Grant: Team Gr.:Intervention Trial in Inflam. for Chronic Condition - General Pool LOI

As people age, the risk of developing dementia increases, especially in those with inflammatory conditions like coronary artery disease and type 2 diabetes mellitus. These conditions can lead to small vessel disease in the brain, which contributes to cognitive decline and dementia risk. Currently, there is no therapy approved to protect the brain's small vessels. Previous studies have shown that exercise can improve brain blood vessel function and cognitive performance, but the effects are not consistent in people with coronary artery disease or type 2 diabetes mellitus. Exercise generates epoxide metabolites from dietary fatty acids that support cerebral blood flow and resolution of inflammation, but as people age, soluble epoxide hydrolase (sEH) breaks down these epoxides into toxic products that may harm the small vessels of the brain. The aim of this Phase 2 trial is to determine if an inhibitor of sEH called EC5026 can protect the small vessels of the brain for both men and women with coronary artery disease and/or type 2 diabetes mellitus, and restore the brain benefit of physical exercise training. The trial will randomly assign 160 patients to EC5026 or placebo daily for 24 weeks. The primary outcome will be cognitive performance. The secondary outcome will be blood flow to the brain. The study will also monitor blood vessel function throughout the body over time to determine how the drug works, and examine blood tests taken before the drug is given to determine if certain people may benefit from the drug more than others. The team, spanning multiple countries and institutions, includes pharmacologists, neurologists, endocrinologists, kinesiologists, imaging scientists, other medical specialists, and a person who previously completed the exercise program. The trial will be the first to target the small vessels in the brain to boost the benefits of exercise. The results will inform further trials, and how to improve exercise training to prevent dementia.