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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)

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ClinicalTrials.gov Identifier: NCT03867110
Recruitment Status : Completed
First Posted : March 7, 2019
Last Update Posted : June 13, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
Hypercholesterolemia Drug: Placebo Drug: Ezetimibe 10 mg Drug: Atorvastatin 10 mg Drug: Atorvastatin 20 mg Drug: Atorvastatin 40 mg Drug: Atorvastatin 80 mg Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 628 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 6, 2000
Actual Primary Completion Date : July 27, 2001
Actual Study Completion Date : July 27, 2001


Arm Intervention/treatment
Placebo Comparator: Placebo
Placebo is to be taken orally once a day (QD) in the morning for 12 consecutive weeks.
Drug: Placebo
Active Comparator: Ezetimibe 10 mg
Ezetimibe 10 mg (MK-0653, SCH 58235) is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Ezetimibe 10 mg
Other Names:
  • MK-0653
  • SCH 58235
  • ZETIA®

Active Comparator: Atorvastatin 10 mg
Atorvastatin 10 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Atorvastatin 10 mg
Other Name: LIPITOR®

Experimental: Ezetimibe 10 mg + Atorvastatin 10 mg
Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 10 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Ezetimibe 10 mg
Other Names:
  • MK-0653
  • SCH 58235
  • ZETIA®

Drug: Atorvastatin 10 mg
Other Name: LIPITOR®

Active Comparator: Atorvastatin 20 mg
Atorvastatin 20 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Atorvastatin 20 mg
Other Name: LIPITOR®

Experimental: Ezetimibe 10 mg + Atorvastatin 20 mg
Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 20 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Ezetimibe 10 mg
Other Names:
  • MK-0653
  • SCH 58235
  • ZETIA®

Drug: Atorvastatin 20 mg
Other Name: LIPITOR®

Active Comparator: Atorvastatin 40 mg
Atorvastatin 40 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Atorvastatin 40 mg
Other Name: LIPITOR®

Experimental: Ezetimibe 10 mg + Atorvastatin 40 mg
Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 40 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Ezetimibe 10 mg
Other Names:
  • MK-0653
  • SCH 58235
  • ZETIA®

Drug: Atorvastatin 40 mg
Other Name: LIPITOR®

Active Comparator: Atorvastatin 80 mg
Atorvastatin 80 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Atorvastatin 80 mg
Other Name: LIPITOR®

Experimental: Ezetimibe 10 mg + Atorvastatin 80 mg
Ezetimibe 10 mg (MK-0653, SCH 58235) + Atorvastatin 80 mg is to be taken orally QD in the morning for 12 consecutive weeks.
Drug: Ezetimibe 10 mg
Other Names:
  • MK-0653
  • SCH 58235
  • ZETIA®

Drug: Atorvastatin 80 mg
Other Name: LIPITOR®




Primary Outcome Measures :
  1. Percent Change from Baseline at Week 12 of Plasma Low Density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline and Week 12 ]
    Plasma LDL-C determined following a standard ultracentrifugation / precipitation (quantification) procedure (direct LDL-C). Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.


Secondary Outcome Measures :
  1. Percent Change from Baseline at Week 12 for Calculated Low Density Lipoprotein-Cholesterol (LDL-C) [ Time Frame: Baseline and Week 12 ]
    Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  2. Percent Change from Baseline at Week 12 for Total Cholesterol (TC) [ Time Frame: Baseline and Week 12 ]
    Participants had TC levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  3. Percent Change from Baseline at Week 12 for Triglycerides (TG) [ Time Frame: Baseline and Week 12 ]
    Participants had TG levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  4. Percent Change from Baseline at Week 12 for High Density-Lipoprotein-Cholesterol (HDL-C) [ Time Frame: Baseline and Week 12 ]
    Participants had HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  5. Percent Change from Baseline at Week 12 for Apolipoprotein B (Apo B) [ Time Frame: Baseline and Week 12 ]
    Participants had Apo B levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  6. Percent Change from Baseline at Week 12 for Non-High Density-Lipoprotein-Cholesterol (Non-HDL-C) [ Time Frame: Baseline and Week 12 ]
    Participants had Non-HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  7. Percent Change from Baseline at Week 12 for High Density-Lipoprotein 2-Cholesterol (HDL2-C) [ Time Frame: Baseline and Week 12 ]
    Participants had HDL2-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  8. Percent Change from Baseline at Week 12 for High Density-Lipoprotein 3-Cholesterol (HDL3-C) [ Time Frame: Baseline and Week 12 ]
    Participants had HDL3-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  9. Percent Change from Baseline at Week 12 for Apolipoprotein A-I (Apo A-I), [ Time Frame: Baseline and Week 12 ]
    Participants had Apo A1 levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  10. Percent Change from Baseline at Week 12 for Direct Low Density-Lipoprotein 3-Cholesterol/High Density-Lipoprotein 3-Cholesterol (LDL-C/HDL-C) Ratio [ Time Frame: Baseline and Week 12 ]
    Participants had LDL-C and HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline in the LDL-C/HDL-C ratio was calculated.

  11. Percent Change from Baseline at Week 12 for Direct Total Cholesterol/High Density-Lipoprotein 3-Cholesterol (TC/HDL-C) Ratio [ Time Frame: Baseline and Week 12 ]
    Participants had TC and HDL-C levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline in the TC/HDL-C ratio was calculated.

  12. Percent Change from Baseline at Week 12 for Lipoprotein (a) (Lp[a]) [ Time Frame: Baseline and Week 12 ]
    Participants had Lp(a) levels assessed at baseline and after 12 weeks of study drug administration. The percent change from baseline was calculated.

  13. 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) [ Time Frame: Week 12 ]
    LDL cholesterol level goal is <100 mg per deciliter (2.60 mmol per L)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03867110


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

Publications of Results:
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03867110     History of Changes
Other Study ID Numbers: P00692
MK-0653-013 ( Other Identifier: Merck Protocol Number )
P00692 ( Other Identifier: Schering-Plough Protocol Number )
First Posted: March 7, 2019    Key Record Dates
Last Update Posted: June 13, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
Hypercholesterolemia
Ezetimibe
Atorvastatin
Low density lipoprotein-cholesterol
Additional relevant MeSH terms:
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Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Atorvastatin
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors