Safety and Efficacy Study Comparing ABT-335 Coadministered With Atorvastatin and Ezetimibe to Atorvastatin Coadministered With Ezetimibe in Subjects With Multiple Abnormal Lipid (Fat) Levels in the Blood - Study Results

Study Type:	Interventional
Study Design:	Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment
Conditions:	Dyslipidemias Coronary Heart Disease Combined (Atherogenic) Dyslipidemia Mixed Dyslipidemia
Interventions:	Drug: ABT-335 Drug: placebo Drug: atorvastatin Drug: ezetimibe

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
One subject was randomized to the atorvastatin and ezetimibe treatment group and never received study drug.

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
STARTED	272^[1]	270^[2]
COMPLETED	246^[3]	240^[4]
NOT COMPLETED	26	30

[1]	All randomized subjects were treated.
[2]	1 subject was randomized but not treated because of an abnormal ECG that precluded treatment.
[3]	26 subjects prematurely discontinued treatment.
[4]	30 subjects prematurely discontinued treatment

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	Total
Number of Participants [units: participants]	272	270	542
Age [units: participants]
<=18 years	0	0	0
Between 18 and 65 years	227	206	433
>=65 years	45	64	109
Age [units: years] Mean ± Standard Deviation	54.4 ± 11.23	56.4 ± 10.67	55.4 ± 10.99
Gender [units: participants]
Female	143	155	298
Male	129	115	244
Region of Enrollment [units: participants]
United States	272	270	542

Outcome Measures

1. Primary:

Median Percent Change in Triglycerides From Baseline to Final Visit [ Baseline to 12 Weeks (Final Visit) ]

Measure Type	Primary
Measure Title	Median Percent Change in Triglycerides From Baseline to Final Visit
Measure Description	[(Week 12 triglycerides minus baseline triglycerides)/baseline triglycerides] x 100
Time Frame	Baseline to 12 Weeks (Final Visit)
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.
All randomized subjects with a baseline triglyceride value and at least 1 postbaseline triglyceride value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	262	262
Median Percent Change in Triglycerides From Baseline to Final Visit [units: Percent change] Median ( Inter-Quartile Range )	-57.3 ( -67.1 to -46.3 )	-39.7 ( -52.5 to -20.9 )

Statistical Analysis 1 for Median Percent Change in Triglycerides From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	A sample size of 212 per arm provided 90% power and > 99% power with a 2-sided alpha = 0.05 level to detect differences between treatment arms of 6% and 17% in the percent change in HDL-C and TG, respectively, assuming an SD of 19% and 30%, respectively. This sample size provided an overall power of approximately 90% for the 2 primary comparisons. If a loss to follow-up rate of 8% was assumed, the sample size needed to be increased to 230 per arm to maintain the above power.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The treatment group comparisons for both primary efficacy variables must have demonstrated superiority of ABT-335 + atorvastatin + ezetimibe to declare this arm successful. Thus, no adjustments were made for multiple comparisons.

2. Primary:

Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit [ Baseline to 12 weeks (Final Visit) ]

Measure Type	Primary
Measure Title	Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit
Measure Description	[(Week 12 HDL-C minus baseline HDL-C)/baseline HDL-C] x 100
Time Frame	Baseline to 12 weeks (Final Visit)
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.
All randomized subjects with a baseline high density lipoprotein cholesterol (HDL-C) value and at least 1 postbaseline HDL-C value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	262	262
Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit [units: Percent change] Mean ± Standard Error	13.0 ± 0.95	4.2 ± 0.95

Statistical Analysis 1 for Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	A sample size of 212 per arm provided 90% power and > 99% power with a 2-sided alpha = 0.05 level to detect differences between treatment arms of 6% and 17% in the percent change in HDL-C and TG, respectively, assuming an SD of 19% and 30%, respectively. This sample size provided an overall power of approximately 90% for the 2 primary comparisons. If a loss to follow-up rate of 8% was assumed, the sample size needed to be increased to 230 per arm to maintain the above power.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Corresponding baseline lipid value as the covariate and with effect for treatment group.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The treatment group comparisons for both primary efficacy variables must have demonstrated superiority of ABT-335 + atorvastatin + ezetimibe to declare this arm successful. Thus, no adjustments were made for multiple comparisons.

3. Secondary:

Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit [ Baseline to 12 weeks (Final Visit) ]

Measure Type	Secondary
Measure Title	Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit
Measure Description	[(Week 12 apoAI minus baseline apoAI)/baseline apoAI] x 100
Time Frame	Baseline to 12 weeks (Final Visit)
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.
All randomized subjects with a baseline apoAI value and at least 1 postbaseline apoAI value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	248	239
Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit [units: Percent change] Mean ± Standard Error	1.8 ± 0.74	-1.3 ± 0.76

Statistical Analysis 1 for Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.004

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Secondary endpoints were tested in fixed sequence. If superiority of ABT-335 + atorvastatin + ezetimibe treatment was demonstrated for primary endpoints, secondary endpoints were tested in ranked order of apoA1, VLDL-C, apoC3, non-HDL-C, apoB, and hsCRP at alpha = 0.05 level until 1 secondary endpoint failed to reach statistical significance.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Corresponding baseline lipid value as the covariate and with effect for treatment group.
[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. Secondary:

Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit [ Baseline to 12 weeks (final visit) ]

