Clinical trial NCT04562467: The Use of Icosapent Ethyl on Vascular Progenitor Cells in Individuals With Elevated Cardiovascular Risk
Official title: The Icosapent Ethyl and Prevention of Vascular Regenerative Cell Exhaustion Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cardiovascular Diseases
Cardiovascular Risk Factor
Triglycerides High
Diabetes Mellitus, Type 2
Keywords: Cardiometabolic Risk
Type 2 Diabetes
Icosapent Ethyl
Omega-3
Vascular Diseases
Progenitor Cells
Vascular Disease
Blood Lipids
Lead sponsor: Canadian Medical and Surgical Knowledge Translation Research Group
Sponsor class: OTHER
Collaborators: name: HLS Therapeutics, Inc
name: Unity Health Toronto
name: Western University, Canada
First posted: 2020-09-24
Enrollment: 70
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Change in the frequency of ALDHhiSSClowCD133+ cells in individuals treated with IPE compared to SOC for 3 months
timeFrame: Baseline - 3 months post-randomization
Secondary outcomes:
Other outcomes:
measure: Change in the ratio of ALDHhiSSCmid pro-inflammatory:anti-inflammatory monocyte precursor cells in individuals treated with IPE compared to SOC for 3-months.
timeFrame: Baseline - 3 months post-randomization
measure: Change in the mean frequency of ALDHhiSSChi cells in individuals treated with IPE compared to SOC for 3-months.
timeFrame: Baseline - 3 months post-randomization
measure: Changes in the concentration of serum oxidative stress markers from baseline to the 3-month visit in individuals treated with IPE compared to SOC
timeFrame: Baseline - 3 months post-randomization
measure: Changes in the concentration of serum inflammatory markers from baseline to the 3-month visit in individuals treated with IPE compared to SOC
timeFrame: Baseline - 3 months post-randomization
Locations:
city: Oshawa
country: Canada
facility: The Oshawa Clinic
state: Ontario
city: Scarborough
country: Canada
facility: Diagnostic Assessment Centre
state: Ontario
city: Vaughan
country: Canada
facility: Langstaff Medical Clinic
state: Ontario
Study officials:
affiliation: Unity Health Toronto
name: Subodh Verma, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Robarts Research Institute, London, Ontario
name: David A Hess, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital, Boston, Massachusetts
name: Deepak L Bhatt, MD, MPH
role: STUDY_CHAIR
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