of the benefits of additional use of statins. J Epidemiol 
Community Health. 2010; 64: 109-13.
[13]
Saito I. Influence which the number of medicines of medication compliance and a 
blood-pressure control hypotensive agent has on medication compliance. Ketsuatu, 
2006, 13: 1019-25.
[14]
Cheong C, Barner JC, Lawson KA, et al. Patient adherence and reimbursement amount 
for antidiabetic fixed-dose combination products compared with dual therapy among 
Texas Medicaid recipients. Clin Ther. 2008; 30: 1893-907.
[15]
Miho Isobe, Kazuma Koizumi, Shinya Hayakawa, et al. Post-marketing Surveillance of 
Ezetimibe (Zetia® Tablets, 10 mg), Inhibitor of Intestine Cholesterol Transporter (the 
2nd Report) - Specific Drug Use Results Survey (52 Weeks) -. J.New Rem. & Clin. 
2012; 61: 1714-33.
[16]
Prescription data from January to December in 2013. provided by Japan medical data 
center.
 
 
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12.0
APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in the design of clinical 
trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or national regulations and in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the party 
(parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This Code is 
not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code does not 
apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine subject 
preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose of the 
trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities and 
staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites are 
evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical Practice.  
Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source documentation 
according to standard operating procedures.  Per Merck policies and procedures, if fraud, misconduct or serious GCP-
non-Compliance are suspected, the issues are promptly investigated. When necessary, the clinical site will be closed, 
the responsible regulatory authorities and ethics review committees notified and data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC approval. 
For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, only 
the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical records 
that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by an 
Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to enroll 
subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on chart 
review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter the 
wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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12.2 List of Abbreviations
Abbreviation
Details
EZ
Ezetimibe
Rosuvastatin
Ros
Rosuvastatin calcium
EZ 10 mg+Ros 2.5 mg
Co-administration of Ezetimibe 10 mg and Rosuvastatin 
calcium 2.5 mg
EZ 10 mg+Ros 5 mg
Co-administration of Ezetimibe 10 mg and Rosuvastatin 
calcium 5 mg
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
CHD
Coronary heart disease
CAD
Coronary artery disease
LDL-C
Low-density lipoprotein cholesterol
HDL-C
High-density lipoprotein cholesterol
JAS2012
2012 Japan Atherosclerosis Society Guidelines for 
Prevention of Atherosclerotic Cardiovascular Diseases
 
 
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[Instruction for this study]

Smoking should be counted as 1 risk if patient have had ≥ 1 cigarette within last month.

Patient who is ≥ 75 years old should be assessed based on the criteria of 60’s for each gender.

Male patients who are under 40’s should be assessed based on the criteria of males of 40’s. 
Female patients who are under 40’s should be assessed based on the criteria of females of 
40’s and 50’s.
[Definition of CAD by events, procedures, symptoms or imaging]
1. Event:

Myocardial infarction (MI) (e.g., subendocardial myocardial infarction, non-Q wave MI, 
unstable angina, acute coronary syndrome)
2. Procedure:

Percutaneous Transluminal Coronary Angioplasty (PTCA).  

Coronary Stenting

Coronary Artery Bypass Graft (CABG)
3. Symptoms:

Angina (chest pain deemed to be of cardiac origin)
4. Imaging:

Angiography with evidence of CAD

Stress test using treadmill, echocardiography or nuclear testing consistent with CAD
Note:  The above lists are not all inclusive. If your patient has a medical/physical condition 
and you are unsure if the condition excludes them from participation in the study, please 
contact the SPONSOR.
 
 
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12.4 Lipid Management Goals Based on Risk Assessment
Principle of the 
Therapeutic Strategy
Category
Absolute Risk†
Additional 
Risk‡
Lipid Control Target Values
(mg/dL)
LDL-C
HDL-C
Primary prevention
(No history of CAD)
Drug treatment should be 
considered 
after 
first 
improving the patient’s 
lifestyle.
I
< 0.5% 
No
< 160
≥40
II
< 0.5% 
Yes
< 140
≥0.5%, < 2.0% 
No
III
≥0.5%, < 2.0%
Yes
< 120
≥2.0%
No/ Yes
Secondary prevention
(History 
of 
CAD)
Drug treatment should be 
considered, together with 
improving the patient’s 
lifestyle.
History of CAD
< 100
†Absolute Risk is defined as Probability of death form CAD in 10 years based on NIPPON DATA 80
‡ Additional Risk are defined as 1) Hypo HDL-cholesterolemia (HDL-C < 40 mg/dL), 2) Family history of 
premature CAD in first-degree relatives (a man aged < 55 years or a woman aged < 65 years), 3) Impaired
glucose tolerance.
Note: Patient who has diabetes mellitus, chronic kidney disease, non cardio-embolic stroke (CKD) or peripheral arterial 
disease (PAD) are definded as categoly III
Revised JAS Guidelines, 2012 version (The Japan Atherosclerosis Society)
 
