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Twice-Daily Vs. Once-Daily Dosing with 0.075% Bromfenac in Durasite: Outcomes from a 14-Day Phase 2 Study

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Twice-Daily Vs. Once-Daily Dosing with 0.075% Bromfenac in Durasite: Outcomes from a 14-Day Phase 2 Study Ophthalmol Ther DOI 10.1007/s40123-017-0102-x ORIGINAL RESEARCH Twice-Daily vs. Once-Daily Dosing with 0.075% Bromfenac in DuraSite: Outcomes from a 14-Day Phase 2 Study William Trattler . Kamran Hosseini Received: June 25, 2017 Ó The Author(s) 2017. This article is an open access publication ABSTRACT Results: A total of 45 subjects had cleared ACC (grade ‘‘0’’) at day 15, of whom 21 were in the Introduction: Bromfenac is a well-known topi- BID group (52.5%) and 24 were in the QD group cal ophthalmic nonsteroidal anti-inflammatory (53.5%). A secondary analysis found 7/40 drug (NSAID) that is commercialized in the USA (17.5%) subjects in the BID group and 10/45 and other regions of the world. A new formu- (22.2%) subjects in the QD group achieved an lation, 0.075% bromfenac in DuraSiteÒ, was ACC grade of 0 at day 8. There were more n = developed to treat postoperative inflammation adverse events in the QD group ( 16) than in n = and reduce pain in patients who have under- the BID group ( 12). gone cataract surgery. We hypothesized that Conclusion: Similar outcomes were observed efficacy and safety would be enhanced with for subjects using Bromfenac 0.075% in Dur- Ò twice-daily (BID) dosing compared to once- aSite in the BID and QD dosing regimens for daily (QD) dosing. the treatment of post-cataract surgery Methods: This was a multicenter, dou- inflammation. Trial registration ble-masked, comparative study in which 40 and : ClinicalTrials.gov identifier, 45 subjects were randomized to groups receiv- NCT01190878. Funding ing BID dosing and QD dosing, respectively. : InSite Vision (now a division of Sun Subjects self-instilled the study drug for 14 days Pharma). postoperative and were followed for an addi- tional 2-week evaluation phase. The primary Keywords: Bromfenac; Cataract surgery; efficacy endpoint was the proportion of subjects Cyclooxygenase inhibitor; DuraSiteÒ; with an anterior chamber cell (ACC) grade of 0 Nonsteroidal anti-inflammatory drugs at day 15. INTRODUCTION Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/ 0AF8F060651D636A. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a well-accepted treatment to reduce post- W. Trattler operative pain after ocular surgery and to con- Center for Excellence in Eye Care, Miami, FL, USA trol inflammation [1–5]. There are numerous NSAIDs approved for ophthalmic use in the & K. Hosseini ( ) USA, including bromfenac. Bromfenac is a InSite Vision, Alameda, CA, USA e-mail: [email protected] potent cyclooxygenase inhibitor with a long Ophthalmol Ther history of use in various strengths for oph- the evaluation phase (days 15 and Day 29). In thalmic indications dating back to 2006 addition, there was a telephone call on day 3 to [1, 2, 6–9]. DuraSiteÒ (InSite Vision, Alameda, obtain visual analog scale (VAS) values for pain/ CA) is a synthetic polymer-based formulation discomfort and photophobia. The subject designed to improve solubility, absorption, self-instilled the study medication, not the bioavailability and residence time. Both clinical investigator or his/her study staff. and nonclinical studies have shown the Dur- Key entry criteria included an anterior aSiteÒ drug delivery system to be safe and chamber cell (ACC) grade of C2 and anterior non-toxic [10]. DuraSiteÒ is commercially chamber flare of C2 in the study eye at the available in the USA in two antibiotic formula- baseline examination on the day after surgery tions (one with 1% azithromycin and the other (day 1); uneventful phacoemulsification sur- with 0.6% besifloxacin), and DuraSiteÒ tech- gery and intraocular lens implantation; avoid- nology has also been used in a formulation of ance of topical, systemic or inhaled salicylates loteprednol gel. or NSAIDs within 1 week before cataract sur- In 2016, the Food and Drug Administration gery, with the exception of oral doses of approved bromfenac 0.075% administered aspirin at 165 mg/day or lower; avoidance of twice daily (BID) for the treatment of postop- topical, inhaled or oral corticosteroid within erative inflammation and prevention of ocular 15 days before cataract surgery and any pain in patients undergoing cataract surgery. depot-corticosteroid within 45 days before cat- The on-label indication recommends that BID aract surgery; no concurrent use of ocular or dosing begin 1 day before surgery and continue systemic antihistamines or mast cell stabilizers on the day of surgery and for 14 days post- within 1 week before surgery, a best-corrected surgery [11]. visual acuity (BCVA) of at least ?1.0 logMAR The purpose of this analysis was to compare (Snellen equivalent of 20/200) in the fellow two dosing regimens of bromfenac 0.075%: eye (non-study eye) and an intraocular