Hypercholesterolemia
Conditions
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 study of Vytorin 10/10 (ezetimibe 10 mg with simvastatin 10 mg), Vytorin 10/20 (ezetimibe 10 mg with simvastatin 20 mg), and Vytorin 10/40 (ezetimibe 10 mg with simvastatin 40 mg) compared to placebo administered daily for 8 consecutive weeks in subjects with primary hypercholesterolemia (LDL-C \>3.64 mmol/L \[140 mg/dL\]). The efficacy of daily Vytorin versus placebo in reducing the concentration of LDL-C will be evaluated, and the efficacy of daily Vytorin versus placebo with respect to change in the concentrations of total cholesterol, triglycerides, and HDL-C will be compared. The safety of Vytorin versus placebo will also be assessed.
Interventions
Ezetimibe 10 mg with Simvastatin 10 mg once daily for a total of eight weeks
Ezetimibe 10 mg with Simvastatin 20 mg once daily for a total of eight weeks
DRUGPlacebo
Placebo once daily for a total of eight weeks
Sponsors
Schering-Plough
Merck Sharp & Dohme LLC
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
* Subjects must be \>=18 years and \<=75 years of age, male or female. * Primary hypercholesterolemic subject with a plasma LDL cholesterol concentration \>3.64 mmol/L (140 mg/dL) to \<=6.3 mmol/L (250 mg/dL) using the Friedewald calculation; total cholesterol (TC) \>5.2 mmol/L (200 mg/dL) to \<12.7 mmol/L (500 mg/dL) and triglyceride concentrations of \<=3.99 mmol/L (350 mg/dL) should be met at the same time. At the time of recruitment (Visit 1), these values may be lower if the subject is on lipid-lowering therapy. (ie, prior to the start of lipid lowering drug washout) or may be higher at the start of dietary therapy. * Liver transaminases (ALT, AST) \<=50% above the upper limit of normal, with no active liver disease and CK \<=50% above the upper limit of normal. * Clinical laboratory tests (complete blood count \[CBC\], blood chemistries, urinalysis) must be within normal limits, or clinically acceptable to the investigator/sponsor. * 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. * Subjects must be free of any clinically significant diseases other than hyperlipidemia that would interfere with study evaluations. * Subjects must understand and be able to adhere to the dosing and visit schedules. * Subject must agree to remain on a cholesterol-lowering diet for the duration of the study (according to China Adult Treatment Panel of High Blood Cholesterol).
Exclusion criteria
* Subjects whose body mass index (BMI=weight \[kg\]/height2 \[m\]) is \>=30 kg/m2 at Visit 3 (Baseline Visit). * Subjects who have known hypersensitivity to HMG CoA reductase inhibitors. * 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. * Subjects who have not observed the designated washout periods for any of the prohibited medications. * Congestive heart failure defined by NYHA as Class III or IV. * Uncontrolled cardiac arrhythmia. * Myocardial infarction, coronary bypass surgery, or angioplasty within 6 months of study entry. * Unstable or severe peripheral artery disease within 3 months of study entry. * Unstable angina pectoris within 6 months of study entry. * Uncontrolled hypertension (treated or untreated) with systolic blood pressure \>160 mm Hg or diastolic \>100 mm Hg at study entry. * Uncontrolled (as determined by fasting glucose \>180 mg/mL or HbA1c \>9%) or newly diagnosed (within 1 month of study entry) diabetes mellitus. * Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins, ie, secondary causes of hyperlipidemia, such as secondary hypercholesterolemia due to hypothyroidism (thyroid stimulating hormone \[TSH\] above upper limit of normal). 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 before enrollment. * Known impaired renal function (plasma creatinine \>2.0 mg/dL), or nephrotic syndrome at study entry. * Disorders of the hematologic, digestive, or central nervous systems, including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. * Known 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. * Female subject receiving hormonal therapy, including hormone replacement, any estrogen antagonist/agonist, or oral contraceptives.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment | Baseline, 8 weeks |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vytorin 10/10 Ezetimibe 10 mg with Simvastatin 10 mg | 97 |
| Vytorin 10/20 Ezetimibe 10 mg with Simvastatin 20 mg | 97 |
| Vytorin 10/40 Ezetimibe 10 mg with Simvastatin 40 mg | 98 |
| Placebo | 97 |
| Total | 389 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 1 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 7 | 2 |
Baseline characteristics
| Characteristic | Vytorin 10/10 | Vytorin 10/20 | Vytorin 10/40 | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 10.7 | 57.4 years STANDARD_DEVIATION 9.7 | 56.4 years STANDARD_DEVIATION 10.3 | 60.2 years STANDARD_DEVIATION 9.2 | 58.2 years STANDARD_DEVIATION 10.07 |
| Region of Enrollment China | 97 participants | 97 participants | 98 participants | 97 participants | 389 participants |
| Sex: Female, Male Female | 59 Participants | 61 Participants | 66 Participants | 60 Participants | 246 Participants |
| Sex: Female, Male Male | 38 Participants | 36 Participants | 32 Participants | 37 Participants | 143 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 97 | 0 / 97 | 0 / 98 | 0 / 97 |
| serious Total, serious adverse events | 0 / 97 | 0 / 97 | 0 / 98 | 0 / 97 |
Outcome results
Primary
Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment
Time frame: Baseline, 8 weeks
Population: The number of participants for analysis included those from the ITT data set. 392 subjects were randomized in the study, but 3 of the randomized subjects were not treated and were excluded from the ITT data set. Therefore, only 389 subjects were included in the ITT data set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vytorin 10/10 | Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment | -41.69 percent change of LDL-C | Standard Error 2.06 |
| Vytorin 10/20 | Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment | -46.83 percent change of LDL-C | Standard Error 2.08 |
| Vytorin 10/40 | Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment | -49.10 percent change of LDL-C | Standard Error 2.07 |
| Placebo | Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment | -7.53 percent change of LDL-C | Standard Error 2.04 |
p-value: <0.0001ANOVA
p-value: <0.0001ANOVA
p-value: <0.0001ANOVA