Hyperlipidemia
Conditions
Brief summary
The purpose of the ACCENTUATE study is to evaluate whether the study drug known as evacetrapib is effective in treating participants with high cholesterol and atherosclerotic cardiovascular disease (ASCVD) and/or diabetes.
Interventions
DRUGEvacetrapib
Administered orally
DRUGAtorvastatin
Administered orally
DRUGEzetimibe
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be treated with atorvastatin 40 mg/day for at least 30 days prior to screening * Have an LDL-C \>70 mg/deciliter(dL) or non-HDL-C \>100 mg/dL * Have screening triglycerides ≤400 mg/dL (≤4.5 millimoles/Liter) * Individuals with ASCVD and/or individuals with type 1 or type 2 diabetes
Exclusion criteria
* Have a hemoglobin A1c (HbA1c) \>9.5% * New York Heart Association (NYHA) class III or IV congestive heart failure * History of either a transient ischemic stroke or ischemic stroke \<30 days * History of acute coronary syndrome (ACS) \<30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to 3 Months in Low-Density Lipoprotein Cholesterol (LDL-C) | Baseline, 3 Months | Change in LDL-C levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. LDL-C was measured by beta quantification. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. Least Square Means (LS means) and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to 3 Months in Apolipoprotein AI (apoAI) | Baseline, 3 Months | Change in apoAI levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable. |
| Percent Change From Baseline to 3 Months in Non-HDL-C | Baseline, 3 Months | Change in Non-HDL-C levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. LS medians and median differences were analyzed in log units and converted to standard units. Statistics are from mixed model repeated measures analysis with log baseline measurement, treatment, visit, and treatment by visit interaction included in the model. Log percent change from baseline response is the dependent variable. Within-participant repeated measures at multiple visits are modeled by a compound symmetry covariance structure. |
| Percent Change From Baseline to 3 Months in High-Density Lipoprotein Cholesterol (HDL-C) | Baseline, 3 Months | Change in HDL-C levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. LS medians and median differences were analyzed in log units and converted to standard units. Statistics are from mixed model repeated measures analysis with log baseline measurement, treatment, visit, and treatment by visit interaction included in the model. Log percent change from baseline response is the dependent variable. Within-participant repeated measures at multiple visits are modeled by a compound symmetry covariance structure. |
| Percent Change From Baseline to 3 Months in Cholesterol Efflux Capacity | Baseline, 3 Months | Change in cholesterol efflux capacity from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable. |
| Percent Change From Baseline to 3 Months in Lipoprotein(a) (Lp[a]) | Baseline, 3 Months | Change in Lp(a) levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable. |
| Percent Change From Baseline to 3 Months in Apolipoprotein B (apoB) | Baseline, 3 Months | Change in apoB levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin + Evacetrapib Atorvastatin 40 mg orally once daily for 28 days during lead in period. Atorvastatin 40 mg plus evacetrapib 130 mg with placebo for blinding orally once daily for 90 days. Open label extension (atorvastatin 40 mg plus evacetrapib 130 mg) is available for compliant participants. | 123 |
| Atorvastatin 40 mg Atorvastatin 40 mg orally once daily for 28 days during lead in period. Atorvastatin 40 mg with placebo for blinding orally once daily for 90 days. Open label extension (atorvastatin 40 mg plus evacetrapib 130 mg) is available for compliant participants. | 54 |
| Atorvastatin 80 mg Atorvastatin 40 mg orally once daily for 28 days during lead in period. Atorvastatin 80 mg orally with placebo for blinding once daily for 90 days. Open label extension (atorvastatin 40 mg plus evacetrapib 130 mg) is available for compliant participants. | 62 |
| Atorvastatin + Ezetimibe Atorvastatin 40 mg orally once daily for 28 days during lead in period. Atorvastatin 40 mg plus ezetimibe 10 mg with placebo for blinding orally once daily for 90 days. Open label extension (atorvastatin 40 mg plus evacetrapib 130 mg) is available for compliant participants. | 127 |
| Total | 366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Double-Blind Phase | Adverse Event | 3 | 2 | 1 | 3 | 0 |
| Double-Blind Phase | Physician Decision | 1 | 0 | 0 | 1 | 0 |
