To Evaluate Ezetimibe Plus Atorvastatin Versus Atorvastatin in Patients With High Cholesterol Not Controlled on Atorvastatin 20 mg. - Study Results

Study Type:	Interventional
Study Design:	Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment
Condition:	Hypercholesterolemia
Interventions:	Drug: Comparator: atorvastatin Drug: Comparator: Placebo Drug: Comparator: ezetimibe Drug: Comparator: Placebo.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Phase III First Patient In: 4/5/2006; Last Patient Last Visit 1/17/2008 72 centers worldwide (US, Canada, Austria, Costa Rica) Eligible patients include those on a stable dose of atorvastatin 20 mg; or patients with adjusted LDL-C pre-screen ranges who were treated with other lipid modifying therapy, or were statin and/or ezetimibe naïve.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients received and were blinded to atorvastatin 20 mg for a 4/5- week run-in period. Patients needed an LDL-C ≥ 100 mg/dL and ≤ 160 mg/dL at Visit 2 (week -1). Eligible patients were randomized at Visit 3 (Week 0) to either atorvastatin 40 mg or addition of ezetimibe 10 mg to their 20 mg dose of atorvastatin for a 6-week treatment period.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Patients received and were blinded to atorvastatin 20 mg for a 4/5- week run-in period.

Patients needed an LDL-C ≥ 100 mg/dL and ≤ 160 mg/dL at Visit 2 (week -1). Eligible patients were randomized at Visit 3 (Week 0) to either atorvastatin 40 mg or addition of ezetimibe 10 mg to their 20 mg dose of atorvastatin for a 6-week treatment period.

Reporting Groups

	Description
Atorvastatin + Ezetimibe	Atorvastatin 20 mg + Ezetemibe 10 mg daily for 6 weeks
Atorvastatin	Atorvastatin 40 mg Daily for 6 weeks

Participant Flow: Overall Study

	Atorvastatin + Ezetimibe	Atorvastatin
STARTED	98	98
COMPLETED	92	91
NOT COMPLETED	6	7
Adverse Event	0	2
Lost to Follow-up	2	2
Protocol Violation	4	3

Baseline Characteristics

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Reporting Groups

	Description
Atorvastatin + Ezetimibe	Atorvastatin 20 mg + Ezetemibe 10 mg daily for 6 weeks
Atorvastatin	Atorvastatin 40 mg Daily for 6 weeks

Baseline Measures

	Atorvastatin + Ezetimibe	Atorvastatin	Total
Number of Participants [units: participants]	98	98	196
Age [units: years] Mean ( Full Range )	56.4 ( 24 to 78 )	58.0 ( 34 to 76 )	57.2 ( 24 to 78 )
Gender [units: participants]
Female	40	49	89
Male	58	49	107
Race/Ethnicity, Customized [units: participants]
White	58	60	118
American Indian or Alaska Native	1	0	1
Asian	7	8	15
Black	3	9	12
Multi-Racial	29	21	50
Apolipoprotein A-I [units: mg/dL] Mean ± Standard Deviation	161.8 ± 25.2	163.4 ± 24.6	162.6 ± 24.8
Apolipoprotein A-I:Apolipoprotein B ratio [units: Ratio] Mean ± Standard Deviation	0.8 ± 0.2	0.7 ± 0.2	0.8 ± 0.2
Apolipoprotein B [units: mg/dL] Mean ± Standard Deviation	122.9 ± 22.4	119.9 ± 21.0	121.4 ± 21.7
C Reactive Protein [units: mg/dL] Mean ± Standard Deviation	1.6 ± 2.6	1.2 ± 1.7	1.5 ± 2.1
High Density Lipoprotein (HDL) [units: mg/dL] Mean ± Standard Deviation	51.1 ± 12.1	51.7 ± 11.5	51.4 ± 11.8
Low Density Lipoprotein (LDL) [units: mg/dL] Mean ± Standard Deviation	119.9 ± 19.4	117.9 ± 16.8	118.9 ± 18.1
Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) ratio [units: Ratio] Mean ± Standard Deviation	2.4 ± 0.6	2.5 ± 0.7	2.4 ± 0.7
Non- High Density Lipoprotein (Non-HDL) Cholesterol [units: mg/dL] Mean ± Standard Deviation	151.6 ± 24.1	148.4 ± 21.1	150.0 ± 22.7
NonHigh Density Lipoprotein-Cholesterol (NonHDL-C):High Density Lipoprotein-Cholesterol (HDL-C)ratio [units: Ratio] Mean ± Standard Deviation	3.2 ± 1.0	3.0 ± 0.9	3.1 ± 1.0
Total Cholesterol [units: mg/dL] Mean ± Standard Deviation	202.6 ± 25.2	200.0 ± 21.5	201.3 ± 23.4
Total cholesterol:High Density Lipoprotein Cholesterol (HDL-C) ratio [units: Ratio] Mean ± Standard Deviation	4.2 ± 1.0	4.0 ± 0.9	4.1 ± 1.0
Triglycerides (TG) [units: mg/dL] Mean ± Standard Deviation	152.5 ± 68.8	147.8 ± 75.3	149.0 ± 75.3

