A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High-Risk Patients With Hypertriglyceridemia and on Statin

Overview

AMR101 (icosapent ethyl [ethyl-EPA]) is a highly purified ethyl ester of eicosapentaenoic acid (EPA) developed by Amarin Pharma Inc. for the treatment of cardiovascular disease in statin-treated patients with hypertriglyceridemia. The purpose of this study was to evaluate whether this drug, combined with a statin therapy, will be superior to the statin therapy alone, when used as a prevention in reducing long-term cardiovascular events in high-risk patients with mixed dyslipidemia.

Full Title of Study: “Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events With EPA – Intervention Trial)”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Prevention
  • Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Study Primary Completion Date: May 2018

Interventions

• Drug: AMR101
  • Parallel Assignment
• Drug: Placebo
  • Parallel Assignment
• Drug: Statin therapy
  • Stable statin therapy (± ezetimibe) for at least 28 days before lipid qualification measurement (LDL-C >40 mg/dL and ≤100 mg/dL)

Arms, Groups and Cohorts

• Experimental: AMR101
  • AMR101 (icosapent ethyl) + statin therapy, daily
• Placebo Comparator: Placebo
  • Placebo + statin therapy, daily

Clinical Trial Outcome Measures

Primary Measures

• Composite of CV Death, Nonfatal MI (Including Silent MI), Nonfatal Stroke, Coronary Revascularization, or Unstable Angina Determined to be Caused by Myocardial Ischemia by Invasive / Non-invasive Testing and Requiring Emergent Hospitalization.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • The primary outcome measure was the number of patients with a first occurrence of any component of the composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergent hospitalization during the follow-up period.

Secondary Measures

• Composite of CV Death, Nonfatal MI (Including Silent MI), or Nonfatal Stroke.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • The key secondary outcome measure was the number of patients with a first occurrence of any component of the composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke during the follow-up period.
• Composite of CV Death or Nonfatal MI (Including Silent MI).
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with a first occurrence of any component of the composite of CV death or nonfatal MI (including silent MI) during the follow-up period.
• Fatal or Nonfatal MI (Including Silent MI).
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with a first occurrence of fatal or nonfatal MI (including silent MI) during the follow-up period.
• Non-elective Coronary Revascularization Represented as the Composite of Emergent or Urgent Classifications.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with a first occurrence of non-elective coronary revascularization represented as the composite of emergent or urgent classifications during the follow-up period.
• CV Death.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with an occurrence of CV death during the follow-up period.
• Unstable Angina Determined to be Caused by Myocardial Ischemia by Invasive / Non-invasive Testing and Requiring Emergent Hospitalization.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with a first occurrence of unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergent hospitalization during the follow-up period.
• Fatal or Nonfatal Stroke.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with a first occurrence of fatal or nonfatal stroke during the follow-up period.
• Total Mortality, Nonfatal MI (Including Silent MI), or Nonfatal Stroke.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with a first occurrence of any component of the composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke during the follow-up period.
• Total Mortality.
  • Time Frame: Total follow-up time of up to approximately 6 years.
  • Number of patients with an occurrence of death from any cause during the follow-up period.

Participating in This Clinical Trial

Inclusion Criteria

• Men and non-pregnant or sterile women ages 45 and older – Hypertriglyceridemia – On statin therapy for at least four weeks – Either having established cardiovascular disease or at high risk for cardiovascular disease Exclusion Criteria:

• Severe heart failure – Any life-threatening disease other than cardiovascular disease – Active severe liver disease – Hemoglobin A1c >10.0% – Poorly controlled hypertension – Planned coronary intervention (such as stent placement or heart bypass) or any non-cardiac major surgical procedure – Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III) – Known hypersensitivity to the study product, fish and/or shellfish, or placebo – History of acute or chronic pancreatitis – Patients are excluded if using the following medications: – PCSK9 inhibitors – niacin >200 mg/day or fibrates; – any omega-3 fatty acid medications ; – dietary supplements containing omega-3 fatty acids (e.g., flaxseed oil, fish oil, krill oil, or algal oil); – bile acid sequestrants

Gender Eligibility: All

Minimum Age: 45 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Amarin Pharma Inc.
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Deepak L. Bhatt, MD, MPH, Principal Investigator, Brigham and Women’s Hospital, 75 Francis Street, Boston

References

Bhatt DL, Steg PG, Brinton EA, Jacobson TA, Miller M, Tardif JC, Ketchum SB, Doyle RT Jr, Murphy SA, Soni PN, Braeckman RA, Juliano RA, Ballantyne CM; REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Clin Cardiol. 2017 Mar;40(3):138-148. doi: 10.1002/clc.22692. Epub 2017 Mar 15.