 
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12.5 Diet/Alcohol
Diet
Patient should follow the nutrient recommendation provided by the JAS2012 for prevention of 
atherosclerotic cardiovascular diseases throughout this study.
1) Maintain an ideal body weight (height(m)2×22) in consideration of energy intake and the 
amount of physical activity
2) Limit the energy percent derived from fat to 20% to 25%, saturated fatty acids to ≥ 4.5% but 
< 7%, and cholesterol intake to <200 mg/day
3) Increase the intake of n-3 polyunsaturated fatty acids
4) Limit the energy percent derived from carbonhydrates to 50% - 60%, and increase the dietary 
fiber intake
5) Aim to reduce the salt intake to < 6 g/day
6) Limit alcohol consumption to ≤ 25 g/day
Alcohol
The amount of 25 g alcohol is defined as follows:
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
 
 
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12.6 Standard Operating Procedure for Liver and Muscle Enzyme Evaluations
Every increase in ALT, AST, and/or CK above the limits described in the protocol (i.e., 
ALT/AST ≥3 times the upper limit of normality [ULN], and CK ≥5 times ULN), the central 
laboratory will alert the investigators/ coordinators and the SPONSOR clinical personnel.  The 
study and central laboratory SOP calls for immediate repeat testing within 3 days every time 
these tests reach these limits or are otherwise questionable.
Under these circumstances, the investigators/coordinators must recall the patient and attempt to 
identify the cause of the elevation.  This evaluation should include:
A. For CK Increases
1. Patients should return to the center within 3 days after result available for the following 
(history can be obtained over the phone in the interim):
･
A search for potential drug interactions with known inhibitors or substrate of cytochrome P-
450 CYP3A4.
･
Rule out myocardial ischemia as a cause for the elevation.
･
Documentation of unusual and/or strenuous physical activities, recent trauma, or IM 
injections preceding the blood testing.
2. Actions
･
Patients with persistent (2 or more) CK elevations between 5 and <10 times the ULN and 
muscle symptoms will also be discontinued.
･
Patients with persistent (2 or more) CK elevations between 5 and <10 times the ULN without 
symptoms may remain on drug (at the discretion of the SPONSOR medical monitor) with 
more intensive monitoring (as agreed to by the monitor and investigator).  These patients 
should remain on drug until repeat labs are obtained.
･
Patients with persistent (i.e., 2 consecutive measurements), unexplained 10 fold elevation in 
CK with or without symptoms will be discontinued from the study.
NOTE: All discontinued patients should be monitored and have repeat lab draws completed until 
critical elevations have resolved.
B. For ALT or AST Increases
1. Patients should return to the center within 3 days after result available for the evaluations 
listed below (history can be obtained over the phone in the interim).  In cases where the ALT 
and/or AST value is ≥3-fold ULN patients should generally remain on drug until the follow-
up visit.
･Careful questioning of recent alcohol consumption.  Recent change in pattern.
･Search for iatrogenic causes of hepatitis and liver injuries (acetaminophen, amiodarone, 
aspirin, chlorpromazine, dantrolene, erythromycin, halothane, isoniazid, methyldopa, 
nitrofurantoin, oxyphenisatin, perhexiline maleate, phenytoin, propylthiouracil, rifampin, 
sulfonamides, tetracyclines).
 
 
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･Search for alternative medical causes such as cholelithiasis and ascending cholangitis, viral 
illnesses, hepatitis, or potential exposure to viral hepatitis (transfusion).
2. Action
･
Values of ALT or AST ≥3 X ULN at any visit will result in mandatory retest within 3 days.  
Persistent (2 consecutive measurements) 3-fold elevations in ALT or AST will result in 
withdrawal of the patient from the study.
 
 
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Confidential
12.7 Clinical Study Conduct System
Clinical study conduct system in Japan is provided by Japanese language.
 
 
04N8F9
 
 
04W5DT


Product:  MK-0653H
67
Protocol/Amendment No.: 833-02
MK-0653H-833-02 Final Protocol
11-Apr-2017
Confidential
13.0
SIGNATURES
13.1 Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
13.2 Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol and to 
abide by all provisions of this protocol (including other manuals and documents referenced from 
this protocol).  I agree to conduct the trial in accordance with generally accepted standards of 
Good Clinical Practice.  I also agree to report all information or data in accordance with the 
protocol and, in particular, I agree to report any serious adverse events as defined in Section 7.0
– Assessing and Recording Adverse Events.  I also agree to handle all clinical supplies provided 
by the Sponsor and collect and handle all clinical specimens in accordance with the protocol.  I 
understand that information that identifies me will be used and disclosed as described in the 
protocol, and that such information may be transferred to countries that do not have laws 
protecting such information.  Since the information in this protocol and the referenced 
Investigator’s Brochure is confidential, I understand that its disclosure to any third parties, other 
than those involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure 
that the necessary precautions are taken to protect such information from loss, inadvertent 
disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
04N8F9
 
 
04W5DT