AG-920 (Articaine) Ophthalmic Solution: A Masked,Active-Controlled Evaluation of Its Local Anesthetic Efficacy and Safety in Pediatric Patients

Introduction

Ophthalmologists and optometrists use topical, ocular local anesthetics for a wide variety of diagnostic examinations and procedures. A local anesthetic, articaine, is under development for use as a topical ocular agent. It is formulated as a sterile, non-preserved, unit dose (AG-920 sterile ophthalmic solution, 8%). In preclinical models, it elicited a rapid onset and potentially clinically useful duration of corneal anesthesia, was well tolerated, and did not cause any clinical or histopathological toxicity. Following both preclinical and clinical ocular administration, there was limited systemic exposure. ¹ In two double-masked, placebo-controlled trials in adult subjects, AG-920 provided a rapid onset of local anesthesia (<1 min) with clinically and statistically significantly greater effect in AG-920 (68% and 83%) than placebo (3% and 18% for Study 1 and Study 2, respectively, P < 0.0001). ²

The clinical evaluation of novel drugs has been conducted primarily in adults. In response to input from numerous parties, including pediatricians and parents, the Best Pharmaceuticals for Children Act (BPCA) was passed by the United States (U.S.) Congress in 2002 and renewed every five years since then. The U.S. Food and Drug Administration (FDA) currently requires all applications for new drugs (based on ingredients, dosage forms, routes, or indications) to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable (21 U.S.C. 355c).

We designed and conducted an evaluation of AG-920 in pediatric patients. The primary objective of this study was to evaluate the anesthetic efficacy of AG-920 by measuring the proportion of subjects in which an eye exam was able to be performed. The secondary objective was to evaluate the safety and tolerability of AG-920 by evaluating the incidence of adverse events.

Methods

This was a Phase 3, randomized, active-controlled, single-masked, parallel-group design study in healthy pediatric subjects performed at a private practice retina clinic in the U.S. It was designed to evaluate the safety and anesthetic efficacy of one dose of AG-920 compared to proparacaine hydrochloride (HCl) ophthalmic solution 0.5% (Bausch & Lomb, Tampa, FL). This study was approved by an Institutional Review Board, and parent/legal guardians provided informed consent (and where applicable, subjects provided assent). Subjects who fulfilled all the inclusion criteria and none of the exclusion criteria were randomized in a 1 per 1 ratio. Each dose of AG-920 or proparacaine HCl consisted of two drops administered 30 s apart in the study eye. Two to four minutes after the completion of dosing, subjects underwent an eye exam, and the ability to conduct that eye exam was documented.

Eligible for inclusion in the study were male individual or female individual aged 10 years or less (prepubescent with no childbearing potential) who were capable of undergoing an eye examination with a healthy, normal cornea and for whom an ophthalmic examination was planned. Excluded from the study were individuals who had participated in an investigational study (drug or device) within the past 30 days, had a known contraindication to local anesthetics, with known autism spectrum disorders or known to have heightened sensitivity, or had known ocular structural or functional pathology that would interfere with the study measures.

Due to the obvious differences in bottles, an “overwrap” was used on the marketed product. The subject and parent/legal guardian were masked for the treatment assignment.

Per the protocol, assessment of efficacy was a determination by the investigator as to whether there was adequate local anesthetic effect to perform the eye exam for which the subject was seeing the ophthalmologist. In preverbal subjects, pain was judged as crying, wincing, irregular breathing, squeezing eyes shut, arching body, or flailing arms and legs. To the investigator, these behaviors were distinguishable from wiggling.

All treatment-emergent adverse events (TEAEs) occurring during the study, regardless of the assumption of causal relationship, were to be documented on the electronic case report form (eCRF).

Based upon investigator judgement, visual acuity (VA) was measured with an age-appropriate optotype (if capable) with clinically appropriate test (either Teller acuity charts, Allen pictures, HOTV letters, or Snellen acuity, per standard of care), or reaction to light.

