This was a prospective, single-site, randomized, single-masked, parallel-group pilot study comparing bromfenac ophthalmic solution 0.07% and nepafenac ophthalmic suspension 0.3% in patients undergoing uncomplicated cataract surgery with IOL implantation. The study was initiated at the end of 2013 and completed in March of 2015. The protocol was approved by Sterling Institutional Review Board (Atlanta, GA) on November 2, 2013 and the study was conducted in accordance with the principles of the Declaration of Helsinki approved in 1964 and as revised in 2013. All subjects provided informed consent prior to participation. Participating subjects received study drug, study-related procedures, and study visits at no charge to either themselves or their insurance company.
Adults (≥ 18 years of age) with planned unilateral uncomplicated cataract extraction by phacoemulsification with posterior chamber IOL implantation who could postpone second eye surgery for at least 6 weeks were eligible for participation in the study. No other ophthalmic surgical procedures were allowed within 15 days prior to the initiation of study drug or throughout the duration of the study. Screening (baseline) evaluations were conducted within 8 days before the date planned for cataract surgery and included an assessment of medical history and recording of demographic information, complete bilateral ophthalmic examination [best corrected visual acuity (BCVA), SDOCT, biomicroscopic examination, intraocular pressure (IOP) measurement, and dilated funduscopic examination], and urine pregnancy testing for female participants. Eligible patients were required to have a BCVA of 20/200 or better in either eye at screening, and an IOP between 5 and 22 mmHg in the study eye. Exclusion criteria included known hypersensitivity to bromfenac or nepafenac or their components, salicylates, or other NSAIDs; intraocular inflammation (i.e., cells or flare in the anterior chamber as measured on slit lamp examination) in the study eye at screening; superficial punctate keratitis; other active corneal pathology that was considered nonstable, greater than mild, or might compromise assessment of the safety or efficacy of study treatment; any extraocular/intraocular inflammation in the study eye at screening (blepharitis allowed if mild only, and no concurrent conjunctivitis or lid erythema/edema) or ongoing, unresolved uveitis; and history of radial keratotomy, corneal transplant, or corneal refractive surgery in the study eye within the prior 2 years. Patients with type 1 or 2 diabetes were eligible to participate if there were no ocular findings determined to be clinically significant by the principal investigator. Preexisting macular edema, retinal edema, or more than two microaneurysms within the totality of the fundus constituted exclusions from participation. Use of topical, ocular, or inhaled corticosteroids was not permitted for 14 days prior to screening. The following were not allowed for 7 days prior to study drug initiation: ocular, topical, or systemic NSAIDs; ocular, topical, or systemic gentamicin; or cyclosporine ophthalmic emulsion. Ocular prostaglandin use was not allowed for 30 days prior to study entry.
Enrolled subjects were randomly assigned, according to a computer-generated list, in a ratio of 1:1 to receive either bromfenac ophthalmic solution 0.07% or nepafenac ophthalmic suspension 0.3%. Study drugs were provided in their original FDA-approved packaging. Subjects were instructed to administer one drop daily of their assigned medication beginning 3 days before surgery, one dose on the day of surgery, then QD for 21 days after surgery. The single dose on the day of surgery was felt to be reflective of common clinical practice and differed from the precisely scheduled dosing on surgery day in the nepafenac 0.3% pivotal trial (exactly 30–120 min prior to surgery).
Uncomplicated phacoemulsification with IOL implantation (Tecnis® 9000series; Abbott Medical Optics Inc, Santa Ana, CA or Alcon SN60WF, Alcon Laboratories, Fort Worth, TX) was performed on one eye per subject by a single surgeon. Standard surgical procedure was followed for all subjects, including preoperative anti-infective besifloxacin 0.6% twice daily (BID) and study NSAID 3 days prior to surgery. Intraoperatively, subjects were administered one drop each of prednisolone acetate 1% and moxifloxacin 0.5%; ketorolac 0.4% was administered immediately postoperatively. Besifloxacin 0.6% was given BID for 10 days postoperatively. With the exception of the single drops of prednisolone acetate and ketorolac on the day of surgery, no other ocular steroids or NSAIDs other than study medication were allowed during the period from 7 days prior to initiation of study medication through the duration of the study.
