Hypercholesterolemia, Diabetes Mellitus, Type 2, Coronary Disease
Conditions
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.
Interventions
DRUGEzetimibe 10 mg
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 tablet matching 20-mg simvastatin tablet, provided as blinded study treatment
Sponsors
Schering-Plough
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| 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) |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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, 20-mg simvastatin tablet. | 42 |
| 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, 20-mg simvastatin tablet. | 51 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No evidence of study drug intake | 2 | 1 |
| Overall Study | No post baseline data | 3 | 0 |
Baseline characteristics
| Characteristic | Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg | Ezetimibe Placebo + Simvastatin 40 mg | Total |
|---|---|---|---|
| Age, Continuous | 65.0 years STANDARD_DEVIATION 6.5 | 63.9 years STANDARD_DEVIATION 6.1 | 64.4 years STANDARD_DEVIATION 6.3 |
| Region of Enrollment Italy | 42 participants | 51 participants | 93 participants |
| Sex: Female, Male Female | 18 Participants | 12 Participants | 30 Participants |
| Sex: Female, Male Male | 24 Participants | 39 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 40 | 0 / 50 |
| serious Total, serious adverse events | 1 / 40 | 0 / 50 |
Outcome results
Primary
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint, After 6 Weeks of Treatment
Time frame: 6 weeks of treatment (from Baseline to Endpoint)
Population: Intent-to-treat population only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg + Simvastatin Placebo + Simvastatin 20 mg | Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint, After 6 Weeks of Treatment | -32.2 percentage change | Standard Deviation 15.7 |
| Ezetimibe Placebo + Simvastatin 40 mg | Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint, After 6 Weeks of Treatment | -20.8 percentage change | Standard Deviation 20.1 |
p-value: 0.00595% CI: [-19.4, -3.5]ANOVA