To Evaluate Ezetimibe/Simvastatin and Niacin (Extended Release Tablet) in Patients With Type IIa or Type IIb Hyperlipidemia (0653A-091)(COMPLETED)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Merck

ClinicalTrials.gov Identifier:

NCT00271817

First received: January 3, 2006

Last updated: April 3, 2013

Last verified: April 2013

History of Changes

Results First Received: February 13, 2009

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Hypercholesterolemia
Interventions:	Drug: Comparator: ezetimibe/simvastatin + niacin (ER) Drug: Comparator: Placebo to ezetimibe/simvastatin Drug: Comparator: niacin (ER) tablet Drug: Comparator: ezetimibe (+) simvastatin Drug: Comparator: Placebo to Niacin (ER) Drug: Comparator: ezetimibe/simvastatin and niacin (ER) Drug: Comparator: ezetimibe and simvastatin Drug: Comparator: Placebo to niacin (ER)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Niacin	(Part 1): Niacin titrated to 2000 mg taken orally once daily for 24 weeks. During the first 12 weeks of the study, patients randomized to the niacin containing arms started taking niacin 500 mg and had their niacin dose increased 500 mg every 4 weeks to 2000 mg. Patients in this treatment group were ramdomly reassigned for Part 2 of the study to one of two treatment groups- two-thirds of the patients enrolled in the niacin treatment group were randomly assigned to receive ezetimibe/simvastatin + niacin (ER) and the other one-third were randomly assigned to receive ezetimibe/simvastatin alone.
Ezetimibe/Simvastatin	(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.
Ezetimibe/Simvastatin + Niacin	(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Description

Niacin

(Part 1): Niacin titrated to 2000 mg taken orally once daily for 24 weeks. During the first 12 weeks of the study, patients randomized to the niacin containing arms started taking niacin 500 mg and had their niacin dose increased 500 mg every 4 weeks to 2000 mg. Patients in this treatment group were ramdomly reassigned for Part 2 of the study to one of two treatment groups- two-thirds of the patients enrolled in the niacin treatment group were randomly assigned to receive ezetimibe/simvastatin + niacin (ER) and the other one-third were randomly assigned to receive ezetimibe/simvastatin alone.

Ezetimibe/Simvastatin

(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks.

(Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Ezetimibe/Simvastatin + Niacin

(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks.

(Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Participant Flow for 2 periods

Period 1: Part 1

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin
STARTED	272	272	676
COMPLETED	166 ^[1]	213 ^[2]	391 ^[3]
NOT COMPLETED	106	59	285
Adverse Event	68	25	156
Lost to Follow-up	6	8	24
Protocol Violation	5	4	7
Patient Moved	3	1	5
Withdrawal by Subject	23	17	45
LDL < 50 mg/dL	1	4	48

[1]	6 patients who completed Part 1 did not continue to Part 2; 1 patient never received drug in Part 2
[2]	1 patient who completed Part 1 did not continue to Part 2
[3]	11 patients who completed Part 1 did not continue to Part 2

Period 2: Part 2

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin
STARTED	0 ^[1]	266 ^[2]	485 ^[3]
COMPLETED	0	234	401
NOT COMPLETED	0	32	84
Adverse Event	0	17	33
Lack of Efficacy	0	1	6
Lost to Follow-up	0	6	18
Protocol Violation	0	3	5
Patient Moved	0	0	5
Withdrawal by Subject	0	2	13
LDL < 50 mg/dL	0	3	4

[1]	Patients completing the niacin group in Part 1, were re-allocated to one of the two arms in Part 2
[2]	Includes 54 patients re-allocated from the niacin group in Part 1
[3]	Includes 105 patients re-allocated from the niacin group in Part 1

Baseline Characteristics

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Reporting Groups

	Description
Niacin	(Part 1): Niacin titrated to 2000 mg taken orally once daily for 24 weeks. During the first 12 weeks of the study, patients randomized to the niacin containing arms started taking niacin 500 mg and had their niacin dose increased 500 mg every 4 weeks to 2000 mg.
Ezetimibe/Simvastatin	(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.
Ezetimibe/Simvastatin + Niacin	(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.
Total	Total of all reporting groups

