Efficacy and Safety Study of Ezetimibe (SCH 58235, MK-0653) in Addition to Atorvastatin in Participants With Coronary Heart Disease or Multiple Cardiovascular Risk Factors (P00693/MK-0653-030)

Organon

Status and phase: Completed; Phase 3

Conditions: Hypercholesterolemia

Treatments: Drug: Ezetimibe; Drug: Placebo for Atorvastatin; Drug: Placebo for Ezetimibe; Drug: Atorvastatin

Study type: Interventional

Funder types: Industry

Identifiers

NCT03867318

MK-0653-030 (Other Identifier)

P00693 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 621 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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621 participants in 2 patient groups

Atorvastatin Monotherapy

Experimental group

Description:

Participants receive double-blind atorvastatin 10 mg once daily (QD) via oral tablet PLUS open-label atorvastatin 10 mg QD via oral tablet for the entire duration of the study. Double-blind atorvastatin is to be added to the regimen for participants not achieving LDL-C target (≤100 mg/dL; 2.59 mmol/L). The maximum possible total daily dose of atorvastatin received in this group is 80 mg (10 mg open label plus 70 mg double blind).

Treatment:

Drug: Atorvastatin

Drug: Placebo for Atorvastatin

Ezetimibe + Atorvastatin

Experimental group

Description:

Participants receive double-blind ezetimibe 10 mg QD via oral tablet PLUS open-label atorvastatin 10 mg QD via oral tablet for the entire duration of the study. Double-blind atorvastatin is to be added to the regimen for participants not achieving LDL-C target (≤100 mg/dL; 2.59 mmol/L). The maximum possible total daily dose of atorvastatin received in this group is 40 mg (10 mg open label plus 30 mg double blind).

Treatment:

Drug: Atorvastatin

Drug: Placebo for Atorvastatin

Drug: Placebo for Ezetimibe

Drug: Ezetimibe