MK0653C in High Cardiovascular Risk Patients With High Cholesterol (Switch Study)(MK-0653C-162)

• ClinicalTrials.gov Identifier: NCT01154036
• Recruitment Status: Completed
• First Posted: June 30, 2010
• Results First Posted: February 12, 2014
• Last Update Posted: November 1, 2015
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

This study will compare the lipid-altering efficacy and safety of switching to co-administration of ezetimibe and atorvastatin versus treatment with atorvastatin or rosuvastatin in high cardiovascular risk patients with hypercholesterolemia who have not achieved specified low-density lipoprotein cholesterol (LDL-C) levels. The primary hypothesis is that the co-administration of ezetimibe 10 mg and atorvastatin 10 mg will be superior to both atorvastatin 20 mg and rosuvastatin 10 mg with respect to the percentage reduction in low-density lipoprotein-cholesterol (LDL-C) after 6 weeks of treatment.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: ezetimibe 10 mg; Drug: atorvastatin; Drug: Comparator: rosuvastatin	Phase 3

Detailed Description:

This is a 18 week randomized, double-blind, active-controlled, multicenter study composed of a 6 week screening/run-in and 12 week double-blind treatment period (composed of 2 phases; each 6 weeks in duration). Only those participants who do not meet low density lipoprotein-cholesterol (LDL-C) goals at the end of Phase I (Week 6), were eligible to continue into Phase II (Week 12).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1547 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Active-Controlled, Multicenter Study of Patients With Primary Hypercholesterolemia and High Cardiovascular Risk Who Are Not Adequately Controlled With Atorvastatin 10 mg: A Comparison of the Efficacy and Safety of Switching to Coadministration Ezetimibe and Atorvastatin Versus Doubling the Dose of Atorvastatin or Switching to Rosuvastatin
• Study Start Date: July 2010
• Actual Primary Completion Date: September 2012
• Actual Study Completion Date: October 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase I: ezetimibe (EZ) 10 mg + atorvastatin (Atorva) 10 mg; Co-administration of EZ 10 mg tablet + Atorva 10 mg tablet; once daily for 6 weeks	Drug: ezetimibe 10 mg; Drug: atorvastatin
Active Comparator: Phase I: Atorvastatin 20 mg; Atorvastatin 20 mg tablet once daily for 6 weeks	Drug: atorvastatin
Active Comparator: Phase I: Rosuvastatin 10 mg; Rosuvastatin 10 mg tablet once daily for 6 weeks	Drug: Comparator: rosuvastatin
Experimental: Phase II: EZ 10mg+Atorva 10mg; Participants who had previously received EZ 10 mg + Atorva 10 mg in Phase I and continued on EZ 10 mg + Atorva 10 mg once daily for 6 weeks during Phase II regardless of whether or not LDL-C goals were achieved in Phase I	Drug: ezetimibe 10 mg; Drug: atorvastatin
Experimental: Phase II: EZ 10mg + Atorva 20mg [A]; Participants who had previously received Atorva 20 mg in Phase I and did not reach LDL-C goal and were switched to EZ 10 mg + Atorva 20 mg once daily for 6 weeks in Phase II	Drug: ezetimibe 10 mg; Drug: atorvastatin
Active Comparator: Phase II: Atorva 40mg; Participants who had previously received Atorva 20 mg in Phase I and did not reach LDL-C goal and were switched Atorva 40 mg once daily for 6 weeks in Phase II	Drug: atorvastatin
Experimental: Phase II: EZ 10mg + Atorva 20mg [R]; Participants who had previously received Rosuvastatin 10 mg in Phase I and did not reach LDL-C goal and received EZ 10 mg + Atorva 20 mg once daily for 6 weeks in Phase II	Drug: ezetimibe 10 mg; Drug: atorvastatin
Active Comparator: Phase II: Rosuvastatin 20mg; Participants who had previously received Rosuvastatin 10 mg in Phase I and did not reach LDL-C goal and were switched to Rosuvastatin 20 mg once daily for 6 weeks in Phase	Drug: Comparator: rosuvastatin

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I ) ]
   LDL-C levels measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4. LDL-C was calculated using the Friedewald method when triglyceride (TG)<350 mg/dL (3.95 mmol/L) and beta quantification ultracentrifugation when TG≥350 mg/dL (3.95 mmol/L).

