Cardiovascular Diseases, Statin Adverse Reaction
Conditions
Brief summary
The purpose of this study is to determine if treatment with bempedoic acid (ETC-1002) versus placebo decreases the risk of cardiovascular events in participants who have or are at high risk for cardiovascular disease and are statin intolerant.
Interventions
Patients take bempedoic acid 180 mg tablet orally once daily
Patients take matching placebo tablet orally once daily
Sponsors
The Cleveland Clinic
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 85 Years
Healthy volunteers
No
Inclusion criteria
* Age between 18 and 85 years * History of, or at high risk for, cardiovascular disease (CVD) including coronary artery disease, symptomatic peripheral arterial disease, cerebrovascular atherosclerotic disease, or at high risk for a cardiovascular event * Participant-reported SI due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued resulting in an inability to tolerate: * 2 or more statins at any dose, or * 1 statin at any dose and unwilling to attempt a second statin or advised by a physician to not attempt a second statin. Please note that participants currently tolerating very low dose statin therapy (an average daily dose of rosuvastatin \<5 mg, atorvastatin \<10 mg, simvastatin \<10 mg, lovastatin \<20 mg, pravastatin \<40 mg, fluvastatin \<40 mg, or pitavastatin \<2 mg) are considered to be intolerant to that low dose statin. Patients may continue taking very low dose statin therapy throughout the study provided that it is stable (used for at least 4 weeks prior to screening) and well tolerated. * Written confirmation by both participant and investigator that the participant is statin intolerant as defined above, aware of the benefit of statin use to reduce the risk of MACE including death, and also aware that many other participants who are unable to tolerate a statin are able to tolerate a different statin or dose. * Men and nonpregnant, nonlactating women * Fasting blood LDL-cholesterol ≥ 100 (2.6 mmol/L) at screening
Exclusion criteria
* Fasting blood triglycerides greater than 500 mg/dL (5.6 mmol/L) at screening * Recent (within 90 days of screening) history of major cardiovascular events, transient ischemic attack (TIA), or unstable or symptomatic cardiac arrhythmia * History of severe heart failure * Uncontrolled hypertension or uncontrolled diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE) | Up to 68 months | The primary efficacy end point was a four-component composite of adjudicated MACE, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, as assessed in a time-to first-event analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Time to Cardiovascular Death | Up to 68 months | Number of participants with time to cardiovascular death are presented. |
| Number of Participants With First Occurrence of Three Component MACE | Up to 68 months | The first key secondary end point was a three-component MACE, defined as death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. |
| Number of Participants With Time to First Occurrence of Stroke | Up to 68 months | Number of participants with time to first occurrence of fatal and non-fatal stroke. |
| Number of Participants With Time to First Occurrence of Coronary Revascularization | Up to 68 months | Number of participants with time to first occurrence of coronary revascularization are presented. |
| Number of Participants With Time to All-cause Mortality | Up to 68 months | All-cause mortality is death due to any cause. Number of participants with time to all-cause mortality are presented. |
| Number of Participants With First Occurrence of Myocardial Infarction | Up to 68 months | Number of participants with time to first occurrence of fatal and non-fatal myocardial infarction are presented. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, Estonia, Germany, Hungary, India, Latvia, Lithuania, Mexico, Netherlands, New Zealand, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This was a randomized, double-blind, placebo-controlled, parallel-group study that assessed the occurrence of major adverse cardiovascular event (MACE) in participants with, or at high risk for, cardiovascular disease (CVD) who were unable to tolerate statin therapy.
Pre-assignment details
A total of 13970 participants were enrolled from over 1250 sites in 32 countries.
