Bromfenac Ophthalmic Solution 0.07%
`Dosed Once Daily for Cataract Surgery
`
`Results of 2 Randomized Controlled Trials
`
`Thomas R. Walters, MD,’ Damien F. Goldberg, MD,’ James H. Peace, MD,3 James A. Gow, BSc(Med), MD,‘
`for the Bromfenac Ophthalmic Solution 0.07% Once Daily Study Group*
`
`Purpose: To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution 0.07% (Prolensa)
`dosed once daily for the treatment of ocular inflammation and pain in subjects who unden/vent cataract surgery
`with posterior chamber intraocular lens implantation.
`Design: Two phase 3, randomized, double-masked, placebo-controlled, multicenter clinical trials.
`Participants: Four hundred forty subjects (440 study eyes: 222 in the bromfenac group and 218 in the
`placebo group).
`Methods: Two phase 3, prospective, randomized, double-masked, placebo-controlled clinical trials were
`conducted at 39 ophthalmology clinics in the United States. Subjects 18 years of age or older were randomized to
`receive either bromfenac 0.07% or placebo dosed once daily beginning 1 day before cataract surgery, on the clay
`of surgery, and continuing for 14 days after surgery (for a total of 16 days). Subjects were evaluated on days 1, 3,
`8, 15, and 22 after surgery. The primary efficacy end point was cleared ocular inflammation, as measured by the
`summed ocular inflammation score of zero (anterior chamber cell count = 0 and absence of flare) by day 15.
`Secondary end points included cleared ocular inflammation at day 15 and the number of subjects who were pain
`free at day 1. The data from the 2 clinical trials were integrated for analyses.
`Main Outcome Measures: Sumrned ocular inflammation score and ocular pain.
`Results: A significantly higher proportion of subjects treated with bromfenac 0.07% achieved complete
`clearance of ocular inflammation by day 15 and at day 15 compared with placebo (P<0.0001). A statistically
`significantly higher proportion of subjects in the bromfenac 0.07% group were pain free at all study visits
`compared with those in the placebo group (P<0.0001). Fewer subjects in the bromfenac group (3.2%) dis-
`continued investigational product earfy because of a lack of efficacy than in the placebo group (23.9%;
`P <0.0001). The incidence of adverse events was significantly lower in the bromfenac 0.07% group compared
`with the placebo group (P = 0.0041).
`Conclusions: Bromfenac ophthalmic solution 0.07% dosed once daily was clinically safe and effective
`compared with placebo for the treatment of ocular inflammation and pain in subjects who had undergone cataract
`surgery and may be a beneficial addition to the current standard of care, which commonly includes ophthalmic
`antibiotics and corticosteroids. Ophthalmology 2014;121:25-33 © 2014 by the American Academy of Ophthal-
`mo/ogy.
`
`II ‘Group members listed online in Appendix 1 Qvailable at http://aaojournaI.org).
`
`Cataracts are the leading cause of blindness in the United
`States and worldwide.‘ Although approximately 10 million
`cataract
`surgeries are performed annually worldwide,
`untreated cataract-associated blindness is
`increasing by
`approximately 1 million people per year, and those with
`cataracts leading to a visual acuity of worse than 6/60 is
`increasing by 4 to 5 million annually? By 2020, more than
`30 million people in the United States will have a cataract.3
`Numerous population—based studies have shown that age
`and female gender are leading factors for the onset of cat-
`aract3 7; the incidence of a nuclear cataract has been esti-
`mated to occur in 40% of United States adults older than 75
`
`years.8 Buch et al9"° noted that cataract surgery can reduce
`a patient’s visual
`impairment by more than one third
`Different medications have been developed to reduce
`inflammation after cataract surgery,
`including corticoste-
`roids and nonsteroidal anti-inflammatory drugs (N SAIDs).
