A Study Evaluating the Safety and Efficacy of Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination Compared to Bempedoic Acid, Ezetimibe, and Placebo in Patients Treated With Maximally Tolerated Statin Therapy

• ClinicalTrials.gov Identifier: NCT03337308
• Recruitment Status: Completed
• First Posted: November 8, 2017
• Results First Posted: April 8, 2020
• Last Update Posted: April 8, 2020
• Sponsor: Esperion Therapeutics, Inc.
• Information provided by (Responsible Party): Esperion Therapeutics, Inc.

Study Description

Brief Summary:

The purpose of this study is to determine if Bempedoic Acid (BA) + Ezetimibe (EZE) in a fixed-dose combination (FDC) is effective and safe versus its individual components and placebo in patients with elevated LDL cholesterol treated with maximally tolerated statin therapy.

Condition or disease	Intervention/treatment	Phase
Hyperlipidemias	Combination Product: Bempedoic Acid + Ezetimibe Fixed-Dose Combination; Drug: Bempedoic Acid; Drug: Ezetimibe; Drug: Placebos	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 382 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of Bempedoic Acid 180 Mg + Ezetimibe 10 Mg Fixed-Dose Combination Compared to Bempedoic Acid, Ezetimibe, and Placebo Alone in Patients Treated With Maximally Tolerated Statin Therapy
• Actual Study Start Date: October 23, 2017
• Actual Primary Completion Date: June 18, 2018
• Actual Study Completion Date: July 18, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: BA 180 mg + EZE 10 mg FDC; Bempedoic acid (BA) + ezetimibe (EZE) fixed-dose combination (FDC) 180 mg/10 mg tablets taken orally once daily for 12 weeks	Combination Product: Bempedoic Acid + Ezetimibe Fixed-Dose Combination; bempedoic acid + ezetimibe FDC 180 mg/10 mg tablet; Other Names: Bempedoic Acid + Zetia FDC; ETC-1002 + Zetia; Drug: Placebos; placebo tablet or capsule to match bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or bempedoic acid 180 mg tablet, or ezetimibe 10 mg capsule; Other Name: Placebo
Experimental: BA 180 mg; Bempedoic acid (BA) 180 mg tablets taken orally once daily for 12 weeks	Drug: Bempedoic Acid; bempedoic acid 180 mg tablet; Other Name: ETC-1002; Drug: Placebos; placebo tablet or capsule to match bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or bempedoic acid 180 mg tablet, or ezetimibe 10 mg capsule; Other Name: Placebo
Active Comparator: EZE 10 mg; Ezetimibe (EZE) 10 mg overencapsulated tablets taken orally once daily for 12 weeks	Drug: Ezetimibe; ezetimibe 10 mg overencapsulated tablet; Other Name: Zetia; Drug: Placebos; placebo tablet or capsule to match bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or bempedoic acid 180 mg tablet, or ezetimibe 10 mg capsule; Other Name: Placebo
Placebo Comparator: Placebos; Placebos to match identical bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or identical bempedoic acid 180 mg tablet, or identical ezetimibe 10 mg capsule, taken orally, once daily for 12 weeks	Drug: Placebos; placebo tablet or capsule to match bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or bempedoic acid 180 mg tablet, or ezetimibe 10 mg capsule; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for LDL-C. Baseline was defined as the mean of the LDL-C values from Week -2 and predose Day 1/Week 0. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with treatment group and randomization stratification as a factors and baseline LDL-C as a covariate. Percent change from baseline was calculated as: ([LDL-C value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100. For LDL-C, if measured LDL-C value was available, measured LDL-C was used.

Secondary Outcome Measures :

