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https://doi.org/10.1177/
European Journal of Ophthalmology 2021, Vol. 31(1) 103– © The Author(s) 2019
Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/ journals.sagepub.com/home/ejo
EJO
European Journal of Ophthalmology
Brinzolamide/brimonidine fixed-dose
combination bid as an adjunct to a
prostaglandin analog for open-angle
glaucoma/ocular hypertension
Fotis Topouzis^1 , Ivan Goldberg2,3,4, Katharina Bell^5 ,
Andrew J Tatham^6 , Antonia Ridolfi^7 , Douglas Hubatsch^8 ,
Marcelo Nicolela^9 , Phillipe Denis^10 and S Fabian Lerner^11
Abstract Purpose: To evaluate the additive intraocular pressure–lowering effect of twice-daily brinzolamide 1%/brimonidine 0.2% fixed-dose combination (BBFC) as an adjunct to a prostaglandin analog (PGA) in patients with open-angle glaucoma or ocular hypertension insufficiently controlled with PGA monotherapy. Methods: In this Phase 4, double-masked trial, patients aged ⩾18 years, with a mean intraocular pressure of ⩾19 and <32 mm Hg in at least one eye were randomized (1:1) to receive BBFC + PGA ( n = 96) or vehicle + PGA ( n = 92) for 6 weeks. The primary endpoint was the mean change in diurnal intraocular pressure from baseline (averaged over 09:00 and 11:00 h) at Week 6. Results: The mean diurnal intraocular pressure at baseline was similar in the BBFC + PGA (22.8 mm Hg) and vehicle
- PGA (22.9 mm Hg) groups. The least squares mean change in diurnal intraocular pressure from baseline at Week 6 was greater with BBFC + PGA (−5.59 mm Hg (95% confidence interval: −6.2 to −5.0)) than with vehicle + PGA (−2.15 mm Hg (95% confidence interval: −2.7 to −1.6)); the treatment difference was statistically significant in favor of BBFC + PGA (–3.44 mm Hg, (95% confidence interval: −4.2 to −2.7); p < 0.001). Ocular adverse events were reported in 21.1% and 8.7% of patients in the BBFC + PGA and vehicle + PGA groups, respectively. The most frequent ocular adverse event was ocular hyperemia (5.3%) in the BBFC + PGA group and blurred vision (2.2%) in the vehicle + PGA group. Conclusion: BBFC + PGA significantly reduced mean diurnal intraocular pressure than PGA alone in patients with open-angle glaucoma or ocular hypertension. The safety findings with BBFC + PGA were consistent with the known safety profile of the individual medications.
Keywords Brinzolamide/brimonidine fixed-dose combination, open-angle glaucoma, ocular hypertension, prostaglandin analogs, intraocular pressure reduction
Date received: 14 December 2018; accepted: 19 August 2019
(^1) Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece (^2) Discipline of Ophthalmology, The University of Sydney, Sydney, NSW, Australia (^3) Glaucoma Unit, Sydney Eye Hospital, Sydney, NSW, Australia (^4) Eye Associates, Sydney, NSW, Australia (^5) Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany (^6) Princess Alexandra Eye Pavilion and Department of Ophthalmology, University of Edinburgh, Edinburgh, UK (^7) Novartis Pharma S.A.S, Rueil-Malmaison, France
(^878044) research-article 2019 EJO0010.1177/1120672119878044European Journal of Ophthalmology Topouzis et al.
