A Phase III, Randomized, Active Comparator-controlled, Clinical Trial to Study the Efficacy and Safety of MK-0653H in Japanese Patients With Hypercholesterolemia.
Phase: PHASE3
Conditions: Hypercholesterolemia
Sponsor: Organon and Co

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase III, Randomized, Active Comparator-controlled, Clinical 
Trial to Study the Efficacy and Safety of MK-0653H in Japanese 
Patients With Hypercholesterolemia. 
NCT number: 
NCT02741245 
Document Date: 
20-Sep-2016 

Product:  MK-0653H
1
Protocol/Amendment No.: 832-01
MK-0653H-832-01 Final Protocol
20-Sep-2016
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, Randomized, Active Comparator-controlled, Clinical Trial to Study the Efficacy 
and Safety of MK-0653H in Japanese Patients with Hypercholesterolemia.
  
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 11
2.1
Trial Design ........................................................................................................... 11
2.2
Trial Diagram........................................................................................................ 12
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 13
3.1
Primary Objective(s) & Hypothesis(es) .............................................................. 13
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 13
3.3
Exploratory Objectives......................................................................................... 13
4.0
BACKGROUND & RATIONALE.......................................................................... 14
4.1
Background ........................................................................................................... 14
4.1.1
Pharmaceutical and Therapeutic Background .................................................... 14
Pathophysiology and Epidemiology ............................................................ 14
4.1.1.1
Significance of the Development of Fixed Dose Combination Tablet 
4.1.1.2
(FDC) for Therapy of Hyper-LDL-cholesterolemia.................................... 15
4.1.2
Pre-clinical and Clinical Trials ........................................................................... 16
4.1.3
Ongoing Clinical Trials....................................................................................... 17
4.2
Rationale................................................................................................................ 17
4.2.1
Rationale for the Trial and Selected Subject Population .................................... 17
4.2.2
Rationale for Dose Selection/Regimen/Modification ......................................... 18
Rationale for The Use of Comparator/Placebo............................................ 18
4.2.2.1
Efficacy Endpoints....................................................................................... 18
4.2.2.2
Safety Endpoints .......................................................................................... 19
4.2.2.3
4.3
Benefit/Risk ........................................................................................................... 19
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 .................................................................................. 21
 
 
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5.2
Trial Treatment(s) ................................................................................................ 24
5.2.1
Dose Selection .................................................................................................... 25
Dose Selection (Preparation) ....................................................................... 25
5.2.1.1
5.2.2
Timing of Dose Administration.......................................................................... 25
5.2.3
Trial Blinding...................................................................................................... 25
5.3
Randomization or Treatment Allocation............................................................ 25
5.4
Stratification.......................................................................................................... 25
5.5
Concomitant Medications/Vaccinations ............................................................. 26
5.6
Rescue Medications & Supportive Care............................................................. 26
5.7
Diet/Activity/Other Considerations..................................................................... 26
5.7.1
Diet...................................................................................................................... 26
5.7.2
Activity ............................................................................................................... 26
5.7.3
Alcohol Intake..................................................................................................... 26
5.7.4
Contraception...................................................................................................... 27
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 27
5.9
Subject Replacement Strategy............................................................................. 28
5.10
Beginning and End of the Trial ........................................................................... 28
5.11
Clinical Criteria for Early Trial Termination ................................................... 28
6.0
TRIAL FLOW CHART ........................................................................................... 29
7.0
TRIAL PROCEDURES ........................................................................................... 31
7.1
Trial Procedures ................................................................................................... 31
7.1.1
Administrative Procedures.................................................................................. 31
Informed Consent......................................................................................... 31
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 31
Inclusion/Exclusion Criteria ........................................................................ 32
7.1.1.2
Subject Identification Card .......................................................................... 32
7.1.1.3
Medical History ........................................................................................... 32
7.1.1.4
Prior and Concomitant Medications Review ............................................... 32
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 32
7.1.1.5.2
Concomitant Medications..................................................................... 32
Assignment of Screening Number............................................................... 32
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 32
7.1.1.7
 
 
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Trial Compliance (Medication/Diet/Activity/Other) ................................... 33
7.1.1.8
7.1.2
Clinical Procedures/Assessments........................................................................ 33
Physical Examination................................................................................... 33
7.1.2.1
Vital Sign ..................................................................................................... 33
7.1.2.2
7.1.2.2.1
Height.................................................................................................... 33
7.1.2.2.2
Weight................................................................................................... 33
7.1.2.2.3
Sitting Blood pressure/ pulse ................................................................ 33
7.1.2.2.4
ECG ...................................................................................................... 34
Monitor Medication compliance.................................................................. 34
7.1.2.3
7.1.3
Laboratory Procedures/Assessments .................................................................. 34
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 35
7.1.3.1
7.1.4
Other Procedures................................................................................................. 35
Withdrawal/Discontinuation........................................................................ 35
7.1.4.1
Blinding/Unblinding .................................................................................... 35
7.1.4.2
Calibration of Critical Equipment................................................................ 36
7.1.4.3
7.1.5
Visit Requirements.............................................................................................. 36
Screening (Visit 1) ....................................................................................... 36
7.1.5.1
Placebo run-in (Visit 2)................................................................................ 36
7.1.5.2
Treatment Period (Visits 3 to 6)................................................................... 37
7.1.5.3
Discontinuation............................................................................................ 37
7.1.5.4
Post-Trial (follow up telephone contact) ..................................................... 37
7.1.5.5
7.2
Assessing and Recording Adverse Events .......................................................... 37
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 38
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 38
7.2.3
Immediate Reporting of Adverse Events to the Sponsor.................................... 39
Serious Adverse Events ............................................................................... 39
7.2.3.1
Events of Clinical Interest............................................................................ 40
7.2.3.2
7.2.4
Evaluating Adverse Events ................................................................................. 41
7.2.5
Sponsor Responsibility for Reporting Adverse Events ...................................... 44
7.3
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 44
7.3.1
Scientific Advisory Committee........................................................................... 44
 
 
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8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 44
8.1
Statistical Analysis Plan Summary ..................................................................... 45
8.2
Responsibility for Analyses / In-house Blinding ................................................ 46
8.3
Hypotheses / Estimation....................................................................................... 47
8.4
Analysis Endpoints ............................................................................................... 47
8.4.1
Efficacy Endpoints.............................................................................................. 47
8.4.2
Safety Endpoints ................................................................................................. 47
8.5
Analysis Populations............................................................................................. 47
8.5.1
Efficacy Analysis Populations ............................................................................ 47
8.5.2
Safety Analysis Populations ............................................................................... 48
8.6
Statistical Methods................................................................................................ 48
8.6.1
Statistical Methods for Efficacy Analyses.......................................................... 48
8.6.2
Statistical Methods for Safety Analyses ............................................................. 49
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 51
8.7
Interim Analyses ................................................................................................... 51
8.8
Multiplicity ............................................................................................................ 52
8.9
Sample Size and Power Calculations .................................................................. 53
8.10
Subgroup Analyses and Effect of Baseline Factors ........................................... 53
8.11
Compliance (Medication Adherence).................................................................. 54
8.12
Extent of Exposures.............................................................................................. 54
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 54
9.1
Investigational Product ........................................................................................ 54
9.2
Packaging and Labeling Information ................................................................. 54
9.3
Clinical Supplies Disclosure................................................................................. 55
9.4
Storage and Handling Requirements.................................................................. 55
9.5
Discard/Destruction/Returns and Reconciliation .............................................. 55
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 56
10.1
Confidentiality....................................................................................................... 56
10.1.1 Confidentiality of Data ....................................................................................... 56
10.1.2 Confidentiality of Subject Records..................................................................... 56
10.1.3 Confidentiality of Investigator Information........................................................ 56
 
