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 (Kmax) at month 12. Safety outcomes included adverse events and ophthalmic assessments. At month 12, the LS mean Kmax 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 Kmax 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 Kmax. 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.