Dyslipidemias, Coronary Heart Disease, Combined (Atherogenic) Dyslipidemia, Mixed Dyslipidemia
Conditions
Brief summary
The primary purpose of this study is to compare the safety and efficacy of ABT-335 (investigational drug) coadministered with atorvastatin and ezetimibe to atorvastatin coadministered with ezetimibe in subjects with abnormal lipid (fat) levels in the blood.
Interventions
DRUGABT-335
135 mg capsule, daily, 12 weeks
DRUGplacebo
placebo capsule, daily, 12 weeks
DRUGatorvastatin
40 mg, tablet, daily, 12 weeks
DRUGezetimibe
10 mg capsule, daily, 12 weeks
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with mixed dyslipidemia (trigylcerides, \> or = to 150 mg/dL to \< 400 mg/dL; HDL-C \< 40 mg/dL for males, \< 50 mg/dL for females; LDL-C, \> or = to 130 mg/dL). * Subjects must agree to use adequate birth control methods and to adhere to the American Heart Association (AHA) Diet.
Exclusion criteria
* Subjects with unstable or uncontrolled medical conditions considered inappropriate in a clinical trial. * Subjects with an unstable dose of medications or receiving Coumadin, oral, intravenous or intramuscular cyclosporine, statins, or certain other medications. * Women who are pregnant or plan on becoming pregnant, or women who are lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Percent Change in Triglycerides From Baseline to Final Visit | Baseline to 12 Weeks (Final Visit) | \[(Week 12 triglycerides minus baseline triglycerides)/baseline triglycerides\] x 100 |
| Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit | Baseline to 12 weeks (Final Visit) | \[(Week 12 HDL-C minus baseline HDL-C)/baseline HDL-C\] x 100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit | Baseline to 12 weeks (Final Visit) | \[(Week 12 apoCIII minus baseline apoCIII)/baseline apoCIII\] x 100 |
| Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit | Baseline to 12 weeks (Final Visit) | \[(Week 12 non-HDL-C minus baseline non-HDL-C)/baseline non-HDL-C\] x 100 |
| Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit | Baseline to 12 weeks (Final Visit) | \[(Week 12 apoAI minus baseline apoAI)/baseline apoAI\] x 100 |
| Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit | Baseline to 12 weeks (Final Visit) | \[(Week 12 hsCRP minus baseline hsCRP)/baseline hSCRP\] x 100 |
| Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit | Baseline to 12 weeks (Final Visit) | \[(Week 12 apoB minus baseline apoB)/baseline apoB\] x 100 |
| Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit | Baseline to 12 weeks (final visit) | \[(Week 12 VLDL-C minus baseline VLDL-C)/baseline VLDL-C\] x 100 |
Countries
United States
Participant flow
Pre-assignment details
One subject was randomized to the atorvastatin and ezetimibe treatment group and never received study drug.
