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

• ClinicalTrials.gov Identifier: NCT02993406
• Recruitment Status: Completed
• First Posted: December 15, 2016
• Results First Posted: January 3, 2024
• Last Update Posted: January 3, 2024
• Sponsor: Esperion Therapeutics, Inc.
• Collaborator: The Cleveland Clinic
• Information provided by (Responsible Party): Esperion Therapeutics, Inc.

Tracking Information

• First Submitted Date: December 9, 2016
• First Posted Date: December 15, 2016
• Results First Submitted Date: October 25, 2023
• Results First Posted Date: January 3, 2024
• Last Update Posted Date: January 3, 2024
• Actual Study Start Date: December 22, 2016
• Actual Primary Completion Date: November 7, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2023)

Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE) [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: December 12, 2016): Time from randomization to first occurrence of one of the following adjudicated composite endpoints: CV death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, or coronary revascularization. [ Time Frame: 3.5 years (estimated average treatment duration) ]

Current Secondary Outcome Measures (submitted: December 13, 2023)

• Number of Participants With First Occurrence of Three Component MACE [ Time Frame: 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 First Occurrence of Myocardial Infarction [ Time Frame: Up to 68 months ]
  Number of participants with time to first occurrence of fatal and non-fatal myocardial infarction are presented.
• Number of Participants With Time to First Occurrence of Coronary Revascularization [ Time Frame: Up to 68 months ]
  Number of participants with time to first occurrence of coronary revascularization are presented.
• Number of Participants With Time to First Occurrence of Stroke [ Time Frame: Up to 68 months ]
  Number of participants with time to first occurrence of fatal and non-fatal stroke.
• Number of Participants With Time to Cardiovascular Death [ Time Frame: Up to 68 months ]
  Number of participants with time to cardiovascular death are presented.
• Number of Participants With Time to All-cause Mortality [ Time Frame: Up to 68 months ]
  All-cause mortality is death due to any cause. Number of participants with time to all-cause mortality are presented.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Major Cardiovascular Events in Participants With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo
• Official Title: A Randomized, Double-blind, Placebo-controlled Study to Assess the Effects of Bempedoic Acid (ETC-1002) on the Occurrence of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Cardiovascular Diseases
• Statin Adverse Reaction

Intervention

• Drug: Bempedoic acid 180 mg tablet
  Patients take bempedoic acid 180 mg tablet orally once daily
  Other Name: ETC-1002
• Drug: Matching placebo tablet
  Patients take matching placebo tablet orally once daily
  Other Name: placebo comparator

Study Arms

• Experimental: Bempedoic Acid 180 mg
  Bempedoic acid 180 mg tablet taken orally, once daily.
  Intervention: Drug: Bempedoic acid 180 mg tablet
• Placebo Comparator: Placebo Comparator
  Matching placebo tablet taken orally, once daily
  Intervention: Drug: Matching placebo tablet

Publications *

• Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, Birch CM, Smith BK, Filippov S, Groot PHE, Steinberg GR, Lalwani ND. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016 Nov 28;7:13457. doi: 10.1038/ncomms13457.
• Bilen O, Ballantyne CM. Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61. doi: 10.1007/s11883-016-0611-4.
• Thompson PD, MacDougall DE, Newton RS, Margulies JR, Hanselman JC, Orloff DG, McKenney JM, Ballantyne CM. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016 May-Jun;10(3):556-67. doi: 10.1016/j.jacl.2015.12.025. Epub 2016 Jan 6.
• Thompson PD, Rubino J, Janik MJ, MacDougall DE, McBride SJ, Margulies JR, Newton RS. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015 May-Jun;9(3):295-304. doi: 10.1016/j.jacl.2015.03.003. Epub 2015 Mar 19.
• Nicholls S, Lincoff AM, Bays HE, Cho L, Grobbee DE, Kastelein JJ, Libby P, Moriarty PM, Plutzky J, Ray KK, Thompson PD, Sasiela W, Mason D, McCluskey J, Davey D, Wolski K, Nissen SE. 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 May;235:104-112. doi: 10.1016/j.ahj.2020.10.060. Epub 2020 Oct 24.
• Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, Thompson PD, Libby P, Cho L, Plutzky J, Bays HE, Moriarty PM, Menon V, Grobbee DE, Louie MJ, Chen CF, Li N, Bloedon L, Robinson P, Horner M, Sasiela WJ, McCluskey J, Davey D, Fajardo-Campos P, Petrovic P, Fedacko J, Zmuda W, Lukyanov Y, Nicholls SJ; CLEAR Outcomes Investigators. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Apr 13;388(15):1353-1364. doi: 10.1056/NEJMoa2215024. Epub 2023 Mar 4.
• Nissen SE, Menon V, Nicholls SJ, Brennan D, Laffin L, Ridker P, Ray KK, Mason D, Kastelein JJP, Cho L, Libby P, Li N, Foody J, Louie MJ, Lincoff AM. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA. 2023 Jul 11;330(2):131-140. doi: 10.1001/jama.2023.9696.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 13, 2023): 13970
• Original Estimated Enrollment (submitted: December 12, 2016): 12600
• Actual Study Completion Date: November 7, 2022
• Actual Primary Completion Date: November 7, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location 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, Russian Federation, Serbia, Slovakia, South Africa, Spain, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT02993406
• Other Study ID Numbers: 1002-043
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Esperion Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Esperion Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: The Cleveland Clinic
• Investigators: Not Provided
• PRS Account: Esperion Therapeutics, Inc.
• Verification Date: December 2023