Original research article
(^8) Novartis Pharmaceutical Corporation, Fort Worth, TX, USA (^9) Department of Ophthalmology & Visual Sciences, Dalhousie University, Halifax, NS, Canada (^10) Service d’Ophtalmologie, Hôpital de la Croix-Rousse, Lyon, France (^11) Consultorio Oftalmologico Dr. Fabian Lerner and Facultad de Ciencias Medicas, Universidad Favaloro, Buenos Aires, Argentina Corresponding author: Fotis Topouzis, Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki-56436, Greece. Email: [email protected]
104 European Journal of Ophthalmology 31(1)
Introduction
Elevated intraocular pressure (IOP) is the primary risk fac- tor for development and progression of open-angle glau- coma or for conversion of ocular hypertension to glaucoma that may lead to visual field deterioration if left untreated. 1– Reduction of IOP is the mainstay of treatment of open- angle glaucoma and ocular hypertension. European Glaucoma Society guidelines suggest that treatment can be initiated with a monotherapy with prosta- glandin analogs (PGAs) considered as effective first-line ocular hypotensives.5,6^ However, monotherapy may be insufficient to achieve and maintain target IOP in the long term: ~40%–75% of patients require two or more medica- tions for sufficient IOP reduction after 2–5 years of treat- ment.7,8^ Fifty percent of patients require a change of initial monotherapy during the first 2 years of treatment with insuf- ficient IOP-lowering accounting for 80% of these cases.^9 Use of multiple medications or frequent dosing can decrease patient adherence to and persistence with ther- apy,10,11^ which may contribute to insufficient IOP reduction. Use of fixed-dose combinations provides the convenience of two or more medications in a single formulation and a reduction of dosing frequency and exposure to preserva- tives. Hence, use of fixed-dose combinations potentially improves patient comfort, and adherence to and persistence with treatment.12,13^ While the majority of fixed-dose combi- nation therapies for glaucoma treatment include a topical β-blocker, many patients with glaucoma have contraindica- tions to this compound.^5 Brinzolamide 10 mg/mL / brimonidine 2 mg/mL is the only fixed-dose combination ophthalmic suspension (BBFC; SIMBRINZA ®, Novartis Pharma AG) that does not contain a β-blocker. BBFC is indicated twice daily in the European Union and thrice daily in the United States for the treatment of patients with open-angle glaucoma or ocular hypertension. BBFC dosed thrice daily (approved
dosing in the United States) has been shown to effectively lower IOP in patients with open-angle glaucoma or ocular hypertension inadequately controlled with PGA monother- apy. 14,15^ However, data on a twice-daily regimen of BBFC (approved dosing in most countries) as an adjunct to PGA are not available. In this trial, the additive IOP-lowering effect of twice-daily BBFC in patients with open-angle glaucoma or ocular hypertension who were insufficiently controlled on a PGA were evaluated.
Methods
Study design
This was a 6-week, Phase 4, randomized (1:1), double- masked, parallel group trial conducted across 30 sites in 10 countries (Argentina, Australia, Canada, Chile, France, Germany, Greece, Israel, Spain, and the United Kingdom) from 7 August 2015 to 27 February 2018 (NCT02419508). The study had two sequential phases with five visits (Figure 1). Following screening, eligible patients not on a study-specific branded PGA (Travatan ®^ (Travoprost 0.004%, Novartis Pharma AG), Lumigan®^ (Bimatoprost 0.01%, Allergan), or Xalatan®^ (Latanoprost 0.005%, Pfizer)) were assigned a study-specific branded PGA by the trial investigator for a minimum of 28 days prior to screening. Simultaneously, patients on multiple IOP- lowering medications started the appropriate washout period based on the types of additional ocular hypotensive medications (miotics and carbonic anhydrase inhibitors 5 ± 1 days, α and α/β agonists 14 ± 1 days, β-antagonists and PGAs 28 ± 1 days, combination drugs up to 28 ± 1 days). Following the run-in/washout period, eligible patients were randomized 1:1 using interactive response technology to receive twice-daily BBFC or vehicle (09: and 21:00 h) as an adjunct to once-daily PGA (given at bedtime), for 6 weeks (Figure 1).
Figure 1. Study design. BBFC: brinzolamide 1%/brimonidine 0.2% fixed-dose combination; BID: twice daily; E1: eligibility visit 1; E2: eligibility visit 2; IOP: intraocular pres- sure; PGA: prostaglandin analog; QD: once daily. *One drop instilled at 09:00 and 21:00 h. #One drop instilled at bedtime.
106 European Journal of Ophthalmology 31(1)
from baseline; (4) difference between treatments in IOP change from baseline at 11:00 h; (5) difference between treatments in percentage IOP change from baseline at 11:00 h; (6) difference between treatments in IOP change from baseline at 09:00 h; and (7) difference between treat- ments in percentage IOP change from baseline at 09:00 h. Significance for a comparison was claimed only if the null hypothesis was rejected ( p < 0.05) for the previous end- point in the series. Analysis of treatment differences of all secondary endpoints used the same methods as those for the primary endpoint. Exploratory analyses were descrip- tive in nature. Safety results were summarized descriptively for the safety set, which included all patients who received at least one dose of masked investigational drug.
