Comparison of efficacy and safety of Travoprost and Bimatoprost plus Timolol fixed combinations in open angle glaucoma patients previously treated with Latanoprost plus Timolol fixed combination: The G.R.E.A.T. Study Rossetti L 1, Oddone F 2,3, Gandolfi S 4, Hommer A 5, Bohm A 6, Tanga L 2, Sangermani C 4, Haustein M 3, Manni GL 2 and Centofanti M 2,3 1. Clinica Oculistica, Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milan, San Paolo Hospital, Milan, Italy. 2. UOSD Glaucoma, University of Tor Vergata, Rome, Italy. 3. IRCCS Fondazione G.B.Bietti, Rome, Italy. 4. Department of Ophthalmology, University of Parma. 5. Krankenanstalt "Sanatorium Hera", University of Vienna, Vienna, Austria. 6. Augenklinik, Elblandklinikum Radebeul, Radebeul, Germany

Introduction The aim of glaucoma treatment is to maintain visual function and QoL at a sustainable cost 1 by slowing or preventing disease progression The likelihood of maintaining visual function and QoL depends on the amount of visual field damage, the rate of progression (RoP) and life expectancy Reducing intraocular pressure (IOP) is currently the only way to slow or eliminate glaucoma progression 2–6 Even small increases in IOP can significantly increase the risk of progression 6 Each 1 mmHg increase in IOP is associated with an increase in the risk of VF progression of approximately 13–20% 5,6 1. EGS. Terminology and Guidelines for Glaucoma, 3rd edition, Kass et al. Arch Ophthalmol 2002;120:701– Lichter et al. Ophthalmology 2001;108:1943– AGIS. Am J Ophthalmol 2000;130:429– Heijl et al. Arch Ophthalmol 2002;120:1268– Chauhan et al. Arch Ophthalmol 2008;126:1030–6.

Introduction (continued) European Glaucoma Society Guidelines 1 recommend topical monotherapy as first step in the medical management of glaucoma Of the drugs available for topical monotherapy, prostaglandin analogues are the most widely used, because of their IOP lowering efficacy and safety profile. Of the prostaglandin analogues, 2,3 bimatoprost has been shown to have the greatest overall ability to lower IOP 4 If target IOP is not reached, it is recommended to switch or add another drug. 1 The use of combination therapy is frequently necessary, at any stage of the disease 5,6 The advantages of using a fixed combination include no risk of drug washout, fewer side effects, and thus better tolerability and ultimately better patient compliance and quality of life 1,7 1. EGS. Terminology and Guidelines for Glaucoma, 3rd edition, Alm. Prog Retin Eye Res1998;17:291– Alexander et al. Ann Pharmacother 2002;36:504– Aptel et al. J Glaucoma 2008;17:667– Hoyng & Van Beek. Drugs 2000;59:411– Kass et al. Arch Ophthalmol 2002;120:701–3. 7. Dunker et al. Adv Ther 2007; 24:376–86.

Introduction (continued) The first prostaglandin fixed combination commercially available was latanoprost plus timolol (LTFC),followed by the fixed combinations of travoprost plus timolol (TTFC) and bimatoprost plus timolol (BTFC) While several reports have compared the efficacy and safety of the different prostaglandin analogue monotherapies, 1 fewer studies have compared prostaglandin analogue fixed combinations 2,3 It has previously been shown that BTFC is associated with improved IOP control compared with LTFC, with a comparable tolerability profile 2,3 The GREAT study was conducted to evaluate the efficacy and safety of BTFC compared with TTFC in patients with primary open-angle glaucoma (POAG) or pseudoexfoliation glaucoma (PEX) who were previously treated with LTFC but did not reach their target IOP 1.Aptel et al. J Glaucoma 2008;17:667–73. 2.Centofanti et al. Eur J Ophthalmol 2009;19:66–71. 3.Martinez & Sanchez. Eye 2009;23:810–8.

