A Study to Evaluate the Effectiveness of Ezetimibe/Atorvastatin 10 mg/20 mg Combination Tablet Compared to Marketed Ezetimibe 10 mg and Atorvastatin 20 mg Tablets in Participants With High Cholesterol (MK-0653C-185 AM1)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether ezetimibe/atorvastatin 10 mg/20 mg combination tablet is equivalent to the coadministration of ezetimibe 10 mg and atorvastatin 20 mg in lowering low-density-lipoprotein-cholesterol (LDL-C) after 6 weeks of treatment.

Official Title
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A Randomized, Double-Blind, Active-Controlled, Multicenter, Crossover Study to Evaluate the Efficacy and Safety of Ezetimibe/Atorvastatin 10 mg/20 mg Fixed-Dose Combination Tablet Compared to Co-administration of Marketed Ezetimibe 10 mg and Atorvastatin 20 mg in Patients With Primary Hypercholesterolemia

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Ezetimibe
* Drug: Ezetimibe/atorvastatin
* Drug: Placebo to atorvastatin
* Drug: Placebo to ezetimibe
* Drug: Placebo to ezetimibe/atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: At low, moderate, or moderately high cardiovascular risk (according to National Cholesterol Education Program adult treatment panel III [NCEP ATP III] guidelines) and either statin-naïve with LDL-C ≥130 mg/dL for low risk or ≥100 mg/dL for moderate or moderately high risk OR on an allowable statin with on-therapy LDL-C ≥100 mg/dL in acceptable range and can safely discontinue and switch to study medication. Is willing to maintain a cholesterol-lowering diet throughout the study. Female of reproductive potential agrees to remain abstinent or to use (or have their partner use) 2 acceptable methods of birth control throughout the study. Female receiving non-cyclical hormone therapy, if maintained on a stable dose and regimen for at least 8 weeks prior to the study and if willing to continue the same regimen throughout the study. Off-therapy LDL-C levels are: for low risk patients, ≥130 mg/dL and ≤300 mg/dL; for moderate risk patients, ≥100 mg/dL and ≤300 mg/dL; for moderately high risk patients, ≥100 mg/dL and ≤275 mg/dL. Has liver transaminases ≤2 X upper limit of normal (ULN) with no active liver disease. Has creatine kinase (CK) levels ≤3 X ULN. Has triglyceride (TG) concentrations ≤400 mg/dL. Exclusion criteria: Hypersensitivity or intolerance to ezetimibe, atorvastatin, the ezetimibe/atorvastatin combination tablet, or any component of these medications, or a history of myopathy or rhabdomyolysis with ezetimibe or any statin. Routinely consumes more than 2 alcoholic drinks per day (average >14 alcoholic drinks per week). Is pregnant or lactating. Has been treated with any other investigational drug within 30 days of the study. Has any condition or situation that might pose a risk to the participant or interfere with participation in the study. Is high risk (according to NCEP ATP III guidelines), including but not limited to one or more of the following: diabetes mellitus (Type I or II), myocardial infarction, coronary artery bypass surgery, angioplasty, stable or unstable angina. Has any of the following medical conditions: congestive heart failure; uncontrolled cardiac arrhythmias or recent significant changes in electrocardiogram (ECG); homozygous familial hypercholesterolemia or has undergone LDL apheresis; partial ileal bypass, gastric bypass, or other significant intestinal malabsorption; uncontrolled hypertension; kidney disease; disease known to influence serum lipids or lipoproteins; hematologic, digestive, or central nervous systems disorder; known to be human immunodeficiency virus (HIV) positive; history of malignancy ≤5 years prior to the study, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer; mental instability; drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy. Taking prohibited medications/foods including: systemic azole antifungals (e.g., fluconazole, ketoconazole), erythromycin or clarithromycin, and cyclosporine; ritonavir and saquinavir or lopinavir; >5 cups of grapefruit juice per day; combination therapies of ezetimibe + simvastatin (10/80 mg), ezetimibe + atorvastatin (10/40 mg or 10/80 mg), ezetimibe + rosuvastatin (10/10 mg, 10/20 mg, or 10/40 mg), ezetimibe + pitavastatin (10/4 mg); non-statin lipid-lowering agents including fish oils containing >900 mg/day of eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA), red yeast extract, Cholestin™, bile acid sequestrants, other cholesterol-lowering agents, niacin (>200 mg/day), or fibrates; systemic corticosteroids; psyllium, other fiber-based laxatives, phytosterol margarines, and/or over the counter (OTC) therapies known to affect serum lipid levels; orlistat or other anti-obesity medications and not maintained on a stable dose; any cyclical hormones; warfarin treatment without a stable dose or a stable International Normalized Ratio (INR).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ezetimibe and atorvastatin<br>Medication will be administered in a double dummy fashion as 3 tablets orally on a daily basis, including 10 mg ezetimibe, 20 mg atorvastatin, and placebo to ezetimibe/atorvastatin. | Drug: Atorvastatin<br>* 20 mg tablet administered orally once daily<br>* Other names: Lipitor®;Drug: Ezetimibe<br>* 10 mg tablet administered orally once daily<br>* Other names: Zetia®;Drug: Placebo to ezetimibe/atorvastatin<br>* Administered orally once daily<br>|
| Experimental: Ezetimibe/atorvastatin combination<br>Medication will be administered in a double dummy fashion as 3 tablets orally on a daily basis, including ezetimibe/atorvastatin 10 mg/20 mg, placebo to ezetimibe, and placebo to atorvastatin. | Drug: Ezetimibe/atorvastatin<br>* Ezetimibe/atorvastatin 10 mg/20 mg combination tablet administered orally once daily<br>* Other names: MK-0653C;Drug: Placebo to atorvastatin<br>* Administered orally once daily<br>Drug: Placebo to ezetimibe<br>* Administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment | Serum LDL-C calculated using Friedewald formula at baseline and after 6 weeks of treatment in each of the 2 treatment periods. | Baseline and Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment | Serum TC measured at baseline and after 6 week of treatment in each of the 2 treatment periods. | Baseline and Week 6 | 
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment | Serum HDL-C calculated at baseline and after 6 weeks of treatment in each of the 2 treatment periods. | Baseline and Week 6 | 
| Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment | Non-HDL-C measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods. | Baseline and Week 6 | 
| Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment | Serum Apo B measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods. | Baseline and Week 6 | 
| Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment | Serum TG measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods. | Baseline and Week 6 |