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

• ClinicalTrials.gov Identifier: NCT04562467
• Recruitment Status: Recruiting
• First Posted: September 24, 2020
• Last Update Posted: February 11, 2022
• Sponsor: Canadian Medical and Surgical Knowledge Translation Research Group
• Collaborators: HLS Therapeutics, Inc; Unity Health Toronto; University of Western Ontario, Canada
• Information provided by (Responsible Party): Canadian Medical and Surgical Knowledge Translation Research Group

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cardiovascular Diseases; Cardiovascular Risk Factor; Triglycerides High; Diabetes Mellitus, Type 2	Drug: Icosapent Ethyl 1000 MG Oral Capsule [Vascepa]	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Icosapent Ethyl and Prevention of Vascular Regenerative Cell Exhaustion Study
• Actual Study Start Date: September 24, 2020
• Estimated Primary Completion Date: May 31, 2022
• Estimated Study Completion Date: July 31, 2022

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

1. 20% change in the mean frequency of ALDHhiSSChi granulocyte precursor cells in individuals treated with IPE compared to SOC for 3-months [ Time Frame: Baseline - 3 months post-randomization ]

Secondary Outcome Measures :

1. 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 ]
2. 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 ]

Other Outcome Measures:

1. 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 ]
2. 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 ]
3. Changes in the number of ALDHhiSSClo Myeloid Colony Forming Units (CFU) from baseline to the 3-month visit in vitro [ Time Frame: Baseline - 3 months post-randomization ]
4. Changes in the activity of myeloperoxidase harvested from ALDHhiSSChi granulocytes from baseline to the 3-month visit in vitro [ Time Frame: Baseline - 3 months post-randomization ]

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Ehab Bakbak, BSc; 9057679127; ehab.bakbak@mail.utoronto.ca

Locations

Canada, Ontario

North York Diagnostic and Cardiac Centre; Active, not recruiting

North York, Ontario, Canada, M6B 1N6

The Oshawa Clinic; Recruiting

Oshawa, Ontario, Canada, L1H 1B9

Contact: Asaad Bakbak, MD

Diagnostic Assessment Centre; Recruiting

Scarborough, Ontario, Canada, M1S4N6

Contact: Subodh Verma, MD, PhD

Langstaff Medical Clinic; Recruiting

Vaughan, Ontario, Canada, L4L 0K8

Contact: Kristin A Terenzi, MD

Sponsors and Collaborators

Canadian Medical and Surgical Knowledge Translation Research Group

HLS Therapeutics, Inc

Unity Health Toronto

University of Western Ontario, Canada

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

More Information

Publications:

Mechanick JI, Farkouh ME, Newman JD, Garvey WT. Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Feb 11;75(5):525-538. doi: 10.1016/j.jacc.2019.11.044. Review.

Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003 Jun;9(6):653-60. Review.

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.

Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest. 1999 May;103(9):1231-6. Review.

Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000 Feb 1;95(3):952-8.

Takamura M, Kurokawa K, Ootsuji H, Inoue O, Okada H, Nomura A, Kaneko S, Usui S. Long-Term Administration of Eicosapentaenoic Acid Improves Post-Myocardial Infarction Cardiac Remodeling in Mice by Regulating Macrophage Polarization. J Am Heart Assoc. 2017 Feb 21;6(2). pii: e004560. doi: 10.1161/JAHA.116.004560.

Devaraj S, Chien A, Rao B, Chen X, Jialal I. Modulation of endothelial progenitor cell number and function with n-3 polyunsaturated fatty acids. Atherosclerosis. 2013 May;228(1):94-7. doi: 10.1016/j.atherosclerosis.2013.02.036. Epub 2013 Mar 13.

Morishita T, Uzui H, Ikeda H, Amaya N, Kaseno K, Ishida K, Fukuoka Y, Lee JD, Tada H. Association of CD34/CD133/VEGFR2-Positive Cell Numbers with Eicosapentaenoic Acid and Postprandial Hyperglycemia in Patients with Coronary Artery Disease. Int J Cardiol. 2016 Oct 15;221:1039-42. doi: 10.1016/j.ijcard.2016.07.079. Epub 2016 Jul 5.

Capoccia BJ, Robson DL, Levac KD, Maxwell DJ, Hohm SA, Neelamkavil MJ, Bell GI, Xenocostas A, Link DC, Piwnica-Worms D, Nolta JA, Hess DA. Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity. Blood. 2009 May 21;113(21):5340-51. doi: 10.1182/blood-2008-04-154567. Epub 2009 Mar 26.

Putman DM, Liu KY, Broughton HC, Bell GI, Hess DA. Umbilical cord blood-derived aldehyde dehydrogenase-expressing progenitor cells promote recovery from acute ischemic injury. Stem Cells. 2012 Oct;30(10):2248-60. doi: 10.1002/stem.1206.

Terenzi DC, Al-Omran M, Quan A, Teoh H, Verma S, Hess DA. Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes: Translational Insights Into the Prevention of Ischemic Complications in Diabetes. JACC Basic Transl Sci. 2018 Nov 5;4(1):98-112. doi: 10.1016/j.jacbts.2018.10.005. eCollection 2019 Feb.

Hess DA, Terenzi DC, Trac JZ, Quan A, Mason T, Al-Omran M, Bhatt DL, Dhingra N, Rotstein OD, Leiter LA, Zinman B, Sabongui S, Yan AT, Teoh H, Mazer CD, Connelly KA, Verma S. SGLT2 Inhibition with Empagliflozin Increases Circulating Provascular Progenitor Cells in People with Type 2 Diabetes Mellitus. Cell Metab. 2019 Oct 1;30(4):609-613. doi: 10.1016/j.cmet.2019.08.015. Epub 2019 Aug 30.

Balber AE. Concise review: aldehyde dehydrogenase bright stem and progenitor cell populations from normal tissues: characteristics, activities, and emerging uses in regenerative medicine. Stem Cells. 2011 Apr;29(4):570-5. doi: 10.1002/stem.613. Review.

Gentry T, Foster S, Winstead L, Deibert E, Fiordalisi M, Balber A. Simultaneous isolation of human BM hematopoietic, endothelial and mesenchymal progenitor cells by flow sorting based on aldehyde dehydrogenase activity: implications for cell therapy. Cytotherapy. 2007;9(3):259-74.

Shoulars K, Noldner P, Troy JD, Cheatham L, Parrish A, Page K, Gentry T, Balber AE, Kurtzberg J. Development and validation of a rapid, aldehyde dehydrogenase bright-based cord blood potency assay. Blood. 2016 May 12;127(19):2346-54. doi: 10.1182/blood-2015-08-666990. Epub 2016 Mar 11.

• Responsible Party: Canadian Medical and Surgical Knowledge Translation Research Group
• ClinicalTrials.gov Identifier: NCT04562467
• Other Study ID Numbers: Pro00043561
• First Posted: September 24, 2020
• Last Update Posted: February 11, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Canadian Medical and Surgical Knowledge Translation Research Group:

Cardiometabolic Risk; Type 2 Diabetes; Icosapent Ethyl; Omega-3; Vascular Diseases; Progenitor Cells; Vascular Disease; Blood Lipids

Additional relevant MeSH terms:

Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Eicosapentaenoic acid ethyl ester; Platelet Aggregation Inhibitors; Lipid Regulating Agents