CLEAR Program
The bempedoic acid clinical development program (CLEAR) is a large, scientifically rigorous clinical research initiative that has enrolled >60,000 patients across more than 30 countries investigating the role of bempedoic acid in the management of LDL-C and cardiovascular events.
Ongoing studies are actively enrolling to better understand the role of bempedoic acid in diverse populations such as pregnant and lactating women and pediatrics.
Please visit clinicaltrials.gov for more information on clinical trials.
Cardiovascular Outcomes Trial
The global cardiovascular outcomes trial (CVOT), called CLEAR (Cholesterol Lowering via bempedoic acid, an ACL-Inhibiting Regimen) Outcomes, was a first-of-its-kind CVOT in patients who are unable to take recommended statin therapy, including no statin to determine the effect of bempedoic acid on the primary composite endpoint of major adverse cardiac events (MACE-4) (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).
CLEAR Outcomes was a Phase 3, event-driven, randomized, multicenter, double-blind, placebo-controlled trial designed to evaluate whether daily treatment with 180 mg bempedoic acid vs placebo reduces the risk of cardiovascular events. The primary endpoint of the study is the effect of bempedoic acid on MACE-4. The study enrolled 13,970 patients at over 1,200 sites in 32 countries.1-2
The CLEAR Outcomes study accumulated the targeted 1,620 primary MACE-4 and the study met its primary endpoint, demonstrating statistically significant results. Full study results were presented at the American College of Cardiology Scientific Sessions and simultaneously published in the New England Journal of Medicine on March 4, 2023.
For a comprehensive overview of inclusion and exclusion criteria, and endpoint information, please see the study description on clinicaltrials.gov.
CLEAR Outcomes Trial Facts
Completed enrollment in August 2019 2
Comprised of >1,200 sites in 32 countries 2
48% female 2
13,970
patients 2
Patient Characteristics2
| Baseline LDL-C | Percentage |
| <130mg/dL | 44.1% |
| 130-<160 mg/dL | 31.9% |
| ≥160 mg/dL | 24.0% |
Mean baseline LDL-C 139.0+/-35.1 mg/dL
Mean subject age at time of
enrollment 65.5±9.0 years
Key criteria for enrolled subjects:
- Established cardiovascular disease or at high risk for developing cardiovascular disease
- Documented statin intolerance
- LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy
Primary Endpoint
Time to first occurrence of any component of the major adverse cardiovascular event composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.
References:
- Ruscica M, Banach M, Sahebkar A, Corsini A, Sirtori CR. ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials. Exp Opin Pharmacother. 2019.
- Nicholls, SJ et al. Rationale and design of the CLEAR-outcomes trial: Evaluating the Effect of bempedoic acid on cardiovascular events in patients with statin intolerance. Am Heart J 2021;235:104-112.
- Nissen SE, et al. N Engl J Med. 2023;388(15):1353-1364.
- NEXLETOL® (bempedoic acid) US Full Prescribing Information.
- Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA. 2023 Jul 11;330(2):131-140.
- Data on file. 1002-043. Esperion Therapeutics Inc.
- Suppl to Nissen SE, et. al. JAMA. 2023 Jul 11;330(2):131-140.
CLEAR Outcomes: Use of Bempedoic Acid in Patients with, or at High Risk, of Atherosclerotic Cardiovascular Disease
INDICATION 4
Bempedoic acid (NEXLETOL®) is indicated:
- To reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) and with:
- established cardiovascular disease (CVD), or
- at high risk for a CVD event but without established CVD.
- As an adjunct to diet, in combination with other LDL-C lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.
Please see full prescribing information for NEXLETOL.
Primary composite endpoint, MACE-4:
CV death, nonfatal MI, nonfatal stroke or coronary revascularization
Bempedoic acid: 819/6992 (11.7%) vs. Placebo: 927/6978 (13.3%)
Hazard ratio= 0.87
95%-CI: 0.79-0.96 P=0.004
MACE-3 and Components of Primary Composite Endpoint 3
Click here to download the primary analysis study summary.
Summary of Safety 4
NEXLETOL is contraindicated in patients with a prior serious hypersensitivity reaction to bempedoic acid or any of the excipients. Serious hypersensitivity reactions, such as angioedema, have occurred.
Hyperuricemia: NEXLETOL may increase blood uric acid levels, which may lead to gout. Hyperuricemia may occur early in treatment and persist throughout treatment, returning to baseline following discontinuation of treatment. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.
Tendon Rupture: NEXLETOL is associated with an increased risk of tendon rupture or injury. Tendon rupture may occur more frequently in patients with previous tendon rupture, fluoroquinolone use, corticosteroid use, and over 60 years of age. Discontinue NEXLETOL at the first sign of tendon rupture. Consider alternative therapy in patients who have a history of tendon disorders or tendon rupture.
The most common adverse reactions in the primary hyperlipidemia trials of NEXLETOL in ≥2% of patients and greater than placebo were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.
Concomitant use of NEXLETOL with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided due to the potential for increased risk of simvastatin- or pravastatin-related myopathy.
Discontinue NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Because of the potential for serious adverse reactions in a breast-fed infant, breastfeeding is not recommended during treatment with NEXLETOL.
Report pregnancies to Esperion Therapeutics, Inc. Adverse Event reporting line at 1-833-377-7633.
CLEAR Outcomes: Primary Prevention Subgroup, A Prespecified, Exploratory Analysis of Bempedoic Acid in Patients at High Risk for CVD
Limitations
- This is a secondary analysis of a subpopulation in a larger randomized trial, such analyses can result in false-positive findings due to testing of multiple subgroups and may represent a play of chance.
- The sample size represented a fraction of the total enrolled population and the number of events was smaller resulting in wider confidence intervals.
- The inclusion of patients who reported inability to tolerate statins resulted in a high mean baseline LDL-C level. The effects of cholesterol lowering on cardiovascular events in populations with lower pretreatment LDL-C was not studied.
- The trial selected patients using specific criteria for a high level of risk of a first cardiac event. Whether outcomes would be similar in patients identified using other criteria for an increased risk remains uncertain.
Primary composite endpoint, MACE-4:
CV death, nonfatal MI, nonfatal stroke or coronary revascularization
Bempedoic acid: 111/2100 (5.3%) vs Placebo: 161/2106 (7.6%)
Hazard Ratio= 0.68
95% CI: 0.53-0.87
MACE-3 and Components of Primary Composite Endpoint
in Primary Prevention Subanalysis 5,6,7
* All results are hypothesis generating and are descriptive in nature instead of confirmatory. Multiplicity is not adjusted/corrected.
Click here to download the primary prevention subanalysis study summary.
Summary of Safety 4
NEXLETOL is contraindicated in patients with a prior serious hypersensitivity reaction to bempedoic acid or any of the excipients. Serious hypersensitivity reactions, such as angioedema, have occurred.
Hyperuricemia: NEXLETOL may increase blood uric acid levels, which may lead to gout. Hyperuricemia may occur early in treatment and persist throughout treatment, returning to baseline following discontinuation of treatment. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.
Tendon Rupture: NEXLETOL is associated with an increased risk of tendon rupture or injury. Tendon rupture may occur more frequently in patients with previous tendon rupture, fluoroquinolone use, corticosteroid use, and over 60 years of age. Discontinue NEXLETOL at the first sign of tendon rupture. Consider alternative therapy in patients who have a history of tendon disorders or tendon rupture.
The most common adverse reactions in the primary hyperlipidemia trials of NEXLETOL in ≥2% of patients and greater than placebo were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.
Concomitant use of NEXLETOL with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided due to the potential for increased risk of simvastatin- or pravastatin-related myopathy.
Discontinue NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Because of the potential for serious adverse reactions in a breast-fed infant, breastfeeding is not recommended during treatment with NEXLETOL.
Report pregnancies to Esperion Therapeutics, Inc. Adverse Event reporting line at 1-833-377-7633.