`Ophthalmic NSA]Ds are used to reduce ocular pain and
`inflammation in patients after cataract surgery, and in the
`United States,
`it
`is becoming more prevalent
`to begin
`NSAID dosing anywhere from 1 to 2 days before surgery.“
`Nonsteroidal
`anti-inflarnrnatory
`drugs
`inhibit
`cyclo-
`oxygenase enzymes that s
`thesize prostaglandins via the
`arachidonic acid pathway.‘
`‘5 Prostaglandins have a crucial
`
`© 2014 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/I4/S - see front mamr
`http://dx.doi,orgIl0.l0I6/j.ophtha20l3.07,006
`
`PAGE 1 OF 9
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`SENJU EXHIBIT 2228
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`LUPIN v SENJU
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`IPR2015—01105
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`

`
`Ophthalmology Volume 121, Number 1, January 2014
`
`role in the onset of postoperative pain and inflammation.
`Bromfenac, a well-studied NSAID, has been shown to be
`a potent inhibitor of cyclooxygenase.16 The United States
`Food and Drug Administration (FDA) has approved several
`NSAIDs for the reduction of postoperative inflammation
`after cataract surgery.17
`Bromfenac sodium is designated chemically as sodium
`2-amino-3-(4-bromobenzoyl)
`phenylacetate
`sesquihy-
`drate.18 The
`additional bromine
`atom increases
`the
`absorption into ocular tissue and increases the duration of
`effect.19 21 In a preclinical14 study in New Zealand White
`rabbits, bromfenac was detected in all ocular tissues 24
`hours after a single dose of the 0.09% concentration.22
`Bromfenac has been studied extensively in the Untied
`States and Japan and has demonstrated effectiveness as
`a topical agent.23 30 In 2000, bromfenac sodium hydrate
`ophthalmic solution 0.1% (Bronuck; Senju Pharmaceuticals
`Co, Osaka, Japan) was approved by the Japanese Ministry
`of Health, Labour and Welfare and currently is approved for
`twice-daily use in Japan as a treatment for blepharitis,
`conjunctivitis, scleritis, and postoperative inflammation.31
`Bromfenac ophthalmic solution 0.09% (Xibrom;
`ISTA
`Pharmaceuticals, Inc, Irvine, CA) was approved by the
`United States FDA in 2005 for twice-daily dosing in the
`treatment of ocular inflammation after cataract surgery with
`posterior chamber intraocular lens (IOL) implantation and
`in 2006 for the treatment of postoperative ocular pain with
`no predosing and twice-daily administration.32 The
`Japanese and United States versions of bromfenac 0.09%
`are identical;
`in computing concentrations,
`the Japanese
`formulation is labeled as the sodium salt (0.1%), whereas
`the United States formula is labeled as the free acid
`concentration (0.09%).
`The pivotal studies on which the FDA based the
`approval
`of
`bromfenac
`ophthalmic
`solution
`0.09%
`(Xibrom) were 2 randomized, double-masked, vehicle-
`controlled United States clinical trials evaluating bromfenac
`0.09% instilled twice daily for 14 days; the results indicated
`that bromfenac 0.09% had a significant effect on reducing
`intraocular inflammation after cataract surgery (62% 66%,
`compared with 40% 48% in the placebo group). Eighty
`percent of bromfenac-treated subjects reported no ocular
`pain on postoperative day 1; the bromfenac group also had
`a statistically significant difference in median time to
`resolution of ocular pain of 2 days compared with 4 days
`for the placebo group.32
`Once-daily dosing has the potential benefits of both
`improved patient compliance and limited ocular exposure to
`the active ingredient.33 After the FDA approval of bromfenac
`ophthalmic solution 0.09%, researchers conducted dose-
`ranging studies including bromfenac 0.09% dosed once
`daily. Four randomized, double-masked, placebo- or active-
`controlled clinical trials then were conducted to evaluate
`bromfenac 0.09% dosed once daily for the same indications
`as its twice-daily counterpart.26 As a result of those clinical
`trials, a once-daily version of bromfenac 0.09% (Bromday;
`Bausch and Lomb, Irvine, CA) was approved in the United
`States in 2010 for the treatment of postoperative inflamma-
`tion and reduction of ocular pain in patients who have
`undergone cataract extraction.18
`
`26
`
`then reassessed the 0.09% once-daily
`Researchers
`formulation to determine if a lower concentration of brom-
`fenac ophthalmic solution would be effective in the treat-
`ment of postoperative pain and inflammation associated
`with cataract
`surgery. Bromfenac ophthalmic solution
`0.07% was formulated using a more physiologic pH (7.8),
`which has been shown to improve penetration into ocular
`tissues.23 Limiting the ocular exposure to a medication may
`result in decreased adverse events (AEs), which is important
`because, historically, ocular NSAID use has resulted in
`small numbers of corneal erosions or melts.34 37 We
`hypothesized that bromfenac 0.07% dosed once daily would
`be safe and effective as a treatment for ocular inflammation
`and pain in subjects who underwent cataract surgery with
`posterior chamber IOL implantation.
