The Use of Icosapent Ethyl on Vascular Progenitor Cells in Individuals With Elevated Cardiovascular Risk

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Icosapent Ethyl and Prevention of Vascular Regenerative Cell Exhaustion Study

Conditions
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Cardiovascular Diseases, Cardiovascular Risk Factor, Triglycerides High, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Icosapent Ethyl 1000 MG Oral Capsule [Vascepa]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) 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 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 Elevated triglycerides (≥1.5 mmol/L but <5.6 mmol/L) On stable statin therapy for ≥4 weeks at the baseline visit Willing to provide written informed consent and be compliant with the study requirements Willing and able to follow the diet recommended by the study doctor Exclusion Criteria: Participation in another clinical trial with an investigational agent ≤90 days prior to screening Women who are of childbearing potential Any condition or therapy which the study doctor thinks might pose a risk to the participant Severe (New York Heart Association class IV) heart failure Any life-threatening disease expected to result in death within the next 2 years Diagnosis or laboratory evidence of active severe liver disease HbA1c >10.0% at the baseline visit SBP ≥200 mmHg or DBP ≥100 mmHg (despite being on antihypertensive therapy) Planned coronary intervention or any non-cardiac major surgical procedure Known familial lipoprotein lipase deficiency, apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia Statin intolerant or hypersensitivity to statin therapy Require peritoneal dialysis or hemodialysis eGFR <30 mL/min/1.73m2 History of atrial fibrillation History of major bleeding event(s) Documented history of pancreatitis Malabsorption syndrome and/or chronic diarrhea Known acquired immunodeficiency syndrome Unexplained elevated creatine kinase concentration >5 × the upper limits of normal or elevation due to known muscle disease Use of niacin, fibrates, omega-3 fatty acids, dietary supplements containing omega-3 fatty acids, bile acid sequestrants or PCSK9 inhibitors Known hypersensitivity to fish and/or shellfish, or ingredients of IPE Inability to swallow IPE capsules whole Drug or alcohol abuse within the past 6 months, and inability/unwillingness to abstain from drug abuse and excessive alcohol consumption during the study 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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Icosapent Ethyl + Standard of Care<br>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]<br>* 2 x 1g capsules BID as per REDUCE-IT<br>* Other names: IPE;|
| No Intervention: Standard of Care<br>Standard of care therapy (including statin therapy as per inclusion criteria) | |

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood Lipids, Cardiometabolic Risk, Type 2 Diabetes, Icosapent Ethyl, Omega-3, Vascular Diseases, Progenitor Cells, Vascular Disease