| Double-Blind Phase | Protocol Violation | 0 | 0 | 1 | 1 | 0 |
| Double-Blind Phase | Sponsor Decision | 34 | 15 | 14 | 32 | 0 |
| Double-Blind Phase | Withdrawal by Subject | 2 | 1 | 5 | 2 | 0 |
| Open-Label Extension Phase (OLE) | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| Open-Label Extension Phase (OLE) | Death | 0 | 0 | 0 | 0 | 1 |
| Open-Label Extension Phase (OLE) | Sponsor Decision | 0 | 0 | 0 | 0 | 243 |
| Open-Label Extension Phase (OLE) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Atorvastatin + Evacetrapib | Total | Atorvastatin + Ezetimibe | Atorvastatin 80 mg | Atorvastatin 40 mg |
|---|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 8.7 | 63.4 years STANDARD_DEVIATION 9.2 | 64.7 years STANDARD_DEVIATION 8.9 | 61.7 years STANDARD_DEVIATION 10.2 | 62.7 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 38 Participants | 13 Participants | 9 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 110 Participants | 328 Participants | 114 Participants | 53 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 6 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 56 Participants | 14 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 5 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 97 Participants | 297 Participants | 110 Participants | 46 Participants | 44 Participants |
| Region of Enrollment United States | 123 Participants | 366 Participants | 127 Participants | 62 Participants | 54 Participants |
| Sex: Female, Male Female | 38 Participants | 124 Participants | 53 Participants | 18 Participants | 15 Participants |
| Sex: Female, Male Male | 85 Participants | 242 Participants | 74 Participants | 44 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 123 | 5 / 54 | 4 / 62 | 5 / 127 | 9 / 247 |
| serious Total, serious adverse events | 2 / 123 | 3 / 54 | 3 / 62 | 3 / 127 | 11 / 247 |
Outcome results
Primary
Percent Change From Baseline to 3 Months in Low-Density Lipoprotein Cholesterol (LDL-C)
Change in LDL-C levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. LDL-C was measured by beta quantification. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. Least Square Means (LS means) and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable.
Time frame: Baseline, 3 Months
Population: All randomized participants who had evaluable LDL-C data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in Low-Density Lipoprotein Cholesterol (LDL-C) | -33.44 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in Low-Density Lipoprotein Cholesterol (LDL-C) | 0.04 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in Low-Density Lipoprotein Cholesterol (LDL-C) | -6.19 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in Low-Density Lipoprotein Cholesterol (LDL-C) | -27.30 percent |
p-value: <0.00195% CI: [-44.4, -23.3]ANCOVA
p-value: <0.00195% CI: [-36.6, -18.5]ANCOVA
p-value: 0.04595% CI: [-12.2, -0.22]ANCOVA
Secondary
Percent Change From Baseline to 3 Months in Apolipoprotein AI (apoAI)
Change in apoAI levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable.
Time frame: Baseline, 3 Months
Population: All randomized participants with evaluable apoAI data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in Apolipoprotein AI (apoAI) | 46.08 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in Apolipoprotein AI (apoAI) | -0.27 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in Apolipoprotein AI (apoAI) | -6.14 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in Apolipoprotein AI (apoAI) | -2.36 percent |
p-value: <0.00195% CI: [40.79, 51.98]ANCOVA
p-value: <0.00195% CI: [47.12, 57.33]ANCOVA
p-value: <0.00195% CI: [43.82, 52.86]ANCOVA
Secondary
Percent Change From Baseline to 3 Months in Apolipoprotein B (apoB)
Change in apoB levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable.
Time frame: Baseline, 3 Months
Population: All randomized participants who had evaluable apoB data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in Apolipoprotein B (apoB) | -22.96 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in Apolipoprotein B (apoB) | 0.21 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in Apolipoprotein B (apoB) | -6.54 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in Apolipoprotein B (apoB) | -18.84 percent |
p-value: <0.00195% CI: [-30, -16.5]ANCOVA
p-value: <0.00195% CI: [-22.3, -10.6]ANCOVA
p-value: 0.06295% CI: [-8.47, 0.15]ANCOVA
Secondary
Percent Change From Baseline to 3 Months in Cholesterol Efflux Capacity
Change in cholesterol efflux capacity from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable.
