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”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: March 2008

Intervention(s) in this Clinical Trial

• Drug: Ezetimibe/Simvastatin 10/20 mg
  • 1 tablet containing 10 mg of ezetimibe and 20 mg of simvastatin per day for 6 weeks
• Drug: simvastatin 40 mg
  • 1 tablet containing 40 mg of simvastatin per day for 6 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Ezetimibe/Simvastatin 10/20 mg + Simvastatin placebo
  • 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
• Active Comparator: Ezetimibe/Simvastatin placebo + Simvastatin 40 mg
  • 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.

Primary Measures

• LDL C (low-density-lipoprotein cholesterol) reduction
  • Time Frame: 6 weeks
    Safety Issue?: No

Secondary Measures

• Percentage of subjects who achieve the target LDL-C goal as defined by the NCEP III guidelines (< 2.6 mmol/L; < 100 mg/dL).
  • Time Frame: 6 weeks
    Safety Issue?: No
• percent change from baseline in the concentrations of total Cholesterol, HDL-C , triglycerides and C-reactive protein.
  • Time Frame: 6 weeks
    Safety Issue?: No
• Safety and tolerability.
  • Time Frame: 6 weeks
    Safety Issue?: Yes

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 (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, AST) < 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 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).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Schering-Plough

Overall Clinical Trial Officials and Contacts

Gianfranco Gensini, Professor Principal Investigator Universita degli Studi di Firenze Azienda Ospedaliera Careggi  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00423579

Study ID Number: P04039

ClinicalTrials.gov Identifier: NCT00423579

Health Authority: Italy: Ministry of Health