Topical Ocular TRPV1 Antagonist SAF312 (Libvatrep) for Postoperative Pain After Photorefractive Keratectomy

Abstract

Purpose: Evaluation of safety and efficacy of topical ocular SAF312 (Libvatrep) in post-photorefractive keratectomy (PRK) pain.

Methods: In this placebo (vehicle)-controlled, participant- and investigator-masked study, 40 participants were randomized (1:1) to two treatment sequences in a bilateral PRK crossover design (SAF312 2.5% followed by vehicle [or vice versa], one eye drop, four times daily for 72 hours after PRK). Primary endpoints were visual analog scale (VAS) pain scores at 6 hours after first drop of study drug and average VAS scores over 0 to 12 hours postoperatively. Secondary endpoints included postoperative oral rescue medication (ORM) use and adverse events (AEs).

Results: All 40 participants completed the study. Both primary endpoints were met; mean difference in VAS pain scores between SAF312- and vehicle-treated eyes was -11.13 (P = 0.005, -25%) at 6 hours postoperatively and -8.56 (P = 0.017, -22%) over 0 to 12 hours. Mean VAS pain scores with SAF312 were consistently lower than with vehicle from 1 hour postoperatively up to 30 hours (P ≤ 0.10 observed in 8/11 time points). Less ORM was taken with SAF312 up to 0 to 72 hours postoperatively, with a trend of fewer participants taking ORM at 0 to 24 hours postoperatively with SAF312 versus vehicle. No serious AEs were reported. All ocular AEs were mild and transient, and none were drug related. SAF312-treated eyes showed no delay in wound healing and had a lower grade 4 conjunctival hyperemia 24 hours postoperatively versus vehicle-treated eyes.

Conclusions: SAF312 was well tolerated and effective in reducing ocular pain post-PRK.

Translational relevance: Topical SAF312 presents a new therapeutic option for patients undergoing PRK.

Figure 1.

Study design: phase 2, randomized, masked, crossover trial. *As a result of the crossover design, each participant served as their own control (one eye treated with SAF312 and the other eye treated with vehicle). PRK surgery was first performed in the participant's nondominant eye, as determined at screening and agreed upon by the participant and the investigator. Site staff administered the first study dose inside the operating room at the conclusion of the surgery, and subsequent doses were self-administered. The participant returned for follow-up visits on days 2, 3, 4, and 8 of period 1 after surgery in the first eye, with optional daily visits to monitor the participant until wound healing was complete. The second eye surgery (dominant eye) was performed in period 2 (after the resolution of the epithelial defect in the first eye). After the second surgery (period 2), participants received opposing study drug treatment for 72 hours at same dosing schedules and follow-up visits as in period 1. BL, baseline; D, day; N, total number of participants; n, number of participants; Tx, treatment.

Figure 2.

SAF312 2.5% four times daily lowered VAS pain scores versus vehicle (placebo) consistently starting at 1 hour after dosing and during the first 30 hours after PRK. Both primary endpoints (VAS pain at 6 hours and over 0–12 hours) were met. VAS data from the first 10 participants were not evaluable due to failure of the ePRO device. Plotted means are least squares means from the primary efficacy analysis of VAS using a mixed-model repeated measures approach. Any recorded VAS pain score at time points within 4 hours after ORM use was replaced by the VAS record taken immediately before ORM use. **Statistically significant at α = 0.10. n, number of participants; post-op, postoperative.

Figure 3.

More participants did not use ORM (pain was controlled with eye drops alone) during the first 24 hours postoperatively in SAF312-treated eyes than in the vehicle-treated eyes. Secondary analysis set. For both treatment sequence columns, n represents the number of participants who did not use ORM in any treatment group sequence. P value compares the mean of both treatment groups, obtained from McNemar's test; P values for all time points were greater than 0.1. N, total number of participants; n, number of participants.

Figure 4.

Less grade 4 hyperemia in SAF312- versus vehicle-treated eyes 24 hours postoperatively on day 2 in the superior quadrant with the most surgical manipulation (P = 0.040) and fewer grade 3 hyperemia in all quadrants at 48 hours. BL, baseline; S, SAF312; V, vehicle.

Figure 5.

No delay in wound healing in SAF312-treated versus vehicle-treated eyes: wound healing was completed by 72 hours after PRK (day 4). P value compares the mean between both treatment groups, obtained from paired t-tests. Epithelial defect size was calculated by slit-lamp exam as the area of an ellipse calculated by maximum horizontal and vertical distance from center of epithelial defect.