Clinical trial NCT03867110: An Efficacy and Safety Study of Ezetimibe (MK-0653, SCH 58235) in Addition to Atorvastatin Compared to Placebo in Participants With Primary Hypercholesterolemia (MK-0653-013)
Official title: A Phase 3, Double-Blind Efficacy and Safety Study of Ezetimibe (SCH 58235) 10 mg in Addition to Atorvastatin Compared to Placebo in Subjects With Primary Hypercholesterolemia (Protocol P00692)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Keywords: Hypercholesterolemia
Ezetimibe
Atorvastatin
Low density lipoprotein-cholesterol
Lead sponsor: Organon and Co
Sponsor class: INDUSTRY
First posted: 2019-03-07
Enrollment: 628
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, randomized, double-blind, placebo-controlled, balanced-parallel-group, efficacy and safety trial of ezetimibe coadministered with atorvastatin in adult participants with primary hypercholesterolemia. The primary hypothesis is that the coadministration of ezetimibe 10 mg/day with atorvastatin (pooled across all doses: 10 mg, 20 mg, 40 mg, 80 mg) will result in a significantly greater reduction in direct low density lipoprotein-cholesterol (LDL-C) when compared with atorvastatin (pooled across all doses: 10 mg, 20 mg, 40 mg, 80 mg) alone and ezetimibe 10 mg alone.


Eligibility criteria: Inclusion Criteria:

* If female, is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP), or is a WOCBP who has used a contraceptive consistent with local regulations.
* Postmenopausal women who are receiving postmenopausal hormonal therapy or raloxifene must be maintained on a stable estrogen (ERT), estrogen/progestin (HRT) or raloxifene regimen during the study period.
* Primary hypercholesterolemic participants with a plasma LDL-Cholesterol ≥145 mg/dL (3.75 mmol/L) and ≤250 mg/dL (6.48 mmol/L) and plasma triglyceride ≤350 mg/dL (3.99 mmol/L) after adequate drug washout
* 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:

* Has a history of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy.
* Underlying disease likely to limit life span to less than 1 year.
* Participants with hypercholesterolemia in whom withholding of approved lipid-lowering therapy would be inappropriate.
* Have previously been randomized in any of the studies evaluating Ezetimibe (SCH 58235).
* Known hypersensitivity or any contraindication to atorvastatin (LIPITOR®).
* Pregnant or lactating women.
* Congestive heart failure New York Heart Association (NYHA) Class III or IV.
* Uncontrolled cardiac arrhythmias.
* 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.
* Disorders of the hematologic, digestive or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation.
* Uncontrolled or newly diagnosed (within 1 month of study entry) diabetes mellitus.
* Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins.
* Known impairment of renal function (plasma creatinine \>2.0 mg/dL), dysproteinemia, nephrotic syndrome or other renal disease.
* Active or chronic hepatobiliary or hepatic disease.
* Participants who are known to be Human Immunodeficiency Virus (HIV) positive.
* Participants with known coagulopathy.
* Lipid-altering agents, other than study drugs for the whole duration of the study.
* Oral corticosteroids.
* Cardiovascular drugs such as: beta blockers, calcium channel blockers, ACE inhibitors, nitrates or α-adrenergic blockers or thiazide diuretics will be allowed, provided the dose remains constant for the duration of the study and the participant has received a stable dose for at least 8 weeks before the initial qualifying LDL-C level is drawn. Aspirin up to 325 mg/day is permitted. In addition, aspirin is allowed as a as needed (prn) concomitant medication.
* Treatment with psyllium or other fiber-based laxatives unless treated with a stable regimen for at least 4 weeks before initial qualifying lipid determination. Dose must remain constant throughout the study period.
* Treatment with troglitazone (Rezulin®) unless treated with a stable regimen for at least 6 weeks before initial qualifying lipid determination. Dose must remain constant throughout the study period.
* Treatment with cyclosporine.
* Use of any investigational drugs within 30 days of study entry.
* Treatment with agents with known drug interaction with atorvastatin including antifungal azoles (itraconazole and ketoconazole), macrolide antibiotics (erythromycin and clarithromycin), and nefazodone. In addition, treatment with other agents that may interfere with or induce the CYP3A4 isoenzyme of the cytochrome P450 system should be avoided.

Primary outcomes:
measure: Percent Change from Baseline at Week 12 of Plasma Low Density Lipoprotein Cholesterol (LDL-C)
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Percent Change from Baseline at Week 12 for Calculated Low Density Lipoprotein-Cholesterol (LDL-C)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Total Cholesterol (TC)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Triglycerides (TG)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for High Density-Lipoprotein-Cholesterol (HDL-C)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Apolipoprotein B (Apo B)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Non-High Density-Lipoprotein-Cholesterol (Non-HDL-C)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for High Density-Lipoprotein 2-Cholesterol (HDL2-C)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for High Density-Lipoprotein 3-Cholesterol (HDL3-C)
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Apolipoprotein A-I (Apo A-I),
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Direct Low Density-Lipoprotein 3-Cholesterol/High Density-Lipoprotein 3-Cholesterol (LDL-C/HDL-C) Ratio
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Direct Total Cholesterol/High Density-Lipoprotein 3-Cholesterol (TC/HDL-C) Ratio
timeFrame: Baseline and Week 12
measure: Percent Change from Baseline at Week 12 for Lipoprotein (a) (Lp[a])
timeFrame: Baseline and Week 12
measure: The Percentage of Participants Achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP II) Target Goal for Direct Low Density Lipoprotein-Cholesterol (LDL-C)
timeFrame: Week 12
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP; Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003 May 20;107(19):2409-15. doi: 10.1161/01.CIR.0000068312.21969.C8. Epub 2003 Apr 28.