Ezetimibe and Simvastatin in Primary Hypercholesterolemia, Diabetes Mellitus Type 2, and Coronary Heart Disease (COMPLETED)

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

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.

Study Overview

• Status: Completed
• Conditions: Coronary Disease; Diabetes Mellitus, Type 2; Hypercholesterolemia
• Intervention / Treatment: Drug: Ezetimibe 10 mg; Drug: Simvastatin 20 mg; Drug: Simvastatin 20 mg; Drug: Simvastatin Placebo; Drug: Ezetimibe Placebo

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg; Participants were instructed to take one 10-mg ezetimibe tablet and one simvastatin placebo tablet orally in the evening every day for six weeks in addition to their daily, oral, open-label, 20-mg simvastatin tablet.	Drug: Ezetimibe 10 mg; 1 x 10-mg tablet, provided as blinded study treatment; Drug: Simvastatin 20 mg; 1 x 20-mg tablet, provided as open-label study treatment; Drug: Simvastatin 20 mg; 1 x 20-mg tablet, provided as blinded study treatment; Drug: Simvastatin Placebo; 1 tablet matching 20-mg simvastatin tablet, provided as blinded study treatment
ACTIVE_COMPARATOR: Ezetimibe Placebo + Simvastatin 40 mg; Participants were instructed to take one ezetimibe placebo tablet and one simvastatin 20-mg tablet orally in the evening every day for six weeks in addition to their daily, oral, open-label, 20-mg simvastatin tablet.	Drug: Simvastatin 20 mg; 1 x 20-mg tablet, provided as open-label study treatment; Drug: Simvastatin 20 mg; 1 x 20-mg tablet, provided as blinded study treatment; Drug: Ezetimibe Placebo; 1 tablet matching ezetimibe 10-mg tablet, provided as blinded study treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint, After 6 Weeks of Treatment	6 weeks of treatment (from Baseline to Endpoint)

Collaborators and Investigators

• Sponsor: Organon and Co
• Collaborators: Schering-Plough

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 12, 2005
• Primary Completion (ACTUAL): February 16, 2007
• Study Completion (ACTUAL): February 16, 2007

Study Registration Dates

• First Submitted: January 17, 2007
• First Submitted That Met QC Criteria: January 17, 2007
• First Posted (ESTIMATE): January 18, 2007

Study Record Updates

• Last Update Posted (ACTUAL): February 9, 2022
• Last Update Submitted That Met QC Criteria: February 7, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Ezetimibe
• Other Study ID Numbers: P04037