A placebo-controlled, blinded study to evaluate the functionality and safety of grapefruit enzyme fermentation extract (KL-GEFE, Nunaezone) on improving eye fatigue and dryness

This 12-week randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of grape skin enzyme fermentation extract (KL-GEFE, Nunaezone) in adults aged 18 years or older with symptoms of eye fatigue and dry eye. Of 70 screened participants, 68 eligible subjects were randomized equally to the test and control groups (34 each). Sixty-five completed the study, and the per-protocol set included 33 subjects in the test group and 32 in the control group. The test group received KL-GEFE 400 mg once daily for 12 weeks, while the control group received a matching placebo. Efficacy outcomes included Non-Invasive Break-Up Time (NIBUT), Tear Break-Up Time (TBUT), corneal and conjunctival staining scores, Critical Flicker Fusion (CFF), subjective eye-fatigue questionnaire (Eye Symptom Questionnaire; ESQ), Ocular Surface Disease Index (OSDI), and the Schirmer test. Between-group comparisons were analyzed using ANCOVA (Analysis of Covariance) adjusted for baseline values. Baseline characteristics and product compliance were comparable between groups. At Week 12, the Schirmer test in the right eye increased by 2.73±5.26 mm from baseline in the test group, whereas it decreased by 1.69±3.34 mm in the control group; the adjusted between-group difference was 4.46 mm (95% CI 2.60–6.31, p<0.0001). In the left eye, the test group increased by 1.73±3.96 mm, while the control group decreased by 2.41±4.51 mm, yielding a between-group difference of 4.53 mm (95% CI 2.78–6.28, p<0.0001). The ESQ total score decreased from 17.42±12.89 to 10.03±9.97 in the test group, with a Week 12 between-group difference of -4.29 points (95% CI -8.39 to -0.19, p=0.041). OSDI decreased from 31.85±18.44 to 20.36±16.42 in the test group; the Week 12 between-group difference did not reach statistical significance but showed a favorable trend (-7.22 points, 95% CI -14.76 to 0.32, p=0.060). CFF in the STNS (Seeing-To-Not-Seeing) direction improved significantly within the test group, but the between-group difference was not significant. No significant between-group differences were observed for NIBUT, TBUT, or corneal and conjunctival staining scores. In the safety analysis, one mild adverse event occurred in each group; both were unrelated to the study product and resolved. No serious adverse events occurred, and no clinically meaningful abnormalities were observed in vital signs, body weight, intraocular pressure, best-corrected visual acuity, fundus examination, or slit-lamp examination. Overall, 12-week supplementation with KL-GEFE 400 mg significantly improved aqueous tear secretion and subjective ocular symptoms compared with placebo and demonstrated a favorable safety profile.