Ezetimibe (EZ)/Atorvastatin (Ator) (MK-0653C) vs. Ator in Chinese Hypercholesterolemic Participants (MK-0653C-439)

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the EZ/Ator fixed-dose combination (FDC) tablet (MK-0653C) as second line Low-Density Lipoprotein - Cholesterol (LDL-C) treatment in Chinese participants. The primary hypothesis is that MK-0653C 10/10 mg is superior to atorvastatin 20 mg in percent change from baseline in LDL-C to 12 weeks after treatment.

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

Conditions
-----------------
Hypercholesterolemia

Intervention / Treatment
-----------------
* Combination Product: EZ 10 mg/Ator 10 mg
* Combination Product: EZ 10 mg/Ator 20 mg
* Drug: Atorvastatin
* Drug: Placebo for FDC EZ/Ator
* Drug: Placebo for atorvastatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has hypercholesterolemia diagnosed by investigator according to Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults (2016 Edition). Has been stabilized on atorvastatin treatment at 10 mg or 20 mg (or other statins with LDL-C lowering efficacy equivalent to atorvastatin) for at least 4 weeks prior to Visit 1. If female, is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP), or is a WOCBP who has used a contraceptive consistent with local regulations. If male, has used a contraceptive consistent with local regulations. Agrees to maintain a stable diet and stable exercise during the study. Exclusion Criteria: Has uncontrolled hypertriglyceridemia which needs drug intervention or a fasting triglyceride (TG) value ≥500 mg/dL (4.52 mmol/L). Is currently treated with statin at dose of equivalent LDL-C lowering effect >20 mg atorvastatin. Has active liver disease Has New York Heart Association (NYHA) Class III or IV symptomatic congestive heart failure at Visit 1. Has had uncontrolled cardiac arrhythmias, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, unstable angina, or stroke within 3 months (12 weeks) prior to Visit 1. Has homozygous familial hypercholesterolemia or has undergone LDL apheresis. Has endocrine or metabolic disease known to influence serum lipids or lipoproteins (i.e., secondary causes of hyperlipidemia, e.g., hyper or hypothyroidism, Cushing's syndrome). Has had a gastrointestinal tract bypass, or other significant intestinal malabsorption. 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). Is known to be human immunodeficiency virus (HIV) positive. Has hypersensitivity or intolerance to ezetimibe, atorvastatin, the ezetimibe/atorvastatin combination tablet, or any component of these medications or has a condition or situation, which is described as a contraindication in labeling of EZETROL or Lipitor or may interfere with participation in the study. Has disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. Has a history of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy. Has a history of myopathy or rhabdomyolysis with ezetimibe or any statin. Is a WOCBP who has had a positive urine pregnancy test within 24 hours before the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Is currently taking medications that are potent modulators of cytochrome P-450 3A4 (CYP3A4) including: cyclosporine, systemically administered azole antifungals (e.g., ketoconazole, fluconazole, and itraconazole), macrolide antibiotics (e.g., clarithromycin, and erythromycin), protease inhibitors (e.g., ritonavir, saquinavir, and lopinavir), grapefruit or juice of grapefruit (200 ml/day for >3 times per week) Is taking any cyclical hormones (e.g., cyclical oral contraceptives, cyclical hormone replacement), including the combination of ethinyl estradiol and norethisterone, or non-cyclical hormones, including non-cyclical hormone replacement therapy (HRT) or any estrogen antagonist/agonist within 8 weeks. Note: If participant has been treated with a stable regimen of non-cyclical HRT for > 8 weeks and agree to continue this regimen for the duration of the trial, concomitant therapy is acceptable. Is receiving treatment with systemic corticosteroids (intravenous, intramuscular and oral steroids). Is treated with psyllium, other fiber-based laxatives, phytosterol margarine, and herbal medicine and/or over the counter (OTC) therapies that are known to affect serum lipids. Note: If participant has been treated with a stable regimen for > 8 weeks and agrees to continue this regimen for the duration of the trial, concomitant therapy is acceptable. Is treated with an anti-obesity drug (e.g. mazindol) within 12 weeks prior to Visit 1. Is treated with warfarin or warfarin-like anticoagulants and has not been on a stable dose with a stable International Normalized Ratio (INR) for at least 6 weeks. weeks. Has taken lipid-lowering agents (except probucol) including, Cholestin, bile acid sequestrants, ezetimibe, fibrates or niacin (>200 mg/day), proprotein convertases subtilisin/kexin type 9 (PCSK9) inhibitors within 6 weeks prior to Visit 1. Has taken probucol within 10 weeks prior to Visit 1. Has been treated with any other investigational drug within 30 days. Currently follows an excessive weight reduction diet. Currently engages in a vigorous exercise regimen (e.g., marathon training, body building training) or intends to start training during the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EZ 10 mg/Ator 10 mg<br>Single oral dose of EZ10mg/Ator10mg FDC tablet once daily (QD) for 84 days | Combination Product: EZ 10 mg/Ator 10 mg<br>* FDC of EZ10 mg/Ator 10mg<br>Drug: Placebo for FDC EZ/Ator<br>* A single placebo tablet administered orally QD for 84 days<br>|
| Active Comparator: Atorvastatin 20 mg<br>2 atorvastatin 10 mg tablets administered orally, QD for 84 days | Drug: Atorvastatin<br>* Atorvastatin administered orally QD, either as two 10 mg tablets or as two 20 mg tablets<br>* Other names: Lipitor^®;Drug: Placebo for atorvastatin<br>* Two placebo tablets matching atorvastatin administered orally QD for 84 days<br>|
| Experimental: EZ 10 mg/Ator 20 mg<br>Single oral dose of EZ10mg/Ator20mg FDC tablet QD for 84 days | Combination Product: EZ 10 mg/Ator 20 mg<br>* FDC of EZ10 mg/Ator 20mg<br>Drug: Placebo for FDC EZ/Ator<br>* A single placebo tablet administered orally QD for 84 days<br>|
| Active Comparator: Atorvastatin 40 mg<br>2 atorvastatin 20 mg tablets administered orally, QD for 84 days | Drug: Atorvastatin<br>* Atorvastatin administered orally QD, either as two 10 mg tablets or as two 20 mg tablets<br>* Other names: Lipitor^®;Drug: Placebo for atorvastatin<br>* Two placebo tablets matching atorvastatin administered orally QD for 84 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in LDL-C at Week 12 | Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated. | Baseline (Day 1) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With An Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to approximately 17 weeks | 
| Number of Participants Who Discontinued From Study Treatment | The number of participants who discontinued treatment over the 12-week treatment period was assessed. | Up to approximately 15 weeks |