A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease

Abstract

Purpose: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy.

Design: An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator.

Participants: Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53).

Methods: After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks.

Main outcome measures: The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire.

Results: CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups.

Conclusions: CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.

Trial registration: ClinicalTrials.gov NCT02617667.

Figure 1.

A, Mean change from baseline for total corneal fluorescein staining over the treatment period for worse eye in the full analysis set (FAS) population. B, Mean change from baseline for central corneal fluorescein staining over the treatment period for worse eye in the FAS population. (1) Statistically significant vs. Restasis (P ≤ 0.05) in analysis of covariance (ANCOVA); (2) statistically significant vs. vehicle (P ≤ 0.05) in ANCOVA. The National Eye Institute (NEI) scale was used to calculate the score. The cornea is divided into 5 regions: central, inferior, superior, nasal and temporal. Each region is graded from 0 to 3, where 0 indicates no staining and 3 maximal staining. The total score is the sum of all 5 regions (maximum score of 15).

Figure 2.

Mean change from baseline for total lissamine green conjuctival staining over the treatment period for worse eye in the full analysis set population. (1) Statistically significant vs. Restasis (P ≤ 0.05) in analysis of covariance (ANCOVA); (2) statistically significant vs. vehicle (P ≤ 0.05) in ANCOVA. Staining followed the Oxford grading scale and was the sum score of the nasal and temporal zones. Each zone is graded from 0 to 5, where 0 indicates no staining and 5 maximal staining. Maximum total score is 10.

Figure 3.

Mean change from baseline for the total Ocular Surface Disease Index (OSDI) score over the treatment period for worse eye in the full analysis set population.