 
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10.1.4 Confidentiality of IRB/IEC Information............................................................. 57
10.2
Compliance with Financial Disclosure Requirements....................................... 57
10.3
Compliance with Law, Audit and Debarment ................................................... 57
10.4
Compliance with Trial Registration and Results Posting Requirements........ 59
10.5
Quality Management System............................................................................... 59
10.6
Data Management................................................................................................. 59
10.7
Publications ........................................................................................................... 59
11.0
LIST OF REFERENCES......................................................................................... 61
12.0
APPENDICES........................................................................................................... 63
12.1
Merck Code of Conduct for Clinical Trials........................................................ 63
12.2
List of Abbreviations ............................................................................................ 65
12.3
Category Assessment for Each Patient............................................................... 66
12.4
Lipid Management Goals Based on Risk Assessment....................................... 68
12.5
Diet and Alcohol.................................................................................................... 69
12.6
Standard Operating Procedure for Liver and Muscle Enzyme Evaluations.. 70
12.7
Clinical Study Conduct System ........................................................................... 72
13.0
SIGNATURES........................................................................................................... 73
13.1
Sponsor's Representative ..................................................................................... 73
13.2
Investigator............................................................................................................ 73
 
 
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LIST OF TABLES
    
Table 1  Trial Treatment ......................................................................................................... 24
Table 2  Discontinuation Scenarios ........................................................................................ 27
Table 3  Laboratory Tests ....................................................................................................... 35
Table 4  Evaluating Adverse Events....................................................................................... 42
Table 5 Analysis Strategy for Safety Parameters .................................................................. 51
Table 6 Power Calculations for Pairwise Comparisons......................................................... 53
Table 7 Assumptions on True LDL-C Percent Change from Baseline by Treatment........... 53
Table 8  Product Descriptions................................................................................................. 54
 
 
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LIST OF FIGURES
          
Figure 1  Study Design ........................................................................................................... 12
Figure 2  Schematic Display of Multiplicity Adjustment....................................................... 52
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.1.3
Ongoing Clinical Trials
Phase III long-term safety study in Japanese 
hypercholesterolemia patients is on-going.
Reflect the current status.
5.1.3 
Subject 
Exclusion
#14
Subject is currently taking medications restricted 
by labeling as below.

Cyclosporine

Systemically administered azole 
antifungals(e.g., 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
New information
5.1.3
Subject 
Exclusion
#28
Subject has taken lipid-lowering agents (except 
probucol) including fish oils, Cholestin™, bile 
acid sequestrants, statins, Ezetimibe, fibrates or 
niacin (>200 mg/day) within 6 weeks prior to 
Visit 2. Subject has taken probucol or protein 
convertase subtilisin/kexin type 9 (PCSK 9) 
inhibitor within 10 weeks prior to Visit 2.
PCSK9 
inhibitor has 
been 
launched in Japan.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
11.0
list of references #10
Crestor 2.5 mg, Crestor 5 mg label(Revised: 
Jun/2016, version 13)
New information
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-0653H 
Phase 
III 
Factorial 
Study 
in 
Japanese 
Hypercholesterolemic Patients
Sponsor Product Identifiers
MK-0653H
Trial Phase
III
Clinical Indication
Hypercholesterolemia, Familial Hypercholesterolemia
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Oral 
Trial Blinding
Double-blind
Treatment Groups
Ezetimibe 10 mg
Rosuvastatin 2.5 mg
Rosuvastatin 5 mg
MK-0653H (EZ 10 mg+Ros 2.5 mg)
MK-0653H (EZ 10 mg+Ros 5 mg)
Number of trial subjects
Approximately 306 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 9
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 up to 22 weeks from the time 
the subject signs the Informed Consent Form (ICF) through the final 
visit.  After a screening/washout phase of up to 6 weeks followed by a 
placebo run-in period of 2 weeks, each subject will be receiving 
assigned treatment for 12 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.
2.0 TRIAL DESIGN
2.1
Trial Design
This is a Randomized, active-controlled, parallel-group, multi- site, double-blind trial of MK-
0653H in subjects with hypercholesterolemia to be conducted in conformance with Good 
Clinical Practices.
Randomization Ratio
Subject will be randomized into 1 of the 5 treatment groups including 
Ezetimibe 10 mg, Rosuvastatin 2.5 mg, Rosuvastatin 5 mg, MK-
0653H (EZ 10 mg + Ros 2.5 mg), MK-0653H (EZ 10 mg + Ros 5 mg) 
in 
an 
allocation 
ratio 
of 
1:2:2:2:2.
NOTE: MK-0653H (EZ 10mg + Ros 2.5mg) is co-administration with 
a tablet of Ezetimibe 10 mg and a capsule of Rosuvastatin 2.5 mg and 
a capsule of matching placebo. MK-0653H (EZ 10 mg + Ros 5 mg) is 
co-administration with a tablet of Ezetmibe 10 mg and 2 capsules of 
Rosuvastatin 2.5 mg.
 
 
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The study consists of a screening period, a placebo run-in period, a treatment period, and 
follow up, and the total duration of each subject is 17 to 22 weeks, depending on the length 
of the screening period, which is according to subjects’ prior lipid-lowering therapy. For 
subjects on lipid-lowering therapy, this screening period will be 6 weeks and during this 
period, subject washoff prior lipid lowering therapy. In patients on a lipid lowering therapy 
(ie., statin) at Visit 1, investigators should consider the patients LDL-C level on the statin to 
assess whether the patient is likely to qualify for entry at Visit 2 after the wash-out of statin 
therapy. For subjects not on lipid-lowering therapy, it will be 1-6 weeks depending on the 
state of prior pharmacotherapy other than lipid-lowering agents in each subject. Subjects who 
meet all of the eligibility criteria will be enrolled in 12 weeks of treatment period following a 
2-week placebo run-in period. Subjects will be randomized to one of the 5 treatment groups 
[Ezetimibe monotherapy at 10 mg, Rosuvastatin calcium (hereafter Rosuvastatin or Ros) 
monotherapy at 2.5 mg or 5 mg, MK-0653H (EZ 10 mg + Ros 2.5 mg), or MK-0653H (EZ 
10 mg + Ros 5 mg)] in an allocation ratio of 1:2:2:2:2. Three hundreds six subjects will be 
randomized to ensure 279 completers. Subjects will be centrally randomized using an 
Interactive Voice/Web Response System (IVRS/IWRS). Subjects who complete the study or 
prematurely discontinue during the study will receive a 14-day follow-up phone call to assess 
for serious adverse events.
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.
2.2
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1  Study Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
Objective:  
In Japanese patients with hypercholesterolemia,
1) To evaluate the percent change from baseline in LDL-C of MK-0653H (EZ 10 mg + 
Ros 2.5 mg) compared to Ezetimibe 10 mg and compared to Rosuvastatin 2.5 mg at 
Week 12.
2) To evaluate the percent change from baseline in LDL-C of MK-0653H (EZ 10 mg + 
Ros 5 mg) compared to Ezetimibe 10 mg and compared to Rosuvastatin 5 mg at 
Week 12.
3) To  evaluate the safety and tolerability of MK-0653H (EZ 10 mg + Ros 2.5 mg) and 
MK-0653H (EZ 10 mg + Ros 5 mg) once daily dosing through 12 weeks.
Hypothesis:  
1) MK-0653H (EZ 10 mg + Ros 2.5 mg) is superior to Ezetimibe 10 mg and is superior 
to Rosuvastatin 2.5 mg in percent reduction from baseline in LDL-C after 12 weeks 
of treatment.
2) MK-0653H (EZ 10 mg + Ros 5 mg) is superior to Ezetimibe 10 mg and is superior to
Rosuvastatin 5 mg in percent reduction from baseline in LDL-C after 12 weeks of 
treatment.
There are two families each with 2 primary hypotheses and the overall success is 
determined by a success in at least one family of hypotheses.
3.2
Secondary Objective(s) & Hypothesis(es)
No secondary objectives or hypotheses are planned for this protocol.
3.3
Exploratory Objectives 
In Japanese patients with hypercholesterolemia,
1) To evaluate the percent change from baseline in LDL-C at Weeks 4 and 8 based on 
the following;
MK-0653H (EZ 10 mg + Ros 2.5 mg) compared to single entity, Ezetimibe 10 mg 
and Rosuvastatin 2.5 mg
MK-0653H (EZ 10 mg + Ros 5 mg) compared to single entity, Ezetimibe 10 mg and 
Rosuvastatin 5 mg
2) To evaluate the percent change from baseline in total cholesterol (TC), HDL-C, non-
HDL-C, triglyceride (TG), Apoprotein (Apo) B and hs-CRP at Week 12 based on the 
following;
 
