Atherosclerotic Cardiovascular Disease, Hypercholesterolemia, Statin Adverse Reaction
Conditions
Keywords
hyperlipidemia, cholesterol, familial hypercholesterolemia, atherosclerotic cardiovascular disease, ASCVD, HeFH, LDL, statin intolerance
Brief summary
The purpose of this study is to determine if bempedoic acid (ETC-1002) is effective and safe versus placebo in patients with elevated LDL cholesterol and who are statin-intolerant.
Interventions
DRUGbempedoic acid
bempedoic acid 180 mg tablet
OTHERplacebo
Matching placebo tablet
Sponsors
Esperion Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Require lipid-modifying therapy for primary or secondary prevention of cardiovascular disease * Fasting LDL-C ≥130 mg/dL for primary prevention or LDL-C ≥100 mg/dL for secondary prevention (history of HeFH and/or ASCVD) * Be statin-intolerant (unable to tolerate 2 or more statins)
Exclusion criteria
* Total fasting triglyceride ≥500 mg/dL * Renal dysfunction or nephrotic syndrome or history of nephritis * Body Mass Index (BMI) ≥50 kg/m2 * Significant cardiovascular disease or cardiovascular event in the past 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline (PCFB) in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline; Week 12 | PCFB was calculated as the (\[post-Baseline (BL) value minus the BL value\] divided by the BL value ) x 100. BL was defined as the mean of the last two non-missing values on or prior to Day 1. If only one value was available, that single value was used as BL. PCFB in LDL-C was analyzed using analysis of covariance (ANCOVA), with treatment group and stratification factor (primary prevention; secondary prevention) as fixed effects and BL as a covariate. For participants with missing lipid data at Week 12 who were no longer taking study treatment, missing values were imputed using multiple imputation via a regression-based model including stratification and BL data from placebo participants only. In this imputation model, treatment group was not included. For participants with missing lipid data at Week 12 who were still taking study treatment, missing values were imputed using multiple imputation via a regression-based model including treatment, stratification and BL value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LDL-C at Week 24 | Baseline; Week 24 | PCFB was calculated as the (\[post-BL value minus the BL value\] divided by the BL value ) x 100. BL was defined as the mean of the last two non-missing values on or prior to Day 1. If only one value was available then that single value was used as BL. PCFB in LDL-C was analyzed using ANCOVA, with treatment group and stratification factor (primary prevention; secondary prevention) as fixed effects and BL as a covariate. For participants with missing lipid data at Week 12 who were no longer taking study treatment, missing values were imputed using multiple imputation via a regression-based model including stratification and BL data from placebo participants only. In this imputation model, treatment group was not included. For participants with missing lipid data at Week 12 who were still taking study treatment, missing values were imputed using multiple imputation via a regression-based model including treatment, stratification and BL value. |
| Percent Change From Baseline in the Lipid Profile at Week 12 | Baseline; Week 12 | PCFB was calculated as: (\[post-BL value minus the BL value\] divided by the BL value) x 100. BL was defined as the mean of the last two non-missing values on or prior to Day 1. If only one value was available, that single value was used as BL. apoB and TC BL were defined as the last non-missing value on/prior to Day 1. PCFB was analyzed using ANCOVA, with treatment and group stratification factor (primary prevention; secondary prevention) as fixed effects and BL as a covariate. For participants with missing data at Week 12 who were no longer taking study treatment (ST), missing values were imputed using multiple imputation via a regression-based model including stratification and BL data from placebo participants only. In this imputation model, treatment group was not included. For participants with missing lipid data at Week 12 who were still taking ST, missing values were imputed using multiple imputation via a regression-based model including treatment, stratification and BL value. |
| Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12 | Baseline; Week 12 | Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. Baseline for hsCRP is defined as the last non-missing value on or prior to Day 1. Percent change from Baseline in hsCRP, non-parametric (Wilcoxon rank-sum test) analysis with Hodges-Lehmann estimates and confidence interval was performed. |
| Absolute Change From Baseline in LDL-C at Week 12 and Week 24 | Baseline; Week 12; Week 24 | Change from Baseline is calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value ) x 100. Baseline is defined as the mean of the last two non-missing values on or prior to Day 1. |
Countries
Canada, United States
Participant flow
Recruitment details
602 participants were screened; out of 602, 345 participants were randomized. 76 participants discontinued investigational medicinal product (IMP), and 18 participants withdrew from the study.
