Reexamining Ophthalmic Drugs, Safety and Tolerability in Phase 1 Clinical Trials

Abstract

Background: The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHV) as explored in phase 1 trials. Methods: A total of 166 NHV were identified in six phase 1 trials. These included the exposure to lubricant (n=88), hypotensive (n=48) or antibiotic (n=30) ophthalmic drugs, examined in a retrospective analysis. The primary endpoints were visual comfort, assessed by the ocular comfort index (OCI); and safety, evaluated through laboratory evaluations, vital signs, visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and the incidence of adverse events (AE). Other measured parameters included discomfort (assessed by burning, itching and foreign body sensation) and conjunctival impression cytology. Results: Compared to baseline, 72.3%, 39.6% and 66.7% of participants (for lubricant, hypotensive and antibiotic treatments, respectively), improved their OCI score by their final visit (p=0.001). As expected for NHV, laboratory evaluations and vital signs were within normal ranges in 88% of NHV, with no significant differences observed between treatments. Similar results were found for VA, corneal and conjunctival staining and chemosis. IOP decreased significantly in the hypotensive agents group (p=0.001), trace to mild hyperemia was reported in 20.7%, 26% and 5.2% of NHV in each group (p=0.006). Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (AD) of these groups (OR 0.856, 95% CI [0.365, 1.999], and OR 0.636, 95% CI [0.096, 4.195], respectively). Meanwhile, on antibiotic drugs the risk for ID related AE was higher (OR 1.313, 95% CI [0.309, 5.583]). Conclusions: Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHV do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared. Furthermore, it was also demonstrated that the instillation of ID is as safe and tolerable as that of AD in NHV.Trial registration: The studies were registered at clinicaltrials.gov as follows: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.