pres- once-daily (QD) and BID in post-cataract sur- sure range of [8 and B22 mmHg in the study gery patients to assess safety, tolerability and eye. efficacy. Key exclusion criteria for the study eye included: a history of severe dry eye, active corneal pathology, Fuchs dystrophy, diabetic METHODS retinopathy, previous vitrectomy or epiretinal membrane; any sign of iritis or scleritis; pre- Study Design vious glaucoma or refractive surgery in the previous 2 years; chronic or recurrent ocular or This was a multicenter, randomized, dou- systemic disease that may affect wound heal- ble-masked, parallel-group, comparative sub- ing (e.g. diabetes mellitus, systemic connective group analysis of a larger overall study. Subjects tissue disease, severe atopic disease); use of were randomly assigned in a 1:1 ratio to receive any medication that could interfere with 0.075% bromfenac in DuraSiteÒ BID or 0.075% normal lacrimation within the week prior to bromfenac in DuraSiteÒ QD according to a cataract surgery (including, but not limited to, validated computer-generated central random- NSAIDs/aspirin, antihistamines or mast cell ization schedule. There were a total of 85 sub- stabilizers). jects enrolled: 40 subjects received 0.075% Protocol and informed consent forms for this bromfenac BID (‘‘BID group’’), 45 subjects study were reviewed and approved by an Insti- received 0.075% bromfenac QD (‘‘QD group’’). tutional Review Board (IRB) (New England IRB, Subjects were enrolled post-cataract surgery into Needham, MA) and were provided to the con- a 14-day dosing phase, followed by a 2-week tract research organization (ClinOps LLC, San evaluation phase. Four visits were required for Francisco, CA) before subjects were screened for the study, with two visits taking place during entry. The study is registered with ClinicalTri- the dosing phase (days 1 and 8) and two during als.gov. ID NCT01190878. Ophthalmol Ther Study Drug Secondary Outcome: Efficacy The drug 0.075% bromfenac in DuraSiteÒ is Secondary efficacy endpoints included slit lamp preserved with benzalkonium chloride biomicroscopy results at days 8, 15 and 29, (0.005%). The drug was administered as topical respectively, and VAS results (pain or discom- drops in the postoperative eye either QD or BID fort and photophobia) at days 3, 8, 15 and 29, for 14 days (those in the QD arm were given respectively. vehicle drops for the second administration). DuraSiteÒ is a mucoadhesive material long Statistical Analysis used to enhance the residence time of a phar- maceutical on the ocular surface, has been The frequency of subjects with an ACC grade of evaluated in several other topical ophthalmic 0 was compared between the BID and the QD formulations, and its efficacy and safety data is groups at days 8, 15 and 29 using the standard well known [12–16]. Chi-square test and Fisher’s exact test. To sup- Subject compliance with instillation fre- plement the hypothesis tests, confidence inter- quency was assessed by subject diary. vals for the difference between the BID and the QD groups at each visit in the proportion of Primary Efficacy Outcome subjects with an ACC grade of 0 were computed using Wald’s (asymptotic) method and the The primary efficacy outcome was the propor- Clopper–Pearson (exact) method. tion of subjects with an ACC grade of 0 at day 15 Mean VAS scores for pain were compared (see Table 1 for grading). The proportions of between the BID and the QD groups at days 8, 15 subjects with an ACC grade of 0 for the study eye and 29 using an analysis of covariance model with at days 8, 15 and 29, respectively, were summa- baseline VAS pain score and study site as covari- rized using the last observation carried forward ates. Using the same statistical model as the clin- (LOCF) method for the intent-to-treat (ITT) ical study report, linear contrasts were used to test population and per protocol (PP) population. for equal mean pain scores at each measurement day and to construct confidence intervals (CI) for Table 1 Anterior chamber cell and flare grading the difference. A similar analysis was performed to compare mean VAS scores for photophobia Anterior Anterior chamber flare between the BID and the QD groups. chamber cells Grade Cell Grade Flare count count RESULTS 0 0 0 None: no haze is detected The subject disposition for the two study 1 1–10 1 Mild: a faint haze is detected groups is shown in Table 2. Table 3 shows that there were no major dif- 2 11–20 2 Moderate: haze is easy to detect, ferences between groups at study entry. The but iris details are not majority of subjects were Caucasian in both obscured groups, and the mean age was 71.3 years in the BID group and 70.9 years in the QD group. A 3 21–50 3 Marked: haze is prominent, and similar percentage of subjects were taking at iris details are somewhat least one medication in addition to the study obscured drug: 39/40 (97.5%) in the BID group and 44/45 4 [50 4 Severe: haze is dramatic, and iris (97.8%) in the QD group.
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