The Use of Icosapent Ethyl on Vascular Progenitor Cells in Individuals With Elevated Cardiovascular Risk (IPE-PREVENTION)

March 31, 2024 updated by: Canadian Medical and Surgical Knowledge Translation Research Group

The Icosapent Ethyl and Prevention of Vascular Regenerative Cell Exhaustion Study

IPE-PREVENTION is a prospective, randomized, 3-month long, open-label study. A total of 70 individuals with elevated cardio-metabolic risk and heightened triglyceride levels, and who are on stable statin therapy will be randomized (1:1) to receive either icosapent ethyl (IPE) 2g BID or standard of care.

It is hypothesized that assignment to IPE will lower progenitor cell depletion as well as limit progenitor cell dysfunction. This study may offer some molecular and cellular insights into the mechanisms underlying the cardiovascular benefits of IPE therapy reported in the REDUCE-IT trial.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The development and natural history of atherothrombosis involves the pathophysiological interplay between inflammation, dyslipidemia, oxidative stress and endothelial dysfunction. Unregulated, these processes culminate in endothelial dysfunction, and ultimately cardio-metabolic chronic diseases. Aberrant lipid oxidation due to elevated triglycerides and cholesterol primes and activates innate immune cell activity resulting in elevated inflammation and oxidative stress.

The randomized, placebo-controlled REDUCE-IT trial enrolled individuals with established atherosclerotic heart disease, or diabetes and an additional risk factor, who were on pre-existing statin therapy with persistent hypertriglyceridemia. REDUCE-IT reported that the group allocated to the omega-3 fatty acid icosapent ethyl (IPE; 2g BID) exhibited a 25% relative risk reduction for the primary composite endpoint of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, and a 20% decreased risk of CV death when compared to standard of care. Vascepa® (IPE) is currently approved by Health Canada and the U.S. FDA for the reduction of cardiovascular risk in statin-treated individuals with elevated triglycerides who are either at heightened cardiovascular risk or who have diabetes and at least one risk factor.

The exact mechanism through which IPE decreased cardiovascular events in REDUCE-IT has not yet been elucidated.

The population and function of circulating pro-vascular progenitor cells have been shown to benefit from diminished lipid oxidation, inflammation and oxidative stress. A healthy population of circulating pro-vascular progenitor cells in turn affords timely and efficient blood vessel repair, regeneration and atheroprotection.

The omega-3 fatty acid eicosapentaenoic acid (EPA) has been reported to inhibit M1 macrophage polarization in a murine model and increase human endothelial progenitor cell (EPC) colony formation and functionality in vitro. In vivo, EPA levels have been observed to correlate significantly with circulating EPC number (CD34+CD133+VEGFR2+ cells). Collectively, these findings affirm that EPA, and potentially omega-3 fatty acids, can enhance the number and function of circulating pro-vascular progenitor cells and can alter M1/M2 macrophage balance towards a regenerative blood vessel phenotype.

IPE-PREVENTION is a prospective, 3-month long, open-label study that will randomize a total of 70 individuals with elevated cardio-metabolic risk and heightened triglyceride levels and who are on stable statin therapy to either IPE 2g BID or standard of care. Blood samples will be collected at the baseline and month 3 visits for evaluations of cell populations in the blood as well as measurements of biomarkers that contribute to the proinflammatory and pro-oxidant milieu of individuals at elevated cardio-metabolic risk. The study will utilize the AldefluorTM assay to differentiate between and enumerate hematopoietic progenitor cells, EPCs, granulocyte precursors and macrophage precursors. The overarching goal would be to document how assignment to IPE and standard-of-care impact on circulating progenitor cell depletion and dysfunction. The effect of IPE exposure on the inflammatory and oxidative profile will also be assessed.

The results of this investigation may offer some molecular and cellular insights into the mechanisms underlying the cardiovascular benefits of IPE therapy reported in the REDUCE-IT trial.

Study Type

Interventional

Enrollment (Actual)

70

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • Ontario
      • Oshawa, Ontario, Canada, L1H 1B9
        • The Oshawa Clinic
      • Scarborough, Ontario, Canada, M1S4N6
        • Diagnostic Assessment Centre
      • Vaughan, Ontario, Canada, L4L 0K8
        • Langstaff Medical Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Women ≥65 years of age and men ≥40 years of age with established CVD (see criterion 'a' below) or ≥50 years of age with diabetes and one additional CV risk factor (see criterion 'b' below)

    1. Those with established CVD should have ≥1 of the following clinical history

      • Documented coronary artery disease (CAD)

        • Prior MI
        • Multivessel CAD (≥50% stenosis in ≥2 major epicardial coronary arteries)
        • Hospitalization for high-risk non-ST-segment elevation acute coronary syndrome

      • Documented cerebrovascular or carotid disease (≥1 of the following)

        • Prior ischemic stroke
        • Carotid artery disease with ≥50% stenosis
        • History of carotid revascularization

      • Documented peripheral artery disease (≥1 of the following)

        • Ankle-brachial index (ABI) <0.9 with symptoms of intermittent claudication
        • History of aorto-iliac or peripheral arterial intervention

    2. Those with a history of diabetes (either type 1 or type 2 diabetes mellitus) but no CVD should also have ≥1 of the following:

