Bimatoprost 0.03%/Timolol 0.5% Preservative-Free Ophthalmic
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BJO Online First, published on March 25, 2014 as 10.1136/bjophthalmol-2013-304064 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2013-304064 on 25 March 2014. Downloaded from Bimatoprost 0.03%/timolol 0.5% preservative-free ophthalmic solution versus bimatoprost 0.03%/timolol 0.5% ophthalmic solution (Ganfort) for glaucoma or ocular hypertension: a 12-week randomised controlled trial Ivan Goldberg,1 Rafael Gil Pina,2 Aitor Lanzagorta-Aresti,3 Rhett M Schiffman,4 Charlie Liu,4 Marina Bejanian4 ▸ Additional material is ABSTRACT As topical medications are normally dispensed published online only. To view Aim To compare the efficacy and safety of single-dose from multiuse bottles, preservative (typically ben- please visit the journal online (http://dx.doi.org/10.1136/ bimatoprost 0.03%/timolol 0.5% preservative-free (PF) zalkonium chloride, BAK) is employed to maintain bjophthalmol-2013-304064). ophthalmic solution with bimatoprost 0.03%/timolol sterility. Although many patients use preservative- 0.5% ophthalmic solution in patients with open-angle containing medications without adverse effects,10 11 1Department of Ophthalmology, University of glaucoma or ocular hypertension. some become sensitive to ophthalmic preserva- 12 13 Sydney, Sydney Eye Hospital, Methods In this multicentre, randomised, parallel- tives. A single-dose, preservative-free (PF) oph- Sydney, Australia group study, patients were randomised to bimatoprost/ thalmic fixed combination would benefit this patient 2 Clinica Oftalmologica Rafael timolol PF or bimatoprost/timolol once daily in the subpopulation. Our study evaluated the safety and Gil Pina, Huelva, Spain fi fi fi 3Fundacion Oftalmologica Del morning for 12 weeks. Primary ef cacy endpoints, ef cacy of a new PF xed-combination bimatoprost Mediterraneo, Valencia, Spain reflecting differing regional regulatory requirements, 0.03%/timolol 0.5% (bimatoprost/timolol PF; 4Allergan, Inc., Irvine, included change from baseline in worse eye intraocular Ganfort SD) for patients who are sensitive or aller- California, USA (at the time pressure (IOP) in the per-protocol population at week gic to preservatives. the study was conducted) 12, and the average eye IOP at weeks 2, 6 and 12 in Correspondence to the intent-to-treat population. METHODS Professor Ivan Goldberg, Results 561 patients were randomised (278 to Study design and participants Department of Ophthalmology, bimatoprost/timolol PF; 283 to bimatoprost/timolol); This was a phase 3, multicentre, double-masked, University of Sydney, Sydney 96.3% completed the study. Both treatment groups randomised, active-controlled study (ClinicalTrials. Eye Hospital, Floor 4, 187 fi Macquarie Street, Sydney, NSW showed statistically and clinically signi cant mean gov: NCT01177098) conducted in 55 centres in 2000, Australia; decreases from baseline in worse eye IOP and in average Australia, Czech Republic, Germany, Hungary, eyegoldberg@gmail.com eye IOP at all follow-up time points (p<0.001). Israel, Russia, Spain, UK and the USA. It complied Bimatoprost/timolol PF met all pre-established criteria for with Good Clinical Practice guidelines and was http://bjo.bmj.com/ Received 22 July 2013 non-inferiority and equivalence to bimatoprost/timolol. approved by an institutional review board or inde- Revised 25 January 2014 Accepted 15 February 2014 Ocular adverse events were similar between treatment pendent ethics committee. Written informed groups, with conjunctival hyperaemia being the most consent was obtained from each patient prior to frequent. Most were mild or moderate in severity. study enrolment. Conclusions Bimatoprost/timolol PF demonstrated Eligible participants were aged at least 18 years, non-inferiority and equivalence in IOP lowering had OHT or open-angle glaucoma, and were either fi compared with bimatoprost/timolol, with no signi cant treatment-naive with IOP >24 mm Hg in at least on September 28, 2021 by guest. Protected copyright. differences in safety and tolerability. one eye or were receiving IOP treatment that was Trial registration number NCT01177098. considered to be inadequate (IOP >18 mm Hg in at least one eye). At baseline, following 4 days’ to 4 weeks’ washout of IOP-lowering medications, patients were required to have an IOP of 22– INTRODUCTION 30 mm Hg in each eye, with IOP asymmetry Bimatoprost is a synthetic prostamide,1 which is <4 mm Hg between eyes and a best-corrected highly effective in lowering intraocular pressure visual acuity (BCVA) equivalent to a Snellen score (IOP) in patients with ocular hypertension (OHT) of 20/100 or better in each eye. The minimum or open-angle glaucoma.2 If single agents fail to washout period was 4 days for parasympathomi- achieve a satisfactory IOP reduction or are intoler- metics and topical or systemic carbonic anhydrase able, fixed combinations are preferred to multiple inhibitors, 2 weeks for sympathomimetics and α concurrent medications.34The fixed combination agonists, and 4 weeks for β-adrenergic blocking of bimatoprost 0.03%/timolol 0.5% (bimatoprost/ agents, combination products and prostaglandin To cite: Goldberg I, Gil timolol; Ganfort, Allergan, Irvine, California, USA) agonists. Primary exclusion criteria were: uncon- Pina R, Lanzagorta-Aresti A, administered once daily has been shown to be well trolled systemic disease; known allergy or sensitiv- et al. Br J Ophthalmol Published Online First: tolerated and to be effective in patients with inad- ity to the study medications or their components; [please include Day Month equate IOP lowering with a single ocular hypoten- introduction or anticipated alteration in ongoing – Year] doi:10.1136/ sive medication,5 8 as well as in treatment-naive use of medication that may have a significant effect bjophthalmol-2013-304064 patients.9 on IOP; ocular surface findings (eg, hyperaemia or GoldbergCopyright I, et al. Br Article J Ophthalmol author2014;0 :1(or–6. doi:10.1136/bjophthalmol-2013-304064their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. 1 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2013-304064 on 25 March 2014. Downloaded from irritation equal to +0.5 (trace) or greater) in either eye; history A two-sided 95% CI for the treatment difference was con- (within 6 months prior to baseline) of any ocular anterior structed from the ANOVA model with an estimated treatment segment laser or other intraocular surgery in either eye; required difference based on least squares means. Bimatoprost/timolol PF chronic use of other ocular medications during the study; visual would be considered equivalent to bimatoprost/timolol if the field loss that in the opinion of the investigator was functionally 95% CI upper limit was ≤1.5 mm Hg and the lower limit was significant or evidence of progressive visual field loss; or antici- ≥–1.5 mm Hg at all time points, and the upper limit was pated wearing of contact lens in either eye during the study. ≤1.0 mm Hg and the lower limit was ≥–1.0 mm Hg at the majority of time points. Treatment and assessments The proportion of responders, defined as patients with a Eligible patients were randomly assigned (1:1) at each investiga- ≥20% reduction in worse eye IOP from the corresponding hour tor site (by automated interactive voice/web response systems) to (hour 0, 2 or 8) of baseline at week 12, was also analysed in the once-daily treatment in the morning in each eye with bimato- ITT population. Treatment group differences were assessed prost/timolol PF or bimatoprost/timolol for 12 weeks. The ran- using Pearson’s χ2 test. domisation scheme was prepared by the study sponsor. Randomisation was stratified by baseline mean diurnal IOP Sample size calculations (≤24 mm Hg or >24 mm Hg). Patients were dispensed study Sample size calculations were based on a one-sided α=0.025, medication kits containing unit-dose (single-use) containers that 80% power and an assumption of no difference between treat- were identical for both formulations, thereby ensuring masking ment groups. The sample size needed to demonstrate the non- of patients, investigators and evaluators. The treatment was to inferiority of worse eye IOP (1.5 mm Hg inferiority margin) be instilled in the morning to facilitate timing of study assess- and equivalence in average eye IOP (equivalence limit of ments. Compliance was assessed by the investigator who kept a ±1.5 mm Hg at all follow-up time points, and of ±1.0 mm Hg detailed inventory of the units dispensed and reconciled con- at the majority of follow-up time points) were estimated. The tainers returned to the study site. largest sample size from these estimates ensured adequate power IOP was measured using a slit lamp-mounted Goldmann for all criteria, given an expected 10% dropout rate. applanation tonometer, and a two-person masked reading method (ie, one adjusts the dial in a masked fashion while the RESULTS second reads and records the value) at 8:00 (hour 0), 10:00 and Baseline demographics and patient characteristics 16:00 at baseline, and at weeks 2, 6 and 12. Two consecutive The study was initiated on 31 October 2010 and completed on measurements were taken of each eye; if these two measure- 21 February 2012. A total of 561 patients were enrolled with ments differed by ≤1 mm Hg, the IOP for the given eye was the 540 (96.3%) completing the study; 278 were randomised to average of the two readings. If the difference between measure- bimatoprost/timolol PF and 283 were randomised to bimato- ments was >1 mm Hg, a third measurement was made, and the prost/timolol (see online supplementary figure S1). The demo- IOP for the given eye was the median of the three readings. graphic and baseline data did not show any significant Safety parameters included adverse events (AEs; coded using differences between the groups (table 1). the Medical Dictionary for Regulatory Activities V.14.1), biomi- croscopy, fundus examinations (including vertical cup/disc Efficacy ratio), macroscopic bulbar conjunctival hyperaemia (graded by Worse eye PP analysis http://bjo.bmj.com/ gross inspection in comparison with standard photographs), At baseline, there were no statistically or clinically significant dif- visual acuity, visual field measurements and vital signs.