Participants by arm
| Arm | Count |
|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | 272 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | 270 |
| Total | 542 |
Baseline characteristics
| Characteristic | Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Total | ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 64 Participants | 109 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 206 Participants | 433 Participants | 227 Participants |
| Age Continuous United States | 56.4 participants STANDARD_DEVIATION 10.67 | 55.4 participants STANDARD_DEVIATION 10.99 | 54.4 participants STANDARD_DEVIATION 11.23 |
| Age Continuous | 56.4 years STANDARD_DEVIATION 10.67 | 55.4 years STANDARD_DEVIATION 10.99 | 54.4 years STANDARD_DEVIATION 11.23 |
| Sex: Female, Male Female | 155 Participants | 298 Participants | 143 Participants |
| Sex: Female, Male Male | 115 Participants | 244 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 272 | 51 / 270 |
| serious Total, serious adverse events | 3 / 272 | 5 / 270 |
Outcome results
Primary
Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit
\[(Week 12 HDL-C minus baseline HDL-C)/baseline HDL-C\] x 100
Time frame: Baseline to 12 weeks (Final Visit)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit | 13.0 Percent change | Standard Error 0.95 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Final Visit | 4.2 Percent change | Standard Error 0.95 |
Comparison: 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.p-value: <0.001ANCOVA
Primary
Median Percent Change in Triglycerides From Baseline to Final Visit
\[(Week 12 triglycerides minus baseline triglycerides)/baseline triglycerides\] x 100
Time frame: Baseline to 12 Weeks (Final Visit)
Population: All randomized subjects with a baseline triglyceride value and at least 1 postbaseline triglyceride value, last observation carried forward.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Median Percent Change in Triglycerides From Baseline to Final Visit | -57.3 Percent change | Inter-Quartile Range 22.32 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Median Percent Change in Triglycerides From Baseline to Final Visit | -39.7 Percent change | Inter-Quartile Range 29.44 |
Comparison: 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.p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit
\[(Week 12 apoAI minus baseline apoAI)/baseline apoAI\] x 100
Time frame: Baseline to 12 weeks (Final Visit)
Population: All randomized subjects with a baseline apoAI value and at least 1 postbaseline apoAI value, last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit | 1.8 Percent change | Standard Error 0.74 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Apolipoprotein AI (apoAI) From Baseline to Final Visit | -1.3 Percent change | Standard Error 0.76 |
Comparison: 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.p-value: 0.004ANCOVA
Secondary
Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit
\[(Week 12 apoB minus baseline apoB)/baseline apoB\] x 100
Time frame: Baseline to 12 weeks (Final Visit)
Population: All randomized subjects with a baseline apoB value and at least 1 postbaseline apoB value, last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit | -49.1 Percent change | Standard Error 0.91 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Apolipoprotein B (apoB) From Baseline to Final Visit | -44.7 Percent change | Standard Error 0.93 |
Comparison: 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.p-value: <0.001ANCOVA
Secondary
Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit
\[(Week 12 apoCIII minus baseline apoCIII)/baseline apoCIII\] x 100
Time frame: Baseline to 12 weeks (Final Visit)
Population: All randomized subjects with a baseline apoCIII value and at least 1 postbaseline apoCIII value, last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit | -42.5 Percent change | Standard Error 1.22 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Apolipoprotein CIII (apoCIII) From Baseline to Final Visit | -25.3 Percent change | Standard Error 1.23 |
Comparison: 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.p-value: <0.001ANCOVA
Secondary
Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit
\[(Week 12 non-HDL-C minus baseline non-HDL-C)/baseline non-HDL-C\] x 100
Time frame: Baseline to 12 weeks (Final Visit)
Population: All randomized subjects with a baseline non-HDL-C value and at least 1 postbaseline non-HDL-C value, last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit | -55.6 Percent change | Standard Error 0.94 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Final Visit | -51.0 Percent change | Standard Error 0.94 |
Comparison: 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.p-value: <0.001ANCOVA
Secondary
Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit
\[(Week 12 VLDL-C minus baseline VLDL-C)/baseline VLDL-C\] x 100
Time frame: Baseline to 12 weeks (final visit)
Population: All randomized subjects with a baseline VLDL-C value and at least 1 postbaseline VLDL-C value, last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit | -57.8 Percent change | Standard Error 1.87 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Mean Percent Change in Very Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Final Visit | -41.1 Percent change | Standard Error 1.87 |
Comparison: 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.p-value: <0.001ANCOVA
Secondary
Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit
\[(Week 12 hsCRP minus baseline hsCRP)/baseline hSCRP\] x 100
Time frame: Baseline to 12 weeks (Final Visit)
Population: All randomized subjects with a baseline hsCRP value and at least 1 postbaseline hsCRP value, last observation carried forward.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| ABT-335 + 40 mg Atorvastatin + 10 mg Ezetimibe | Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit | -52.1 Percent change | Inter-Quartile Range 102.82 |
| Placebo + 40 mg Atorvastatin + 10 mg Ezetimibe | Median Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Final Visit | -40.3 Percent change | Inter-Quartile Range 516.56 |
Comparison: 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.p-value: <0.001Wilcoxon (Mann-Whitney)