Corneal Crosslinking for Progressive Keratoconus and Corneal Ectasia: Summary of US Multicenter and Subgroup Clinical Trials

PURPOSE: The multicenter studies reviewed were designed to evaluate the safety and efficacy of corneal collagen crosslinking (CXL) for the treatment of progressive keratoconus and corneal ectasia after laser refractive surgery. The results of these studies led to approval by the United States Food and Drug Agency for both conditions in 2016. This paper reviews these studies, as well as single-center substudies investigating other aspects of crosslinking outcomes. METHODS: As part of prospective, randomized, controlled clinical trials, the treatment group received standard CXL, and the sham control group received only riboflavin ophthalmic solution. The primary efficacy criterion was maximum keratometry (K(max)) 1 year after CXL. Secondary outcomes were corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA). Safety and adverse events were analyzed. In single-center substudies, corneal topography, ocular aberrations, corneal haze measurements, corneal thickness, corneal biomechanics, subjective visual function, and outcomes predictors were also investigated. This paper presents a general review of the design and outcomes of crosslinking in these studies. RESULTS: In the crosslinking treatment group, K(max) flattened by 1.6 diopters (D) and 0.7 D in eyes with keratoconus and ectasia, respectively. In both studies, there was continued progression in the control group. The CDVA improved by an average of 5.7 logMAR letters (LL) in the keratoconus treatment group and by 5.0 LL in the ectasia group. In both studies, corneal haze was the most frequently reported crosslinking-related adverse finding. This was most prominent at 1 month and generally returned to baseline between 3 and 12 months. In general, corneal topography, ocular aberrations, and subjective visual function improved after crosslinking. CONCLUSIONS: In the US multicenter trials, CXL was shown to be safe and effective in stabilizing K(max), CDVA, and UDVA in eyes with progressive keratoconus or corneal ectasia. TRANSLATIONAL RELEVANCE: Corneal crosslinking was originally developed in the laboratory at the University of Dresden in the late 1990s. The combination of ultraviolet-A light and riboflavin was found to be the most effective of a number of different modalities tested to increase the biomechanical strength of the cornea. The clinical study design for the US multicenter clinical trials of crosslinking demonstrated the safety and effectiveness of this technique for treatment of progressive keratoconus and corneal ectasia, bringing this important advancement to patients in the United States.