Ezetimibe and Simvastatin in Primary Hypercholesterolemia, Diabetes Mellitus Type 2, and Coronary Heart Disease (COMPLETED)
Condition: Hypercholesterolemia; Diabetes Mellitus, Type 2; Coronary Disease
MeSH terms: Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypercholesterolemia
Intervention: Ezetimibe 10 mg; Simvastatin 20 mg; Ezetimibe Placebo; Simvastatin 20 mg; Simvastatin Placebo
Intervention description: 1 x 10-mg tablet, provided as blinded study treatment; 1 x 20-mg tablet, provided as open-label study treatment; 1 tablet matching ezetimibe 10-mg tablet, provided as blinded study treatment; 1 x 20-mg tablet, provided as blinded study treatment; 1 tablet matching 20-mg simvastatin tablet, provided as blinded study treatment
Intervention MeSH terms: Simvastatin; Ezetimibe
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 93.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      This multicenter, randomized, double-blind, placebo-controlled study will assess, after 6
      weeks of dosing, whether co-administration of ezetimibe 10 mg with simvastatin 20 mg will be
      more effective than treatment with doubling the dose of simvastatin to 40 mg alone in
      reducing low-density lipoprotein-cholesterol (LDL-C) concentrations and in achieving the
      National Cholesterol Expert Panel (NCEP) III LDL-C target goal of <2.6 mmol/L (<100 mg/dL)
      for subjects with diabetes mellitus and coronary heart disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must have diabetes mellitus type 2 (fasting plasma glucose >7 mmol/L [126
             mg/dL]) of at least 12 months duration at Visit 3 and must be adequately controlled
             (glycated hemoglobin [HbA1c] <=9.0%). Subjects must not have had a change in
             antidiabetic pharmacotherapy [i.e. changes in dosage (with the exception of +/- 10
             units of insulin) or addition of new medication] or experience recent history of
             repeated hypoglycemia or unstable glycemic control within 3 months of Visit (Baseline
             Visit).

          -  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 transluminal coronary intervention (PCTI) 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 have a low-density lipoprotein cholesterol (LDL-C) concentration >=2.6
             mmol/L (100 mg/dL) to <=4.1 mmol/L (160 mg/dL) using the Friedewald calculation
             available 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 and by history has taken 80%
             of daily evening doses for the 6 weeks prior to Visit 3 (Baseline Visit).

          -  Subject must be >=18 years and <=75 years of age.

          -  Subjects must have maintained a cholesterol lowering diet and exercise program for at
             least 4 weeks prior to Screening (Visit 2) and be willing to continue the same diet
             and exercise program during the study.

          -  Subjects must have liver transaminases (alanine aminotransferase [ALT], aspartate
             aminotransferase [AST]) <50% above the upper limit of normal, with no active liver
             disease, and creatinine kinase (CK)<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 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 diabetes
             mellitus 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

          -  Subjects must demonstrate their willingness to participate in the study and comply
             with its procedures by signing a written informed consent.

        Exclusion Criteria:

          -  Subjects whose body mass index (BMI = weight[kg]/height[m]**2) 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.

          -  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.

          -  Uncontrolled hypertension (treated or untreated) with systolic blood pressure >160
             mmHg or diastolic >100 mmHg at Visit 3 (Baseline Visit).

          -  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.

          -  Subjects who have not observed the designated wash-out period for any of the
             prohibited medications.

          -  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 lest 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.