 
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MK-0653H (EZ 10 mg + Ros 2.5 mg) compared to single entity, Ezetimibe 10 mg 
and Rosuvastatin 2.5 mg 
MK-0653H (EZ 10 mg + Ros 5 mg) compared to single entity, Ezetimibe 10 mg and 
Rosuvastatin 5 mg
3) To evaluate the proportion of patients who achieve LDL-cholesterol goal (refer to 
Appendix 12.4) at Week 12 based on the following;
MK-0653H (EZ 10 mg + Ros 2.5 mg) compared to single entity, Ezetimibe 10 mg 
and Rosuvastatin 2.5 mg
MK-0653H (EZ 10 mg + Ros 5 mg) compared to single entity, Ezetimibe 10 mg and 
Rosuvastatin 5 mg
4) To evaluate the percent change from baseline in LDL-C at Week 12 based on the 
following;
MK-0653H (EZ 10 mg + Ros 5 mg) compared to MK-0653H (EZ 10 mg + Ros 2.5
mg)
4.0 BACKGROUND & RATIONALE
4.1
Background
MK-0653H is a fixed dose combination drug containing Ezetimibe, a Niemann-Pick Cl Like 
1 (NPC1L1) 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
Pathophysiology and Epidemiology
4.1.1.1
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 Japan2), 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 risk6). 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 
 
 
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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 prevented8), 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 and another lipid-lowering drug to 
sufficiently lower LDL-C levels is suggested to be an approach for reducing the risk of 
cardiovascular events.
Significance of the Development of Fixed Dose Combination Tablet (FDC) for 
4.1.1.2
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.
 
 
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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 therapy12). In 
addition, data on other diseases show that the treatment compliance rate is correlated with the 
number of tablets (capsules) prescribed13), 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.
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. 
 
 
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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.
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 assess the long term safety and tolerability of MK-0653H in 
japanese patients with hypercholesterolemia(P833) 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, this study will 
be conducted to demonstrate the additional effect by comparing the efficacy between 
monotherapy and FDC.
The target population of this study is patients with hypercholesterolemia 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, that is, patients meeting any of the following 
conditions, judging from the results of laboratory tests at the start of the placebo 
administration period and the presence/absence of CAD history. 
For the hyperlipidemia patient with history of coronary artery disease (CAD), it is assumed 
that most of the patients are treated with lipid lowering agent based on the recommendation 
of JAS2012. And considering the safety of the patients, the patients who has a history of 
CAD or CAD-equivalent disease will be excluded from PN832 because it is considered not 
 
 
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appropriate to stop the lipid lowering therapy for a patient with a history of CAD, and to 
ensure that subjects are not placed on lipid lowering therapy with lower potency than they 
usually receive.
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 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 or 5 mg is an appropriate dose to be 
combined for Rosuvastatin.
Subject will receive one tablet of Ezetimibe 10 mg active or placebo and two capsules of
Rosuvastatin 2.5 mg active or placebo under double-blind in this trial.
Rationale for The Use of Comparator/Placebo
4.2.2.1
Placebo run-in period: in order to confirm the subject’s adherence, all subjects will receive 
placebo for 2 weeks under single blind.
Treatment period: In order to demonstrate the efficacy of MK-0653H comparing with single 
entity, this study has Ezetimibe 10 mg, Rosuvastatin 2.5 mg or 5 mg as parallel comparator. 
In addition, because the exploratory objective is to compare the efficacy between MK-0653H
(EZ 10 mg + Ros 2.5 mg) and MK-0653H (EZ 10 mg + Ros 5 mg), this study is parallel 
study with 5 arms.
Efficacy Endpoints
4.2.2.2
In this study, the percent change in LDL-C at Week 12 from baseline will be used as the 
primary variable. 
Results of many epidemiological surveys in Japan and overseas have shown that the 
incidence rate of CAD or the mortality rate increases with increasing level of LDL-C, and 
results of many large-scale clinical studies have confirmed that LDL-C lowering therapy is 
effective for the primary and secondary prevention of CAD3) 4) 5) 6). In Japan and overseas, 
 
 
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LDL-C level is positioned as an important index for lipid management, and is used as an 
important variable for the development of lipid-improving drugs. LDL-C level is an index 
which has been established from the viewpoint of the prevention of arteriosclerotic diseases 
and lipid management, and the efficacy evaluation has been performed with the percent 
change in LDL-C as the primary variable in the previous clinical studies of Ezetimibe. 
Meanwhile, it is considered that other lipid parameters (TC, HDL-C, non HDL-C, TG and 
Apo-B) and hs-CRP should be sufficiently evaluated similarly to the LDL-C lowering effect, 
and therefore it is planned that those parameters will be analyzed as exploratory variables.
As shown above, the percent changes in TC, HDL-C, non HDL-C, TG, Apo-B and hs-CRP 
will be used as exploratory variables to evaluate the efficacy of MK-0653H.
Safety Endpoints
4.2.2.3
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 serum ALT or serum AST elevations >3xULN, with serum 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 (Tier1 
events) and will be evaluated.
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 the primary objective of this study is to evaluate the efficacy in parallel study under 
double-blind, in order to wash-off the prior medication’s effect, subject is not allow to use 
lipid lowering agents 8 weeks prior to randomization (Visit 3) and see the values of lipid 
panels during treatment period. On the other hand, since there is no placebo arm during 
treatment period, subject is assigned to active arm only.
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.
 
 
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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 -8~ -3>
1. Japanese male or female and between ≥ 20 and ≤ 80 years of age on the day of 
signing informed consent.
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.
<Visit 2: Placebo run-in , Week -2>
6. Subject has TG value < 400 mg/dL at Visit 1.
7. Subject has CK (CPK) value ≤ 3 x upper limit of normal (ULN) [per central 
laboratory reference ranges] at Visit 1.
 
