Randomized, Controlled Study to Evaluate the Safety and Efficacy of Oxygen-Enriched Epithelium-On Corneal Cross-Linking for the Treatment of Keratoconus

This phase 3, multicenter, sham procedure/placebo-controlled, double-masked, randomized clinical trial evaluated the safety and efficacy of oxygen-enriched epithelium-on corneal collagen cross-linking (CXL) for the treatment of keratoconus. The trial enrolled patients aged 13 to 51 years diagnosed with keratoconus. Eyes were randomized in a 2:1 ratio to CXL treatment or sham/placebo. The CXL treatment group (200 eyes) received cross-linking using riboflavin 5′-phosphate ophthalmic solutions 0.239% and 0.177% with ultraviolet A (UV-A) irradiation and supplemental oxygen while the sham/placebo group (112 eyes) received placebo solutions and a sham irradiation procedure. The primary efficacy endpoint was the between-group difference in least squares (LS) mean change from baseline in maximum corneal curvature ( K max ) at month 12. Safety outcomes included adverse events and ophthalmic assessments. At month 12, the LS mean K max in the CXL treatment group improved as a change from baseline by 0.5 D (95% confidence interval [CI] 0.7, 0.3; p < 0.0001) and the LS mean K max in the untreated sham/placebo group deteriorated by 0.4 D (95% CI 0.1, 0.8: p = 0.0045). The difference between groups was − 1.0 D (95% CI − 1.3, − 0.6; p < 0.0001). Therefore, the study met the primary efficacy endpoint criterion with both a statistically significant and clinically meaningful change in the mean K max . There were no serious ocular adverse events nor severe treatment-related adverse events in the study eye. The most common adverse event was punctate keratitis (6.5% vs. 1.8% in the CXL and sham/placebo groups, respectively). Epithelium-on CXL using riboflavin ophthalmic solutions (riboflavin 5′-phosphate ophthalmic solutions 0.239% and 0.177%) with UV-A irradiation and supplemental oxygen is safe and effective for the treatment of keratoconus in pediatric patients and adults. ClinicalTrials.gov identifier NCT 05759559.