The Effects of Ezetimibe/Simvastatin 10/20 mg Versus Simvastatin 40 mg in High Cholesterol and Coronary Heart Disease Study (P04039AM2)(COMPLETED)

Organon

Status and phase: Completed; Phase 4

Conditions: Hypercholesterolemia; Coronary Disease

Treatments: Drug: simvastatin 40 mg; Drug: Ezetimibe/Simvastatin 10/20 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT00423579

P04039

Details and patient eligibility

About

This study is being conducted to compare the efficacy, safety, and tolerability of ezetimibe/simvastatin 10/20 mg when administered daily versus doubling the dose of simvastatin to 40 mg in patients with hypercholesterolemia and coronary heart disease.

Enrollment: 120 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Subjects must have documented coronary heart disease (CHD). For the purposes of this study, CHD will include one or more of the following features: documented stable angina (with evidence of ischemia on exercise testing); history of myocardial infarction; history of percutaneous coronary intervention [PCI] (primarily PCI with or without stent placement); symptomatic peripheral vascular disease (claudication); documented history of atherothrombotic cerebrovascular disease; and/or documented history of unstable angina or non-Q wave myocardial infarction.
• Subjects must demonstrate their willingness to participate in the study and comply with its procedures by signing a written informed consent.
• History of myocardial infarction (heart attack).
• Subjects must be >= 18 years and <= 75 years of age.
• Subjects must have an LDL-C concentration >= 2.6 mmol/L (100 mg/dL) to <= 4.1 mmol/L (160 mg/dL) at the time of randomization (Visit 3/Baseline Visit).
• Subjects must have triglyceride concentrations of < 3.99 mmol/L (350 mg/dL) at (Visit 3 Baseline Visit).
• Subject must be currently taking simvastatin 20 mg daily.
• Subjects must have liver transaminases (ALT [alanine aminotransferase], AST [aspartate aminotransferase]) < 50% above the upper limit of normal, with no active liver disease, and CK (creatine kinase) < 50% above the upper limit of normal at Visit 3 (Baseline Visit).
• Clinical laboratory tests (complete blood count [CBC], blood chemistries, urinalysis) must be within normal limits or clinically acceptable to the investigator at Visit 3 (Baseline Visit).
• Subjects must have maintained a cholesterol-lowering diet and exercise program for at least 4 weeks prior to the study and be willing to continue the same diet and exercise program during the study.
• Subjects must report a stable weight history for at least 4 weeks prior to entry into study at Visit 3 (Baseline Visit).
• Women receiving hormonal therapy, including hormone replacement, any estrogen antagonist/agonist, or oral contraceptives, must have been maintained on a stable dose and regimen for at least 8 weeks and be willing to continue the same regimen for the duration of the study.
• 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 (e.g., hormonal contraceptive, medically prescribed intrauterine device [IUD], condom in combination with spermicide) or be surgically sterilized (e.g., hysterectomy or tubal ligation).
• Subjects must be free of any clinically significant diseases other than hyperlipidemia or coronary heart disease that would interfere with study evaluations.
• Subjects must understand and be able to adhere to the dosing and visit schedules, and must agree to remain on their cholesterol-lowering diet and their exercise regimen for the duration of the study.

Exclusion criteria

• Subjects whose body mass index (BMI = weight [kg]/height2 [m]) is >= 35 kg/m^2 at Visit 3 (Baseline Visit).
• 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.

Exclusion Criteria: subjects who have the following medical conditions:

• Congestive heart failure defined by New York Heart Association (NYHA) as Class III or IV.
• Uncontrolled cardiac arrhythmia.
• Myocardial infarction, acute coronary insufficiency, coronary artery bypass surgery, or angioplasty within 3 months of Visit 3 (Baseline Visit).
• Unstable or severe peripheral artery disease within 3 months of Visit 3 (Baseline Visit).
• Newly diagnosed or currently unstable angina pectoris (chest pain).
• Uncontrolled hypertension (treated or untreated) with systolic blood pressure > 160 mm Hg or diastolic > 100 mm Hg at Visit 3 (Baseline Visit).
• Type I or Type II diabetes mellitus.
• Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins, i.e., secondary causes of hyperlipidemia, such as secondary hypercholesterolemia due to hypothyroidism (thyroid stimulating hormone [TSH] above upper limit of normal) at Visit 3. 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 at Visit 3 (Baseline Visit).
• Impaired renal function (creatinine > 2.0 mg/dL) or nephrotic syndrome at Visit 3 (Baseline Visit).
• Disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation.
• Known Human Immunodeficiency Virus (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.

Exclusion Criteria: subjects who are on any of the following concomitant medications:

• Subjects who have not observed the designated wash-out period for any of the prohibited medications.
• Subjects who have not stopped taking various prohibited medications for a minimum period of time before Visit 3, including amiodarone hydrochloride (6 months) and probucol (12 months).
• Subjects currently consuming large amounts of grapefruit juice (> 1 liter/day).
• Oral corticosteroids, unless used as replacement therapy for pituitary/adrenal disease and the subject is on a stable regimen for at least 6 weeks prior to Visit 3 (Baseline Visit).
• Subjects who are currently using cardiovascular medication (e.g. antihypertensive, antiarrhythmic) and have not been on a stable regimen for at least 6 weeks prior to Visit 3 (Baseline Visit) and it is expected to change during the study.
• Subjects who are currently using psyllium, other fiber-based laxatives, and/or any other over-the-counter (OTC) therapy known to affect serum lipid levels (phytosterol margarine), and have not been on a stable regimen for at least 5 weeks prior to study entry Visit 3 (Baseline Visit) and who do not agree to remain on this regimen throughout the study.
• Subject who are currently using orlistat or sibutramine.
• Subjects who are currently using amiodarone hydrochloride.
• Subjects who are currently using danazol.
• Subjects who are currently using coumarin anticoagulants (warfarin).
• Subjects who are using (at the Screening Visit / Visit 1) any statin other than simvastatin 20 mg, or ezetimibe alone or in combination with any statin (including the fixed combination with simvastatin).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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120 participants in 2 patient groups

Ezetimibe/Simvastatin 10/20 mg + Simvastatin placebo

Experimental group

Description:

Subjects will receive 2 tablets. The first tablet is Ezetimibe/Simvastatin 10/20 mg. The second tablet is simvastatin placebo. Subjects will receive a maximum of 6 weeks of treatment

Treatment:

Drug: Ezetimibe/Simvastatin 10/20 mg

Ezetimibe/Simvastatin placebo + Simvastatin 40 mg

Active Comparator group

Description:

Subjects will receive 2 tablets. The first tablet is Ezetimibe/Simvastatin placebo. The second tablet is simvastatin 40 mg. Subjects will receive a maximum of 6 weeks of treatment.

Treatment:

Drug: simvastatin 40 mg