`
`Methods
`
`Patients
`
`These 2 multicenter, prospective, randomized, double masked,
`placebo controlled clinical trials received approval from an insti
`tutional review board (Sterling Institutional Review Board, Atlanta,
`Georgia). These clinical trials were conducted in accordance and
`adherence with the Declaration of Helsinki (Edinburgh 2000), the
`Code of Federal Regulations, and the International Conference on
`Harmonisation, including the maintenance of patient confidenti
`ality and compliance with the United States Health Insurance
`Portability and Accountability Act. Both clinical
`trials were
`registered with ClinicalTrials.gov (accessed July 2, 2013) with the
`single identifier of NCT01367249. Written informed consent was
`received from each subject at each of the 39 study sites across the
`United States.
`
`Study Design
`
`The FDA requires that phase 3 clinical trials in this therapeutic area
`be properly controlled by including a placebo control group. This
`phase 3 trial was inclusive of 2 pivotal studies that were conducted
`under the same protocol. Study S00124 ER (ER) enrolled United
`States clinical sites east of the Mississippi River and study S00124
`WR (WR) enrolled United States clinical sites west of the Mis
`sissippi River. The sample size was determined based on previous
`studies26 assessing the use of bromfenac ophthalmic solution
`0.09% with identical study designs in which 27.4% of subjects
`in the control group and 51.1% of subjects in the bromfenac
`group achieved complete clearance of ocular inflammation by
`day 15. Separate randomization sequences were used in each
`study, and each of the 4 groups (ER bromfenac, ER placebo,
`WR bromfenac, and WR placebo) enrolled at least 75 subjects to
`generate sufficient data to demonstrate statistical significance. A
`sample size of 75 subjects per treatment arm would provide 80%
`power to detect a treatment effect, and the calculation was based
`on a 2 sided Fisher exact test of independent proportions con
`ducted with a ¼ 0.05 and was performed using PASS version 2005
`(NCSS Statistical Software, Kaysville, UT). To account
`for
`a potential dropout rate of 30%, the required sample size was
`increased to 200 subjects, 100 per group. A total of 220 subjects
`were enrolled in the ER study and 220 in the WR study and were
`included in the intent to treat group; 416 subjects received at least
`1 dose of either bromfenac 0.07% or placebo and are included in
`the safety analysis.
`
`PAGE 2 OF 9
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`

`
`Walters et al
`
` Once Daily Bromfenac 0.07%
`
`Study Protocol
`
`All subjects were enrolled between May 2011 and July 2011. All
`subjects were screened anywhere from 1 to 8 days before study
`enrollment; subjects who signed the informed consent and met all
`inclusion and exclusion criteria were randomized to receive either
`bromfenac 0.07% or placebo. The enrolled subjects were assigned
`sequentially according to a computer generated randomization list
`to receive either bromfenac ophthalmic solution 0.07% or placebo
`in a 1:1 ratio. The study investigators, staff, and subjects were
`appropriately masked to the identity of the investigational product
`(IP). Subjects were exposed only to the IP that they were provided.
`Dosing began 1 day before surgery, continued on the day of
`surgery, and then continued for 14 days after surgery (for a total of
`16 days). The subjects were instructed to instill one drop of the IP
`into the lower conjunctival cul de sac of the study eye. Concom
`itant medications (i.e., ophthalmic antibiotics) were allowed per the
`investigators’ postoperative standard of care with the exception of
`those listed in the exclusion criteria. Although ophthalmic corti
`costeroids commonly may be used in the management of pain and
`inflammation after cataract surgery, their use was not allowed to
`assess the effect of the IP properly compared with placebo. Follow
`up was at days 1, 31, 81, and 151 after surgery. Subjects then
`were seen on day 22 (þ3) after cataract surgery or, if the subject
`prematurely discontinued the test agent, on day 7 (þ3) after the
`subject’s last dose. The IP could have been discontinued because of
`an AE, lack of efficacy, the use of disallowed medications, or other
`reasons (i.e., cataract surgery did not occur, informed consent was
`withdrawn before the first dose, etc.). For subjects in whom the IP
`was discontinued, attempts were made to have the subject return
`for a safety follow up visit. Rescue medications consisted only of
`ophthalmic NSAIDs, corticosteroids, or both and were given only
`after the subject discontinued because of an AE or because of lack
`of efficacy.
