Hypercholesterolemia
Conditions
Brief summary
The main purpose of this study is to evaluate the efficacy and safety of the study drug known as evacetrapib when administered in combination with atorvastatin for 12 weeks in Japanese participants with primary hypercholesterolemia.
Interventions
DRUGEvacetrapib
Administered orally
DRUGEzetimibe
Administered orally
DRUGAtorvastatin
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be treated with atorvastatin 10 mg/day for at least 30 days prior to study initiation. * Japanese outpatients who are diagnosed with primary hypercholesterolemia with LDL-C levels (measured by a direct method) that meet the following criteria. (Participant categories are based on the definition in Japan Atherosclerosis Society 2012 guidelines.) * Category I: 160 mg/deciliter (dL)≤LDL-C * Category II: 140 mg/dL≤LDL-C * Category III: 120 mg/dL≤LDL-C * Secondary prevention: 100 mg/dL≤LDL-C * Have triglycerides (TG) ≤400 mg/dL. * Have HDL-C \<100 mg/dL.
Exclusion criteria
* Participants on LDL apheresis or plasma apheresis. * Participants with secondary hypercholesterolemia or homozygous familial hypercholesterolemia. * Any planned angiography. If angiography is planned, participants may be screened and enrolled after all such planned procedures are completed. * History of any of the following conditions \< 90 days prior to study initiation * acute coronary syndrome (unstable angina, acute myocardial infarction) * symptomatic peripheral arterial disease * invasive treatment of carotid artery disease * ischemic stroke or transient ischemic attack (TIA) * intracranial hemorrhage * History of abdominal aortic aneurysm. * Participants with a history of intolerance/hypersensitivity to ezetimibe or statins. * Have systolic blood pressure (SBP) \> 160 millimeters of mercury (mm Hg) or diastolic blood pressure (DBP) \> 100 mm Hg. * Have a hemoglobin A1c ≥8.4% (National Glycohemoglobin Standardization Program). * During the study period, participants who plan to use, are likely to require, or unwilling or unable to stop with adequate washout any prescription, over the counter (OTC) medication, supplements or health foods with the intent to treat serum lipids (LDL-C, HDL-C, TG) including but not limited to these classes of drugs: statin (except for atorvastatin 10 mg), ezetimibe, bile acid sequestrant, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Participants taking probucol, fibrate or nicotinic agents within 8 weeks before study initiation are excluded from the study. * Have been exposed to cholesteryl ester transfer protein (CETP) inhibitors (for example, anacetrapib or dalcetrapib).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) Measured by Beta Quantification | Baseline, Week 12 | The mixed-effects model for repeated measures (MMRM) was used for the Least Squares Mean (LS Mean) estimates at Week 12 for LDL-C adjusting for baseline as response variables, baseline measurement as a covariate, treatment, Visit (4,5,6, or 7), and treatment-by-visit interaction as fixed effects, and participant as a random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 12 in LDL-C (Direct) | Baseline, Week 12 | The MMRM was used for the LS Mean estimates at Week 12 for LDL-C (direct) adjusting for baseline as response variables, baseline measurement as a covariate, treatment, visit, and treatment-by-visit interaction as fixed effects, and participant as a random effect. |
| Percent Change From Baseline to Week 12 in Non HDL-C | Baseline, Week 12 | The MMRM was used for the LS Mean estimates at Week 12 for Non HDL-C adjusting for baseline as response variables, baseline measurement as a covariate, treatment, visit, and treatment-by-visit interaction as fixed effects, and participant as a random effect. |
| Percent Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol (HDL-C) | Baseline, Week 12 | The MMRM was used for the LS Mean estimates at Week 12 for HDL-C adjusting for baseline as response variables, baseline measurement as a covariate, treatment, visit, and treatment-by-visit interaction as fixed effects, and participant as a random effect, and treatment-by-visit interaction as fixed effects, and participant as a random effect. |
| Percent Change From Baseline to Week 12 in Apolipoprotein A-I | Baseline, Week 12 | The ANCOVA model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline. |
| Percent Change From Baseline to Week 12 in Apolipoprotein B | Baseline, Week 12 | The ANCOVA model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline. |
| Percent Change From Baseline to Week 12 in Lipoprotein-a | Baseline, Week 12 | The analysis of covariance (ANCOVA) model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Evacetrapib 130 mg evacetrapib and 10 mg atorvastatin administered PO once a day for 12 weeks. | 53 |
| Placebo Placebo and 10 mg atorvastatin administered PO once a day for 12 weeks. | 46 |
| Ezetimibe 10 mg ezetimibe and 10 mg atorvastatin administered PO once a day for 12 weeks as a reference arm. | 50 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 1 |
| Overall Study | Discontinue Due to Study Termination | 13 | 12 | 7 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Evacetrapib | Total | Ezetimibe | Placebo |