Citations Reporting on Results

Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10.

Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Gregson J, Pocock SJ, Ballantyne CM; REDUCE-IT Investigators. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol. 2019 Jun 11;73(22):2791-2802. doi: 10.1016/j.jacc.2019.02.032. Epub 2019 Mar 18.

Bhatt DL, Miller M, Brinton EA, Jacobson TA, Steg PG, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Olshansky B, Chung MK, Gibson CM, Giugliano RP, Budoff MJ, Ballantyne CM; REDUCE-IT Investigators. REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States. Circulation. 2020 Feb 4;141(5):367-375. doi: 10.1161/CIRCULATIONAHA.119.044440. Epub 2019 Nov 11.

Olshansky B, Bhatt DL, Miller M, Steg PG, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Mehta C, Mukherjee R, Ballantyne CM, Chung MK; REDUCE-IT Investigators. REDUCE-IT INTERIM: accumulation of data across prespecified interim analyses to final results. Eur Heart J Cardiovasc Pharmacother. 2021 May 23;7(3):e61-e63. doi: 10.1093/ehjcvp/pvaa118. No abstract available.

Peterson BE, Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Juliano RA, Jiao L, Doyle RT Jr, Granowitz C, Gibson CM, Pinto D, Giugliano RP, Budoff MJ, Tardif JC, Verma S, Ballantyne CM; REDUCE-IT Investigators. Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses. Circulation. 2021 Jan 5;143(1):33-44. doi: 10.1161/CIRCULATIONAHA.120.050276. Epub 2020 Nov 5.

Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Jiao L, Tardif JC, Gregson J, Pocock SJ, Ballantyne CM; REDUCE-IT Investigators. Reduction in First and Total Ischemic Events With Icosapent Ethyl Across Baseline Triglyceride Tertiles. J Am Coll Cardiol. 2019 Aug 27;74(8):1159-1161. doi: 10.1016/j.jacc.2019.06.043. No abstract available.

Gaba P, Bhatt DL, Giugliano RP, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Juliano RA, Jiao L, Doyle RT Jr, Granowitz C, Tardif JC, Ballantyne CM, Pinto DS, Budoff MJ, Gibson CM. Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT. J Am Coll Cardiol. 2021 Oct 12;78(15):1525-1537. doi: 10.1016/j.jacc.2021.08.009.

Majithia A, Bhatt DL, Friedman AN, Miller M, Steg PG, Brinton EA, Jacobson TA, Ketchum SB, Juliano RA, Jiao L, Doyle RT Jr, Granowitz C, Budoff M, Preston Mason R, Tardif JC, Boden WE, Ballantyne CM. Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL. Circulation. 2021 Nov 30;144(22):1750-1759. doi: 10.1161/CIRCULATIONAHA.121.055560. Epub 2021 Oct 28.

Verma S, Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Dhingra NK, Ketchum SB, Juliano RA, Jiao L, Doyle RT Jr, Granowitz C, Gibson CM, Pinto D, Giugliano RP, Budoff MJ, Mason RP, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG. Circulation. 2021 Dec 7;144(23):1845-1855. doi: 10.1161/CIRCULATIONAHA.121.056290. Epub 2021 Oct 28.

Singh N, Bhatt DL, Miller M, Steg PG, Brinton EA, Jacobson TA, Jiao L, Tardif JC, Mason RP, Ballantyne CM; REDUCE-IT Investigators. Consistency of Benefit of Icosapent Ethyl by Background Statin Type in REDUCE-IT. J Am Coll Cardiol. 2022 Jan 18;79(2):220-222. doi: 10.1016/j.jacc.2021.11.005. No abstract available.