Participants by arm
| Arm | Count |
|---|---|
| Bempedoic Acid Participants received bempedoic acid 180 milligram (mg) tablet taken orally once a day. | 234 |
| Placebo Participants received matching oral placebo once a day. | 111 |
| Total | 345 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Sponsor Decision | 5 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
| Overall Study | Withdrawn by Mistake | 1 | 0 |
Baseline characteristics
| Characteristic | Bempedoic Acid | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65.2 Years STANDARD_DEVIATION 9.66 | 65.1 Years STANDARD_DEVIATION 9.21 | 65.2 Years STANDARD_DEVIATION 9.5 |
| Baseline Apolipoprotein B (apoB) | 141.0 mg/dL STANDARD_DEVIATION 31.64 | 141.9 mg/dL STANDARD_DEVIATION 30.44 | 141.3 mg/dL STANDARD_DEVIATION 31.22 |
| Baseline High-Sensitivity C-Reactive Protein (hsCRP) Values | 2.920 milligrams per liter (mg/L) | 2.780 milligrams per liter (mg/L) | 2.900 milligrams per liter (mg/L) |
| Baseline LCL-C, Non-HDL-C, TC, HDL-C, and TG Values HDL-C | 52.17 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 14.535 | 50.41 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 14.384 | 51.60 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 14.489 |
| Baseline LCL-C, Non-HDL-C, TC, HDL-C, and TG Values LDL-C | 158.48 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 40.387 | 155.58 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 38.812 | 157.55 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 39.854 |
| Baseline LCL-C, Non-HDL-C, TC, HDL-C, and TG Values Non-HDL-C | 193.49 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 45.101 | 190.69 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 43.781 | 192.59 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 44.637 |
| Baseline LCL-C, Non-HDL-C, TC, HDL-C, and TG Values TC | 245.66 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 47.252 | 241.09 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 44.289 | 244.19 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 46.304 |
| Baseline LCL-C, Non-HDL-C, TC, HDL-C, and TG Values TG | 178.96 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 87.522 | 186.62 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 96.203 | 181.42 milligrams per deciliter (mg/dL) STANDARD_DEVIATION 90.336 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 10 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 211 Participants | 96 Participants | 307 Participants |
| Sex: Female, Male Female | 133 Participants | 61 Participants | 194 Participants |
| Sex: Female, Male Male | 101 Participants | 50 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 234 | 0 / 111 |
| other Total, other adverse events | 88 / 234 | 45 / 111 |
| serious Total, serious adverse events | 14 / 234 | 4 / 111 |
Outcome results
Primary
Percent Change From Baseline (PCFB) in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12
PCFB was calculated as the (\[post-Baseline (BL) value minus the BL value\] divided by the BL value ) x 100. BL was defined as the mean of the last two non-missing values on or prior to Day 1. If only one value was available, that single value was used as BL. PCFB in LDL-C was analyzed using analysis of covariance (ANCOVA), with treatment group and stratification factor (primary prevention; secondary prevention) as fixed effects and BL as a covariate. For participants with missing lipid data at Week 12 who were no longer taking study treatment, missing values were imputed using multiple imputation via a regression-based model including stratification and BL data from placebo participants only. In this imputation model, treatment group was not included. For participants with missing lipid data at Week 12 who were still taking study treatment, missing values were imputed using multiple imputation via a regression-based model including treatment, stratification and BL value.
Time frame: Baseline; Week 12
Population: The Full Analysis Set (FAS), also known as the intention-to-treat (ITT) set of participants, is defined as all randomized participants. Participants were included in their randomized treatment group, regardless of the treatment they actually received. Only those participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid | Percent Change From Baseline (PCFB) in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12 | -22.58 percent change | Standard Error 1.29 |
| Placebo | Percent Change From Baseline (PCFB) in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12 | -1.17 percent change | Standard Error 1.421 |
p-value: <0.00195% CI: [-25.132, -17.697]ANCOVA
Secondary
Absolute Change From Baseline in LDL-C at Week 12 and Week 24
Change from Baseline is calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value ) x 100. Baseline is defined as the mean of the last two non-missing values on or prior to Day 1.