 
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8. Subject has ALT and AST value ≤ 2 x ULN [per central laboratory reference ranges] 
at Visit 1.
<Visit 3: Randomization>
9. 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 2. 
Friedewald method : LDL-C = Total cholesterol – HDL-cho – TG/5.
(1) Subject is categorized “Category I” and has LDL-C value ≥160 mg/dL to 
<220 mg/dL
(2) Subject is categorized “Category II” and has LDL-C value ≥140 mg/dL to 
<190 mg/dL
(3) Subject is categorized “Category III” and has LDL-C value ≥120 mg/dL to 
<160 mg/dL
10. Subject able to follow the instruction for drug administration and is greater than 75% 
compliant with study medication during the single-blind placebo run-in period.
5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
<Visit 1: Screening, Week -8~ -3>
Prohibited medical conditions
1. Subject has uncontrolled hypertension (treated or untreated) with 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 in the opinion of 
the investigator.
5. Subject has a history of coronary artery disease (CAD), CAD-equivalent disease  [e.g., 
peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery 
disease transient ischemic attack, stroke].
6. Subject has familial hypercholesterolemia or has undergone LDL apheresis.
 
 
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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).
Note: Definitions of hyper- and hypothyroidism are as follows:
Hyperthyroidism: TSH below the central laboratory's LLN.
Hypothyroidism: TSH >20% above the central laboratory's 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 
randomization visit (Visit 3). 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 by labeling as below.

Cyclosporine

Systemically administered azole antifungals(e.g., 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)
 
 
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
Simeprevir

Eltrombopag
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 ≥8 weeks prior to Visit 3 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 within 8 weeks prior to Visit 3.
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 ≥8 weeks prior to Visit 3 
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 that are known to affect 
serum lipids.
Note: If subject has been treated with a stable regimen for ≥8 weeks prior to Visit 3 
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: Placebo run-in , Week -2>
28. Subject has taken lipid-lowering agents (except probucol) including fish oils, 
Cholestin™, bile acid sequestrants, statins, Ezetimibe, fibrates or niacin (>200 
mg/day) within 6 weeks prior to Visit 2. Subject has taken probucol or protein 
convertase subtilisin/kexin type 9 (PCSK 9) inhibitor within 10 weeks prior to Visit 2.
<Visit 1 to 3>
29. Subject has developed a new medical condition, suffered a change in status of an 
established medical condition or required a new tratement or medication, which meets 
any previously described study exclusion criteria.
30. The subject who is considered inappropriate for participation in the study by the 
investigator for any other reason.
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.
Table 1 Trial Treatment
Treatment group
Study Drug Containers Dispensed
Bottle A
Blister card B
Blister card C
Placebo 
run-in 
period 
(single-blind)
Ezetimibe
Placebo tablet
Rosuvastatin
Placebo capsule
Rosuvastatin
Placebo capsule
Treatment period (double-blind)
Ezetimibe
10 mg
Ezetimibe
10 mg tablet
Rosuvastatin
Placebo capsule
Rosuvastatin
Placebo capsule
Rosuvastatin
2.5 mg
Ezetimibe
Placebo tablet
Rosuvastatin 
2.5 mg capsule
Rosuvastatin
Placebo capsule
Rosuvastatin 
5 mg
Ezetimibe
Placebo tablet
Rosuvastatin
2.5 mg capsule
Rosuvastatin
2.5 mg capsule
MK-0653H
(EZ 10 mg+Ros 2.5 mg)
Ezetimibe
10 mg tablet
Rosuvastatin
2.5 mg capsule
Rosuvastatin
Placebo capsule
MK-0653H
(EZ 10 mg+Ros 5 mg)
Ezetimibe
10 mg tablet
Rosuvastatin
2.5 mg capsule
Rosuvastatin
2.5 mg capsule
 
 
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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
Dose Selection (Preparation)
5.2.1.1
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.
5.2.2
Timing of Dose Administration
Study drug will be administered orally once daily after 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 the medication after all procedure 
is completed. The scheduled last study drug is a day before Visit6.
5.2.3
Trial Blinding
A single-blinding technique will be used. In Placebo Run-in period, Ezetimibe 10 mg 
matching placebo tablet and Rosuvastatin 2.5 mg matching placebo capsule will be packaged 
identically so that blind/masking is maintained. The subject will not know the treatment they 
are administered, however the investigator and Sponsor personnel or delegate(s) who are 
involved in the treatment or clinical evaluation of the subjects will be aware of the group 
assignments.
A double-blinding technique will be used.  In treatment period, Ezetimibe 10 mg tablet and 
Rosuvastatin 2.5 mg capsule will be packaged identically relative to their matching placebos
so that blind/masking is maintained. The subject, the investigator and Sponsor personnel or 
delegate(s) who are involved in the treatment or clinical evaluation of the subjects are 
unaware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
5.3
Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 5 treatment arms.  
Subjects will be assigned randomly in a 1:2:2:2:2 ratio to Ezetimibe 10 mg, Rosuvastatin 2.5 
mg, Rosuvastatin 5 mg, MK-0653H (EZ 10 mg+Ros 2.5 mg) and MK-0653H (EZ 10 
mg+Ros 5 mg), respectively.
5.4
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
 
 
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To achieve balance across treatment groups, randomization will be stratified according to the 
risk category determined at Visit 3.
1. Category I 
2. Category II 
3. Category III 
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. It is 
preferable that doses of these medications remain stable throughout the study.
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 
Appendix 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.
5.7.2
Activity
Subjects should continue any activity he/she was accustomed to prior to entering the study 
(including smoking), 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 guideline. Subject also should keep exclusion criterion #22 and #23. 
(Subject does not follow excessive weight reduction diet from study duration, 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.
 
 
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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 Appendix 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 
restricted in 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 2 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.
Table 2 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
The subject’s treatment assignment has been 
unblinded by the investigator, Merck subsidiary or 
through the emergency unblinding call center..
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 
Pregnancy (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 
Any subject who is unblinded to treatment regimen 
during study. (The subject’s treatment assignment 
has been unblinded by subject him/herself.)
Discontinuation from Treatment and Trial
Adverse experiences: Subject may be withdrawn 
from the study in the event that the investigator 
Discontinuation from Treatment and Trial
 
 
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Reason for Discontinuation Scenario
Action
assesses that administration of the study drug should 
be discontinued due to the occurrence of adverse 
experiences which would interfere with study 
continuation.
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
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
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 
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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6.0 TRIAL FLOW CHART
Phase
Screening 
(1~6 
weeks)
Placebo 
run-in 
(2 weeks)
Treatment (12 weeks)
Follow up
Week
Week 
-8~ -31
Week -2
Week 0
Week 4
Week 8
Week 12/ 
Discontinuati
on
14 days after 
last dosing
Visit number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit window permitted (Day)2
N/A
7~42+7
14+/-3
28+/-7
28+/-7
28+/-7
Administrative procedure
Obtain Informed Consent3
X
Collect Medical History 
X
Review Inclusion/Exclusion criteria
X
X
X
Review Prior/Concomitant Therapies
X
X
X
X
X
X
Contact Patient Registration Center
X
X
X
X
X
X
Risk assessment 4
X
X
X
Review Diet/Exercise and Instruct on JAS Guidelines
X
Monitor Dietary/Exercise Compliance
X
X
X
X
X
Dispense Study Drug5
X
X
X
X
Randomized (assignment of randomization number)
X
Monitor Medication compliance/patient diary
X
X
X
X
Safety assessment
Review adverse event
X
X
X
X
X
X
X 15
Perform Physical Examination 6
X
X
Vital sign
Height/Weight7
X
X
X
Sitting Blood Pressure/Pulse
X
X
X
X
X
X
ECG
X
Laboratory test8
Lipid Panel A9
X
X
X
X
X
X
hs CRP
X
X
Apo protein (Apo) B
X
X
X
X
Blood Chemistry 10
X
X
X
X
X
X
Hematology11
X
X
TSH
X
HbA1C
12
X
X
Urinalysis13
X
X
X
Pregnancy test14
X
X
X
X
X
X
 