`
`Outcome Measures
`Efficacy. The primary efficacy outcome was cleared intraocular
`inflammation, defined as the proportion of subjects who achieved
`a summed ocular inflammation score (SOIS) of grade 0 by day 15
`(Table 1). The SOIS was assessed by adding the subject’s anterior
`chamber cells and flare grades with the minimum score of
`0 and a maximum score of 8; this protocol has been described
`previously.26,28
`A secondary end point was the proportion of subjects who
`achieved complete clearance of ocular inflammation (SOIS ¼ 0) at
`day 15. The difference between the “at” and “by” day results is that
`the “at” day results included only the subjects who were observed
`to have complete clearance at that visit. Another secondary efficacy
`outcome was ocular pain as evaluated by the ocular comfort
`grading assessment (OCGA) reported in the subjects’ diaries.
`Subjects recorded their ocular pain as none, mild, moderate, or
`severe at screening and throughout all study days. Subjects
`completed their assessment of the 7 symptoms (eye pain, tearing,
`itching, foreign body sensation, photophobia, eye discharge, and
`haziness) within 1 hour after instilling the drop into the study eye.
`A subject was considered to be pain free at a particular visit if there
`was a score of none on the pain scale of the OCGA in the subject
`diary at that visit. The end point determined the proportion of
`subjects who were pain free at day 1. Only the ocular pain data
`from the OCGA was integrated from the 2 trials.
`Other secondary efficacy outcomes included the proportion of
`subjects who achieved an SOIS of grade 0 by and at day 1, day 3,
`and day 8, and the proportion of subjects who achieved an ocular
`pain score of none at day 3, at day 8, and at day 15.
`
`Table 1. Ocular Inflammation Grading Scale for the Calculation
`of the Summed Ocular Inflammation Score
`
`Anterior Chamber Cells*
`Grade
`Cell Count
`
`y
`Anterior Chamber Flare
`Flare Count
`
`Grade
`
`0
`0.5
`1
`2
`3
`4
`
`0
`1e5 cells (trace)
`6e15
`16e25
`26e50
`>50
`
`0
`
`1
`2
`3
`4
`
`Complete absence
`
`Very slight (barely detectable)
`Moderate (iris and lens clear)
`Marked (iris and lens hazy)
`Intense (fibrin clot)
`
`The summed ocular inflammation score was calculated by adding the
`subject’s anterior chamber cells and flare grades with the minimum score of
`0 indicating the absence of inflammation and a maximum score of 8. A
`subject could not be enrolled in the trial if there was the presence of cell or
`flare at the screening visit in either eye.
`*To evaluate, investigators were instructed to use the following methods:
`slit-lamp biomicroscope, use 16 magnification; 11-mm oblique high-
`intensity beam; aim central cornea in pupillary axis; focus in anterior
`aqueous humor; at plane of focus, perform first count of cells; do not focus
`on multiple planes; move focus to central cornea; refocus in anterior
`aqueous humor; at plane of focus, perform second count of cells; convert
`each cell count to a grade (see grading scale above); sum the 2 grades,
`divide by 2 to determine the average final cell score; try to score white
`blood cells only.
`y
`To evaluate, investigators were instructed to use the following methods:
`slit-lamp biomicroscope, use 16 magnification; 11-mm oblique high-
`intensity beam; aim central cornea in pupillary axis; focus in anterior
`aqueous humor; single determination; convert flare analysis to grade (see
`grading scale above); record the flare grade.