Time frame: Baseline, 3 Months
Population: All randomized participants who had evaluable cholesterol efflux capacity
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in Cholesterol Efflux Capacity | 35.09 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in Cholesterol Efflux Capacity | -2.96 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in Cholesterol Efflux Capacity | -7.03 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in Cholesterol Efflux Capacity | -4.55 percent |
p-value: <0.00195% CI: [30.17, 45.88]ANCOVA
p-value: <0.00195% CI: [34.29, 49.76]ANCOVA
p-value: <0.00195% CI: [33.2, 46.08]ANCOVA
Secondary
Percent Change From Baseline to 3 Months in High-Density Lipoprotein Cholesterol (HDL-C)
Change in HDL-C levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. LS medians and median differences were analyzed in log units and converted to standard units. Statistics are from mixed model repeated measures analysis with log baseline measurement, treatment, visit, and treatment by visit interaction included in the model. Log percent change from baseline response is the dependent variable. Within-participant repeated measures at multiple visits are modeled by a compound symmetry covariance structure.
Time frame: Baseline, 3 Months
Population: All randomized participants who had evaluable HDL-C data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in High-Density Lipoprotein Cholesterol (HDL-C) | 125.39 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in High-Density Lipoprotein Cholesterol (HDL-C) | 0.11 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in High-Density Lipoprotein Cholesterol (HDL-C) | -6.10 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in High-Density Lipoprotein Cholesterol (HDL-C) | -2.18 percent |
p-value: <0.00195% CI: [117.1, 133.6]Mixed Models Analysis
p-value: <0.00195% CI: [123.5, 139.5]Mixed Models Analysis
p-value: <0.00195% CI: [120.1, 135]Mixed Models Analysis
Secondary
Percent Change From Baseline to 3 Months in Lipoprotein(a) (Lp[a])
Change in Lp(a) levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. Statistics are from analysis of covariance with log baseline measurement and treatment is included in the model. LS means and median differences were analyzed in log units and converted to standard units. Log Percent change from baseline response is the dependent variable.
Time frame: Baseline, 3 Months
Population: All randomized participants who had evaluable Lp(a) data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in Lipoprotein(a) (Lp[a]) | -28.73 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in Lipoprotein(a) (Lp[a]) | 4.45 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in Lipoprotein(a) (Lp[a]) | 3.90 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in Lipoprotein(a) (Lp[a]) | 13.42 percent |
p-value: <0.00195% CI: [-44.9, -22.3]ANCOVA
p-value: <0.00195% CI: [-44, -21.8]ANCOVA
p-value: <0.00195% CI: [-50.9, -33.4]ANCOVA
Secondary
Percent Change From Baseline to 3 Months in Non-HDL-C
Change in Non-HDL-C levels from baseline to the 3-month visit expressed as a percentage of the baseline levels. LS medians and median differences were analyzed in log units and converted to standard units. Statistics are from mixed model repeated measures analysis with log baseline measurement, treatment, visit, and treatment by visit interaction included in the model. Log percent change from baseline response is the dependent variable. Within-participant repeated measures at multiple visits are modeled by a compound symmetry covariance structure.
Time frame: Baseline, 3 Months
Population: All randomized participants who had evaluable non-HDL-C data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin + Evacetrapib | Percent Change From Baseline to 3 Months in Non-HDL-C | -31.42 percent |
| Atorvastatin 40 mg | Percent Change From Baseline to 3 Months in Non-HDL-C | -4.95 percent |
| Atorvastatin 80 mg | Percent Change From Baseline to 3 Months in Non-HDL-C | -9.40 percent |
| Atorvastatin + Ezetimibe | Percent Change From Baseline to 3 Months in Non-HDL-C | -24.37 percent |
p-value: <0.00195% CI: [-33.4, -20]Mixed Models Analysis
p-value: <0.00195% CI: [-28.4, -15.9]Mixed Models Analysis
p-value: <0.00195% CI: [-11.5, -2.68]Mixed Models Analysis