A single-center, randomized, parallel design study to evaluate the efficacy of donepezil in improving visuospatial abilities in patients with mild cognitive impairment using eye-tracker: the COG-EYE study protocol for a phase II trial

BACKGROUND: Cholinesterase inhibitors (ChEIs) decrease long-term cognitive decline in patients with Alzheimer’s disease (AD); however, there is little evidence that ChEIs affect cognitive test scores in patients with mild cognitive impairment (MCI). Conventional endpoints, such as cognitive tests or clinical rating scores, may lack the sensitivity to subtle treatment effects in participants with MCI. Therefore, there is an immediate need to refocus on direct physiological assessments to detect the effects of ChEIs in patients with MCI due to AD. METHODS: We propose a randomized controlled trial to evaluate the effect of donepezil, a ChEI, on patients with MCI due to AD. We plan to recruit 78 participants (39 in each arm) with MCI who had amyloid positron emission tomography (PET)-positive results for this open-label study. To evaluate subtle differences, we will measure eye-tracking metrics and digital pen data while participants perform the simplified Rey Complex Figure (RCFT) and clock drawing tests. The primary outcome is a change in the ratio of the number of fixations (working space/perceptual space) performed using the simplified RCFT, from baseline to 12 weeks, as assessed using eye-tracking metrics. The secondary outcomes are changes in general cognition, clinical severity, activities of daily living, and visuospatial function assessed using standard rating scores and digital pen data. The analyses of the primary and secondary outcomes will be based on the difference in changes during follow-up between the donepezil and control groups using the t-test or Mann–Whitney U test, as well as adjusting for baseline values. DISCUSSION: This study is designed to determine whether eye-tracking metrics can detect the effect of donepezil on visuospatial dysfunction more sensitively in patients with MCI. It is expected that multimodal data, such as eye-tracking and digital pen data, may provide helpful biomarkers for identifying subtle changes that are difficult to measure using conventional methods. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea (CRIS, cris.nih.go.kr) KCT0006236. Registered on June 10, 2021.