`
`Safety. The safety for these clinical trials was assessed by the
`incidence and frequency of ocular and systemic AEs using the
`MedDRA version 14.0 (MedDRA MSSO, McLean, VA). The
`ophthalmologic evaluations
`included visual acuity,
`slit lamp
`examination, intraocular pressure (IOP) assessment, and dilated
`funduscopic examination. The OCGA also was used.
`
`Inclusion Criteria
`
`After completion of the informed consent process, male and female
`subjects 18 years of age or older were eligible for participation in
`the clinical
`trial
`if they were scheduled for unilateral cataract
`surgery (phacoemulsification or extracapsular cataract extraction)
`with posterior chamber IOL implantation without other ophthalmic
`surgical procedures (such as limbal relaxing incisions, iridectomy,
`or conjunctival excisions). At clinical trial entry, baseline medical
`and ophthalmic histories were obtained. The key inclusion criteria
`were visual acuity of 0.6 logarithm of the minimum angle of
`resolution units or better in the nonstudy eye; no ocular, topical, or
`systemic NSAIDs within 1 week of investigational product initia
`tion; no ocular, topical, inhaled, or systemic corticosteroids within
`15 days of the IP initiation; and an IOP between 5 and 22 mmHg in
`the study eye at screening. For women of childbearing potential,
`a negative urine pregnancy test result and agreement
`to use
`a medically acceptable form of birth control for the study period,
`including 1 week before and 1 week after completion of the clinical
`trial, was necessary.
`
`Exclusion Criteria
`
`Subjects were excluded at the screening visit if they had a known
`hypersensitivity to bromfenac or any component of the investiga
`tional products, procedural medications, salicylates, sulfites, or
`
`27
`
`PAGE 3 OF 9
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`

`
`Ophthalmology Volume 121, Number 1, January 2014
`
`other NSAIDs; had extraocular or intraocular inflammation (i.e.,
`any cells or flare in the anterior chamber as assessed using slit lamp
`examination) in either eye at screening, including ongoing, unre
`solved uveitis; had ocular pain (greater than none) on the pain scale
`of the OCGA in either eye at the screening visit; had any active or
`chronic or recurrent ocular or systemic disease that was uncon
`trolled and was likely to affect wound healing; had an uncontrolled
`systemic disease including a bleeding disorder; or had taken anti
`coagulants within 7 days of initiating dosing for this study.
`Additional exclusion criteria included the use of ocular, topical, or
`systemic NSAIDs or gentamicin within the 7 days before initiation
`of dosing with IP or throughout the study; any use of opioid,
`narcotic, or other pain relieving medication that could bias study
`results (with the exception of up to 4000 mg/day of acetaminophen
`or use of an opioid during surgery within 7 days before initiation of
`dosing with the IP or throughout the study); the use of immuno
`modulators such as topical cyclosporine 0.05% within 7 days
`before initiation of dosing with the IP or throughout the study; the
`use of any corticosteroid within 15 days before initiation of dosing
`with the IP or throughout the study; the use of tamsulosin, silo
`dosin, afluzoxin, or finasteride; or the use of any medication within
`7 days before initiation of dosing with the IP or throughout the
`study that could have interfered with normal lacrimation.
`Exclusionary eye pathologic features included any active
`corneal pathologic feature in either eye at screening that was
`nonstable or worse than mild or that would compromise assessment
`of the safety or efficacy of treatment (with the exception of
`superficial punctate keratitis in the nonstudy eye), or use of anterior
`capsule staining for capsulorrhexis. Subjects also were excluded if
`they had undergone corneal transplantation or corneal refractive
`surgery in the study eye within the 2 years before study enrollment.
`
`Study Medications
`
`All study participants were instructed to self instill 1 drop once
`daily into their study eye for a maximum total of 16 days (day
`before surgery, day of surgery, and 14 days after surgery). All IPs
`were provided by the study sponsor (ISTA Pharmaceuticals, Inc)
`and included bromfenac 0.07% and vehicle controlled ophthalmic
`solution (placebo; Bausch and Lomb, Inc). These solutions were
`formulated identically, with the exception that the vehicle did not
`include bromfenac. Bromfenac sodium is a yellow to orange
`crystalline powder that may have caused a slight difference in color
`between the active and the placebo solutions; all other character
`istics of the solutions were indistinguishable. All drops were
`supplied in identical bottles with trial specific labels, and each of
`the bottles was placed into a tamper evident carton. Both the
`bottles and the cartons were masked to all study participants.
