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

Sponsor

Canadian Medical and Surgical Knowledge Translation Research Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT04562467

Collaborator

HLS Therapeutics, Inc (Other), Unity Health Toronto (Other), University of Western Ontario, Canada (Other)

Enrollment

Locations

Arms

26.2

Anticipated Duration (Months)

17.5

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

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

Anticipated 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 :

Sep 24, 2020

Anticipated Primary Completion Date :

Jul 31, 2022

Anticipated Study Completion Date :

Nov 30, 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)

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

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

Secondary Outcome Measures

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+ [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. [Baseline - 3 months post-randomization]

Other Outcome Measures

Changes in the concentration of serum oxidative stress markers from baseline to the 3-month visit in individuals treated with IPE compared to SOC [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 [Baseline - 3 months post-randomization]
Changes in the number of ALDHhiSSClo Myeloid Colony Forming Units (CFU) from baseline to the 3-month visit in vitro [Baseline - 3 months post-randomization]
Changes in the activity of myeloperoxidase harvested from ALDHhiSSChi granulocytes from baseline to the 3-month visit in vitro [Baseline - 3 months post-randomization]

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	North York Diagnostic and Cardiac Centre	North York	Ontario	Canada	M6B 1N6
2	The Oshawa Clinic	Oshawa	Ontario	Canada	L1H 1B9
3	Diagnostic Assessment Centre	Scarborough	Ontario	Canada	M1S4N6
4	Langstaff Medical Clinic	Vaughan	Ontario	Canada	L4L 0K8

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