Baseline Measures

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin	Total
Number of Participants [units: participants]	272	272	676	1220
Age [units: years] Mean ± Standard Deviation	56.4 ± 10.6	57.5 ± 10.3	56.9 ± 10.9	56.9 ± 10.7
Gender [units: participants]
Female	136	120	352	608
Male	136	152	324	612
Race/Ethnicity, Customized [units: participants]
Asian	11	4	11	26
Black	13	17	38	68
Hispanic	14	11	49	74
Other	3	0	2	5
White	231	240	576	1047
Body Mass Index [units: Participants]
<25 kg/m2	48	39	135	222
25 to <30 kg/m2	110	119	252	481
30 to <40 kg/m2	97	94	251	442
≥ 40 kg/m2	16	19	34	69
No BMI Data	1	1	4	6

Outcome Measures

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1. Primary:

Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) [ Time Frame: Baseline and 24 Weeks ]

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2. Primary:

Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) [ Time Frame: Baseline and 24 weeks ]

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3. Secondary:

Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [ Time Frame: Baseline and 24 weeks ]

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4. Secondary:

Percent Change From Baseline in High-Density Lipoprotein-Cholesterol (HDL-C) [ Time Frame: Baseline and 24 weeks ]

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5. Secondary:

Percent Change From Baseline in Triglycerides (TG) [ Time Frame: baseline and 24 Weeks ]

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6. Secondary:

Percent Change From Baseline in High-Density Lipoprotein-Cholesterol (HDL-C) [ Time Frame: Baseline and 64 weeks ]

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7. Secondary:

Percent Change From Baseline in Triglycerides (TG) [ Time Frame: Baseline and 64 weeks ]

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8. Secondary:

Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [ Time Frame: Baseline and 64 weeks ]

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Measure Type	Secondary
Measure Title	Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C)
Measure Description	Ezetimibe/simvastatin co-administered with niacin extended release compared to ezetimibe/simvastatin monotherapy on the percent change from baseline in non-HDL-C after 64 weeks - 64 week measure minus baseline
Time Frame	Baseline and 64 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.
The analysis population is the modified intention-to-treat population, which includes patients that were randomized to ezetimibe/simvastatin + niacin or ezetimibe/simvastatin treatment groups and have a baseline measurement and at least on measurement beyond Week 24.

Reporting Groups

	Description
Ezetimibe/Simvastatin	Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks. Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.
Ezetimibe/Simvastatin + Niacin	Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg) taken orally once daily for 24 weeks. Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Measured Values

	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin
Number of Participants Analyzed [units: participants]	207	369
Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [units: Percent change] Mean ± Standard Error	-45.1 ± 1.3	-52.4 ± 0.9

Statistical Analysis 1 for Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C)

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	<0.001
Mean Difference (Final Values) ^[4]	-7.3
Standard Error of the mean	± 1.6
95% Confidence Interval	( -10.4 to -4.2 )

[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:
	ANCOVA with terms for treatment, baseline LDL-C, baseline TG, and gender.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	A fixed sequence testing procedure was employed where testing followed a prespecified order and each subsequent hypothesis was tested at the 0.05 level of significance only if all previously tested hypotheses have been rejected.
[4]	Other relevant estimation information:
	Median difference = Ezetimibe/Simvastatin + Niacin minus Ezetimibe/Simvastatin

9. Secondary:

Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) [ Time Frame: Baseline and 64 weeks ]

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10. Secondary:

Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [ Time Frame: Baseline and 24 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:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

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
Part 1 population is all patients enrolled in Part 1 of the study. Part 2 is those patients who received either niacin, ezetimibe/simvastatin, or ezetimibe/simvastatin + niacin during Part 1 until they finished the study at week 64 or discontinued.

Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372

Publications:

Guyton JR, Brown BG, Fazio S, Polis A, Tomassini JE, Tershakovec AM. Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. J Am Coll Cardiol. 2008 Apr 22;51(16):1564-72.

Publications automatically indexed to this study:

Guyton JR, Fazio S, Adewale AJ, Jensen E, Tomassini JE, Shah A, Tershakovec AM. Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial. Diabetes Care. 2012 Apr;35(4):857-60. Epub 2012 Feb 14.

Responsible Party:	Merck
ClinicalTrials.gov Identifier:	NCT00271817 History of Changes
Other Study ID Numbers:	2005_091, MK0653A-091
Study First Received:	January 3, 2006
Results First Received:	February 13, 2009
Last Updated:	April 3, 2013
Health Authority:	United States: Food and Drug Administration

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