`
`Adverse Event Reporting
`
`Adverse events included the incidence and frequency of both
`ocular and systemic events and were collected by the study
`investigators. Event information was collected for any subject who
`had instilled at least 1 dose of the IP. MedDRA version 14.0 was
`used to standardize reporting of the AEs.
`
`Data Analysis and Statistical Methods
`All randomized subjects were included in the intent to treat pop
`ulation. If a subject missed a follow up appointment, the investi
`gators used the last observation carried forward for efficacy
`outcomes. The safety population included all randomized subjects
`who had instilled at least 1 dose of the IP. All data from the
`bromfenac 0.07% groups were pooled for the integrated analyses,
`as were all data from the placebo groups. All data in this summary
`analysis are based on the pooled data. The bromfenac 0.07%
`
`28
`
`treatment group and the placebo group were compared using the
`chi square or Fisher exact test for dichotomous or nonordered
`categorical response measures and the t test or Wilcoxon rank sum
`test for continuous variable and ordered categorical response
`measures.
`
`Results
`
`Demographics and Treatment Allocation
`In the 2 clinical trials, a total of 440 subjects were randomized to
`bromfenac ophthalmic solution 0.07% (n ¼ 222 subjects) or to
`placebo (n ¼ 218; Fig 1). Overall, approximately two thirds of
`subjects in each group were female and approximately three
`quarters were white (Table 2). The proportion of subjects in the
`intent to treat population who completed treatment (defined as
`receiving 16 doses of either the bromfenac 0.07% or placebo) was
`significantly higher in the bromfenac 0.07% group than in the
`placebo group in the pooled data (64.4% [143/222] v. 45.9% [100/
`218]; P ¼ 0.0001). The mean proportion of patient compliance,
`calculated as the number of doses received multiplied by 100 and
`divided by 16, also was significantly higher in the bromfenac
`0.07% group compared with the placebo group (91.2% vs. 76.0%,
`respectively; P < 0.0001).
`
`Efficacy End Points
`
`The primary efficacy end point, the proportion of subjects who
`achieved complete clearance (SOIS of 0) of ocular inflammation by
`day 15, was significantly higher in the bromfenac 0.07% group
`(48.6% [108/222]) than in the placebo group (24.3% [53/218];
`P < 0.0001; Fig 2). The proportion of subjects who had cleared
`ocular inflammation as determined by an SOIS score of 0 was
`significantly greater in the bromfenac 0.07% group than in the
`placebo group by day 8 (29.7% [66/222] vs. 11.9% [26/218],
`respectively; P < 0.0001),
`and this
`continued through the
`remaining study visits. A significantly higher proportion of
`subjects in the bromfenac 0.07% group, compared with those in
`the placebo group, also achieved complete clearance (SOIS of 0)
`at day 8 (27.0% [60/222] vs. 10.1% [22/218],
`respectively;
`P < 0.0001) and at day 15 (45.5% [101/222] vs. 20.6% [45/218],
`respectively; P < 0.001; Fig 3). A secondary efficacy outcome
`was the proportion of subjects who were pain free at each study
`visit. A significantly greater proportion of subjects were pain free
`in the bromfenac 0.07% group than in the placebo group at day 1
`(78.8% [175/222] vs. 49.5% [108/218], respectively; P < 0.0001),
`and this continued through the remaining follow up visits (Fig 4).
`The mean pain scores in the bromfenac 0.07% group were
`significantly lower than those in the placebo group at all follow
`up visits (P < 0.0001 for all comparisons).
`
`Safety End Points
`
`Of the 440 subjects enrolled in these clinical trials, 416 subjects
`received at
`least 1 eye drop and were included in the safety
`analysis.
`
`Adverse Events
`
`A total of 148 (35.6%) of 416 subjects included in the safety
`analysis experienced an AE. There were a total of 276 AEs re
`ported, 170 of which were unique (i.e., excluding repeated reports
`by of the same AE by a subject). The incidence of AEs was
`significantly lower in the bromfenac 0.07% group (28.8% [61/
`212]) than in the placebo group (42.6% [87/204]; P ¼ 0.0041).