Outcome Measures

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1. Primary:

Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) at Week 6 [ 6 weeks ]

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2. Secondary:

Percent Change in High Density Lipoprotein -Cholesterol (HDL-C)at Week 6 [ 6 weeks ]

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3. Secondary:

Percent Change in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 6 [ 6 Weeks ]

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4. Secondary:

Percent Change From Baseline in Total-Cholesterol at Week 6 [ 6 Weeks ]

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5. Secondary:

Percent Change From Baseline in Triglycerides (TG) at Week 6 [ 6 weeks ]

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6. Secondary:

Percent Change From Baseline in Apolipoprotein B at Week 6 [ 6 Weeks ]

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7. Secondary:

Percent Change From Baseline in Total-Cholesterol:High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 [ 6 Weeks ]

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8. Secondary:

Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 [ 6 Weeks ]

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9. Secondary:

Percent Change From Baseline in Apolipoprotein B: Apolipoprotein A-I Ratio at Week 6 [ 6 Weeks ]

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10. Secondary:

Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 [ 6 Weeks ]

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11. Secondary:

Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6 [ 6 Weeks ]

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Measure Type	Secondary
Measure Title	Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6
Measure Description	[(6 week value – baseline value)/baseline value]*100%.
Time Frame	6 Weeks
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.

Reporting Groups

	Description
Atorvastatin + Ezetimibe	Atorvastatin 20 mg + Ezetemibe 10 mg daily for 6 weeks
Atorvastatin	Atorvastatin 40 mg Daily for 6 weeks

Measured Values

	Atorvastatin + Ezetimibe	Atorvastatin
Number of Participants Analyzed [units: participants]	89	89
Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6 [units: percent] Least Squares Mean ( 95% Confidence Interval )	-6.7 ( -23.7 to 14.2 )	-9.2 ( -25.8 to 11.1 )

Statistical Analysis 1 for Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6

Groups ^[1]	All groups
Method ^[2]	Longitudinal Data Analysis (LDA)
P Value ^[3]	0.841
Mean Difference (Final Values) ^[4]	2.5
95% Confidence Interval	( -23.8 to 28.8 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	LDA method of Liang and Zeger with model terms: treatment, time, and the interaction of time by treatment
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	Data for analysis was transformed by the natural log and the difference in geometric mean % change from BL calculated based on the difference in the back-transformed least squares means. (Atorva + EZ minus Atorva)

12. Secondary:

Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6 [ 6 weeks ]

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13. Post-Hoc:

Percent Change in Apolipoprotein A-I at Week 6 [ 6 Weeks ]

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14. Post-Hoc:

Percent Change in C-Reactive Protein (CRP) at Week 6 [ 6 weeks ]

Show Outcome Measure 14

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
194 out of 196 randomized patients took at least one dose of blinded study therapy and were included in the safety analysis

Results Point of Contact:

Name/Title: Senior Vice President, Clinical and Quantitative Sciences
Organization: Merck & Co., Inc.
phone: 1-800-672-6372

Publications:

Conard SE, Bays HE, Leiter LA, Bird SR, Rubino J, Lowe RS, Tomassini JE, Tershakovec AM. Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol. 2008 Dec 1;102(11):1489-94. Epub 2008 Oct 23.

Responsible Party:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2005_104, MK0653-079
Study First Received:	January 10, 2006
Results First Received:	December 18, 2008
Last Updated:	May 14, 2009
ClinicalTrials.gov Identifier:	NCT00276458 History of Changes
Health Authority:	United States: Food and Drug Administration