Clinical trial NCT00423579: The Effects of Ezetimibe/Simvastatin 10/20 mg Versus Simvastatin 40 mg in High Cholesterol and Coronary Heart Disease Study (P04039AM2)(COMPLETED)
Official title: A Multicenter, Randomized, Parallel-Groups, Double-Blind Placebo-Controlled Study Comparing the Efficacy, Safety, and Tolerability of Administration of Ezetimibe/Simvastatin Tablet 10/20 mg Versus Doubling the Dose of Simvastatin 20 mg [Simvastatin 40 mg] in Subjects With Primary Hypercholesterolemia and Coronary Heart Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypercholesterolemia
Coronary Disease
Lead sponsor: Organon and Co
Sponsor class: INDUSTRY
Collaborators: name: Schering-Plough
First posted: 2007-01-18
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Change in Low-density-lipoprotein Cholesterol (LDL-C) at 6 Weeks
timeFrame: Baseline and 6 weeks
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
References:
citation: Averna M, Zaninelli A, Le Grazie C, Gensini GF. Ezetimibe/simvastatin 10/20 mg versus simvastatin 40 mg in coronary heart disease patients. J Clin Lipidol. 2010 Jul-Aug;4(4):272-8. doi: 10.1016/j.jacl.2010.05.002. Epub 2010 Jun 1.
citation: Rotella CM, Zaninelli A, Le Grazie C, Hanson ME, Gensini GF. Ezetimibe/simvastatin vs simvastatin in coronary heart disease patients with or without diabetes. Lipids Health Dis. 2010 Jul 27;9:80. doi: 10.1186/1476-511X-9-80.