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Efficacy and Tolerability of Fixed-Combination Brinzolamide/Timolol in Latin American Patients with Open-Angle Glaucoma or Ocular Hypertension Previously on Brimonidine/Timolol Fixed Combination

Introduction Fixed-combination glaucoma medications are commonly used to achieve target intraocular pressure (IOP) reduction in patients uncontrolled with monotherapy; however, ocular discomfort associated with eye drops can decrease adherence. This study assessed the efficacy and tolerability of twice-daily fixed-combination brinzolamide 1%/timolol 0.5% (BRINZ/TIM-FC) in Latin American patients transitioned from fixed-combination brimonidine 0.2%/timolol 0.5% (BRIM/TIM-FC) because of insufficient IOP control or treatment intolerance. Methods This 8-week, open-label, prospective study was conducted at six sites in Argentina, Chile, and Mexico. Enrolled patients were aged ≥18 years with open-angle glaucoma (including primary, exfoliative, or pigment-dispersion glaucoma) or ocular hypertension with IOP of 19–35 mmHg in ≥1 eye at baseline (on BRIM/TIM-FC). Patients self-administered BRINZ/TIM-FC to both eyes at 8 a.m. and 8 p.m. daily for 8 weeks. The primary and secondary efficacy endpoints were mean IOP change from baseline at week 8 and percentage of patients achieving target IOP (≤18 mmHg) at week 8, respectively. Exploratory endpoints included patient and investigator preference for treatment at week 8. Adverse events (AEs) were assessed as the safety endpoint. Results Fifty patients (mean ± SD age, 66.7 ± 11.5 years) received BRINZ/TIM-FC, and 49 were included in the intent-to-treat population. Mean ± SD IOP was significantly reduced from baseline after 8 weeks of treatment with BRINZ/TIM-FC (−3.6 ± 3.0 mmHg; P < 0.0001, Wilcoxon signed-rank test; 17.1% reduction). Overall, 55.3% of patients achieved IOP ≤18 mmHg at week 8. Significantly more patients (89.4%) and investigators (95.7%) preferred BRINZ/TIM-FC to BRIM/TIM-FC (both P < 0.0001, exact binomial test). Of the 13 AEs observed, 8 were related to BRINZ/TIM-FC; the most common treatment-related AEs were eye irritation (n = 4) and abnormal sensation in the eye (n = 2). Conclusion BRINZ/TIM-FC provides an effective and well-tolerated treatment option for patients transitioned from BRIM/TIM-FC. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0145-5) contains supplementary material, which is available to authorized users.


INTRODUCTION
Glaucoma is a leading cause of blindness in Latin America and worldwide [1]. Globally, nearly 80 million people are projected to be diagnosed with glaucoma in 2020, more than 8 million of whom are expected to be from Latin America [1]. Elevated intraocular pressure (IOP) is a major risk factor for primary open-angle glaucoma [2]; the primary treatment approach to slow progression of glaucoma and ocular hypertension is reducing IOP [3]. Several topical IOP-lowering medications exist; these include medications that decrease aqueous humor production and increase aqueous humor outflow (e.g., carbonic anhydrase inhibitors, bblockers, a-agonists) [3]. Treatment with a single topical agent is often insufficient to control IOP, and many patients require an additional IOP-lowering agent to achieve their targets [3,4]. Concomitant use of multiple ocular hypotensive agents may be inconvenient and has been associated with increased risk of drug washout [5], decreased adherence and persistence [6,7], increased exposure to preservatives and risk of preservative-related ocular surface disease [8,9], and potentially higher treatment costs [10].
Fixed-combination medications for glaucoma enable treatment with multiple mechanisms of action in a single topical medication, providing additive IOP-lowering efficacy without increasing treatment complexity or introducing risk of drug washout. The fixed-combination therapy brinzolamide 1%/timolol 0.5% (BRINZ/TIM-FC; Azarga Ò ; Alcon Laboratories, Inc., Fort Worth, TX, USA) combines a carbonic anhydrase inhibitor (CAI) with a b-blocker and has IOP-lowering efficacy greater than the component monotherapies [11]. Although the safety and efficacy of BRINZ/TIM-FC have been demonstrated in previous studies [12,13], there are few data on the IOP-lowering efficacy of BRINZ/TIM-FC in patients who transitioned to BRINZ/TIM-FC because of insufficient IOP control or intolerance of a fixed combination containing the a-agonist brimonidine. Brimonidine 0.2%/timolol 0.5% fixedcombination therapy (BRIM/TIM-FC; Combigan Ò ; Allergan, Inc., Irvine, CA, USA) has shown efficacy greater than brimonidine or timolol monotherapy alone in patients with glaucoma or ocular hypertension [14].