Secondary Outcome Measures :

1. Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) (Phase II). [ Time Frame: Baseline (Week 6) and Week 12 ]
   LDL-C levels measured at Baseline (Week 6; end of Phase 1) and after 6 weeks of study drug administration (Week 12). Baseline was defined as the average of the values at Visits 5 and 6. LDL-C was calculated using the Friedewald method when triglyceride (TG)<350 mg/dL (3.95 mmol/L) and beta quantification ultracentrifugation when TG ≥350 mg/dL (3.95 mmol/L).
2. Percentage of Participants That Reach Target LDL-C Level of < 100 mg/dL (Phase I) [ Time Frame: Week 6 (End of Phase I) ]
3. Percentage of Participants That Reach Target LDL-C Level of < 100 mg/dL (Phase II) [ Time Frame: Week 12 (End of Phase II) ]
4. Percentage of Participants That Reach Target LDL-C Level of < 70 mg/dL (Phase I) [ Time Frame: Week 6 (End of Phase I) ]
5. Percentage of Participants That Reach Target LDL-C Level of < 70 mg/dL (Phase II) [ Time Frame: Week 12 (end of Phase II) ]
6. Percent Change From Baseline in Total Cholesterol (TC) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
   TC measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
7. Percent Change From Baseline in Total Cholesterol (TC) (Phase II) [ Time Frame: Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) ]
   TC levels measured at Baseline (end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
8. Percent Change From Baseline in Triglycerides (TG) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
   TG measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4. Baseline and post-baseline measurements were log-transformed in the response vector, with fixed effects for treatment, time and the interaction of time by treatment.
9. Percent Change From Baseline in Triglycerides (TG) (Phase II) [ Time Frame: Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) ]
   TG levels measured at Baseline (Week 6: end of Phase I) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6. Baseline and post-baseline measurements were log-transformed in the response vector, with fixed effects for treatment, time and the interaction of time by treatment.
10. Percent Change From Baseline in High-density Lipoprotein-Cholesterol (HDL-C) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    HDL-C measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
11. Percent Change From Baseline in HDL-C (Phase II) [ Time Frame: Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) ]
    HDL-C levels measured at Baseline (end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
12. Percent Change From Baseline in Apolipoprotein B (Apo B) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    Apo-B measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
13. Percent Change From Baseline in Apo B (Phase II) [ Time Frame: Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) ]
    Apo-B levels measured at Baseline (Week 6; end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
14. Percent Change From Baseline in Apolipoprotein A-I (Apo A-I) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    Apo-A-I measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
15. Percent Change From Baseline in Apo A-I (Phase II) [ Time Frame: Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) ]
    Apo-A-I levels measured at Baseline (end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
16. Percent Change From Baseline in Non-HDL-C (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    Non-HDL-C measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
17. Percent Change From Baseline in Non-HDL-C (Phase II) [ Time Frame: Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) ]
    Non-HDL-C levels calculated at Baseline (end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
18. Percent Change From Baseline in TC/HDL-C Ratio (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    TC/HDL-C ratio calculated at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
19. Percent Change From Baseline in TC/HDL-C Ratio (Phase II) [ Time Frame: Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) ]
    TC/HDL-C Ratio calculated at Baseline (end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
20. Percent Change From Baseline in LDL-C/HDL-C Ratio (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    LDL-C/HDL-C ratio calculated at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
21. Percent Change From Baseline in LDL-C/HDL-C Ratio (Phase II) [ Time Frame: Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) ]
    LDL-C/HDL-C Ratio calculated at Baseline (end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
22. Percent Change From Baseline in Apo B/Apo A-I Ratio (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    Apo B/Apo A-I ratio calculated at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
23. Percent Change From Baseline in Apo B/Apo A-I Ratio (Phase II) [ Time Frame: Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) ]
    Apo B/Apo A-I Ratio calculated at Baseline (Week 6; end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
24. Percent Change From Baseline in Non-HDL-C/HDL-C Ratio (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    Non HDL-C/HDL-C ratio calculated at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4
25. Percent Change From Baseline in Non-HDL-C/HDL-C Ratio (Phase II) [ Time Frame: Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) ]
    Non HDL-C/HDL-C Ratio calculated at baseline (Week 6; end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6.
26. Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) (Phase I) [ Time Frame: Baseline and Week 6 (end of Phase I) ]
    hs-CRP measured at Baseline and after 6 weeks of treatment (Week 6; end of Phase I). Baseline was defined as the average value of the measurements taken at Visits 3 and 4. Baseline and post-baseline measurements were log-transformed in the response vector, with fixed effects for treatment, time and the interaction of time by treatment.
27. Percent Change From Baseline in Hs-CRP (Phase II) [ Time Frame: Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) ]
    hs-CRP measured at Baseline (Week 6; end of Phase 1) and after 6 weeks of study drug administration (Week 12; end of Phase II). Baseline was defined as the average of the values at Visits 5 and 6. Baseline and post-baseline measurements were log-transformed in the response vector, with fixed effects for treatment, time and the interaction of time by treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 79 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patient is at high cardiovascular risk and meets one of the following conditions: has never taken lipid-lowering therapy or has been off such therapy for at least 6 weeks; or, is currently taking a stable dose of certain lipid-lowering agents
• Patient is willing to maintain a cholesterol lowering diet during the study
• Female patients receiving non-cyclical hormone therapy have maintained a stable dose and regimen for at least 8 weeks and are willing to continue the same regimen during the study

