Hypercholesterolemia
Conditions
Brief summary
The overall objective is to evaluate the efficacy and safety of ezetimibe (SCH 058235/MK-0653) 10 mg administered daily in conjunction with atorvastatin in participants with Heterozygous Familial Hypercholesterolemia (HeFH) or in participants with coronary heart disease (CHD) or multiple cardiovascular risk factors (≥2 risk factors) and primary hypercholesterolemia not controlled by a starting dose (10 mg/day) of atorvastatin. The primary hypothesis is that the coadministration of ezetimibe 10 mg/day with atorvastatin therapy will result in a significantly greater proportion of participants achieving target low-density lipoprotein cholesterol (LDL-C) (≤100 mg/dL) when compared to the atorvastatin administered alone.
Interventions
DRUGAtorvastatin
Atorvastatin administered orally QD as 10 mg tablets.
DRUGEzetimibe
Ezetimibe administered orally QD as 10 mg tablets
Single placebo tablet administered orally QD
Single placebo tablet administered orally QD
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Primary hypercholesterolemic participants with known coronary heart disease (CHD) or multiple risk factors for CHD (≥2) not meeting the target low-density-lipoprotein cholesterol (LDL-C) of ≤100 mg/dL (2.59 mmol/L), with plasma LDL-C ≥130 mg/dL (3.37 mmol/L) and plasma triglycerides (TG) ≤350 mg/dL (3.99 mmol/L) while on starting-dose (10 mg) atorvastatin at least 4 weeks before initial qualifying lipid determination. * Participants with heterozygous familial hypercholesterolemia (HeFH) not meeting the target LDL-C of ≤100 mg/dL (2.59 mmol/L), with plasma LDL-C ≥130 mg/dL (3.37 mmol/L) and plasma TG ≤350 mg/dL (3.99 mmol/L) while on starting-dose (10 mg) atorvastatin for at least 4 weeks before initial lipid qualifying determination. HeFH is defined by: a) genetic testing; or b) LDL-C \>190 mg/dL (4.9 mmol/L) and at least one of the following: (1) xanthomata in first or second degree relative; (2) family history of myocardial infarction under age 60 years in a first degree relative or family history of myocardial infarction under age 50 years in a second degree relative; (3) family history of total cholesterol (TC) \>290 mg/dL (\>7.5 mmol/L) in a first or second degree relative. * All women must have a negative pregnancy test prior to study entry. Women of child-bearing potential must agree to practice an effective barrier method of birth control for the duration of the study, as well as for 1 month following study completion. * Postmenopausal women who are receiving postmenopausal hormonal therapy or raloxifene must be maintained on a stable estrogen replacement therapy (ERT), estrogen/progestin hormone replacement therapy (HRT) or raloxifene regimen during the study period. * Participants must be willing to observe the National Cholesterol Education Program (NCEP) Step I diet as determined by a Ratio of Ingested Saturated fat and Cholesterol to Calories (RISCC) score not greater than 24 throughout this study. Ability to complete diet diaries needs to be demonstrated.
Exclusion criteria
* Individuals with a history of mental instability, drug/alcohol abuse within the past 5 years or individuals who have been treated or are being treated for severe psychiatric illness which in the opinion of the Investigator, may interfere with optimal participation in the study. * Underlying disease likely to limit life span to less than 1 year. * Participants who have previously been randomized in any of the studies evaluating ezetimibe. * Participants with known hypersensitivity or any contraindication to atorvastatin * Pregnant or lactating women. * Participants with congestive heart failure New York Heart Association (NYHA) Class III or IV. * Participants with uncontrolled cardiac arrhythmias * Participants with myocardial infarction, coronary bypass surgery or angioplasty within 3 months of study entry. * Participants with unstable or severe peripheral artery disease within 3 months of study entry. * Participants with unstable angina pectoris. * Participants with disorders of the hematologic, digestive or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. * Participants with uncontrolled (as determined by hemoglobin A1c \[HbA1c\]) or newly diagnosed (within 1 month of study entry) diabetes mellitus. * Participants with uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins. Clinically euthyroid participants on replacement doses of thyroid hormone are eligible for enrollment. * Participants with known impairment of renal function (creatinine \>2.0 mg/dL), dysproteinemia, nephrotic syndrome or other renal disease (24-hour urinary protein 3+ or 1 gram). * Participants with active or chronic hepatobiliary or hepatic disease (participants with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2 times the upper limit of the central laboratory reference range \[ULN\] will be excluded). * Participants who are known to be human immunodeficiency virus (HIV) positive. * Participants with known coagulopathy (prothrombin time \[PT\] or partial thromboplastin time \[PTT\] at Visit 2 \>1.25 times control).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Target Low-Density-Lipoprotein Cholesterol (LDL-C) Levels of ≤100 mg/dL | Week 14 | The percentage of participants achieving the target low-density-lipoprotein cholesterol (LDL-C) levels (≤100 mg/dL \[2.59 mmol/L\]) as determined from blood samples following a standard ultracentrifugation/precipitation procedure (β-quantification). |
| Percentage of Participants With an Adverse Event | 14 weeks (Up to 16 weeks) | An adverse event (AE) is defined as any physical or clinical change or disease reported by a participant or observed by the investigator or member of the staff at any time during the study, regardless of potential relationship to study treatment, and included onset or discovery of new illness and exacerbation of any pre-existing condition. |
| Percentage of Participants Who Discontinued the Study due to an Adverse Event | 14 weeks (Up to 16 weeks) | An adverse event (AE) is defined as any physical or clinical change or disease reported by a participant or observed by the investigator or member of the staff at any time during the study, regardless of potential relationship to study treatment, and included onset or discovery of new illness and exacerbation of any pre-existing condition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Changes from Baseline for Total Cholesterol (TC) | Baseline and Week 4 | Participants are to have their TC levels assessed at baseline and after 4 weeks of study drug administration. The change from baseline will be calculated. |
| Percentage of Participants Achieving Target LDL-C level (≤100 mg/dL) | Week 4 | The percentage of participants achieving the target low-density-lipoprotein cholesterol (LDL-C) levels (≤100 mg/dL \[2.59 mmol/L\]) as determined from blood samples following a standard ultracentrifugation/precipitation procedure (β-quantification). |
| Mean Percent Changes from Baseline for High-Density-Lipoprotein Cholesterol (HDL-C) | Baseline and Week 4 | Participants hare to have their HDL-C levels assessed at baseline and after 4 weeks of study drug administration. The change from baseline will be calculated. |
| Mean Percent Changes from Baseline for Triglycerides (TG) | Baseline and Week 4 | Participants are to have their TG levels assessed at baseline and after 4 weeks of study drug administration. The change from baseline will be calculated. |
| Mean Percent Change from Baseline in Direct LDL-C | Baseline and Week 4 | Participants are to have their direct LDL-C levels assessed at baseline and after 4 weeks of study drug administration. The change from baseline will be calculated. |
| Mean Percent Changes from Baseline for Calculated LDL-C | Baseline and Week 4 | Participants are to have their calculated LDL-C levels assessed at baseline and after 4 weeks of study drug administration. The change from baseline will be calculated. |
Outcome results
None listed