Efficacy Outcomes
The primary efficacy variable was change in IOP from baseline to week 8. The percentage of patients with IOP B18 mmHg at week 8 was the secondary efficacy variable. IOP was assessed by the same operator with the same tonometer at

Safety Outcomes
Safety was assessed by monitoring adverse event (AE) reports. Ocular signs (evaluated by slitlamp biomicroscopy) and BCVA were evaluated for each eye at all study visits.

Statistical Analysis
If only one eye was eligible for inclusion and treatment, this eye was selected for the efficacy analysis; if both eyes were eligible, the worse eye (i.e., the eye with the higher IOP at baseline) was selected. If both eyes had equal IOP at baseline, the right eye was selected. Efficacy outcomes were analyzed in the intent-to-treat

Patients
Fifty patients were screened and enrolled in the study and included in the safety population.
Open anterior chamber angle was confirmed for all patients. Mean ± SD patient age was 66.7 ± 11.5 years (range 29-87 years); 61.2% of patients were female, and 89.8% were Hispanic (Table 1). Three patients discontinued because of AEs (keratitis, bacterial conjunctivitis, and eye irritation); one patient discontinued between baseline and week 4 and was excluded from the ITT analysis (n = 49), and two patients discontinued between weeks 4 and 8.
The proportion of patients reporting the symptoms described in the ocular symptom survey decreased from baseline to week 8, except for crusting around the eyes, which increased from 12.2% (n = 6/49) to 27.7% (n = 13/47; Table 2). Dry eyes; excessive tearing; and itching of the eyes, eyelids, or the area around the eyes were significantly improved from baseline to week 8 (all P\0.05; Table 2). All but 1 patient (97.9%, n = 46/47) were very confident that they would adhere to their preferred glaucoma medication if it was prescribed by their doctor, compared with 61.7% (n = 29/47) who were very confident that they would adhere to their non-preferred medication if it was prescribed (Table 3). In total, 87.2% (n = 41/47) of patients were very confident they would use a prescribed medication if it did not make their eyes burn or sting, whereas 59.6% (n = 28/47) of patients were very confident that they would use a prescribed medication if it did cause such symptoms (Table 3).   [17]; this study also found that the risk of progression increased by 19% for every 1-mmHg increase in mean IOP [17].
Similarly, the Early Manifest Glaucoma Trial demonstrated that the risk of progression decreased by *10% for every 1-mmHg decrease in IOP from baseline at follow-up visits [18]. This finding was further supported by the Canadian Glaucoma Study follow-up  [20].
The difference in IOP with BRINZ/TIM-FC versus BRIM/TIM-FC in the current study was of greater magnitude than was previously reported [20]; however, the current study did not control for potential non-compliance with prior BRIM/TIM-FC.
The safety and tolerability profiles of BRINZ/ TIM-FC and BRIM/TIM-FC in the current study were similar to previous reports. In a large, multicenter, observational study of more than 14,000 patients throughout Germany who transitioned to BRINZ/TIM-FC from prior IOPlowering medications, nearly 90% of patients judged the tolerability of BRINZ/TIM-FC positively [13]. A total of 75.9% of evaluable patients reported a preference for BRINZ/TIM-FC compared with 8.6% who reported a preference for their previous therapy [13]. Of

ACKNOWLEDGMENTS
This study and article processing charges were sponsored by Alcon Research, Ltd., Fort Worth, TX, USA. Medical writing support was provided by Jane A. Phillips, PhD, and Heather D.
Starkey, PhD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA, USA) and was funded by Alcon. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Conflict of interest. Arturo Alezzandrini and Rene Alfaro have no conflicts to disclose.
Douglas Hubatsch is an employee of Alcon. Funding. This study was sponsored by Alcon Research, Ltd., Fort Worth, TX, USA.
Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.