Results
In total, 188 patients were randomized, BBFC + PGA ( n = 96) and vehicle + PGA ( n = 92); of whom, 174 (92.6%) completed the study; AEs were the most common reason for study discontinuation in both groups (Figure 2). The full analysis set and safety set included 187 (99.5%) patients (one patient in the BBFC + PGA group did not receive the investigational drug and was excluded). The mean (SD) age of patients in the full analysis set was 67.2 (11.17) years, 52.4% were female and 92% were White. The proportion of patients diagnosed with open- angle glaucoma and ocular hypertension in the study eye was 81.3% and 18.2%, respectively. Patient demographics and baseline characteristics were similar between the treat- ment groups, except for numerically more female patients in
the BBFC + PGA versus vehicle + PGA group (Table 1). The mean (SD) diurnal IOP at baseline was comparable in the BBFC + PGA (22.8 (2.39) mm Hg) and vehicle + PGA (22.9 (2.32) mm Hg) groups.
Efficacy outcomes
The least squares mean change in diurnal IOP from baseline at Week 6 was greater with BBFC + PGA (−5.59 mm Hg (95% confidence interval (CI): −6.2 to −5.0)) than with vehicle + PGA (−2.15 mm Hg (95% CI: −2.7 to −1.6)); the treatment difference was statisti- cally significant in favor of BBFC + PGA (−3.44 mm Hg, (95% CI: −4.2 to −2.7); p < 0.001). The study met its primary objective (Figure 3). Results of the primary end- point were similar in the subset of patients with 16:00 h data (BBFC + PGA, n = 58; vehicle + PGA, n = 63) at baseline and at Weeks 2 and 6 (Supplementary Table 1). The least squares mean diurnal IOP at Week 6 was 17. (95% CI: 16.7 to 17.9) mm Hg with BBFC + PGA and 20.75 (95% CI: 20.2 to 21.3) mm Hg with vehicle + PGA; the treatment difference was statistically significant −3.44 mm Hg (95% CI: −4.2 to −2.7; p < 0.001). The mean percentage change in diurnal IOP at Week 6 was higher with BBFC + PGA versus vehicle + PGA (treatment difference: –15.1%; p < 0.001, Figure 4(a)). Similarly, the mean change and mean percentage change from baseline at the peak (11:00 h), and trough (09:00 h) time points at Week 6 were also greater with BBFC + PGA versus vehicle + PGA (all p < 0.001, Figure 4(b) and (c)). There was a notable change in mean (SD) diurnal IOP from baseline at Week 2 with BBFC + PGA (–5.
Figure 2. Patient disposition. AE: adverse event; BBFC: brinzolamide 1%/brimonidine 0.2% fixed-dose combination; N : total number of patients; n : number of patients; PGA: prostaglandin analog. *Nineteen patients were screened but not randomized due to an AE ( n = 1), withdrawal by patient ( n = 16), and other ( n = 2).
Topouzis et al. 107
(2.59) mm Hg) versus vehicle + PGA (–1.3 (2.14) mm Hg); the mean percentage reduction was 22.8% and 5.9%, respectively. Target IOP ⩽ 18 mm Hg at Week 6 was achieved by 60.0% of patients with BBFC + PGA versus 20.7% patients with vehicle + PGA. The proportion of patients achieving IOP targets of ⩽12 to ⩽18 mm Hg at Week 6 was higher in the BBFC + PGA group than the vehicle group (Supplementary Figure 1). The ocular perfusion pressure at baseline was comparable between the two groups (Supplementary Table 2). The mean (SD) change from baseline at Week 6 in ocular perfusion pressure was 2.4 (4.30) mm Hg with BBFC + PGA and 0.6 (3.74) mm Hg with vehicle + PGA. The mean change at the 09:00-h and 11:00-h time points at Week 6 were also higher with BBFC
- PGA versus vehicle + PGA (Supplementary Table 2).
