Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE-EPA)

Impact of Icosapent Ethyl on Alzheimers Disease Biomarkers in Preclinical Adults

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: icosapent ethyl (IPE); Other: gel cap placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 131
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705-2254
      • William S. Middleton Memorial Veterans Hospital, Madison, WI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI	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.	18 month study visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease	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.	18 month study visit
Cognitive Performance	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.	18 month study visit

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: University of Wisconsin, Madison
• Investigators: Principal Investigator: Cynthia M. Carlsson, MD MS, William S. Middleton Memorial Veterans Hospital, Madison, WI

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2017
• Primary Completion (Actual): September 29, 2023
• Study Completion (Actual): September 29, 2023

Study Registration Dates

• First Submitted: March 21, 2016
• First Submitted That Met QC Criteria: March 21, 2016
• First Posted (Estimated): March 25, 2016

Study Record Updates

• Last Update Posted (Actual): November 26, 2024
• Last Update Submitted That Met QC Criteria: October 31, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Alzheimer's disease; cognition; Cerebrospinal fluid; omega-3 fatty acids; brain blood flow; eicosapentaenoic acid; icosapent ethyl; Vascepa
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Platelet Aggregation Inhibitors; Lipid Regulating Agents; Eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: CLNA-001-15S; CX001261 (Other Grant/Funding Number: VA Merit)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes