Clinical trial NCT00423488: Ezetimibe and Simvastatin in Primary Hypercholesterolemia, Diabetes Mellitus Type 2, and Coronary Heart Disease (COMPLETED)
Official title: A Multicenter, Randomized, Parallel-Groups, Double-Blind Placebo Controlled Study Comparing the Efficacy, Safety, and Tolerability of Co-administration of Ezetimibe 10 mg With Ongoing Treatment With Simvastatin 20 mg Versus Doubling the Dose of Simvastatin in Subjects With Primary Hypercholesterolemia Diabetes Mellitus Type 2 and Coronary Heart Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Diabetes Mellitus, Type 2
Coronary Disease
Lead sponsor: Organon and Co
Sponsor class: INDUSTRY
Collaborators: name: Schering-Plough
First posted: 2007-01-18
Enrollment: 93
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 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.

Primary outcomes:
measure: Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint, After 6 Weeks of Treatment
timeFrame: 6 weeks of treatment (from Baseline to Endpoint)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
References:
citation: Bardini G, Giorda CB, Pontiroli AE, Le Grazie C, Rotella CM. Ezetimibe + simvastatin versus doubling the dose of simvastatin in high cardiovascular risk diabetics: a multicenter, randomized trial (the LEAD study). Cardiovasc Diabetol. 2010 May 21;9:20. doi: 10.1186/1475-2840-9-20.
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.