An Efficacy and Safety Study of Ezetimibe (MK-0653, SCH 58235) in Addition to Atorvastatin Compared to Placebo in Participants With Primary Hypercholesterolemia (MK-0653-013)

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, randomized, double-blind, placebo-controlled, balanced-parallel-group, efficacy and safety trial of ezetimibe coadministered with atorvastatin in adult participants with primary hypercholesterolemia. The primary hypothesis is that the coadministration of ezetimibe 10 mg/day with atorvastatin (pooled across all doses: 10 mg, 20 mg, 40 mg, 80 mg) will result in a significantly greater reduction in direct low density lipoprotein-cholesterol (LDL-C) when compared with atorvastatin (pooled across all doses: 10 mg, 20 mg, 40 mg, 80 mg) alone and ezetimibe 10 mg alone.

Official Title
-----------------
A Phase 3, Double-Blind Efficacy and Safety Study of Ezetimibe (SCH 58235) 10 mg in Addition to Atorvastatin Compared to Placebo in Subjects With Primary Hypercholesterolemia (Protocol P00692)

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

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Ezetimibe 10 mg
* Drug: Atorvastatin 10 mg
* Drug: Atorvastatin 20 mg
* Drug: Atorvastatin 40 mg
* Drug: Atorvastatin 80 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Postmenopausal women who are receiving postmenopausal hormonal therapy or raloxifene must be maintained on a stable estrogen (ERT), estrogen/progestin (HRT) or raloxifene regimen during the study period. Primary hypercholesterolemic participants with a plasma LDL-Cholesterol ≥145 mg/dL (3.75 mmol/L) and ≤250 mg/dL (6.48 mmol/L) and plasma triglyceride ≤350 mg/dL (3.99 mmol/L) after adequate drug washout Must be willing to observe the National Cholesterol Education Program (NCEP) Step I diet as determined by a Ratio of Ingested Saturated fat and Cholesterol to Calories (RISCC) score not greater than 24 throughout this study. Ability to complete Diet Diaries needs to be demonstrated. Exclusion Criteria: 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. Underlying disease likely to limit life span to less than 1 year. Participants with hypercholesterolemia in whom withholding of approved lipid-lowering therapy would be inappropriate. Have previously been randomized in any of the studies evaluating Ezetimibe (SCH 58235). Known hypersensitivity or any contraindication to atorvastatin (LIPITOR®). Pregnant or lactating women. Congestive heart failure New York Heart Association (NYHA) Class III or IV. Uncontrolled cardiac arrhythmias. Myocardial infarction, coronary bypass surgery or angioplasty within 6 months of study entry. Unstable or severe peripheral artery disease within 3 months of study entry. Unstable angina pectoris. Disorders of the hematologic, digestive or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. Uncontrolled or newly diagnosed (within 1 month of study entry) diabetes mellitus. Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins. Known impairment of renal function (plasma creatinine >2.0 mg/dL), dysproteinemia, nephrotic syndrome or other renal disease. Active or chronic hepatobiliary or hepatic disease. Participants who are known to be Human Immunodeficiency Virus (HIV) positive. Participants with known coagulopathy. Lipid-altering agents, other than study drugs for the whole duration of the study. Oral corticosteroids. Cardiovascular drugs such as: beta blockers, calcium channel blockers, ACE inhibitors, nitrates or α-adrenergic blockers or thiazide diuretics will be allowed, provided the dose remains constant for the duration of the study and the participant has received a stable dose for at least 8 weeks before the initial qualifying LDL-C level is drawn. Aspirin up to 325 mg/day is permitted. In addition, aspirin is allowed as a as needed (prn) concomitant medication. Treatment with psyllium or other fiber-based laxatives unless treated with a stable regimen for at least 4 weeks before initial qualifying lipid determination. Dose must remain constant throughout the study period. Treatment with troglitazone (Rezulin®) unless treated with a stable regimen for at least 6 weeks before initial qualifying lipid determination. Dose must remain constant throughout the study period. Treatment with cyclosporine. Use of any investigational drugs within 30 days of study entry. Treatment with agents with known drug interaction with atorvastatin including antifungal azoles (itraconazole and ketoconazole), macrolide antibiotics (erythromycin and clarithromycin), and nefazodone. In addition, treatment with other agents that may interfere with or induce the CYP3A4 isoenzyme of the cytochrome P450 system should be avoided.