An external eye examination was conducted at Visit 1 (screening). External eye examination may have been performed using a slit lamp. Magnification was consistent with standard clinical practice. The clinician examined the eyelid, conjunctiva, cornea, anterior chamber, iris, pupil, and lens. Biomicroscopy was only performed post-dose if there was a suspected adverse event that would require the exam.

The study planned to randomize at least 60 evaluable subjects in a 1 per 1 allocation ratio for AG-920 and reference groups. This sample size was as directed by the U.S. FDA for an approved Pediatric Study Plan, rather than being estimated based on a predefined non-inferiority margin commonly used for the trial design of therapeutical equivalence.

Results

Sixty-one subjects were screened, of which 60 were randomized and treated, all of whom completed the study. There were similar proportions of female individuals and male individuals; the mean age was 5.8 (± 2.9) years (range 7 months to <11 years), and the majority of subjects were white (59/60, 98%). The most frequent eye color was brown (58/60, 97%). There were no statistically significant differences between groups (Table 1). In this pediatric population, there were relatively few ocular or systemic medical history conditions or concomitant medications reported. All subjects underwent dilated ophthalmoscopy and scleral depression. Visual acuity was assessed by Snellen acuity (33/60, 55%), reaction to light (18/60, 30%), or Allen pictures (9/60, 15%).

In all subjects in each treatment group, the investigator was able to perform the eye examination without additional local anesthetic (Fig. 1).

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FIG. 1.

Physician Performed Eye Exam.

There were no adverse events reported in this study. In both the study eye and fellow eye, there were no changes of note after dosing, and both treatment groups were similar. All external eye exams in all subjects in both treatment groups were normal.

Discussion

In this active-controlled, single-masked study, the planned ophthalmic examination was able to be conducted in all subjects in each treatment group. From a safety perspective, there were no adverse events, and no changes observed in biomicroscopy in either treatment group.

Under guidance from the U.S. FDA, we allowed the inclusion of patients as young as newborns, as regulatory policy allows extrapolation up to older patients but not down to younger patients. The challenges of conducting an evaluation of anesthesia in a pediatric population, including younger, nonverbal patients, are well recognized. Measures such as Cochet–Bonnet ethesiometry are clearly not possible in this population. The selection of the primary outcome as “was an examination able to be performed” was made based upon discussion with FDA.

We searched the literature and U.S. package inserts for controlled studies of local ocular anesthetics in children. The only article we found was that of Enyedi et al. ³ in which the authors evaluated postoperative treatments (topical lidocaine gel or sub-Tenon’s bupivacaine and appropriate placebos) on pain in a pediatric population (aged 13–87 months) over a period of one hour or greater using the Children’s Hospital Eastern Ontario Pain Scale. This scale is validated for children aged 1–8 years. This scale was not relevant for the present study given the much younger patients, and the relatively brief period of the stimulus, an eye examination rather than longer lasting postoperative pain.

In healthy adult volunteers in previous studies, the Sponsor had selected a conjunctival pinch test as a way to measure efficacy out to 30 min after dosing. ² We did consider using the same methodology in some of the older children in the present study as in the adult efficacy studies; however, this would have led to a confusing efficacy analysis—i.e., different measures within the same study.

We considered the potential for systemic exposure to articaine in pediatric subjects. In this pediatric study, the total dose administered was ∼0.18 to 2.7 mg/kg (based on an estimated range of body weight of 3 to 45 kg). This dose is much less than the no-observed adverse effect level demonstrated in multiple nonclinical toxicity studies, ⁴ and much less than the maximum recommended dose of dental product for pediatric patients (7 mg/kg articaine). While systemic exposure was not evaluated in this pediatric clinical study, extrapolation of the exposure in nonclinical and clinical studies indicates that exposure to articaine in plasma in this study would be well below that associated with any systemic toxicity.

In conclusion, in this pediatric population aged 7 months to >11 years, AG-920 was therapeutically equivalent to marketed proparacaine with respect to having an ophthalmic examination performed without needing additional local anesthetic. Further, AG-920 was well tolerated, and there were no clinically significant safety findings.