Measure Type	Secondary
Measure Title	Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit
Measure Description	[(Week 12 VLDL-C minus baseline VLDL-C)/baseline VLDL-C] x 100
Time Frame	Baseline to 12 weeks (final visit)
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.
All randomized subjects with a baseline VLDL-C value and at least 1 postbaseline VLDL-C value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	261	262
Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit [units: Percent change] Mean ± Standard Error	-57.8 ± 1.87	-41.1 ± 1.87

Statistical Analysis 1 for Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Secondary endpoints were tested in fixed sequence. If superiority of ABT-335 + atorvastatin + ezetimibe treatment was demonstrated for primary endpoints, secondary endpoints were tested in ranked order of apoA1, VLDL-C, apoC3, non-HDL-C, apoB, and hsCRP at alpha = 0.05 level until 1 secondary endpoint failed to reach statistical significance.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Corresponding baseline lipid value as the covariate and with effect for treatment group.
[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.

5. Secondary:

Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit [ Baseline to 12 weeks (Final Visit) ]

Measure Type	Secondary
Measure Title	Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit
Measure Description	[(Week 12 apoCIII minus baseline apoCIII)/baseline apoCIII] x 100
Time Frame	Baseline to 12 weeks (Final Visit)
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.
All randomized subjects with a baseline apoCIII value and at least 1 postbaseline apoCIII value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	249	242
Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit [units: Percent change] Mean ± Standard Error	-42.5 ± 1.22	-25.3 ± 1.23

Statistical Analysis 1 for Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Secondary endpoints were tested in fixed sequence. If superiority of ABT-335 + atorvastatin + ezetimibe treatment was demonstrated for primary endpoints, secondary endpoints were tested in ranked order of apoA1, VLDL-C, apoC3, non-HDL-C, apoB, and hsCRP at alpha = 0.05 level until 1 secondary endpoint failed to reach statistical significance.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Corresponding lipid value as the covariate and with effect for treatment group.
[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.

6. Secondary:

Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit [ Baseline to 12 weeks (Final Visit) ]

Measure Type	Secondary
Measure Title	Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit
Measure Description	[(Week 12 non-HDL-C minus baseline non-HDL-C)/baseline non-HDL-C] x 100
Time Frame	Baseline to 12 weeks (Final Visit)
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.
All randomized subjects with a baseline non-HDL-C value and at least 1 postbaseline non-HDL-C value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	262	262
Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit [units: Percent change] Mean ± Standard Error	-55.6 ± 0.94	-51.0 ± 0.94

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

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Secondary endpoints were tested in fixed sequence. If superiority of ABT-335 + atorvastatin + ezetimibe treatment was demonstrated for primary endpoints, secondary endpoints were tested in ranked order of apoA1, VLDL-C, apoC3, non-HDL-C, apoB, and hsCRP at alpha = 0.05 level until 1 secondary endpoint failed to reach statistical significance.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Corresponding baseline lipid value as the covariate and with effect for treatment group.
[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.

7. Secondary:

Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit [ Baseline to 12 weeks (Final Visit) ]

Measure Type	Secondary
Measure Title	Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit
Measure Description	[(Week 12 apoB minus baseline apoB)/baseline apoB] x 100
Time Frame	Baseline to 12 weeks (Final Visit)
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.
All randomized subjects with a baseline apoB value and at least 1 postbaseline apoB value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	248	239
Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit [units: Percent change] Mean ± Standard Error	-49.1 ± 0.91	-44.7 ± 0.93

Statistical Analysis 1 for Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Secondary endpoints were tested in fixed sequence. If superiority of ABT-335 + atorvastatin + ezetimibe treatment was demonstrated for primary endpoints, secondary endpoints were tested in ranked order of apoA1, VLDL-C, apoC3, non-HDL-C, apoB, and hsCRP at alpha = 0.05 level until 1 secondary endpoint failed to reach statistical significance.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Corresponding baseline lipid value as the covariate and with effect for treatment group.
[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.

8. Secondary:

Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit [ Baseline to 12 weeks (Final Visit) ]

Measure Type	Secondary
Measure Title	Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit
Measure Description	[(Week 12 hsCRP minus baseline hsCRP)/baseline hSCRP] x 100
Time Frame	Baseline to 12 weeks (Final Visit)
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.
All randomized subjects with a baseline hsCRP value and at least 1 postbaseline hsCRP value, last observation carried forward.

Reporting Groups

	Description
ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.
Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe	No text entered.

Measured Values

	ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe	Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe
Number of Participants Analyzed [units: participants]	261	262
Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit [units: Percent change] Median ( Inter-Quartile Range )	-52.1 ( -67.4 to -25.4 )	-40.3 ( -60.6 to -13.4 )

Statistical Analysis 1 for Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	< 0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Secondary endpoints were tested in fixed sequence. If superiority of ABT-335 + atorvastatin + ezetimibe treatment was demonstrated for primary endpoints, secondary endpoints were tested in ranked order of apoA1, VLDL-C, apoC3, non-HDL-C, apoB, and hsCRP at alpha = 0.05 level until 1 secondary endpoint failed to reach statistical significance.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Rank-sum test
[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.

Responsible Party:	Abbott ( Maureen Kelly, MD )
Study ID Numbers:	M10-275
Study First Received:	March 14, 2008
Results First Received:	October 2, 2009
Last Updated:	November 16, 2009
ClinicalTrials.gov Identifier:	NCT00639158 History of Changes
Health Authority:	United States: Food and Drug Administration