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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: ezetimibe 10 mg
* Drug: atorvastatin
* Drug: Comparator: rosuvastatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: ezetimibe (EZ) 10 mg + atorvastatin (Atorva) 10 mg<br>Co-administration of EZ 10 mg tablet + Atorva 10 mg tablet; once daily for 6 weeks | Drug: ezetimibe 10 mg<br> <br> Drug: atorvastatin<br> <br> |
| Active Comparator: Phase I: Atorvastatin 20 mg<br>Atorvastatin 20 mg tablet once daily for 6 weeks | Drug: atorvastatin<br> <br> |
| Active Comparator: Phase I: Rosuvastatin 10 mg<br>Rosuvastatin 10 mg tablet once daily for 6 weeks | Drug: Comparator: rosuvastatin<br> <br> |
| Experimental: Phase II: EZ 10mg+Atorva 10mg<br>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<br> <br> Drug: atorvastatin<br> <br> |
| Experimental: Phase II: EZ 10mg + Atorva 20mg [A]<br>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<br> <br> Drug: atorvastatin<br> <br> |
| Active Comparator: Phase II: Atorva 40mg<br>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<br> <br> |
| Experimental: Phase II: EZ 10mg + Atorva 20mg [R]<br>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<br> <br> Drug: atorvastatin<br> <br> |
| Active Comparator: Phase II: Rosuvastatin 20mg<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) (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). | Baseline and Week 6 (end of Phase I ) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) (Phase II). | 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). | Baseline (Week 6) and Week 12 | 
| Percentage of Participants That Reach Target LDL-C Level of < 100 mg/dL (Phase I) |  | Week 6 (End of Phase I) | 
| Percentage of Participants That Reach Target LDL-C Level of < 100 mg/dL (Phase II) |  | Week 12 (End of Phase II) | 
| Percentage of Participants That Reach Target LDL-C Level of < 70 mg/dL (Phase I) |  | Week 6 (End of Phase I) | 
| Percentage of Participants That Reach Target LDL-C Level of < 70 mg/dL (Phase II) |  | Week 12 (end of Phase II) | 
| Percent Change From Baseline in Total Cholesterol (TC) (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Total Cholesterol (TC) (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. | Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in Triglycerides (TG) (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. | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Triglycerides (TG) (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. | Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in High-density Lipoprotein-Cholesterol (HDL-C) (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in HDL-C (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. | Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in Apolipoprotein B (Apo B) (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Apo B (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. | Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in Apolipoprotein A-I (Apo A-I) (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Apo A-I (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. | Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in Non-HDL-C (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Non-HDL-C (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. | Baseline (Week 6; end of Phase I) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in TC/HDL-C Ratio (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in TC/HDL-C Ratio (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. | Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in LDL-C/HDL-C Ratio (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in LDL-C/HDL-C Ratio (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. | Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in Apo B/Apo A-I Ratio (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Apo B/Apo A-I Ratio (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. | Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in Non-HDL-C/HDL-C Ratio (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 | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Non-HDL-C/HDL-C Ratio (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. | Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) | 
| Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) (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. | Baseline and Week 6 (end of Phase I) | 
| Percent Change From Baseline in Hs-CRP (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. | Baseline (Week 6; end of Phase 1) and Week 12 (end of Phase II) |