Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance
Nicholls, Stephen J.; Lincoff, A. Michael; Bays, Harold E.; Cho, Leslie; Grobbee, Diederick E.; Kastelein, John JP; Libby, Peter; Moriarty, Patrick M.; Plutzky, Jorge; Ray, Kausik K.; Thompson, Paul D.; Sasiela, William; Mason, Denise; McCluskey, Jaclyn; Davey, Deborah; Wolski, Kathy; Nissen, Steven E.
(2021) American Heart Journal, volume 235, issue 5, pp. 104 - 112
(Article)
Abstract
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
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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.
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Keywords: Aged, Biomarkers/blood, Cardiovascular Diseases/blood, Cholesterol, LDL/blood, Dicarboxylic Acids/therapeutic use, Double-Blind Method, Drug Tolerance, Fatty Acids/therapeutic use, Female, Global Health, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Hypolipidemic Agents/therapeutic use, Incidence, Male, Treatment Outcome, Journal Article, Multicenter Study, Randomized Controlled Trial
ISSN: 0002-8703
Publisher: Mosby Inc.
Note: Funding Information: SJN is a recipient of a Principal Research Fellowship from the National Health and Medical Research Council of Australia, has received research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience and is a consultant for AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim. AML has received research funding from Esperion, Astra Zeneca, CSL, AbbVie, Novartis and is a consultant for Eli Lily and Novo Nordisk. LC has received research support from Amgen and Novartis and is a consultant for Amgen, Esperion and AstraZeneca. PDT has received research support to his institution from: Sanofi, Regeneron, Esperion, Amarin, Amgen; has consulted or received speaker honoraria from Amgen, Amarin, Kowa, Regeneron, Sanofi, Esperion, Kowa and Boerhringer-Engelheim; and owns stock in Abbvie, Abbott Labs, CVS, General Electric, J&J, Medtronic, Sarepta, Boston Scientific, Myokardia, Moderna and Boston Scientific. PMM has received speaker fees from Regeneron, Sanofi, Amgen, Amarin, NLA and Horizon CME, consulting fees from Esperion, Kaneka, Stage II Innovations/Renew, First Manhattan and Eli Lilly, advisor fees from Esperion, Medicines Company and Norvartis and research support from Regeneron, Sanofi, Amgen, Ionis, Novartis, Stage II Innovations/Renew, Renew, Kowa, Akcea, FH Foundation, GB Life Sciences, Aegerion, Gemphire, Esperion and Pfizer. JP reports receiving an institutional research grant from Boehringer Ingelheim and is a consultant for Amarin, Amgen, Cirius, Eli Lilly, Esperion, Janssen, NovoNordisk, Regeneron, Sanofi and Vivus. In the past 12 months, HB's research site has received research grants from Acasti, Akcea, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Civi, Esperion, Ionis, LIB Therapeutics, MedImmune, Merck, Novartis, Omthera, Pfizer, Regeneron, Sanofi, and The Medicines Company. In the past 12 months, HB has served as a consultant/advisor for Amarin, Esperion, Matinas, and Gelesis, and speaker for Esperion. JJJP reports personal/consultant fees from AstraZeneca, CIVI Biotechnology, CSL Behring, Draupnir, Esperion, Gemphire, Madrigal Pharmaceuticals, Matinas Biopharma, North Sea Therapeutics, Novo Nordisk, Novartis, Regeneron, RegenXBio, Staten Biotech, 89 Bio, Omeicos, and Serometrix. PL is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech, Inc. PL is a member of scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc. PL serves on the Board of XBiotech, Inc. PL's laboratory has received research funding in the last 2 years from Novartis. KKR acknowledges support from the NIHR Imperial Biomedical Research Centre and reports honoraria from Resverlogix, Aegerion, Amgen, Pfizer, AstraZeneca, Cerenis, Akcea, The Medicines Company, Kowa, Novartis, Cipla, Eli Lilly, Algorithm, Takeda, Boehringer Ingelheim, Abbvie, Silence Therapeutics, Dr. Reddys, Bayer, Daiichi Sankyo, Esperion, Zuelling Pharma, Sanofi-Regeneron and Merck and grants from Sanofi-Regeneron and Merck. DEG received research funds from Esperion to his institution. The CLEAR Outcomes study is funded by Esperion Therapeutics. SEN reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Pfizer, The Medicines Company, Silence Therapeutics, Takeda, and Orexigen. WS is an employee of Esperion. DM, JM, DD and KW have no potential conflicts to disclose. SEN is involved in these clinical trials, but receives no personal remuneration for his participation. SEN consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Publisher Copyright: © 2020 Elsevier Inc.
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