Back to resultsEfficacy 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)
Primary Purpose
Hypercholesterolemia
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Atorvastatin
Ezetimibe
Placebo for Ezetimibe
Placebo for Atorvastatin
Sponsored by
About this trial
This is an interventional treatment trial for Hypercholesterolemia
Eligibility Criteria
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).
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Atorvastatin Monotherapy
Ezetimibe + Atorvastatin
Arm 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).
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).
Outcomes
Primary Outcome Measures
Percentage of Participants Achieving Target Low-Density-Lipoprotein Cholesterol (LDL-C) Levels of ≤100 mg/dL
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
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
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 Outcome Measures
Percentage of Participants Achieving Target LDL-C level (≤100 mg/dL)
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 Change from Baseline in Direct LDL-C
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
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.
Mean Percent Changes from Baseline for Total Cholesterol (TC)
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.
Mean Percent Changes from Baseline for Triglycerides (TG)
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 Changes from Baseline for High-Density-Lipoprotein Cholesterol (HDL-C)
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03867318
Brief Title
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)
Official Title
A Phase III Double-Blind Efficacy and Safety of Ezetimibe (SCH 58235) 10 MG in Addition to Atorvastatin in Subjects With Coronary Heart Disease or Multiple Cardiovascular Risk Factors and With Primary Hypercholesterolemia Not Controlled by a Starting Dose (10 mg) of Atorvastatin
Study Type
Interventional
2. Study Status
Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
April 24, 2000 (Actual)
Primary Completion Date
November 16, 2001 (Actual)
Study Completion Date
November 16, 2001 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Organon and Co
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
621 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Atorvastatin Monotherapy
Arm Type
Experimental
Arm 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).
Arm Title
Ezetimibe + Atorvastatin
Arm Type
Experimental
Arm 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).
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Other Intervention Name(s)
LIPITOR®, SCH 412387, MK-9396
Intervention Description
Atorvastatin administered orally QD as 10 mg tablets.
Intervention Type
Drug
Intervention Name(s)
Ezetimibe
Other Intervention Name(s)
ZETIA®, SCH 058235, MK-0653
Intervention Description
Ezetimibe administered orally QD as 10 mg tablets
Intervention Type
Drug
Intervention Name(s)
Placebo for Ezetimibe
Intervention Description
Single placebo tablet administered orally QD
Intervention Type
Drug
Intervention Name(s)
Placebo for Atorvastatin
Intervention Description
Single placebo tablet administered orally QD
Primary Outcome Measure Information:
Title
Percentage of Participants Achieving Target Low-Density-Lipoprotein Cholesterol (LDL-C) Levels of ≤100 mg/dL
Description
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).
Time Frame
Week 14
Title
Percentage of Participants With an Adverse Event
Description
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.
Time Frame
14 weeks (Up to 16 weeks)
Title
Percentage of Participants Who Discontinued the Study due to an Adverse Event
Description
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.
Time Frame
14 weeks (Up to 16 weeks)
Secondary Outcome Measure Information:
Title
Percentage of Participants Achieving Target LDL-C level (≤100 mg/dL)
Description
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).
Time Frame
Week 4
Title
Mean Percent Change from Baseline in Direct LDL-C
Description
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.
Time Frame
Baseline and Week 4
Title
Mean Percent Changes from Baseline for Calculated LDL-C
Description
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.
Time Frame
Baseline and Week 4
Title
Mean Percent Changes from Baseline for Total Cholesterol (TC)
Description
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.
Time Frame
Baseline and Week 4
Title
Mean Percent Changes from Baseline for Triglycerides (TG)
Description
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.
Time Frame
Baseline and Week 4
Title
Mean Percent Changes from Baseline for High-Density-Lipoprotein Cholesterol (HDL-C)
Description
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.
Time Frame
Baseline and Week 4
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
15389231
Citation
Stein E, Stender S, Mata P, Sager P, Ponsonnet D, Melani L, Lipka L, Suresh R, Maccubbin D, Veltri E; Ezetimibe Study Group. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J. 2004 Sep;148(3):447-55. doi: 10.1016/j.ahj.2004.03.052.
Results Reference
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Learn more about this trial
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)
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