 
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1.
Interval between Visit 1 and Visit 2 is determined depending on the presence of the prior treatments. Subjects washing out lipid-lowering therapy will 
have Visit 1 at -6 weeks from Visit 2; subjects not requiring washout will have Visit 1 at -1~-6 weeks from Visit 2 depending on the state of prior 
pharmacotherapy other than lipid-lowering agents in each subject.
2.
Visit window is relative to previous Visit. 
3.
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).
4.
Subject’s risk category assessment is determined at Visit 3 according to the Japan Atherosclerosis Society (JAS) Guideline 2012 based on the results 
obtained at Visit 1 and 2 (refer to Appendix 12.3).
5.
First 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.
6.
Auscultation and palpation and interview of condition will be conducted for physical examination.
7.
Weight will be measured at Visit 1, 3, 6. Height will be measured only at Visit 1. 
8.
All laboratory draws for the study will be conducted after at least 10-hour fast.
9.
Lipid panel A: LDL-C, total cholesterol (TC), HDL-C, non-HDL-C, and Triglyceride (TG)
10. Chemistry: Glucose, ALT, AST, ALP, uric acid, total bilirubin, BUN, CK (CPK), creatinine, Cl, potassium, sodium, γ-glutamyl transferase
11. Hematology: hemoglobin, platelet count, red blood cell count, white blood cell count, hematocrit
12. Subjects who have diagnosed with diabetes only may have their sample collected.
13. Urinalysis: pH, glucose (qualitative), protein (qualitative)
14. Urine pregnancy test (urine hCG) will be measured 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.
15. Post study 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
Informed Consent
7.1.1.1
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.
 
 
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Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
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.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
7.1.1.5
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 the randomization (Visit 3). Please note that the prior medications for 
hypercholesterolemia just before washout must be reported to eCRF.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Assignment of Screening Number
7.1.1.6
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.
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
 
 
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A single subject cannot be assigned more than 1 treatment/randomization number.
Randomization number will be allocated at Week 0 (Visit 3) via interactive voice response
system / integrated web response system (IVRS/IWRS).
Trial Compliance (Medication/Diet/Activity/Other)
7.1.1.8
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).
Physical Examination
7.1.2.1
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 3), any physical examination abnormalities will be recorded as part of the 
subject's medical history.
Vital Sign
7.1.2.2
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/ 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. 
 
 
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2. Situate the individual in a quiet environment with the arm resting at heart level.
3. Select the appropriately sized cuff.  
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: A pulse rate evaluates 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.
Monitor Medication compliance
7.1.2.3
Subjects should be instructed to record date and the number of tablet/capsule 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.
 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 3.
Table 3 Laboratory Tests
Category
Test
Lipid Panel A
LDL-C, total cholesterol (TC), HDL-C, non-HDL-C, and Triglyceride (TG)
hs-CRP
Apo protein (Apo) B
Blood Chemistry
Glucose, ALT, AST, ALP, uric acid, total bilirubin, BUN, CK (CPK), 
creatinine, Cl, potassium, sodium, γ-glutamyl transferase
Hematology
hemoglobin, platelet count, red blood cell count, white blood cell count, 
hematocrit
TSH
HbA1C
NOTE: Subjects who have diagnosed with diabetes only
Urinalysis
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. All Lipid Panel A, Apo B and hs-CRP data will be blinded once the subject 
is centrally randomized. Once a subject is randomized (Visit 3), no attempts should be made 
on the part of the investigator or subject to have a local evaluation of the subject’s lipid 
values (Lipid Panel A, Apo B and hs-CRP).
7.1.4
Other Procedures
Withdrawal/Discontinuation
7.1.4.1
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit (Visit 6) 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.
Blinding/Unblinding
7.1.4.2
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse experiences, 
he/she will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or sub-investigator the emergency 
unblinding call center will provide the information to him/her promptly and report unblinding 
to the sponsor.  The emergency unblinding call center will make a record promptly however, 
the investigator or sub-investigator must enter the intensity, relationship to the study 
medications and reason etc., of the adverse experiences observed,   their relation to study 
 
 
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drug, the reason thereof, etc., in the medical chart etc., before unblinding is performed.
Subjects whose treatment assignment has been unblinded must be discontinued from study 
drug.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
Calibration of Critical Equipment
7.1.4.3
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
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.
Screening (Visit 1)
7.1.5.1
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.
Screening visit will be performed 1 to 6 weeks prior to Visit 2. Subject must discontinue the 
prior medication (except probucol) for hypercholesterolemia [fish oils, Cholestin™, bile acid 
sequestrants, statins, Ezetimibe, fibrates or niacin (>200 mg/day)] at least 6 weeks prior to 
Visit 2. If subject has taken probucol, probucol must be discontinued from at least 10 weeks 
prior to Visit 2. If a subject is eligible for study participation, a 10 hour fasting blood sample 
will be drawn.
Subject will be instructed on the JAS2012 diet and exercise, and will agree to maintain the 
diet/exercise regimen throughout the study.
Placebo run-in (Visit 2)
7.1.5.2
Visit 2 will be performed 2 weeks prior to randomization (Visit 3). 
 
 
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Visit 1 lab results must be reviewed and subject must meet all eligibility criteria at Visit 1 
prior to performing any procedures at Visit 2. If a subject is eligible for study participation, a 
10 hour fasting blood sample will be drawn. After initiating study drug (placebo) 
administration, subject who is determined to be not appropriate by the investigator will be 
excluded the study as screen failed. If a subject is not eligible for study participation, the 
investigator should contact with the subject, stop dosing study drug and performing the study 
immediately. NOTE: it is not necessary for screen failed subject to perform examination at 
discontinuation visit.
Subject will be instructed to take one tablet from a bottle and 1 capsule from each blister card 
and record medication compliance in a patient diary by following instruction. In principle, 
the day before scheduled visit should be administered study drug after dinner since blood 
sample is obtained at trough. All subjects will be asked to bring the bottle, blister cards and 
patient diary to their next scheduled clinic visit for compliance assessment.
Treatment Period (Visits 3 to 6)
7.1.5.3
If the subject meets all inclusion criteria and does not meet any of the exclusion criteria, the 
site will perform all procedures for Visit 3 and the subject will be randomized.
Blood sample will be obtained after at least 10 hour fasting and prior to administrating the 
study medication. After the all procedures have been completed, the study drugs will be 
dispensed to the subject and his/her will take them.
All lipid evaluations will be blinded once the subject is centrally randomized. No attempts 
could be made to have local evaluation of the subject’s lipid levels once they have been 
issued active therapy. The investigator will not be blinded to laboratory safety results. 
Discontinuation
7.1.5.4
After performing Visit 3, subject who is determined to be not appropriate by the investigator 
will be discontinued from the study. The investigator should contact with the subject to 
perform the examination listed at Visit 6 (12w/Discon) immediately, and be discontinued 
from the study.
Post-Trial (follow up telephone contact)
7.1.5.5
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), 
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.
 
 
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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 1 tablet/capsule from either bottle or blister 
card per day during the study.
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 
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.
 
 
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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
Serious Adverse Events
7.2.3.1
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.
Refer to Table 4 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 
 
 
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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.
Events of Clinical Interest
7.2.3.2
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.*
*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.
 
 
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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 4. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 4 for instructions in evaluating adverse events.
 
 
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Table 4 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. If, after 
the study has begun, but prior to unblinding, changes are made to the primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in a supplemental Statistical Analysis Plan (sSAP) and 
referenced in the Clinical Study Report (CSR) for the study. Post-hoc exploratory 
analyses will be clearly identified in the CSR.
 
 
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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 
Factorial 
Study 
in 
Japanese 
Hypercholesterolemic Patients
Treatment Assignment
Subjects will be randomized to the following 5 arms in a 
1:2:2:2:2 ratio.

EZ 10 mg

Ros 2.5 mg

Ros 5 mg

MK-0653H (EZ 10 mg + Ros 2.5 mg)

MK-0653H (EZ 10 mg + Ros 5 mg)
The study will be conducted as a double-blind study.
Analysis Populations
Efficacy
Full Analysis Set (FAS) population, defined as all randomized 
subjects who:

received at least one dose of double-blind study treatment

have baseline or post-baseline data

have baseline data for those analyses that require baseline 
data.
Safety
All Subject as Treated (ASaT) population, defined as all 
randomized subjects who received at least one dose of double-
blind study treatment.
Primary Endpoint
Percent change from baseline in LDL-C at Week 12
Statistical Methods for 
Key Efficacy Analyses
Percent change from baseline in LDL-C at Week 12 will be 
analyzed using a constrained longitudinal data analysis 
(cLDA) model proposed by Liang and Zeger17) . The model 
will include terms for treatment, time, risk category, 
interactions of treatment by time and time by risk category. 
The primary hypotheses will be evaluated by comparing MK-
0653H (EZ 10 mg + Ros 2.5 mg) to EZ 10 mg and to Ros 2.5 
mg, as well as MK-0653H (EZ 10 mg + Ros 5 mg) to EZ 10 
mg and to Ros 5 mg, based on the above model.
 
 
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Statistical Methods for 
Key Safety Analyses
Safety events of special interest such as elevations in liver 
function tests will be pre-specified as Tier 1 events. (Refer to 
Section 8.6.2 for a full list of events.)
The Tier 2 events are as follows.

AE

drug-related AE

serious AE (SAE)

drug-related SAE

discontinuation due to AE

discontinuation due to drug-related AE

discontinuation due to SAE

discontinuation due to drug-related SAE

specific AEs and system organ classes (SOCs) with 
incidence ≥4 subjects in at least one treatment group
The percentage of subjects experiencing respective Tier 1 and 
Tier 2 events will be analyzed using the Miettinen and 
Nurminen method18). p-Values for treatment comparisons (Tier 
1 only) and 95% confidence intervals (CIs) for treatment 
differences (Tier 1 and Tier 2) will be provided.
Interim Analyses
No interim analyses are planned.
Multiplicity
The study has two families of primary hypotheses, each 
comparing one arm of MK-0653H to the corresponding 
monotherapy components [i.e., EZ 10 mg and Ros (2.5 or 5 
mg)]. Successful demonstration of a family of primary 
hypotheses requires superiority of MK-0653H to both EZ and 
Ros, and hence, no adjustment for multiplicity within a family 
of primary hypotheses is required. Multiplicity across the two 
families of primary hypotheses will be adjusted by the 
Hochberg procedure.
Sample 
Size 
and 
Power
With 31 subjects for EZ 10 mg and 62 subjects for each of the 
other 4 arms, the study will have a power of approximately 
97% to successfully demonstrate both of the two families of 
primary hypotheses (α=0.05, two-sided). This calculation is 
based on the true percent change from baseline in LDL-C of -
15% for EZ 10 mg, -34% for Ros 2.5 mg, -40% for Ros 5 mg, 
-46% for MK-0653H (EZ 10 mg + Ros 2.5 mg) and -52% for 
MK-0653H (EZ 10 mg + Ros 5 mg), and a true standard 
deviation (SD) of 16%. To account for discontinuation, a total 
of 306 subjects will be randomized.
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 study will be conducted as a 
double-blind study under in-house blinding procedures. The official, final database will 
 
 
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not be unblinded until medical/scientific review has been performed, protocol deviations 
have been identified, and data have been declared final and complete.
The Clinical Biostatistics department will generate the randomized allocation schedule for
study treatment assignment.
8.3
Hypotheses / Estimation
The study has the following two families of primary hypotheses in terms of percent 
reduction from baseline in LDL-C at Week 12.
(1) MK-0653H (EZ 10 mg + Ros 2.5 mg) is superior to Ezetimibe 10 mg and is superior 
to Rosuvastatin 2.5 mg in percent reduction from baseline in LDL-C after 12 weeks 
of treatment.
(2) MK-0653H (EZ 10 mg + Ros 5 mg) is superior to Ezetimibe 10 mg and is superior to 
Rosuvastatin 5 mg in percent reduction from baseline in LDL-C after 12 weeks of 
treatment.
Successful demonstration of a family of primary hypotheses requires superiority of MK-
0653H (EZ 10 mg + Ros 2.5 mg, or EZ 10 mg + Ros 5 mg) to both of the corresponding 
monotherapy components [i.e., EZ 10 mg and Ros (2.5 or 5 mg)]. Successful 
demonstration of at least one family of primary hypotheses is required to declare study 
success.
8.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below. For each of the efficacy and safety parameters, the baseline 
value is defined as the last available measurement prior to randomization, which typically 
corresponds to the measurement obtained at Visit 3.
8.4.1
Efficacy Endpoints
The primary efficacy endpoint is percent change from baseline in LDL-C at Week 12. 
The exploratory endpoints include percent change from baseline in LDL-C at Weeks 4 
and 8, proportion of subjects achieving LDL-C goal at Week 12, as well as percent 
change from baseline in the other efficacy parameters (refer to Section 4.2.3.1) at Week 
12.
8.4.2
Safety Endpoints
Refer to Section 4.2.3.2 for a list of safety endpoints.
8.5
Analysis Populations
8.5.1
Efficacy Analysis Populations
The FAS population will serve as the population for the analyses of efficacy data in this 
study. The FAS population consists of all randomized subjects who:

received at least one dose of double-blind study treatment

have baseline or post-baseline data

have baseline data for those analyses that require baseline data.
 
 
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Even though no Per-Protocol analysis is planned, major deviations from the protocol that 
may substantially affect the results of the primary efficacy endpoint will be identified and 
documented in a separate memo prior to unblinding. Such major deviations include:

off-drug periods during the treatment period

noncompliance

concomitant use of prohibited medications with presumed lipid lowering efficacy

errors in assigned study medication during the study.
Subjects will be included in the treatment group to which they are randomized for 
analyses of efficacy data.
8.5.2
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all randomized subjects who received at least one dose of double-
blind study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are 
randomized. Subjects who take incorrect study treatment for the entire treatment period 
will be included in the treatment group corresponding to the study treatment actually 
received. At least one laboratory or vital sign measurement obtained subsequent to at least 
one dose of double-blind study treatment is required for inclusion in the analysis of each
specific parameter. To assess change from baseline, a baseline measurement is also 
required.
8.6
Statistical Methods
8.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary objectives. 
Methods related to the exploratory objectives will be described in the sSAP.
The primary endpoint, percent change from baseline in LDL-C at Week 12, will be 
analyzed using a cLDA model proposed by Liang and Zeger. The model will include 
terms for treatment, time, risk category, and the interactions of treatment by time and time 
by risk category. This model assumes a common mean across treatment groups at 
baseline and a different mean for each treatment at each of the post-baseline time points. 
In this model, the response vector consists of baseline and the values (percent change) 
observed at each post-baseline time point. Time is treated as a categorical variable so that 
no restriction is imposed on the trajectory of the means over time. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements. 
The cLDA model uses the maximum likelihood principle to estimate the parameters and 
account for missing data in an implicit fashion. The treatment difference in terms of mean
percent change from baseline to Week 12 will be estimated and tested from this model to 
address the primary hypotheses. Sensitivity analysis will be performed to assess the 
robustness of the results to the assumptions about missing data. The details will be 
described in sSAP.
The above analysis based on restricted maximum likelihood (REML) assumes that the 
vector of model-based residuals follows a multivariate normal distribution. Under severe 
departures from normality, the REML-based analysis can be inefficient or potentially 
 