1. Percent Change From Baseline to Week 12 in High-sensitivity C-reactive Protein (hsCRP) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for hsCRP. Baseline was defined as the predose Day 1/Week 0 value. Percent change from baseline in hsCRP was analyzed using a non-parametric analysis. Percent change from baseline was calculated as: ([hsCRP value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
2. Percent Change From Baseline to Week 12 in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for non-HDL-C. Baseline was defined as the mean of the non-HDL-C values from Week -2 and predose Day 1/Week 0. Percent change from baseline in non-HDL-C was analyzed using ANCOVA with treatment group and randomization stratification as a factors and baseline non-HDL-C as a covariate. Percent change from baseline was calculated as: ([non-HDL-C value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
3. Percent Change From Baseline to Week 12 in Total Cholesterol (TC) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for TC. Baseline was defined as the mean of the TC values from Week -2 and predose Day 1/Week 0. Percent change from baseline in TC was analyzed using ANCOVA with treatment group and randomization stratification as a factors and baseline TC as a covariate. Percent change from baseline was calculated as: ([TC value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
4. Percent Change From Baseline to Week 12 in Apolipoprotein B (Apo B) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for apo B. Baseline was defined as the predose Day 1/Week 0 value. Percent change from baseline in apo B was analyzed using ANCOVA with treatment group and randomization stratification as a factors and baseline apo B as a covariate. Percent change from baseline was calculated as: ([apo B value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
5. Percent Change From Baseline to Week 12 in High-density Lipoprotein Cholesterol (HDL-C) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for HDL-C. Baseline was defined as the mean of the HDL-C values from Week -2 and predose Day 1/Week 0. Percent change from baseline was calculated as: ([HDL-C value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.
6. Percent Change From Baseline to Week 12 in Triglycerides (TGs) [ Time Frame: Baseline; Week 12 ]
   Blood samples were drawn after a minimum 10-hour fast (water was allowed) at pre-specified intervals. Samples were collected and analyzed for TGs. Baseline was defined as the mean of the TGs values from Week -2 and predose Day 1/Week 0. Percent change from baseline was calculated as: ([TGs value at Week 12 minus Baseline value] divided by [Baseline Value]) multiplied by 100.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Require lipid-modifying therapy for primary or secondary prevention of cardiovascular disease
• Fasting LDL-C ≥ 130 mg/dL for primary prevention or LDL-C ≥ 100 mg/dL for secondary prevention (history of HeFH and/or ASCVD)
• Treated with maximally tolerated statin therapy at stable dose for at least 4 weeks prior to screening

Exclusion Criteria:

• Total Fasting Triglyceride ≥ 400 mg/dL
• Renal Dysfunction or nephrotic syndrome or history of nephritis
• Significant cardiovascular disease or cardiovascular event within the past 3 months

Contacts and Locations

Locations

United States, Iowa

PMG Research of McFarland

Ames, Iowa, United States, 50010

United States, New Hampshire

Foundation Cardiology

Nashua, New Hampshire, United States, 03060

United States, North Carolina

PMG Research of Piedmont Healthcare

Statesville, North Carolina, United States, 28625

PMG Research of Wilmington

Wilmington, North Carolina, United States, 28401

United States, Tennessee

PMG Research of Knoxville

Knoxville, Tennessee, United States, 37912

Sponsors and Collaborators

Esperion Therapeutics, Inc.

Investigators

• Study Director: Ron Haberman, MD; Esperion Therapeutics, Inc.

  Study Documents (Full-Text)

Documents provided by Esperion Therapeutics, Inc.:

Study Protocol  [PDF] October 18, 2017

Statistical Analysis Plan  [PDF] June 8, 2018

More Information

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.

Cholesterol Treatment Trialists' (CTT) Collaboration; Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5. Epub 2010 Nov 8.

Authors/Task Force Members:; Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016 Oct;253:281-344. doi: 10.1016/j.atherosclerosis.2016.08.018. Epub 2016 Sep 1. No abstract available.

Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, Braunwald E, Sabatine MS. Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis. JAMA. 2016 Sep 27;316(12):1289-97. doi: 10.1001/jama.2016.13985.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45. doi: 10.1161/01.cir.0000437738.63853.7a. Epub 2013 Nov 12. No abstract available. Erratum In: Circulation. 2014 Jun 24;129(25 Suppl 2):S46-8. Circulation. 2015 Dec 22;132(25):e396.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, Stroes ES, MacDougall D, Zhao X, Catapano 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. 2020 Apr;27(6):593-603. doi: 10.1177/2047487319864671. Epub 2019 Jul 29.

• Responsible Party: Esperion Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03337308
• Other Study ID Numbers: 1002FDC-053
• First Posted: November 8, 2017
• Results First Posted: April 8, 2020
• Last Update Posted: April 8, 2020
• Last Verified: March 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Esperion Therapeutics, Inc.:

hyperlipidemia; heterozygous familial hypercholesterolemia; atherosclerotic cardiovascular disease; high cholesterol; ASCVD; HeFH; LDL

Additional relevant MeSH terms:

Hyperlipidemias; Hyperlipoproteinemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; Ezetimibe; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Enzyme Inhibitors; Hypoglycemic Agents; Physiological Effects of Drugs