`Overall, 31.3% of subjects (n ¼ 130) experienced an AE affecting
`
`PAGE 4 OF 9
`
`

`
`Walters et al
`
` Once Daily Bromfenac 0.07%
`
`Figure 1. Subject disposition flow diagram (consolidated standards of reporting trials [CONSORT]).
`
`the study eye. The incidence of AEs affecting the study eye by
`subjects in the bromfenac 0.07% group (22.6% [48/212]) was
`significantly lower than in the placebo group (40.2% [82/204]; P ¼
`0.0001). Three subjects in the bromfenac 0.07% group (1.4%) and
`4 subjects in the placebo group (2.0%) experienced a serious AE.
`The number of subjects who experienced an AE related to the
`instilled eye drop was lower in the bromfenac 0.07% group (7.1%
`[15/212]) than in the placebo group (21.6% [44/204]).
`Among the subjects treated with bromfenac 0.07%, eye pain,
`anterior chamber inflammation, and foreign body sensation were
`the most frequently reported AEs in the study eye (5.7%, 4.7%, and
`
`Table 2. Subject Demographics
`
`Parameter
`
`Intent-to-treat population, no. of subjects
`Age (yrs)
`Mean (standard deviation)
`Gender, n (%)
`Male
`Female
`Race, n (%)
`American Indian or Alaska Native
`Asian
`Black/African American
`White
`Other
`Iris color (study eye), n (%)
`Black
`Blue
`Brown
`Gray
`Green
`Hazel
`Other
`
`Pooled
`Bromfenac 0.07%
`
`Pooled
`Placebo
`
`222
`
`218
`
`68.4 (10.70)
`
`68.5 (9.68)
`
`81 (36.5)
`141 (63.5)
`
`1 (0.5)
`4 (1.8)
`22 (9.9)
`167 (75.2)
`28 (12.6)
`
`0 (0)
`57 (25.7)
`109 (49.1)
`1 (0.5)
`24 (10.8)
`31 (14.0)
`0 (0)
`
`72 (33.0)
`146 (67.0)
`
`0 (0%)
`8 (3.7)
`17 (7.8)
`162 (74.3)
`31 (14.2)
`
`0 (0)
`65 (29.8)
`93 (42.7)
`5 (2.3)
`21 (9.6)
`33 (15.1)
`1 (0.5)
`
`3.3%, respectively). Among the placebo treated subjects, eye pain,
`anterior chamber inflammation, conjunctival hyperemia, photo
`phobia, and corneal edema were the most frequently reported AEs
`in the study eye (9.8%, 8.8%, 7.4%, 5.4%, and 4.9%, respectively).
`Other reported AEs in the bromfenac 0.07% group included blur
`red vision and photophobia (each 1.9%); conjunctival hyperemia,
`increased IOP, and pruritus (each 1.4%); and corneal edema and
`increased lacrimation (each 0.9%). Other reported AEs in the
`placebo group included foreign body sensation (3.9%); increased
`lacrimation (3.4%); ocular hyperemia (2.9%); vitreous floaters
`(2.5%); and blurred vision, ocular pruritus, and increased IOP
`(each 2.0%).
`Overall, 5.3% (22/416) of subjects experienced a systemic AE.
`The bromfenac 0.07% group and the placebo treatment group did
`
`Figure 2. Graph showing the percentage of subjects with summed ocular
`inflammation score (SOIS) of grade 0 by each study visit.
`
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`Ophthalmology Volume 121, Number 1, January 2014
`
`Discussion
`
`These integrated efficacy and safety clinical results are
`consistent with the individual study findings of bromfenac
`ophthalmic solution 0.07% showing significant improve-
`ments in both primary and secondary end points (Klier SM,
`et al. Phase III clinical trial of low concentration bromfenac
`ophthalmic solution dosed once daily for postoperative
`ocular inflammation and pain. Paper presented at: Annual
`American Society of Cataract and Refractive Surgery
`Symposium on Cataract, IOL, and Refractive Surgery, April
`21-24, 2012; Chicago. Klier SM, et al. Efficacy of low-
`concentration, modified bromfenac ophthalmic solution
`administered once daily for ocular inflammation and pain
`associated with cataract surgery. Paper presented at: Asso-
`ciation for Resarch in Vision and Ophthalmology Annual
`Meeting, May 6-10, 2012; Fort Lauderdale, FL). In these 2
`clinical trials, a significantly greater proportion of subjects
`randomized to bromfenac 0.07% achieved clearance of
`ocular inflammation by day 15 and were pain free at day 1,
`compared with subjects
`randomized to placebo. The
`differences between the “at” versus “by” results for the
`percentage of subjects with an SOIS of grade 0 at each study
`visit were minimal. The subjects treated with bromfenac
`0.07% also had significantly lower numbers of AEs and
`significantly lower IP discontinuation rates compared with
`participants in the placebo group.
