Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease - A dose-ranging, randomized trial

Objective: To investigate the efficacy, safety, formulation tolerability, a nd optimal dosing of a novel cyclosporin A oil-in-water emulsion formulatio n for the treatment of moderate-to-severe dry eye disease. Design: Randomized, multicenter, double-masked, parallel-group, dose-respon se controlled trial. Participants: Total enrollment: 162 patients; cyclosporin A groups: 129 pat ients; vehicle group: 33 patients. Intervention: Patients instilled study medication (cyclosporin A ophthalmic emulsion 0.05%, 0.1%, 0.2%, or 0.4%, or vehicle) twice daily into both eye s for 12 weeks, followed by a 4-week posttreatment observation period. Main Outcome Measures: Efficacy: rose bengal staining, superficial punctate keratitis, Schirmer tear test, symptoms of ocular discomfort, and the Ocul ar Surface Disease Index (OSDI; a measure of symptom frequency and impact o n vision-related functioning). Safety: biomicroscopy, cyclosporin A blood l evels, conjunctival microbiology, intraocular pressure, visual acuity, and monitoring of adverse events. Results: In a subset of 90 patients with moderate-to-severe keratoconjuncti vitis sicca, the most significant improvements with cyclosporin A treatment were in rose bengal staining, superficial punctate keratitis, sandy or gri tty feeling, dryness, and itching, with improvements persisting into the po sttreatment period in some treatment groups. There was also a decrease in O SDI scores, indicating a decrease in the effect of ocular symptoms on patie nts' daily lives. There was no clear dose-response relationship, but cyclos porin A 0.1% produced the most consistent improvement in objective and subj ective end points and cyclosporin A 0.05% gave the most consistent improvem ent in patient symptoms. The vehicle also performed well, perhaps because o f its long residence time on the ocular surface. There were no significant adverse effects, no microbial overgrowth, and no increased risk of ocular i nfection in any treatment group. The highest cyclosporin A blood concentrat ion detected was 0.16 ng/ml. All treatments were well tolerated by patients . Conclusions: Cyclosporin A ophthalmic emulsions, 0.05%, 0.1%, 0.2%, and 0.4 %, were safe and well tolerated, significantly improved the ocular signs an d symptoms of moderate-to-severe dry eye disease, and decreased the effect of the disease on vision-related functioning. Cyclosporin A 0.05% and 0.1% were deemed the most appropriate formulations for future clinical studies b ecause no additional benefits were observed with the higher concentrations. (C) 2000 by the American Academy of Ophthalmology.