      • Cigarette smoker or stopped smoking within 3 months before the baseline visit
      • Documented hypertension OR on antihypertensive agents
      • HDL-C ≤1.0 mmol/L for men or ≤1.3 mmol/L for women
      • High sensitivity C-reactive protein >3.0 mg/L
      • eGFR 30 to 60 mL/min/1.73m2
      • Documented micro- or macro-albuminuria

      • Retinopathy

        • Non-proliferative retinopathy
        • Preproliferative or proliferative retinopathy
        • Maculopathy
        • Advanced diabetic retinopathy
        • History of photocoagulation
      • ABI <0.9 without symptoms of intermittent claudication
  2. Elevated triglycerides (≥1.5 mmol/L but <5.6 mmol/L)
  3. On stable statin therapy for ≥4 weeks at the baseline visit
  4. Willing to provide written informed consent and be compliant with the study requirements
  5. Willing and able to follow the diet recommended by the study doctor

Exclusion Criteria:

  1. Participation in another clinical trial with an investigational agent ≤90 days prior to screening
  2. Women who are of childbearing potential
  3. Any condition or therapy which the study doctor thinks might pose a risk to the participant
  4. Severe (New York Heart Association class IV) heart failure
  5. Any life-threatening disease expected to result in death within the next 2 years
  6. Diagnosis or laboratory evidence of active severe liver disease
  7. HbA1c >10.0% at the baseline visit
  8. SBP ≥200 mmHg or DBP ≥100 mmHg (despite being on antihypertensive therapy)
  9. Planned coronary intervention or any non-cardiac major surgical procedure
  10. Known familial lipoprotein lipase deficiency, apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia
  11. Statin intolerant or hypersensitivity to statin therapy
  12. Require peritoneal dialysis or hemodialysis
  13. eGFR <30 mL/min/1.73m2
  14. History of atrial fibrillation
  15. History of major bleeding event(s)
  16. Documented history of pancreatitis
  17. Malabsorption syndrome and/or chronic diarrhea
  18. Known acquired immunodeficiency syndrome
  19. Unexplained elevated creatine kinase concentration >5 × the upper limits of normal or elevation due to known muscle disease
  20. Use of niacin, fibrates, omega-3 fatty acids, dietary supplements containing omega-3 fatty acids, bile acid sequestrants or PCSK9 inhibitors
  21. Known hypersensitivity to fish and/or shellfish, or ingredients of IPE
  22. Inability to swallow IPE capsules whole
  23. Drug or alcohol abuse within the past 6 months, and inability/unwillingness to abstain from drug abuse and excessive alcohol consumption during the study
  24. Mental/psychological concerns or any other reason to expect difficulty in complying with the study requirements or understanding the goal and potential risks of being a part of the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Icosapent Ethyl + Standard of Care
Icosapent Ethyl 1000 MG Oral Capsule [Vascepa] 2 x 1g capsules BID (4g total) as per REDUCE-IT
Drug: Icosapent Ethyl 1000 MG Oral Capsule [Vascepa]
2 x 1g capsules BID as per REDUCE-IT
Other Names:
  • Vascepa
  • IPE
No Intervention: Standard of Care
Standard of care therapy (including statin therapy as per inclusion criteria)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in the frequency of ALDHhiSSClowCD133+ cells in individuals treated with IPE compared to SOC for 3 months
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization

Secondary Outcome Measures

Outcome Measure
Time Frame
40% change in the ratio of M1:M2 monocyte precursor cells in individuals treated with IPE compared to SOC for 3-months. M1 monocyte precursor cells defined as ALDHhiSSCmidCD14+CD86+ and M2 monocyte precursor cells defined as ALDHhiSSCmidCD14+CD163+
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization
20% change in the mean frequency of ALDHhiSSCloCD133+ cells with pro-vascular progenitor cells phenotype in individuals treated with IPE compared to SOC for 3-months.
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization

Other Outcome Measures

Outcome Measure
Time Frame
Changes in the concentration of serum oxidative stress markers from baseline to the 3-month visit in individuals treated with IPE compared to SOC
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization
Changes in the concentration of serum inflammatory markers from baseline to the 3-month visit in individuals treated with IPE compared to SOC
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization
Change in the ratio of ALDHhiSSCmid pro-inflammatory:anti-inflammatory monocyte precursor cells in individuals treated with IPE compared to SOC for 3-months.
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization
Change in the mean frequency of ALDHhiSSChi cells in individuals treated with IPE compared to SOC for 3-months.
Time Frame: Baseline - 3 months post-randomization
Baseline - 3 months post-randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Canadian Medical and Surgical Knowledge Translation Research Group

Collaborators

Unity Health Toronto
Western University, Canada
HLS Therapeutics, Inc

Investigators

  • Principal Investigator: Subodh Verma, MD, PhD, Unity Health Toronto
  • Principal Investigator: David A Hess, PhD, Robarts Research Institute, London, Ontario
  • Study Chair: Deepak L Bhatt, MD, MPH, Brigham and Women's Hospital, Boston, Massachusetts

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 24, 2020

Primary Completion (Actual)

May 25, 2023

Study Completion (Actual)

May 25, 2023

Study Registration Dates

First Submitted

September 13, 2020

First Submitted That Met QC Criteria

September 18, 2020

First Posted (Actual)

September 24, 2020

Study Record Updates

Last Update Posted (Actual)

April 2, 2024

Last Update Submitted That Met QC Criteria

March 31, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00043561

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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