Study design 6-month prospective, multicentre, randomised, investigator masked, crossover study comprising 2 treatment periods of 3 months each *89 patients continued, 2 were lost to follow up **Patients on concomitant latanoprost + timolol for ≥ 3 months underwent wash-in, whereas patients already on LTFC for ≥ 6 weeks did not undergo wash-in Wash-in Baseline 3 months6 months LTFC for at least 6 weeks** BTFC once daily, pm TTFC once daily, pm R 91* patients with POAG or PEX treated with LTFC for ≥ 6 months but not achieving target IOP 6 weeks Screening

Materials and methods Inclusion criteria Diagnosis of POAG or PEX, based on EGS Guidelines criteria 1 Treatment with non-FC of latanoprost and timolol ≥ 3 months or LTFC ≥ 6 months IOP < 21 mmHg at the baseline h time point on LTFC Target IOP not reached as set by treating physician Assessments Screening: VA, refraction, biomicroscopy, gonioscopy, VF (SAP) and IOP measurement at 08.00, 11.00, 14.00, and h Baseline: as above, plus demographics, adverse events (AEs), pachimetry Months 1 and 4: slit lamp, IOP at h, AEs Month 3: IOP measurement at 08.00, 11.00, 14.00, and h, AEs Month 6: as at screening, plus pachimetry Primary outcome Mean diurnal IOP, calculated from the daily IOP curve after 3 months in patients treated with BTFC or TTFC 1.EGS. Terminology and Guidelines for Glaucoma, 3rd edition, 2008.

Results: Mean IOP throughout the day At 3 months, both treatments led to additional reductions from baseline in mean IOP at all 5 time points; BTFC led to significantly greater reductions than TTFC at 3 out of 5 time points* *Combined data from both treatment arms Time point Mean IOP (mmHg) p = p = p = 0.059p = p = 0.19 Baseline TTFC BTFC n = 89

Results: IOP lowering from baseline BTFC provided a 0.7 mmHg greater reduction in mean diurnal IOP at 3 months compared with TTFC (p = )** TTFC BTFC Baseline IOP: 16.5 mmHg * vs baseline p < † BTFC vs TTFC, p = Mean IOP change from baseline (mmHg) * *†*† **Combined data from both treatment arms n = 89

Results: IOP before and after crossover Crossover from TTFC to BTFC led to a reduction in mean IOP of 0.91 mmHg; crossover in the opposite direction led to an increase of 0.43 mmHg TTFC BTFC n = 89 Mean IOP (mmHg) Mean baseline Month 1 (11.00) Mean month 3 Month 4 (11.00) Mean month 6

Results: Tolerability The treatments were equally well tolerated, and neither resulted in an increase in the severity of conjunctival hyperaemia BTFCTTFCp Dry eye2.2% NS Burning eye3.4%0%NS Blurred vision0%1.1%NS Eyelash growth0%1.1%NS Change in severity of conjunctival hyperaemia 0% NS All adverse events in all patients (n = 89)

Summary In this randomised clinical trial, both TTFC and BTFC provided further IOP reduction in glaucoma patients previously treated with LTFC, but BTFC was most effective in reducing IOP: Mean daily IOP after 3 months of treatment was significantly lower during BTFC treatment than during TTFC treatment Following > 6 weeks of LTFC therapy, resulting in a mean baseline IOP of 16.5 mmHg, BTFC resulted in a further 1.72 mmHg reduction in mean diurnal IOP at 3 months As a result, 54.5% of patients achieved mean IOP reductions of 10–40% Overall, BTFC provided a reduction in mean diurnal IOP ~0.7 mmHg greater than that for TTFC (p = 0.004) Crossover from TTFC to BTFC led to a further reduction in mean IOP of 0.91 mmHg; whereas crossover in the opposite direction led to an increase of 0.43 mmHg Both treatments were equally well tolerated, and neither resulted in an increase in the severity of conjunctival hyperaemia

Conclusions IOP lowering remains the only way to treat glaucoma Drug combinations are needed to reach the target IOP in the majority of glaucoma patients A 1 mmHg increase in IOP is associated with a 13–20% increase in the risk of VF progression BTFC is the most efficacious FC we have today For the progressing patient, the earlier and greater the IOP reduction, the better the chances of avoiding visual disability in the patient’s lifetime