Abstract / Summary
Dry eye disease impairs visual function and quality of life. This trial evaluated the efficacy and safety of grape skin enzyme fermentation extract (KL-GEFE; Nunaezone, Kitto Life Co., Ltd., Pyeongtaek, Republic of Korea), a grape skin enzyme fermentation extract, in adults with ocular fatigue and dry-eye-related symptoms. In this 12-week, randomized, double-blind, placebo-controlled trial at Dankook University Hospital, 68 adults were allocated 1:1 to KL-GEFE (400 mg/day) or placebo. The study protocol specified the Schirmer I test, adapted Eye Strain Questionnaire (ESQ), noninvasive break-up time (NIBUT), fluorescein tear break-up time (TBUT), ocular-surface staining, critical flicker fusion frequency (CFF), and Ocular Surface Disease Index (OSDI) as efficacy outcomes but did not assign them a formal hierarchy. The protocol-specified efficacy analysis used baseline-adjusted analysis of covariance (ANCOVA) in the per-protocol set (PPS; n = 65), with supportive analysis in the full analysis set (FAS; n = 68) using last observation carried forward (LOCF). At week 12, the adjusted KL-GEFE-minus-placebo difference was 4.46 mm for the Schirmer I test (95% CI 2.96–5.95; P < 0.001) and −4.29 points for the adapted ESQ total score (95% CI −8.39 to −0.19; P = 0.041). The corresponding FAS–LOCF estimates were 4.36 mm (95% CI 2.92–5.80; P < 0.001) and −4.56 points (95% CI −8.57 to −0.56; P = 0.026), respectively. The week 12 OSDI difference was not statistically significant, and no statistically significant week 12 between-group differences were observed for NIBUT, fluorescein TBUT, CFF, or ocular-surface staining. Two mild adverse events unrelated to the study product occurred; no serious adverse events occurred. KL-GEFE supplementation was associated with week 12 between-group differences in Schirmer I test values and adapted ESQ total scores, whereas no statistically significant week 12 between-group differences were observed for the other efficacy outcomes. Given the absence of a prospectively defined outcome hierarchy and multiplicity-control framework, these findings should be considered exploratory and require confirmation in prospectively designed trials. Trial registration: Clinical Research Information Service (CRIS; https://cris.nih.go.kr ), KCT0012279, registered on 14 July 2026; retrospectively registered.