Time frame: Baseline; Week 12; Week 24
Population: FAS. Only those participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bempedoic Acid | Absolute Change From Baseline in LDL-C at Week 12 and Week 24 | Week 12 | -39.3 mg/dL | Standard Deviation 33.37 |
| Bempedoic Acid | Absolute Change From Baseline in LDL-C at Week 12 and Week 24 | Week 24 | -37.0 mg/dL | Standard Deviation 35.27 |
| Placebo | Absolute Change From Baseline in LDL-C at Week 12 and Week 24 | Week 12 | -3.1 mg/dL | Standard Deviation 23.66 |
| Placebo | Absolute Change From Baseline in LDL-C at Week 12 and Week 24 | Week 24 | -5.1 mg/dL | Standard Deviation 26.5 |
Secondary
Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] divided by the Baseline value) x 100. Baseline for hsCRP is defined as the last non-missing value on or prior to Day 1. Percent change from Baseline in hsCRP, non-parametric (Wilcoxon rank-sum test) analysis with Hodges-Lehmann estimates and confidence interval was performed.
Time frame: Baseline; Week 12
Population: FAS. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bempedoic Acid | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12 | -25.37 percent change |
| Placebo | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12 | 2.67 percent change |
p-value: <0.00195% CI: [-35.888, -12.712]Wilcoxon rank sum test
Secondary
Percent Change From Baseline in LDL-C at Week 24
PCFB was calculated as the (\[post-BL value minus the BL value\] divided by the BL value ) x 100. BL was defined as the mean of the last two non-missing values on or prior to Day 1. If only one value was available then that single value was used as BL. PCFB in LDL-C was analyzed using ANCOVA, with treatment group and stratification factor (primary prevention; secondary prevention) as fixed effects and BL as a covariate. For participants with missing lipid data at Week 12 who were no longer taking study treatment, missing values were imputed using multiple imputation via a regression-based model including stratification and BL data from placebo participants only. In this imputation model, treatment group was not included. For participants with missing lipid data at Week 12 who were still taking study treatment, missing values were imputed using multiple imputation via a regression-based model including treatment, stratification and BL value.
Time frame: Baseline; Week 24
Population: FAS. Only those participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bempedoic Acid | Percent Change From Baseline in LDL-C at Week 24 | -21.17 percent change | Standard Error 1.411 |
| Placebo | Percent Change From Baseline in LDL-C at Week 24 | -2.26 percent change | Standard Error 1.552 |
p-value: <0.00195% CI: [-22.951, -14.865]ANCOVA
Secondary
Percent Change From Baseline in the Lipid Profile at Week 12
PCFB was calculated as: (\[post-BL value minus the BL value\] divided by the BL value) x 100. BL was defined as the mean of the last two non-missing values on or prior to Day 1. If only one value was available, that single value was used as BL. apoB and TC BL were defined as the last non-missing value on/prior to Day 1. PCFB was analyzed using ANCOVA, with treatment and group stratification factor (primary prevention; secondary prevention) as fixed effects and BL as a covariate. For participants with missing data at Week 12 who were no longer taking study treatment (ST), missing values were imputed using multiple imputation via a regression-based model including stratification and BL data from placebo participants only. In this imputation model, treatment group was not included. For participants with missing lipid data at Week 12 who were still taking ST, missing values were imputed using multiple imputation via a regression-based model including treatment, stratification and BL value.
Time frame: Baseline; Week 12
Population: FAS. Only those participants with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Bempedoic Acid | Percent Change From Baseline in the Lipid Profile at Week 12 | non-HDL-C | -18.08 percent change | Standard Error 1.114 |
| Bempedoic Acid | Percent Change From Baseline in the Lipid Profile at Week 12 | TC | -15.37 percent change | Standard Error 0.879 |
| Bempedoic Acid | Percent Change From Baseline in the Lipid Profile at Week 12 | apoB | -14.65 percent change | Standard Error 1.08 |
| Placebo | Percent Change From Baseline in the Lipid Profile at Week 12 | non-HDL-C | -0.14 percent change | Standard Error 1.169 |
| Placebo | Percent Change From Baseline in the Lipid Profile at Week 12 | TC | -0.61 percent change | Standard Error 0.961 |
| Placebo | Percent Change From Baseline in the Lipid Profile at Week 12 | apoB | 0.32 percent change | Standard Error 1.177 |
Comparison: non-HDL-Cp-value: <0.00195% CI: [-21.07, -14.811]ANCOVA
Comparison: TCp-value: <0.00195% CI: [-17.283, -12.239]ANCOVA
Comparison: apoBp-value: <0.00195% CI: [-18.062, -11.866]ANCOVA