Exclusion Criteria:

• Patient is Asian
• Patient routinely has more than 2 alcoholic drinks per day
• Female patient is pregnant or breastfeeding
• Patient has congestive heart failure
• Patient has had a myocardial infarction, coronary bypass surgery, angioplasty, or acute coronary syndrome within 3 months of screening
• Patient has uncontrolled cardiac arrhythmias
• Patient has had a partial ileal or gastric bypass or other significant intestinal malabsorption
• Patient has uncontrolled high blood pressure
• Patient has kidney disease
• Patient has any disease known to influence blood lipid levels
• Patient has any disorders of the blood, digestive system, or nervous system including stroke and degenerative disease that would limit study participation
• Patient has poorly controlled or newly diagnosed diabetes
• Patient is known to be HIV positive
• Patient has a history of cancer in the last 5 years, except certain skin and cervical cancers

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Monitor; Merck Sharp & Dohme Corp.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Krempf M, Simpson RJ Jr, Ramey DR, Brudi P, Giezek H, Tomassini JE, Lee R, Farnier M. Patient and physician factors influence decision-making in hypercholesterolemia: a questionnaire-based survey. Lipids Health Dis. 2015 May 19;14:45. doi: 10.1186/s12944-015-0037-y.

Bays HE, Averna M, Majul C, Muller-Wieland D, De Pellegrin A, Giezek H, Lee R, Lowe RS, Brudi P, Triscari J, Farnier M. Efficacy and safety of ezetimibe added to atorvastatin versus atorvastatin uptitration or switching to rosuvastatin in patients with primary hypercholesterolemia. Am J Cardiol. 2013 Dec 15;112(12):1885-95. doi: 10.1016/j.amjcard.2013.08.031. Epub 2013 Sep 21.

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT01154036
• Other Study ID Numbers: 0653C-162; 2010_517 ( Other Identifier: Merck Study Number )
• First Posted: June 30, 2010
• Results First Posted: February 12, 2014
• Last Update Posted: November 1, 2015
• Last Verified: October 2015

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin; Rosuvastatin Calcium; Ezetimibe; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors