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.

Click here for the latest publication. 

Ongoing studies are actively enrolling to better understand the role of bempedoic acid in diverse populations such as pregnant and lactating women, end stage renal disease and pediatrics.

Please visit clinicaltrials.gov for more information on clinical trials.

Cardiovascular Outcomes Trial

Our global cardiovascular outcomes trial (CVOT), called CLEAR (Cholesterol Lowering via bempedoic acid, an ACL-Inhibiting Regimen) Outcomes, is a first-of-its-kind CVOT in patients with statin intolerance to determine the effect of bempedoic acid on the MACE-4 composite endpoint.

CLEAR Outcomes is a Phase 3, event-driven, randomized, multicenter, double-blind, placebo-controlled trial designed to evaluate whether treatment with bempedoic acid reduces the risk of cardiovascular events. The primary endpoint of the study is the effect of bempedoic acid on four-component major adverse cardiovascular events (MACE). The study enrolled nearly 14,000 patients at over 1,200 sites in 32 countries.1-2

The CLEAR Outcomes study accumulated the targeted 1,620 primary major adverse cardiovascular events (MACE-4) (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) and the study met its primary endpoint, demonstrating statistically significant and clinically meaningful 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

Comprised of >1,200 sites in 32 countries

48.2% female

Nearly 14,000
patients

Patient Characteristics

Baseline LDL-CPercentage
<130mg/dL44.1%
130-<160 mg/dL31.9%
≥160 mg/dL24.0%

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:

  1. Established atherosclerotic cardiovascular disease (ASCVD) or a high risk for developing ASCVD
  2. Documented statin intolerance
  3. 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:

  1. 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.
  2. 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.
Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients

Publication

Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA. 330(2):131-140.

Trial ID: NCT02993406

PMID: 37354546

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients

Publication

Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023;388:1353-1364.

Trial ID: NCT02993406

PMID: 36876740

CLEAR Outcomes Rationale and Design*

Background

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied.

Study design

Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months.

Conclusions

CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.

*Language is verbatim from publication abstract.

Publication:

Nicholls S, Lincoff AM, Bays HE, et al. Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of Bempedoic acid on cardiovascular events in patients with statin intolerance. American Heart Journal 2021 May 1;235:104-12.

Trial ID: NCT02993406

PMID: 33470195

Bempedoic acid is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

Limitation of use: The effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined.

CLEAR Wisdom*

Importance

Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies.

Objective

To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy.

Design, Setting, and Participants

Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy.

Interventions

Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks.

Main Outcomes and Measures

The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers.

Results

Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (–15.1% vs 2.4%, respectively; difference, –17.4% [95% CI, –21.0% to –13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non–high-density lipoprotein cholesterol (–10.8% vs 2.3%; difference, –13.0% [95% CI, –16.3% to –9.8%]; P < .001), total cholesterol (–9.9% vs 1.3%; difference, –11.2% [95% CI, –13.6% to –8.8%]; P < .001), apolipoprotein B (–9.3% vs 3.7%; difference, –13.0% [95% CI, –16.1% to –9.9%]; P < .001), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%; difference, –8.7% [asymptotic confidence limits, –17.2% to –0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%).

Conclusions and Relevance

Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety.

Nexletol® (bempedoic acid) is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

Limitations of Use 

The effect of Nexletol on cardiovascular morbidity and mortality has not been determined.

Safety Information 

Elevations in serum uric acid have occurred. Access 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 has occurred. Discontinue Nexletol at the first sign of tendon rupture. Avoid Nexletol in patients who have a history of tendon disorders or tendon rupture.

The most common adverse reactions in >=2% of patients and greater than placebo include upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia and elevated liver enzymes.

Publication:

Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019;322(18):1780–1788.

Trial ID: NCT02991118

PMID: 31714986

*Language is verbatim from publication abstract.

CLEAR Harmony*

Background

Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.

Methods

We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks.

Results

The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of −16.5% from baseline (difference vs. placebo in change from baseline, –18.1 percentage points; 95% confidence interval, –20.0 to –16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.

Conclusions

In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. 

Nexletol® (bempedoic acid) is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

Limitations of Use 

The effect of Nexletol on cardiovascular morbidity and mortality has not been determined.

Safety Information 

Elevations in serum uric acid have occurred. Assess serum 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 has occurred. Discontinue Nexletol at the first sign of tendon rupture. Avoid Nexletol in patients who have a history of tendon disorders or tendon rupture.

The most common adverse reactions in >=2% of patients and greater than placebo include upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia and elevated liver enzymes.

Publication:

Ray KK, Bays HE, Catapano AL, et al.  Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019;380:1022-32.

Trial ID: NCT02666664

PMID: 30865796

*Language is verbatim from publication abstract.

CLEAR Tranquility

Publication

Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018;277:195-203.

Trial ID: NCT03001076

PMID: 29910030

CLEAR Serenity

Publication

Laufs U, Banach M, Mancini J, et al.  Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance.  Am Heart Assoc. 2019;8:e011662. 

Trial ID: NCT02988115

PMID: 30922146

CLEAR Harmony Open-Label Extension (OLE)

Publication

Ballantyne CM, Banach M, Bays HE, et al. Long-Term Safety and Efficacy of Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study). Am J Cardiol 2022;174:1−11.

Trial ID: NCT03067441

PMID: 35483979

CLEAR Pooled Analysis

Publication

Bays HE, Banach M, Catapano AL, et al. Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials. J Clin Lipidol. 2020;14(5):649-659.e6.

Trial IDs: NCT02666664NCT03001076; NCT02988115; NCT02991118

PMID: 35346603

Bempedoic Acid and Ezetimibe Fixed-Dose Combination

Publication

Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. E Pub; July 29, 2019.

Trial ID: NCT03337308

PMID: 31357887

For more information on bempedoic acid and how to access these publications, please click here.

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