 
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misleading. Accordingly, the residuals from the REML-based analysis, scaled by the 
inverse Cholesky root of the marginal variance-covariance matrix, will be subjected to a 
test for normality.  If normality is not rejected at the α=0.001 level, then the above 
REML-based analysis will serve as the primary analysis. However, if normality is 
rejected, then the primary analysis will be conducted using multiple imputation (MI) of 
missing values (if any) in conjunction with a robust regression approach that uses M-
estimation. The model will include factors for treatment and risk category, and baseline 
value as a covariate. Of note, the 0.001 level for the normality test was chosen so that the 
default REML-based analysis is abandoned only under a clear departure from normality; 
moreover, this choice guarantees that there is no material inflation in the type I error rate 
for the treatment effect comparison due to a potential correlation between the test 
statistics for the treatment effect and the normality test.
The strategy to address multiplicity issues with regard to multiple treatment comparisons 
is described in Section 8.8, Multiplicity.
8.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters 
including AEs, laboratory tests, and vital signs. The treatment comparisons or treatment 
differences in this section pertain to the MK-0653H (EZ 10 mg + Ros 2.5 mg, or EZ 10 
mg + Ros 5 mg) versus corresponding monotherapy components [i.e., EZ 10 mg and Ros 
(2.5 or 5 mg)].
The analysis of safety results will follow a tiered approach. The tiers differ with respect to 
the analyses that will be performed. Safety parameters or adverse experiences of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be subject 
to inferential testing for statistical significance with p-values for treatment comparisons as 
well as point estimates and corresponding 95% CIs for between-group differences. Other 
safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed 
via point estimates and corresponding 95% CIs provided for between-group differences; 
only point estimates by treatment group are provided for Tier 3 safety parameters.
AEs (specific terms as well as SOC terms) that are not pre-specified as Tier 1 endpoints 
will be classified as belonging to "Tier 2" or "Tier 3", based on the number of subjects 
who experiences the events.  Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other AEs will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when treatment groups of equal 
size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% CIs may be provided without 
adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to 
be used in review, not a formal method for assessing the statistical significance of the 
between-group differences in AEs.
Continuous measures such as changes from baseline in laboratory and vital signs 
parameters that are not pre-specified as Tier 1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by treatment group in table format.
Refer to Table 5 for a list of safety endpoints by tier.
p-Values (Tier 1 only) for treatment comparisons and 95% CIs for between-treatment 
differences in the percentage of subjects with respective Tier 1 and Tier 2 events will be 
 
 
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calculated using the Miettinen and Nurminen method. The analysis will not be stratified 
by risk category.
 
 
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Table 5 Analysis Strategy for Safety Parameters
Safety 
tier
Safety endpoint†
p-
Value
95% CI for
treatment difference
Descriptive 
statistics
Tier 1

gastrointestinal related AEs

gallbladder-related AEs

allergic reaction or rash AEs

hepatitis-related AEs

consecutive elevations in ALT ≥3x ULN

consecutive elevations in AST ≥3x ULN

consecutive elevations in ALT or AST ≥3x
ULN

ALT elevations ≥5x ULN

AST elevations ≥5x ULN

ALT or AST elevations ≥5x ULN

ALT elevations ≥10 xULN

AST elevations ≥10x ULN

ALT or AST elevations ≥10x ULN

potential Hy's Law condition (ALT or AST
elevations >3x ULN, with ALP <2x ULN and
TBL ≥2x ULN)

CK elevations ≥10x ULN

CK elevations ≥10x ULN with muscle
symptoms

CK elevations ≥10x ULN with muscle
symptoms that are considered drug-related
X
X
X
Tier 2

AE

drug-related AE

SAE

drug-related SAE

discontinuation due to AE

discontinuation due to drug-related AE

discontinuation due to SAE

discontinuation due to drug-related SAE

specific AEs, SOCs (incidence ≥4 subjects in 
at least one treatment group)
X
X
Tier 3

Specific AEs, or SOCs‡
(incidence <4 
subjects in all treatment groups)

Change from baseline results (laboratory, and
vital signs)
X
† AE references refer to both clinical and laboratory AEs.
‡ Includes only those endpoints not pre-specified as Tier 1 or Tier 2 endpoints.
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant characteristic will be assessed 
by the use of tables and/or graphs. No statistical hypothesis tests will be performed on 
these characteristics. The number and percentage of subjects screened, randomized, 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 by treatment either by 
descriptive statistics or categorical tables.
8.7
Interim Analyses
No interim analyses are planned for the study.
 
 
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8.8
Multiplicity
The study has two families of primary hypotheses, each comparing one arm of MK-
0653H (i.e., EZ 10 mg + Ros 2.5 mg, or EZ 10 mg + Ros 5 mg) to the corresponding 
monotherapy components [i.e., EZ 10 mg and Ros (2.5 or 5 mg)]. Successful 
demonstration of a family of primary hypotheses requires superiority of MK-0653H to 
both EZ and Ros, and hence, no adjustment for multiplicity within a family of primary 
hypotheses is required. Multiplicity across the two families of primary hypotheses will be 
adjusted by the Hochberg procedure, which is implemented as follows.
Let p1E and p1R be the p-values associated with the treatment comparisons of EZ 10 mg +
Ros 2.5 mg to EZ 10 mg and to Ros 2.5 mg, respectively, and p1max be the larger of p1E
and p1R. Define p2E, p2R and p2max similarly for the treatment comparisons of EZ 10 mg + 
Ros 5 mg to EZ 10 mg and to Ros 5 mg.
Let pFmax and pFmin be the larger and smaller of p1max and p2max, respectively. Then the 
conclusions of the study will be as follows, depending on the values of pFmax and/or pFmin:

if pFmax ≤0.05, then both of the two families of primary hypotheses are considered 
successfully demonstrated

if pFmax >0.05 and pFmin ≤0.025, then only the family of primary hypotheses 
associated with pFmin is considered successfully demonstrated but the other family is 
not

otherwise, neither of the two families of primary hypotheses is considered 
successfully demonstrated.
A schematic display of multiplicity adjustment is shown in Figure 2 below.
Figure 2 Schematic Display of Multiplicity Adjustment
Maximum p-value
within each family
Ordered p-values
across families
Success declared for
only one family
associated with pFmin
Success declared for
both families
Success not declared
for either families
Decision strategy
pFmin ≤0.025
p-Values
pFmax ≤0.05
pFmax >0.05
pFmin >0.05
0.025< pFmin ≤0.05
vs. Ros 2.5 mg
[p1R]
Family 1
MK-0653H (EZ 10 mg + Ros 2.5 mg)
vs. EZ 10 mg
[p2E]
pFmin = min (p1max, p2max)
pFmax = max (p1max, p2max)
vs. Ros 5 mg
[p2R]
Family 2
MK-0653H (EZ 10 mg + Ros 5 mg)
p1max = max (p1E, p1R)
p2max = max (p2E, p2R)
vs. EZ 10 mg
[p1E]
 