Safety outcomes
The median time of exposure was 43 days (minimum: 2 days, maximum: 71 days) in both groups. Overall, 37.9%
and 14.1% of patients in the BBFC + PGA and vehicle + PGA groups experienced at least one AE, respectively. The ocular AE with the highest incidence was ocular hypere- mia (5.3%) in the BBFC + PGA group and blurred vision (2.2%) in the vehicle + PGA group (Table 2). The non- ocular AE with the highest incidence was dry mouth (5.3%) in the BBFC + PGA group (Table 2). One serious AE was reported during the study; an event of cardiac failure (of moderate severity) in the BBFC + PGA group. It was considered by the investigator to not be treatment related. No deaths were reported during this study. Treatment-related AEs occurred in 22 (23.2%) patients in the BBFC + PGA group and 4 (4.3%) patients in the vehi- cle + PGA group (Supplementary Table 3). Treatment dis- continuations owing to AEs were reported for eight (8.4%) patients in the BBFC + PGA group (ocular discomfort in two patients, and arrhythmia, cardiac failure, allergic con- junctivitis, ocular hyperemia, and dizziness in one patient each) and three (3.3%) patients in the vehicle + PGA group (allergic conjunctivitis, eye allergy, and anxiety in one patient each).
Table 1. Demographics and baseline characteristics (full analysis set).
Characteristics BBFC + PGA N = 95
Vehicle + PGA N = 92
Age, years (mean (±SD)) 66.5 (10.70) 67.9 (11.65) Gender, female, n (%) 55 (57.9) 43 (46.7) Race, n (%) White 87 (91.6) 85 (92.4) Black or African American 5 (5.3) 7 (7.6) Asian 3 (3.2) 0 (0.0) Ethnicity, n (%) Hispanic or Latino 23 (24.2) 29 (31.5) Not Hispanic or Latino 72 (75.8) 62 (67.4) Unknown 0 (0.0) 1 (1.1) Baseline diurnal IOP (mean (±SD), mm Hg) 22.8 (2.39) 22.9 (2.32) Baseline IOP category, n (%) 19–26 mm Hg 89 (93.7) 84 (91.3) 27–32 mm Hg 6 (6.3) 7 (7.6) PGA monotherapy, n (%) Bimatoprost 0.01% 32 (33.7) 30 (32.6) Latanoprost 0.005% 38 (40.0) 37 (40.2) Travoprost 0.004% 25 (26.3) 25 (27.2) Corneal thickness (mean (± SD) μm) 539.1 (34.43) 545.5 (33.73) Corneal thickness categories ⩽0.55 μm 57 (60.0) 45 (48.9)
0.55–0.60 μm 35 (36.8) 43 (46.7) 0.60 μm 3 (3.2) 4 (4.3) Diagnosis, n (%) Open-angle glaucoma 78 (82.1) 74 (80.4) Ocular hypertension 17 (17.9) 17 (18.5)
BBFC: brinzolamide 1%/brimonidine 0.2% fixed-dose combination; N : total number of patients; PGA: prostaglandin analog; SD: standard deviation; n : number of patients; IOP: intraocular pressure. One patient with an IOP level < 19 mm Hg was randomized in error from the site and received treatment. This patient was included in the full analysis set. Baseline IOP is expressed as mean (SD) and defined as the average of 09:00 a.m. and 11:00 a.m. values.
Topouzis et al. 109
reported with thrice-daily dosing of BBFC in earlier studies (Fechner et al. (BBFC + PGA): AEs 35.5%, serious AEs (SAEs) 1.1%, ocular hyperemia 5.4%, and blurred vision 9.7%; Feldman et al. (BBFC + travoprost): AEs 37.6%, SAEs nil, ocular (conjunctival) hyperemia 12.8%, blurred vision 6%).14,15^ However, this is not unexpected given the twice-daily versus thrice-daily dosing regimens of BBFC.
An added advantage of BBFC in patients with open- angle glaucoma/ocular hypertension is that it is the only available fixed-dose combination without a β-blocker. Many patients with glaucoma have co-morbidities such as chronic pulmonary obstructive disease, asthma, or bradycardia. β-blockers are known to cause systemic adverse reactions, including bradycardia, irregular pulse,
Figure 4. (a) Mean percentage change in diurnal IOP from baseline at Week 6 (full analysis set), (b) mean change in IOP from baseline at 11:00 (peak) and 09:00 (trough) time points at Week 6 (full analysis set), and (c) mean percentage change in IOP from baseline at 11:00 (peak) and 09:00 (trough) time points at Week 6 (full analysis set). n : number of patients with non-missing values of diurnal IOP change and any of the other covariates in the model at the corresponding time point of interest; BBFC: brinzolamide 1% and brimonidine 0.2% fixed-dose combination; CI: confidence interval; IOP: intraocular pressure; LS: least squares; SE: standard error; PGA: prostaglandin analog.
