To Evaluate Ezetimibe Plus Atorvastatin Versus Atorvastatin in Patients With High Cholesterol Not Controlled on Atorvastatin 40 mg - Study Results

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

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: 4/6/2006; Last Patient Last Visit 2/26/2008 96 centers worldwide (US, Canada) Eligible patients include those on a stable dose of atorvastatin 40 mg; or patients with adjusted LDLC 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 40 mg for a 4/5- week run-in period. Patients needed an LDL-C ≥ 70 mg/dL and ≤ 160 mg/dL at Visit 2 (week -1). Eligible patients were randomized at Visit 3 (Week 0) to either atorvastatin 80 mg or addition of ezetimibe 10 mg to their 40 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 40 mg for a 4/5- week run-in period.

Patients needed an LDL-C ≥ 70 mg/dL and ≤ 160 mg/dL at Visit 2 (week -1). Eligible patients were randomized at Visit 3 (Week 0) to either atorvastatin 80 mg or addition of ezetimibe 10 mg to their 40 mg dose of atorvastatin for a 6-week treatment period.

Reporting Groups

	Description
Atorvastatin + Ezetemibe	Atorvastatin 40 mg + Ezetemibe 10 mg every day for 6 weeks
Atorvastatin	Atorvastatin 80 mg every day for 6 weeks

Participant Flow: Overall Study

	Atorvastatin + Ezetemibe	Atorvastatin
STARTED	288	291
COMPLETED	279	278
NOT COMPLETED	9	13
Adverse Event	4	7
Lost to Follow-up	1	1
Protocol Violation	0	1
Withdrawal by Subject	4	3
Could not take time off work	0	1

Baseline Characteristics

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Reporting Groups

	Description
Atorvastatin + Ezetemibe	Atorvastatin 40 mg + Ezetemibe 10 mg every day for 6 weeks
Atorvastatin	Atorvastatin 80 mg every day for 6 weeks

Baseline Measures

	Atorvastatin + Ezetemibe	Atorvastatin	Total
Number of Participants [units: participants]	288	291	579
Age [units: years] Mean ( Full Range )	60.6 ( 31 to 80 )	62 ( 34 to 79 )	61.3 ( 31 to 80 )
Gender [units: participants]
Female	115	113	228
Male	173	178	351
Race/Ethnicity, Customized [units: Participants]
White	237	232	469
Asian	4	8	12
Black	32	29	61
Multi-Racial	15	22	37
Apolipoprotein A-I [units: mg/dL] Mean ± Standard Deviation	154.0 ± 25.5	154.6 ± 25.0	154.3 ± 25.3
Apolipoprotein B [units: mg/dL] Mean ± Standard Deviation	101.3 ± 19.0	102.0 ± 18.8	101.7 ± 18.9
Apolipoprotein B:Apolipoprotein A-I ratio [units: Ratio] Mean ± Standard Deviation	0.7 ± 0.2	0.7 ± 0.2	0.7 ± 0.2
C Reactive Protein [units: mg/dL] Mean ± Standard Deviation	1.8 ± 2.7	1.5 ± 3.0	1.6 ± 2.8
High-Density Lipoprotein [units: mg/dL] Mean ± Standard Deviation	47.4 ± 10.5	47.2 ± 10.6	47.3 ± 10.5
Low-Density Lipoprotein [units: mg/dL] Mean ± Standard Deviation	88.8 ± 16.2	89.8 ± 16.2	89.4 ± 16.2
Low-Density Lipoprotein-C:High-Density Lipoprotein-C ratio [units: Ratio] Mean ± Standard Deviation	2.0 ± 0.6	2.0 ± 0.6	2.0 ± 0.6
Non-High-Density Lipoprotein Cholesterol [units: mg/dL] Mean ± Standard Deviation	117.7 ± 20.8	118.1 ± 21.9	117.9 ± 21.4
Non-High-Density Lipoprotein-C:High-Density Lipoprotein-C ratio [units: Ratio] Mean ± Standard Deviation	2.6 ± 0.8	2.6 ± 0.8	2.6 ± 0.8
Total Cholesterol [units: mg/dL] Mean ± Standard Deviation	165.2 ± 21.4	165.3 ± 22.8	165.2 ± 22.1
Total cholesterol:High-Density Lipoprotein-C ratio [units: Ratio] Mean ± Standard Deviation	3.6 ± 0.8	3.6 ± 0.8	3.6 ± 0.8
Triglycerides [units: mg/dL] Median ± Standard Deviation	132.5 ± 72.1	134.0 ± 72.1	133.5 ± 72.1

Outcome Measures

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1. Primary:

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

Show Outcome Measure 1

2. Secondary:

Percent Change From Baseline to Week 6 in High-Density Lipoprotein Cholesterol (HDL-C) [ Baseline and 6 weeks ]

Show Outcome Measure 2

3. Secondary:

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

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4. Secondary:

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

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5. Secondary:

Percent Change From Baseline to Week 6 in Triglycerides (TG) [ Baseline and 6 Weeks ]

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6. Secondary:

Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B) [ Baseline and 6 Weeks ]

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Measure Type	Secondary
Measure Title	Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B)
Measure Description	Percent Change in Apo B = [(week 6 value - baseline value)/baseline value]*100%
Time Frame	Baseline and 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

Reporting Groups

	Description
Atorvastatin + Ezetemibe	Atorvastatin 40 mg + Ezetemibe 10 mg every day for 6 weeks
Atorvastatin	Atorvastatin 80 mg every day for 6 weeks

Measured Values

	Atorvastatin + Ezetemibe	Atorvastatin
Number of Participants Analyzed [units: participants]	275	276
Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B) [units: Percent Change] Least Squares Mean ( 95% Confidence Interval )	-17.8 ( -19.6 to -16.0 )	-7.7 ( -9.5 to -5.8 )

Statistical Analysis 1 for Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B)

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	<0.001
Mean Difference (Final Values) ^[4]	-10.1
Standard Error of the mean	± 1.3
95% Confidence Interval	( -12.7 to -7.6 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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[2]	Other relevant information, such as adjustments or degrees of freedom:
	Model terms: treatment and baseline Apo B value
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4]	Other relevant estimation information:
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7. Secondary:

Percent Change From Baseline to Week 6 in Apolipoprotein A-I (Apo A-I) [ Baseline and 6 Weeks ]

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8. Secondary:

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

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9. Secondary:

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

Show Outcome Measure 9

10. Secondary:

Percent Change From Baseline to Week 6 in Apolipoprotein B:Apolipoprotein A-I (Apo B:Apo A-I) Ratio [ Baseline and 6 Weeks ]

Show Outcome Measure 10

11. Secondary:

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

Show Outcome Measure 11

12. Secondary:

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

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13. Secondary:

Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6 [ 6 Weeks ]

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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
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Results Point of Contact:

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

Publications:

Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, Tomassini JE, Tershakovec AM. Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 2008 Dec 1;102(11):1495-501. Epub 2008 Oct 23.

Responsible Party:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2005_105, MK0653-090
Study First Received:	January 11, 2006
Results First Received:	February 6, 2009
Last Updated:	October 23, 2009
ClinicalTrials.gov Identifier:	NCT00276484 History of Changes
Health Authority:	United States: Food and Drug Administration