Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo

Overview

About this study

The purpose of this study is to determine if treatment with bempedoic acid (ETC-1002) versus placebo decreases the risk of cardiovascular events in patients who are statin intolerant.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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.
  • Patient reported history of statin intolerance (inability to tolerate 2 or more statins, one at a low 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.

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

La Crosse, Wis.

Mayo Clinic principal investigator

Tahir Tak, M.D., Ph.D.

Closed for enrollment

More information

Publications

  • Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. Read More on PubMed
  • 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. Read More on PubMed
  • Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy. Read More on PubMed
  • Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients. Read More on PubMed
  • ETC-1002 is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia. Read More on PubMed
  • Once-daily, oral ETC-1002 reduces low-density lipoprotein cholesterol (LDL-C) and has beneficial effects on other cardiometabolic risk factors but has not been examined in statin intolerant patients. Read More on PubMed

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