Reproxalap Activity and Estimation of Clinically Relevant Thresholds for Ocular Itching and Redness in a Randomized Allergic Conjunctivitis Field Trial

Abstract

Introduction: This clinical trial assessed the activity of reproxalap, a novel reactive aldehyde species modulator, and estimated clinically relevant thresholds for changes in ocular itching and redness in an allergic conjunctivitis field trial.

Methods: This was a randomized, double-masked, vehicle-controlled phase 2 trial. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days in an environmental setting with approximately four doses per day of either 0.25% reproxalap, 0.5% reproxalap, or vehicle. Patients recorded ocular itching, redness, tearing, and eyelid swelling scores (each with a 0-4 scale, except for a 0-3 scale for swelling), and completed the Allergic Conjunctivitis Quality of Life Questionnaire at the beginning and end of the trial.

Results: Mixed model of repeated measures analysis demonstrated statistically lower itching and tearing scores (pooled P = 0.026 and P < 0.001, respectively) and numerically lower redness and eyelid swelling scores than vehicle on days when pollen exceeded the 95th percentile value. Using three anchor-based and three distribution-based approaches, the meaningful within-patient change and the between-group meaningful difference for patient-reported ocular itching and redness was estimated to be approximately 0.5. The most common treatment-emergent adverse event associated with reproxalap was transient irritation upon instillation.

Conclusion: In a field clinical trial, reproxalap was well tolerated and superior to vehicle in reducing ocular itching on high-pollen days. The clinical meaningfulness threshold estimates of 0.5 units are among the first such calculations generated for the standard ocular itching and redness scores, providing important context for the clinical interpretation of clinical trials in allergic conjunctivitis.

Keywords: Allergic conjunctivitis; Clinical relevance; Clinical trial; Ocular itching; Ocular redness; RASP modulator; Reproxalap.

Fig. 1

Patient disposition

Fig. 2

Ragweed pollen count by patient day. Frequency represents days across all patients by pollen count

Fig. 3

Patient-reported symptom scores for a ocular tearing, b ocular itching, c ocular redness, and d eyelid swelling during high-pollen days. The range of each scale is 0 (none) to 4 (severe) except for eyelid swelling, which is 0–3. P values were derived from mixed-effect models for repeated measures analysis of change from baseline (the first day of treatment) over all time points in aggregate through the end of the trial (day 28). High pollen was defined as > 95th percentile weed pollen count (325 g/m³) [16]. SEM, standard error of the mean

Fig. 4

Relationship of a ocular itching and b ocular redness scores to quality-of-life scores. For all randomized participants, patient-reported ocular itching and redness scores were plotted relative to Allergic Conjunctivitis Quality of Life Questionnaire (ACQLQ) items for itching and redness, respectively

Fig. 5

Threshold estimates for a meaningful within-patient change, as assessed by anchor-based analyses, and b between-group meaningful difference, as assessed by distribution-based analyses. Squares indicate ocular itching score estimates, and circles indicate ocular redness score estimates. Both ocular itching and redness scores were reported by patients over a range of 0 (none) to 4 (severe). ACQLQ Allergic Conjunctivitis Quality of Life Questionnaire, SD standard deviation, SEM standard error of the mean