 
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8.9
Sample Size and Power Calculations
A total of 306 subjects will be randomized in a ratio of 1:2:2:2:2 to the following 5 arms: 
EZ 10 mg, Ros 2.5 mg, Ros 5 mg, MK-0653H (EZ 10 mg + Ros 2.5 mg), MK-0653H
(EZ 10 mg + Ros 5 mg). Assuming that valid LDL-C measurements can be obtained at 
Week 12 from 31 subjects in the EZ 10 mg arm and from 62 subjects in each of the other 
4 arms, the study will have a power of approximately 97% to successfully demonstrate 
both of the two families of primary hypotheses at α=0.05, two-sided. For each of the two 
families of primary hypotheses, the study will have a power of approximately 97% that 
the family of primary hypotheses can be demonstrated at α=0.025, two-sided. The study 
will have a probability of approximately 98% to show a numerically greater LDL-C 
percent reduction at Week 12 with MK-0653H (EZ 10 mg + Ros 5 mg) compared with 
MK-0653H (EZ 10 mg + Ros 2.5 mg). These calculations were performed using 
simulations. Power calculations for pairwise comparisons are shown in Table 6 below.
Table 6 Power Calculations for Pairwise Comparisons
Endpoint
N1
N2
Minimum detectable 
difference with 90% power
[α=0.05 (0.025), two-sided]
Half-width of
95 (97.5) % CI
SD
LDL-C % change
62
62
62
31
9.4 (10.2) %
11.5 (12.6) %
5.7 (6.5) %
7.0 (8.0) %
16%
16%
The calculations shown in Table 6, and the calculations above performed using 
simulations, are based on the assumptions on the true percent change from baseline in 
LDL-C at Week 12 for each treatment arm as shown in Table 7, and a true SD of 16%. 
These are conservative estimates from previously conducted factorial studies with EZ 10 
mg and statins, as well as placebo-controlled monotherapy studies with EZ 10 mg or 
Rosuvastatin.
Table 7 Assumptions on True LDL-C Percent Change from Baseline by Treatment
Ezetimibe
Rosuvastatin
0 mg
2.5 mg
5 mg
0 mg
--
-34%
-40%
10 mg
-15%
-46%
-52%
8.10 Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary
endpoint will be estimated and plotted within each category of each subgroup.

age category (<65 years, ≥65 years)

gender (male, female)

prior lipid-lowering agent therapy [none, treatment with a statin (with or without 
other lipid-lowering agent therapies), treatment without a statin]

diabetes mellitus (yes, no)

hypertension (yes, no)

baseline LDL-C (≤or > median)

risk category (category I, category II, category III)
 
 
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The consistency of the treatment effect will be assessed using the same model as the 
primary efficacy analysis model.
8.11 Compliance (Medication Adherence)
A day within the study will be considered an “On-Therapy” day if the subject takes one 
tablet / capsule each from Bottle A and Blister cards B and C. For a subject who is 
followed for the entire study period, the “Number of Days Should be on Therapy” is the 
total number of days from the day of randomization to the last scheduled day for 
treatment administration for that subject. For a patient who discontinued from the study 
permanently, the “Number of Days Should be on Therapy” is the total number of days 
from the day of randomization to the date of the last dose of study medication.
For each subject, percent compliance 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 by treatment group for the
FAS population.
8.12 Extent of Exposures
The dose level and treatment duration will be summarized for the ASaT population.
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 8.
Table 8 Product Descriptions
Product Name & Potency
Dosage Form
Ezetimibe 10 mg or matching placebo
Tablet
Rosuvastatin Calcium 2.5 mg or matching placebo
Capsule
All placebos were created by the Sponsor to match the active product.
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
In the placebo run-in period, subjects will receive one (1) single blinded bottle of 
Ezetimibe 10 mg matching placebo and two (2) single blinded blister card of 
Rosuvastatin Calcium 2.5 mg matching placebo. In the treatment period, subjects will 
receive one (1) blinded bottle of Ezetimibe 10 mg or matching placebo and two (2) 
blinded blister card of Rosuvastatin Calcium 2.5 mg or matching placebo every four (4) 
weeks.
 
 
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9.3
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment allocation/randomization 
schedule for the trial to unblind subjects and to unmask treatment identity . The Sponsor 
will not provide random code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the subject.  Every effort should be made not to unblind the subject unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and 
the Sponsor Clinical Director notified as soon as possible.  Only the principal investigator 
or delegate and the respective subject’s code should be unblinded.  Trial site personnel 
and Sponsor personnel directly associated with the conduct of the trial should not be 
unblinded to treatment assignment. Subjects whose treatment assignment has been 
unblinded (by the investigator, Merck subsidiary, or through the emergency unblinding 
call center) must be discontinued from study drug.
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 coordinating investigator to review 
the trial report that summarizes the trial results and confirm that, to the best of his/her 
 
 
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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 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 
 
 
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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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17. Liang K, Zeger S. Longitudinal data analysis of continuous and discrete responses 
for pre-post designs. Sankhyā: The Indian Journal of Statistics 2000;62 (Series 
B):134-48.
18. Miettinen OS, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213 -26.
 
 
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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 Rosuvastatincalcium 2.5 mg
EZ 10 mg+Ros 5 mg
Co-administration of Ezetimibe 10 mg and Rosuvastatincalcium 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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12.3 Category Assessment for Each Patient
Subjects will be assessed using following chart based on JAS 2012.
Baseline Risk
No. of Risk Factors
Category
Gender
Age
1)
Hypertension
2)
Smoking
3)
Hypo HDL cholesterolemia (HDL-C < 40 mg/dL)
4)
Family history of premature CAD in first-degree 
relatives (a man aged < 55 years or a woman aged <
65 years)
5)
Impaired glucose tolerance
Male
40’s
0
Category I
1-2
Category II
≥3
Category III
50’s
0
Category II
1
Category II
≥2
Category III
60’s
(up to 74 years)
0
Category II
≥1
Category III
Female
40’s and 50’s
0-1
Category I
≥2
Category II
60’s
(up to 74 years)
0-1
Category II
≥2
Category III
 
 
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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.
Patient who has diabetes mellitus, chronic kidney disease (CKD), non cardio-embolic stroke or peripheral arterial 
disease (PAD) are definded as category III
Revised JAS Guidelines, 2012 version (The Japan Atherosclerosis Society)
 
 
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12.5 Diet and Alcohol
Diet
Patient should follow the nutrient recommendation provided by the JAS2012 for 
prevention of atherosclerotic cardiovascular diseases throughout this study.
1) with consideration for energy intake and amount of physical examination, maintain 
normal body weight ([Height(m)]2×22)
2) control energy rate of fat 20 to 25%, unsaturated fatty acid 4.5% to not more than 7%, 
and amount of cholesterol intake, <200 mg/day
3) increase n-3 poly unsaturated fatty acids intake
4) control energy rate of carbonhydrates 50 to 60%, and increase fiber intake
5) control salt intake 6 g/day
6) limit alcohol intake <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 subject 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 results 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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12.7 Clinical Study Conduct System
Clinical study conduct system in Japan is provided by Japanese language.
 
 
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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
 
 
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