All subjects were required to attend follow-up assessments the day after surgery and then at 7, 21, and 42 days after surgery. For the entire trial, the investigator and any study personnel involved in recording study data were masked to study drug assignment; unmasking was allowed only if necessary for patient safety reasons. The study coordinator reviewed informed consent, inclusion/exclusion criteria with subjects, received the computer-generated list, dispensed study medication, and was responsible for scheduling study visits. Screening evaluations were conducted within 8 days before the date planned for cataract surgery and included a review of medical history and recording of demographic information, complete bilateral ophthalmic examination (BCVA, SDOCT, biomicroscopic examination, IOP measurement, and dilated funduscopic examination), and urine pregnancy test for female participants.
Assessments performed at each study visit included BCVA evaluation [Early Treatment Diabetic Retinopathy Study (ETDRS) letters], biomicroscopic examination, SDOCT, summed ocular inflammation score (SOIS) cell and flare grading, IOP measurement, adverse event (AE) recording, and a review of concomitant medications. At each follow-up visit, BCVA was measured using the ETDRS chart at 4 m in controlled lighting conditions and acuities were recorded using letters read and the logarithm of the minimum angle of resolution system according to the method described by Kaiser  (LogMAR VA = 0.1 + LogMAR value of best line read − 0.002 × number of letters read). Bilateral slit lamp biomicroscopy (without pupil dilation) examination was performed to assess intra- and extraocular inflammation. Dilated funduscopic exams were performed at the initial visit and again at the final study visit (day 42 ± 3).
An experienced ophthalmic technician obtained all Stratus optical coherence tomography (OCT) (Carl Zeiss Meditec Inc, Dublin, CA) scans for all study subjects. OCT captures the interference pattern between backscattered light and a reference beam to create three-dimensional images, which can provide structural and quantitative data regarding ocular structures, including the retina. Two scan patterns were used; the fast macular thickness protocol, using six radial line scans through a common central axis (fovea) with a retinal thickness/volume tabular output and a retinal-thickness output report. Central retinal thickness was defined as the distance between the inner limiting membrane of the retina and the inner border of the choriocapillaris measured in the central 1-mm area of the (minimum) 7-mm posterior pole scan. The Stratus software, Version 5.0, (Carl Zeiss Meditec Inc, Dublin, CA) calculated total macular volume within the 7-mm-diameter scanned area, representing a weighted average of the central, inner, and outer subfields multiplied by the area of the grid measured. Macular volume is an objective indicator of macular thickening or swelling and can be used to demonstrate the amount of inflammation after cataract surgery. All scans were reviewed by the principal investigator for quality of centration and signal strength. Ocular inflammation was calculated using SOIS to quantify cells and flare present in the anterior chamber. Anterior chamber cells were assessed using a slit lamp biomicroscope at ×16 magnification with a 0.3 × 1-mm oblique high-intensity beam. Cell counts were measured twice and converted to a grade (Table 1), by which the mean score was calculated. Anterior chamber flare was measured once and graded using the scale included in Table 1. The SOIS was calculated by combining the sum of the cell and flare grades.
Endpoints and Statistical Analysis
Primary efficacy endpoints were changes from baseline to postoperative day 42 (± 7 days) in BCVA (ETDRS letters), OCT measurements of macular volume and retinal thickness, and SOIS. Secondary efficacy endpoints included safety assessments including AEs, both serious and non-serious, and IOP measurements.
As a small pilot study with a planned sample size of 50 subjects, this study was not powered to establish statistical superiority. All analyses of efficacy were conducted on the intent-to-treat population, which included all randomized subjects who received at least one dose of study medication. Subjects were analyzed in the group to which they were randomized. Paired t tests were used for within-subject baseline comparison of results and between-group comparisons. A p value of less than 0.05 was considered statistically significant.