Ages Eligible for Study
-----------------
Minimum Age: 18 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo is to be taken orally once a day (QD) in the morning for 12 consecutive weeks. | Drug: Placebo<br> <br> |
| Active Comparator: Ezetimibe 10 mg<br>Ezetimibe 10 mg (MK-0653, SCH 58235) is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Ezetimibe 10 mg<br> <br> * Other names: ZETIA®;|
| Active Comparator: Atorvastatin 10 mg<br>Atorvastatin 10 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Atorvastatin 10 mg<br> <br> * Other names: LIPITOR®;|
| Experimental: Ezetimibe 10 mg + Atorvastatin 10 mg<br>Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 10 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Ezetimibe 10 mg<br> <br> * Other names: ZETIA®;Drug: Atorvastatin 10 mg<br> <br> * Other names: LIPITOR®;|
| Active Comparator: Atorvastatin 20 mg<br>Atorvastatin 20 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Atorvastatin 20 mg<br> <br> * Other names: LIPITOR®;|
| Experimental: Ezetimibe 10 mg + Atorvastatin 20 mg<br>Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 20 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Ezetimibe 10 mg<br> <br> * Other names: ZETIA®;Drug: Atorvastatin 20 mg<br> <br> * Other names: LIPITOR®;|
| Active Comparator: Atorvastatin 40 mg<br>Atorvastatin 40 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Atorvastatin 40 mg<br> <br> * Other names: LIPITOR®;|
| Experimental: Ezetimibe 10 mg + Atorvastatin 40 mg<br>Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 40 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Ezetimibe 10 mg<br> <br> * Other names: ZETIA®;Drug: Atorvastatin 40 mg<br> <br> * Other names: LIPITOR®;|
| Active Comparator: Atorvastatin 80 mg<br>Atorvastatin 80 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Atorvastatin 80 mg<br> <br> * Other names: LIPITOR®;|
| Experimental: Ezetimibe 10 mg + Atorvastatin 80 mg<br>Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 80 mg is to be taken orally QD in the morning for 12 consecutive weeks. | Drug: Ezetimibe 10 mg<br> <br> * Other names: ZETIA®;Drug: Atorvastatin 80 mg<br> <br> * Other names: LIPITOR®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline at Week 12 of Plasma Low Density Lipoprotein Cholesterol (LDL-C) | Plasma LDL-C determined following a standard ultracentrifugation / precipitation (quantification) procedure (direct LDL-C). Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline at Week 12 for Calculated Low Density Lipoprotein-Cholesterol (LDL-C) | Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Total Cholesterol (TC) | Participants had TC levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Triglycerides (TG) | Participants had TG levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for High Density-Lipoprotein-Cholesterol (HDL-C) | Participants had HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Apolipoprotein B (Apo B) | Participants had Apo B levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Non-High Density-Lipoprotein-Cholesterol (Non-HDL-C) | Participants had Non-HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for High Density-Lipoprotein 2-Cholesterol (HDL2-C) | Participants had HDL2-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for High Density-Lipoprotein 3-Cholesterol (HDL3-C) | Participants had HDL3-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Apolipoprotein A-I (Apo A-I), | Participants had Apo A1 levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Direct Low Density-Lipoprotein 3-Cholesterol/High Density-Lipoprotein 3-Cholesterol (LDL-C/HDL-C) Ratio | Participants had LDL-C and HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline in the LDL-C/HDL-C ratio was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Direct Total Cholesterol/High Density-Lipoprotein 3-Cholesterol (TC/HDL-C) Ratio | Participants had TC and HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline in the TC/HDL-C ratio was calculated. | Baseline and Week 12 | 
| Percent Change from Baseline at Week 12 for Lipoprotein (a) (Lp[a]) | Participants had Lp(a) levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated. | Baseline and Week 12 | 
| The Percentage of Participants Achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP II) Target Goal for Direct Low Density Lipoprotein-Cholesterol (LDL-C) | LDL cholesterol level goal is <100 mg per deciliter (2.60 mmol per L) | Week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypercholesterolemia, Ezetimibe, Atorvastatin, Low density lipoprotein-cholesterol