110 European Journal of Ophthalmology 31(1)
and asthma, especially in the elderly. 21,22^ For example, the use of timolol maleate has increased the need for bronchodilator therapy in 47% of patients with glau- coma. 23 BBFC may be a suitable treatment option for elderly patients with glaucoma and patients in whom β- blockers are contraindicated. This is evident from the present study as well as from earlier studies in which BBFC has been safe and effective in patients with glau- coma or hypertension (mean age > 65 years). 14, However, indication for use depends on the ever-present balance between benefit versus risk. Use of BBFC in elderly patients with the risk of glaucoma, but without a definitive diagnosis of measurable damage, needs to be justified. One strength of this study is that it included patients from multiple countries; one weakness was the relatively short duration of follow-up, another was the lack of 24-h IOP monitoring.
Conclusion
The study results suggest twice-daily BBFC as an adjunct to PGA is a suitable treatment option for patients with open-angle glaucoma or ocular hypertension for whom PGA monotherapy provides insufficient IOP reduction. The safety profile of BBFC + PGA was consistent with the known safety profiles of brinzolamide, brimonidine, and PGAs.
Acknowledgements The medical writing support and editorial assistance during the development of the manuscript was provided by Swati Bhandari (Novartis Healthcare Pvt Ltd, Hyderabad, India).
Declaration of conflicting interests The author(s) declared following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.T. received grants/research support from Alcon, Pfizer, Novartis, and Thea; consultation fees from Alcon, Bayer, Allergan, Pfizer, and Thea; company sponsored speaker’s bureau: Novartis, Thea, Alcon, Allergan, and Santen. M.N. received research grant from Allergan, Novartis/Alcon, and Aerie; and advisory boards for Allergan and Novartis/Alcon. S.F.L. received grants/research support/speaker from Allergan, Glaukos, Iridex, and Novartis/Alcon. A.J.T. received grants/research support from Novartis, Heidelberg Engineering, Allergan, Inc., Sensimed, and Thea; is a consultant for Allergan, Inc. P.D. is a consultant for Thea, Allergan, Novartis. I.G. is a Advisory Board Member for Novartis, Allergan, and Mundipharma; speaker at supported Symposia for Novartis, Allergan, Mundipharma, and Pfizer. A.R. and D.H. are employees of Novartis. K.B. had nothing to disclose.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by Novartis Pharma AG, Basel, Switzerland.
Trial registration This trial was registered with ClinicalTrials.gov (NCT02419508).
Supplemental material Supplemental material for this article is available online.
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Table 2. Adverse events (safety set).
System organ class; preferred term
BBFC + PGA N = 95
Vehicle + PGA N = 92
Any event, n (%) 36 (37.9) 13 (14.1) Ocular AEs (any event) 20 (21.1) 8 (8.7) Ocular AEs (⩾2%) Ocular hyperemiaa^ 5 (5.3) 1 (1.1) Conjunctival hyperemia a^ 4 (4.2) 1 (1.1) Vision blurred 2 (2.1) 2 (2.2) Dry eye 3 (3.2) 0 (0.0) Eye irritation 3 (3.2) 0 (0.0) Ocular discomfort 3 (3.2) 0 (0.0) Non-ocular AEs (any event) 19 (20.0) 6 (6.5) Non-ocular AEs (>2%) Dry mouth 5 (5.3) 0 (0.0) Fatigue 2 (2.1) 0 (0.0) Nasopharyngitis 4 (4.2) 0 (0.0) Dizziness 2 (2.1) 0 (0.0) Hypertension 2 (2.1) 0 (0.0)
BBFC: brinzolamide 1%/brimonidine 0.2% fixed-dose combination; PGA: prostaglandin analog; IOP, intraocular pressure; N : total number of patients; n : number of patients; AE: adverse event; MedDRA: Medical Dictionary for Regulatory Activities A patient with multiple occurrences of an AE under one treatment was counted only once in this AE category for that treatment. MedDRA version 17.0 used for reporting of AEs. aBased on investigator’s judgment.
