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

NCT00423488 | Completed Phase 3 Results

• 1 other identifier: P04037
• Study Type: interventional
• Target: 93
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Hypercholesterolemia; Diabetes Mellitus, Type 2; Coronary Disease

Outcome Measures

Primary Outcomes (1)

• 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)

Study Arms (2)

Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg

EXPERIMENTAL

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; Drug: Simvastatin 20 mg; Drug: Simvastatin Placebo

Ezetimibe Placebo + Simvastatin 40 mg

ACTIVE COMPARATOR

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; Drug: Ezetimibe Placebo

Interventions

Ezetimibe 10 mg DRUG

1 x 10-mg tablet, provided as blinded study treatment

Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg

Simvastatin 20 mg DRUG

1 x 20-mg tablet, provided as open-label study treatment

Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg; Ezetimibe Placebo + Simvastatin 40 mg

Ezetimibe Placebo DRUG

1 tablet matching ezetimibe 10-mg tablet, provided as blinded study treatment

Ezetimibe Placebo + Simvastatin 40 mg

Simvastatin Placebo DRUG

1 tablet matching 20-mg simvastatin tablet, provided as blinded study treatment

Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Organon and Co: lead
• Schering-Plough: collaborator

Related Publications (2)

• 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.

  PMID: 20492655 RESULT

• 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.

  PMID: 20663203 DERIVED

MeSH Terms

Conditions

Hypercholesterolemia; Diabetes Mellitus, Type 2; Coronary Disease

Interventions

Ezetimibe; Simvastatin

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Endocrine System Diseases; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2007
• First Posted: January 18, 2007
• Study Start: July 12, 2005
• Primary Completion: February 16, 2007
• Study Completion: February 16, 2007
• Last Updated: February 9, 2022
• Results First Posted: March 9, 2010

Record last verified: 2022-02