Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid

Phase 2

Completed

Brief Summary: 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: 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.

Recruitment & Eligibility

Inclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
icosapent ethyl (IPE)	icosapent ethyl (IPE)	Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo
placebo	gel cap placebo	Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo

Primary Outcome Measures

Name	Time	Method
Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI	18 month study visit	For the primary outcome we chose an anatomical region, posterior cingulate gyrus, that aligned with statistical region of interest sensitive to changes in cerebral blood flow in cognitively-unimpaired adults at risk for Alzheimer's disease. Brain blood flow was averaged across the right and left posterior cingulate gyrus.

Secondary Outcome Measures

Name	Time	Method
Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease	18 month study visit	CSF beta-amyloid-42, total tau, and phosphorylated tau-181 (Roche Cobas Elecsys e611). Lower CSF beta-amyloid-42 and higher phosphorylated tau-181 or total tau are associated with risk for Alzheimer's disease.
Cognitive Performance	18 month study visit	Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (ADCS-PACC). Composite scores at each time point are standardize to baseline values such that at baseline the mean=0 and the standard deviation = 1. Standardized scores range from -3.15 to 3.09. Higher scores indicate better cognition.

Locations (1): William S. Middleton Memorial Veterans Hospital, Madison, WI
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Madison, Wisconsin, United States