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

Phase 3

Completed

Conditions: Hypercholesterolemia

Interventions: Drug: atorvastatin
Drug: ezetimibe 10 mg

Registration Number: NCT01154036

Lead Sponsor: Organon and Co

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.

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1547

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I: Atorvastatin 20 mg	atorvastatin	Atorvastatin 20 mg tablet once daily for 6 weeks
Phase I: ezetimibe (EZ) 10 mg + atorvastatin (Atorva) 10 mg	ezetimibe 10 mg	Co-administration of EZ 10 mg tablet + Atorva 10 mg tablet; once daily for 6 weeks
Phase I: ezetimibe (EZ) 10 mg + atorvastatin (Atorva) 10 mg	atorvastatin	Co-administration of EZ 10 mg tablet + Atorva 10 mg tablet; once daily for 6 weeks
Phase II: EZ 10mg+Atorva 10mg	ezetimibe 10 mg	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
Phase II: EZ 10mg+Atorva 10mg	atorvastatin	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
Phase II: EZ 10mg + Atorva 20mg [A]	ezetimibe 10 mg	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
Phase II: Atorva 40mg	atorvastatin	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
Phase II: EZ 10mg + Atorva 20mg [R]	ezetimibe 10 mg	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
Phase II: EZ 10mg + Atorva 20mg [R]	atorvastatin	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
Phase II: EZ 10mg + Atorva 20mg [A]	atorvastatin	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

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) (Phase I)	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

Name	Time	Method
Percent Change From Baseline in TC/HDL-C Ratio (Phase II)	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.
Percent Change From Baseline in Non-HDL-C (Phase II)	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.
Percent Change From Baseline in TC/HDL-C Ratio (Phase I)	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
Percent Change From Baseline in Apo B/Apo A-I Ratio (Phase I)	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
Percent Change From Baseline in Apo B/Apo A-I Ratio (Phase II)	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.
Percent Change From Baseline in Non-HDL-C/HDL-C Ratio (Phase I)	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
Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) (Phase II).	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).
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)	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
Percent Change From Baseline in Total Cholesterol (TC) (Phase II)	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.
Percent Change From Baseline in Triglycerides (TG) (Phase I)	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.
Percent Change From Baseline in Triglycerides (TG) (Phase II)	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.
Percent Change From Baseline in High-density Lipoprotein-Cholesterol (HDL-C) (Phase I)	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
Percent Change From Baseline in HDL-C (Phase II)	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.
Percent Change From Baseline in Apolipoprotein B (Apo B) (Phase I)	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
Percent Change From Baseline in Apo B (Phase II)	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.
Percent Change From Baseline in Apolipoprotein A-I (Apo A-I) (Phase I)	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
Percent Change From Baseline in Apo A-I (Phase II)	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.
Percent Change From Baseline in Non-HDL-C (Phase I)	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
Percent Change From Baseline in Non-HDL-C/HDL-C Ratio (Phase II)	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.
Percent Change From Baseline in Hs-CRP (Phase II)	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.
Percent Change From Baseline in LDL-C/HDL-C Ratio (Phase I)	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
Percent Change From Baseline in LDL-C/HDL-C Ratio (Phase II)	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.
Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) (Phase I)	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.