Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid

Study Overview
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Brief Summary
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The number of Americans diagnosed with Alzheimer's disease (AD) is expected to triple by 2050. Compared to the general population, Veterans have a greater risk of AD, likely in part due to their increased incidence of traumatic brain injury, post-traumatic stress disorder, depression, and other vascular-related health issues. Based on available data, 423,000 new cases of AD are anticipated in Veterans by 2020. Thus, the discovery of effective therapies to prevent or delay the onset of AD in Veterans is critical. The goal of this study is to evaluate the efficacy of a purified form of the omega-3 fatty acid eicosapentaenoic acid (EPA) called icosapent ethyl (IPE), on improving brain blood flow, spinal fluid markers of AD pathology, and cognitive performance in middle-aged, cognitively-healthy Veterans with increased risk of AD. If IPE delays the onset of AD by even 5 years, the incidence of AD would be reduced by 50% in this population and could have a profound effect on Veteran quality of life and healthcare costs.

Detailed Description
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The proposed study is a proof-of-concept, randomized, placebo-controlled, double-blind, parallel-group clinical trial assessing the efficacy of 18 months of icosapent ethyl (IPE) therapy on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and cognitive biomarkers for AD in 150 cognitively-healthy Veterans ages 50-75 years. The overarching goal of this trial is to assess whether icosapent ethyl beneficially affects intermediate physiological measures associated with onset of AD in order to evaluate whether larger, multi-site, longer-duration Alzheimer's prevention trials are warranted to assess more definitive clinical outcomes. The proposed study aims to: 1) investigate the effects of 18 months of IPE vs. placebo on regional cerebral blood flow as measured by arterial spin-labeling MRI; 2) determine the impact of 18 months of IPE vs. placebo on CSF biomarkers of AD pathology; and 3) evaluate the effects of 18 months of IPE vs. placebo on cognitive performance.

Official Title
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Impact of Icosapent Ethyl on Alzheimers Disease Biomarkers in Preclinical Adults

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: icosapent ethyl (IPE)
* Other: gel cap placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: United States Veteran eligible for VA care Age 50-75 years, inclusive Cognitively healthy Exclusion Criteria: Dementia or mild cognitive impairment on screening evaluation Current use of fish oil supplements (requires 3 month wash-out period) Active liver disease with AST or ALT greater than twice the upper limit of normal Elevated creatine kinase greater than twice the upper limit of normal Prior adverse reaction to statins or fish oil Pregnant, nursing, or pregnancy planned Use of medications that interact with icosapent ethyl Current use of anticoagulants Known hypersensitivity to fish and/or shellfish Current use of other investigational drug History of significant atherosclerotic cardiovascular disease or diabetes mellitus Low-density lipoprotein (LDL) cholesterol > or =190 mg/dL or <80 mg/dL Triglycerides > or = 500 mg/dL Creatinine >1.8 mg/dL Previous lumbar surgery with contraindication to lumbar puncture Claustrophobia requiring sedation for MRI Pacemaker or other contraindication for MRI Consumption of >200 mg per day omega-3 fatty acids in diet

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 randomization of icosapent ethyl 4 g daily vs matching placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: icosapent ethyl (IPE)<br>Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo | Drug: icosapent ethyl (IPE)<br>* Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo<br>* Other names: Vascepa;|
| Placebo Comparator: placebo<br>Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo | Other: gel cap placebo<br>* Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regional cerebral blood flow using arterial spin-labeling MRI | Brain blood flow in a statistical region of interest will be measured through arterial spin-labeling MRI | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease | CSF beta-amyloid, total tau, and phosphorylated tau | 18 months | 
| cognitive performance | Preclinical Alzheimer's Cognitive Composite (PACC) | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, Cerebrospinal fluid, brain blood flow, cognition, icosapent ethyl, Vascepa, omega-3 fatty acids, eicosapentaenoic acid