A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease

Abstract

Purpose: The aim of this study was to evaluate the safety and efficacy of OTX-101, a clear nanomicellar aqueous solution of cyclosporine, in the treatment of dry eye disease (DED).

Patients and methods: This was a 12-week multicenter, randomized, prospective, double-masked, vehicle-controlled, dose-ranging clinical trial. Subjects were adults aged ≥18 years, with a total conjunctival staining score of ≥3 and ≤9, and global DED symptom score ≥40 (0-100 visual analogue scale). Following a 14-day vehicle run-in, subjects were randomized in a 1:1:1 ratio to twice daily treatment with OTX-101 0.09%, OTX-101 0.05%, or vehicle for 84 days. Co-primary efficacy end points were changes, from baseline to Day 84, in the total lissamine green conjunctival staining score in the designated study eye and in the global symptom score (both eyes). Secondary end points included total corneal fluorescein staining score, tear breakup time, and Schirmer's test score.

Results: In total, 455 subjects were randomized. Subjects treated with active drug experienced greater improvement in conjunctival staining than vehicle-treated patients (P<0.01 for both concentrations). All groups demonstrated improvements in global symptom score, but there were no differences among groups. Nominally significant differences were found between the active drug arms and vehicle for corneal staining scores and Schirmer's test scores. Most treatment-emergent adverse events were mild in severity; no serious ocular adverse events were reported.

Conclusions: Both concentrations of OTX-101 met the co-primary sign end point (conjunctival staining) but not the co-primary symptom end point. OTX-101 0.09% demonstrated a notable impact on multiple signs of DED relative to vehicle and was well-tolerated.

Keywords: Schirmer’s test; cyclosporine; dry eye disease; inflammation.

Figure 1

Schematic representation of the study design.

Figure 2

Subject disposition throughout the study.

Figure 3

The mean CFB in total conjunctival lissamine green staining scores by study visit is presented for the vehicle group (open squares), OTX-101 0.05% group (light blue diamonds), and OTX-101 0.09% group (dark blue circles). Note: Statistically significant reductions in the mean CFB relative to vehicle were observed for OTX-101 0.09% at Day 42 (P=0.048), Day 56 (P=0.029), and Day 84 (P=0.0076) and at Day 84 for the OTX-101 0.05% group (P=0.006). Abbreviations: CFB, change from baseline; SE, standard error.

Figure 4

The mean CFB in total corneal fluorescein staining scores by study visit is presented for the vehicle group (unshaded bars), OTX-101 0.05% group (light blue shading), and OTX-101 0.09% group (dark blue shading). Note: Statistically significant reductions in the mean CFB relative to vehicle were observed for OTX-101 0.05% at Day 28 (P=0.0025), Day 42 (P=0.0015), and Day 84 (P=0.024), as well as at Day 28 (P=0.015) and Day 84 (P=0.0003) for the OTX-101 0.09% group. Abbreviations: CFB, change from baseline; SE, standard error.

Figure 5

Schirmer’s tear test responders. Notes: The proportion of subjects with a ≥10 mm improvement in Schirmer’s tear test scores at Day 84, as compared to baseline, is presented for the vehicle group (unshaded bars), OTX-101 0.05% group (light blue shading), and OTX-101 0.09% group (dark blue shading). A statistically higher proportion of subjects with a ≥10 mm improvement in Schirmer’s test scores was observed in the OTX-101 0.09% group (P=0.007) relative to vehicle.