Effects of Vytorin Versus Placebo in Subjects With Primary Hypercholesterolemia (Study P04420)

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 study of Vytorin 10/10 (ezetimibe 10 mg with simvastatin 10 mg), Vytorin 10/20 (ezetimibe 10 mg with simvastatin 20 mg), and Vytorin 10/40 (ezetimibe 10 mg with simvastatin 40 mg) compared to placebo administered daily for 8 consecutive weeks in subjects with primary hypercholesterolemia (LDL-C >3.64 mmol/L [140 mg/dL]). The efficacy of daily Vytorin versus placebo in reducing the concentration of LDL-C will be evaluated, and the efficacy of daily Vytorin versus placebo with respect to change in the concentrations of total cholesterol, triglycerides, and HDL-C will be compared. The safety of Vytorin versus placebo will also be assessed.

Official Title
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A Multicenter, Double-blind, Randomized, Placebo-controlled Parallel Groups Study Comparing the Efficacy and Safety of Vytorin Versus Placebo in Subjects With Primary Hypercholesterolemia

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: ezetimibe with simvastatin
* Drug: Ezetimibe with Simvastatin
* Drug: Ezetimibe with Simvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be >=18 years and <=75 years of age, male or female. Primary hypercholesterolemic subject with a plasma LDL cholesterol concentration >3.64 mmol/L (140 mg/dL) to <=6.3 mmol/L (250 mg/dL) using the Friedewald calculation; total cholesterol (TC) >5.2 mmol/L (200 mg/dL) to <12.7 mmol/L (500 mg/dL) and triglyceride concentrations of <=3.99 mmol/L (350 mg/dL) should be met at the same time. At the time of recruitment (Visit 1), these values may be lower if the subject is on lipid-lowering therapy. (ie, prior to the start of lipid lowering drug washout) or may be higher at the start of dietary therapy. Liver transaminases (ALT, AST) <=50% above the upper limit of normal, with no active liver disease and CK <=50% above the upper limit of normal. Clinical laboratory tests (complete blood count [CBC], blood chemistries, urinalysis) must be within normal limits, or clinically acceptable to the investigator/sponsor. Women of childbearing potential (includes women who are less than 1 year postmenopausal and women who become sexually active) must be using an acceptable method of birth control. Subjects must be free of any clinically significant diseases other than hyperlipidemia that would interfere with study evaluations. Subjects must understand and be able to adhere to the dosing and visit schedules. Subject must agree to remain on a cholesterol-lowering diet for the duration of the study (according to China Adult Treatment Panel of High Blood Cholesterol). Exclusion Criteria: Subjects whose body mass index (BMI=weight [kg]/height2 [m]) is >=30 kg/m2 at Visit 3 (Baseline Visit). Subjects who have known hypersensitivity to HMG CoA reductase inhibitors. Subjects who consume >14 alcoholic drinks per week. (A drink is: a can of beer, glass of wine, or single measure of spirits). Any condition or situation, which in the opinion of the investigator, might pose a risk to the subject or interfere with participation in the study. Women who are pregnant or nursing. Subjects who have not observed the designated washout periods for any of the prohibited medications. Congestive heart failure defined by NYHA as Class III or IV. Uncontrolled cardiac arrhythmia. 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 within 6 months of study entry. Uncontrolled hypertension (treated or untreated) with systolic blood pressure >160 mm Hg or diastolic >100 mm Hg at study entry. Uncontrolled (as determined by fasting glucose >180 mg/mL or HbA1c >9%) or newly diagnosed (within 1 month of study entry) diabetes mellitus. Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins, ie, secondary causes of hyperlipidemia, such as secondary hypercholesterolemia due to hypothyroidism (thyroid stimulating hormone [TSH] above upper limit of normal). Subjects with a history of hypothyroidism who are on a stable therapy of thyroid hormone replacement for at least 6 weeks are eligible for enrollment if TSH levels are within normal limits before enrollment. Known impaired renal function (plasma creatinine >2.0 mg/dL), or nephrotic syndrome at study entry. Disorders of the hematologic, digestive, or central nervous systems, including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. Known HIV positive. Cancer within the past 5 years (except for successfully treated basal and squamous cell carcinomas). History of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy. Female subject receiving hormonal therapy, including hormone replacement, any estrogen antagonist/agonist, or oral contraceptives.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vytorin 10/10<br>Ezetimibe 10 mg with Simvastatin 10 mg | Drug: ezetimibe with simvastatin<br>* Ezetimibe 10 mg with Simvastatin 10 mg once daily for a total of eight weeks<br>|
| Experimental: Vytorin 10/20<br>Ezetimibe 10 mg with Simvastatin 20 mg | Drug: Ezetimibe with Simvastatin<br>* Ezetimibe 10 mg with Simvastatin 20 mg once daily for a total of eight weeks<br>|
| Experimental: Vytorin 10/40<br>Ezetimibe 10 mg with Simvastatin 40 mg | Drug: Ezetimibe with Simvastatin<br>* Ezetimibe 10 mg with Simvastatin 40 mg once daily for a total of eight weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo once daily for a total of eight weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment |  | Baseline, 8 weeks |