`The results with bromfenac 0.07% dosed once daily are
`similar
`to those reported with the use of bromfenac
`ophthalmic solution 0.09% with either once- or twice-daily
`trials,24,25,38 40 bromfenac
`dosing.
`In previous clinical
`ophthalmic solution 0.09% dosed twice daily effectively
`reduced ocular inflammation and resolved ocular pain more
`rapidly than placebo. Studies of once-daily dosing of
`bromfenac 0.09%26,28 also found the NSAID to treat ocular
`inflammation and pain associated with cataract surgery
`effectively. However, the results reported herein involved
`a lower concentration of the active ingredient delivered in
`a modified formulation. Although all of the bromfenac once-
`daily trials used a similar study design, direct comparisons
`between the studies cannot be made. The consistency of the
`results between bromfenac 0.09% dosed twice daily,
`bromfenac 0.09% dosed once daily, and now bromfenac
`0.07% dosed once daily emphasizes the clinical usefulness
`and potency of the bromfenac molecule. The results with the
`modified formulation of bromfenac 0.07% reported in our
`studies indicate that ocular penetration and clinical efficacy
`can be maintained, and possibly improved, while reducing
`the amount of the NSAID on the ocular surface. Another
`key finding in our trials included the safety results: Subjects
`in the bromfenac 0.07% consistently experienced fewer AEs
`compared with subjects in the placebo group, highlighting
`the safety profile of this product.
`There are potential benefits of a medication that can be
`dosed once daily,
`including the potential for improved
`patient compliance, a more favorable safety profile, and
`decreased exposure of excipients. The benefits of once-daily
`topical dosing have been documented in a glaucoma pop-
`ulation33 and in patients with ocular allergies,41 but similar
`
`Figure 3. Graph showing the percentage of subjects with summed ocular
`inflammation score (SOIS) of grade 0 at each study visit.
`
`not differ significantly in the incidence of systemic AEs (5.7% [12/
`212] vs. 4.9% [10/204]; P ¼ 0.83).
`
`Discontinuation Rates
`
`Of the enrolled subjects, 34 (15.3%) in the bromfenac 0.07% group
`discontinued the IP early compared with 96 (44.0%) in the placebo
`group. The 44% early discontinuation rate in the placebo group was
`attributed to the following reasons: AE, 13.3%; lack of efficacy,
`23.9%; the use of a disallowed medication, 0.9%; and other reasons
`(i.e., cataract surgery was not performed, informed consent was
`withdrawn, etc.), 6.0%. A significantly higher proportion of subjects
`in the placebo group (13.3%; n ¼ 29) than in the bromfenac 0.07%
`group (5.0%; n ¼ 11) discontinued the IP early because of an AE
`(P ¼ 0.0026). The proportion of subjects in the placebo group
`(23.9%; n ¼ 52) who discontinued the IP because of lack of efficacy
`also was significantly higher (P < 0.0001) than in the bromfenac
`0.07% group (3.2%; n ¼ 7; Table 3). The proportion of subjects who
`discontinued from either of
`the studies and required rescue
`medications was significantly higher (P < 0.05) in the placebo
`group (39.0% [85/218]) compared with the bromfenac 0.07%
`group (11.3% [25/222]). When rescue medications were needed,
`prednisolone acetate suspension and bromfenac ophthalmic
`solution 0.09% were the most commonly used medications.
`
`Figure 4. Graph showing percentage of subjects with ocular pain score of
`0 at each study visit.
`
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`Walters et al
`
` Once Daily Bromfenac 0.07%
`
`Table