Participants by arm
| Arm | Count |
|---|---|
| Bempedoic Acid 180 mg Participants were administered with Bempedoic acid 180 mg tablet once daily orally. | 6,992 |
| Placebo Comparator Participants were administered with matching Placebo tablet once daily orally. | 6,978 |
| Total | 13,970 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative decision | 1 | 0 |
| Overall Study | Lost to Follow-up | 12 | 13 |
| Overall Study | Physician Decision | 3 | 5 |
| Overall Study | Sponsor decision | 4 | 5 |
| Overall Study | Unclassifiable Response | 105 | 139 |
| Overall Study | Withdrawal by Subject | 170 | 196 |
Baseline characteristics
| Characteristic | Placebo Comparator | Total | Bempedoic Acid 180 mg |
|---|---|---|---|
| Age, Continuous | 65.5 Years STANDARD_DEVIATION 8.9 | 65.5 Years STANDARD_DEVIATION 9 | 65.5 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1143 Participants | 2333 Participants | 1190 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5835 Participants | 11637 Participants | 5802 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 247 Participants | 487 Participants | 240 Participants |
| Race (NIH/OMB) Asian | 136 Participants | 266 Participants | 130 Participants |
| Race (NIH/OMB) Black or African American | 172 Participants | 328 Participants | 156 Participants |
| Race (NIH/OMB) More than one race | 70 Participants | 118 Participants | 48 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 17 Participants | 37 Participants | 20 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 6335 Participants | 12732 Participants | 6397 Participants |
| Sex: Female, Male Female | 3379 Participants | 6740 Participants | 3361 Participants |
| Sex: Female, Male Male | 3599 Participants | 7230 Participants | 3631 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 437 / 7,001 | 420 / 6,964 |
| other Total, other adverse events | 5,805 / 7,001 | 5,490 / 6,964 |
| serious Total, serious adverse events | 1,767 / 7,001 | 1,733 / 6,964 |
Outcome results
Primary
Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE)
The primary efficacy end point was a four-component composite of adjudicated MACE, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, as assessed in a time-to first-event analysis.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE) | 819 Participants |
| Placebo Comparator | Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE) | 927 Participants |
p-value: 0.00495% CI: [0.79, 0.96]Log Rank
Secondary
Number of Participants With First Occurrence of Myocardial Infarction
Number of participants with time to first occurrence of fatal and non-fatal myocardial infarction are presented.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With First Occurrence of Myocardial Infarction | 261 Participants |
| Placebo Comparator | Number of Participants With First Occurrence of Myocardial Infarction | 334 Participants |
p-value: 0.001695% CI: [0.66, 0.91]Log Rank
Secondary
Number of Participants With First Occurrence of Three Component MACE
The first key secondary end point was a three-component MACE, defined as death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With First Occurrence of Three Component MACE | 575 Participants |
| Placebo Comparator | Number of Participants With First Occurrence of Three Component MACE | 663 Participants |
p-value: 0.005895% CI: [0.76, 0.96]Log Rank
Secondary
Number of Participants With Time to All-cause Mortality
All-cause mortality is death due to any cause. Number of participants with time to all-cause mortality are presented.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With Time to All-cause Mortality | 434 Participants |
| Placebo Comparator | Number of Participants With Time to All-cause Mortality | 420 Participants |
p-value: 0.660895% CI: [0.9, 1.18]Log Rank
Secondary
Number of Participants With Time to Cardiovascular Death
Number of participants with time to cardiovascular death are presented.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With Time to Cardiovascular Death | 269 Participants |
| Placebo Comparator | Number of Participants With Time to Cardiovascular Death | 257 Participants |
p-value: 0.622795% CI: [0.88, 1.24]Log Rank
Secondary
Number of Participants With Time to First Occurrence of Coronary Revascularization
Number of participants with time to first occurrence of coronary revascularization are presented.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With Time to First Occurrence of Coronary Revascularization | 435 Participants |
| Placebo Comparator | Number of Participants With Time to First Occurrence of Coronary Revascularization | 529 Participants |
p-value: 0.001395% CI: [0.72, 0.92]Log Rank
Secondary
Number of Participants With Time to First Occurrence of Stroke
Number of participants with time to first occurrence of fatal and non-fatal stroke.
Time frame: Up to 68 months
Population: Intention-to-Treat Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bempedoic Acid 180 mg | Number of Participants With Time to First Occurrence of Stroke | 135 Participants |
| Placebo Comparator | Number of Participants With Time to First Occurrence of Stroke | 158 Participants |
p-value: 0.159395% CI: [0.67, 1.07]Log Rank