|---|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 11.53 | 58.2 years STANDARD_DEVIATION 10.87 | 58.0 years STANDARD_DEVIATION 10.4 | 57.9 years STANDARD_DEVIATION 10.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 53 Participants | 149 Participants | 50 Participants | 46 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 53 Participants | 149 Participants | 50 Participants | 46 Participants |
| Sex: Female, Male Female | 21 Participants | 67 Participants | 24 Participants | 22 Participants |
| Sex: Female, Male Male | 32 Participants | 82 Participants | 26 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 53 | 13 / 46 | 12 / 50 |
| serious Total, serious adverse events | 0 / 53 | 0 / 46 | 0 / 50 |
Outcome results
Primary
Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) Measured by Beta Quantification
The mixed-effects model for repeated measures (MMRM) was used for the Least Squares Mean (LS Mean) estimates at Week 12 for LDL-C adjusting for baseline as response variables, baseline measurement as a covariate, treatment, Visit (4,5,6, or 7), and treatment-by-visit interaction as fixed effects, and participant as a random effect.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) Measured by Beta Quantification | -26.37 percent change in LDL-C | Standard Error 3.108 |
| Placebo | Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) Measured by Beta Quantification | -3.75 percent change in LDL-C | Standard Error 3.264 |
| Ezetimibe | Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) Measured by Beta Quantification | -27.31 percent change in LDL-C | Standard Error 3.128 |
Secondary
Percent Change From Baseline to Week 12 in Apolipoprotein A-I
The ANCOVA model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in Apolipoprotein A-I | 42.8 percent change in Apolipoprotein A-I | Standard Error 2.27 |
| Placebo | Percent Change From Baseline to Week 12 in Apolipoprotein A-I | 0.6 percent change in Apolipoprotein A-I | Standard Error 2.44 |
| Ezetimibe | Percent Change From Baseline to Week 12 in Apolipoprotein A-I | -0.6 percent change in Apolipoprotein A-I | Standard Error 2.34 |
Secondary
Percent Change From Baseline to Week 12 in Apolipoprotein B
The ANCOVA model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in Apolipoprotein B | -20.4 percent change in Apolipoprotien B | Standard Error 2.42 |
| Placebo | Percent Change From Baseline to Week 12 in Apolipoprotein B | -3.0 percent change in Apolipoprotien B | Standard Error 2.6 |
| Ezetimibe | Percent Change From Baseline to Week 12 in Apolipoprotein B | -20.4 percent change in Apolipoprotien B | Standard Error 2.48 |
Secondary
Percent Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol (HDL-C)
The MMRM was used for the LS Mean estimates at Week 12 for HDL-C adjusting for baseline as response variables, baseline measurement as a covariate, treatment, visit, and treatment-by-visit interaction as fixed effects, and participant as a random effect, and treatment-by-visit interaction as fixed effects, and participant as a random effect.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol (HDL-C) | 108.96 percent change in HDL-C | Standard Error 5.15 |
| Placebo | Percent Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol (HDL-C) | -0.90 percent change in HDL-C | Standard Error 5.363 |
| Ezetimibe | Percent Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol (HDL-C) | -3.12 percent change in HDL-C | Standard Error 5.166 |
Secondary
Percent Change From Baseline to Week 12 in LDL-C (Direct)
The MMRM was used for the LS Mean estimates at Week 12 for LDL-C (direct) adjusting for baseline as response variables, baseline measurement as a covariate, treatment, visit, and treatment-by-visit interaction as fixed effects, and participant as a random effect.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in LDL-C (Direct) | -27.17 percent change in LDL-C (Direct) | Standard Error 2.708 |
| Placebo | Percent Change From Baseline to Week 12 in LDL-C (Direct) | -3.40 percent change in LDL-C (Direct) | Standard Error 2.845 |
| Ezetimibe | Percent Change From Baseline to Week 12 in LDL-C (Direct) | -28.96 percent change in LDL-C (Direct) | Standard Error 2.726 |
Secondary
Percent Change From Baseline to Week 12 in Lipoprotein-a
The analysis of covariance (ANCOVA) model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in Lipoprotein-a | -33.17 percent change in Lipoprotein-a | Standard Error 4.024 |
| Placebo | Percent Change From Baseline to Week 12 in Lipoprotein-a | 7.78 percent change in Lipoprotein-a | Standard Error 3.895 |
| Ezetimibe | Percent Change From Baseline to Week 12 in Lipoprotein-a | 0.68 percent change in Lipoprotein-a | Standard Error 3.704 |
Secondary
Percent Change From Baseline to Week 12 in Non HDL-C
The MMRM was used for the LS Mean estimates at Week 12 for Non HDL-C adjusting for baseline as response variables, baseline measurement as a covariate, treatment, visit, and treatment-by-visit interaction as fixed effects, and participant as a random effect.
Time frame: Baseline, Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Evacetrapib | Percent Change From Baseline to Week 12 in Non HDL-C | -22.01 percent change in non HDL-C | Standard Error 2.455 |
| Placebo | Percent Change From Baseline to Week 12 in Non HDL-C | -6.42 percent change in non HDL-C | Standard Error 2.577 |
| Ezetimibe | Percent Change From Baseline to Week 12 in Non HDL-C | -27.35 percent change in non HDL-C | Standard Error 2.468 |