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12-Week, Randomized, Multicenter Study Comparing Fixed-Combination Brimonidine-Timolol and Timolol as Adjunctive Th

12-Week, Randomized, Multicenter Study Comparing Fixed-Combination Brimonidine-Timolol and Timolol as Adjunctive Therapy to Latanoprost.

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12-Week, Randomized, Multicenter Study Comparing Fixed-Combination Brimonidine-Timolol and Timolol as Adjunctive Th

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  1. 12-Week, Randomized, Multicenter Study Comparing Fixed-Combination Brimonidine-Timolol and Timolol as Adjunctive Therapy to Latanoprost Robert D. Fechtner, MD1; Paul Harasymowycz, MD2; Donald R. Nixon, MD3; Steven D. Vold, MD4; FiazZaman, MD5; Julia Williams, MA6; David A. Hollander, MD, MBA6 1Glaucoma Division, UMDNJ-New Jersey Medical School, Newark, NJ, USA; 2University of Montreal, Montreal, QC, Canada; 3Royal Victoria Hospital, Barrie, ON, Canada; 4Boozman-Hof Regional Eye Clinic, Rogers, AR, USA; 5Houston Eye Associates, Houston, TX, USA; 6Allergan, Inc., Irvine, CA, USA Study funded by Allergan, Inc. Robert D. Fechtner, MD is a consultant to and has received research support from Allergan, Inc. Drs. Paul Harasymowycz , Donald R. Nixon, Steven D. Vold, and FiazZaman received research support from Allergan, Inc. Ms. Julia Williams and Dr. David A. Hollanderare employees of Allergan, Inc.

  2. Introduction • Patients with glaucoma and ocular hypertension (OHT) frequently require multiple IOP-lowering medications to control their intraocular pressure (IOP). • Over 20% of patients treated with a prostaglandin analog (PGA), the most efficacious class of IOP-lowering medications, may be required to add another IOP-lowering medication to their treatment regimen within a year of initiating treatment.1 • Approximately 42% of patients in the Ocular Hypertension Treatment Study (OHTS) initial medical treatment group were on 2 or more IOP-lowering medications at year 13.2 • When multiple-drug therapy is needed, use of a fixed combination of 2 IOP-lowering medications in 1 bottle may be preferred to enhance patient convenience and compliance.3 • The fixed combination of brimonidine 0.2%-timolol 0.5% (Combigan®; Allergan, Inc.) has been demonstrated to reduce IOP more effectively than either brimonidine 0.2% or timolol 0.5% used alone and to be better tolerated than brimonidine 0.2% monotherapy.4 • Combigan®has also been shown to be as efficacious and well tolerated as concomitant use of separate bottles of brimonidine 0.2% and timolol 0.5%.5 • The efficacy and safety of Combigan®used as adjunctive therapy to PGAs such as latanoprost has not been extensively studied. • The purpose of this study was to evaluate the additive IOP-lowering efficacy and safety of Combigan® compared with timolol 0.5% when used as adjunctive therapy to latanoprost in glaucoma and OHT patients who require additional IOP lowering.

  3. Methods • This was a prospective, randomized, multicenter, investigator-masked, parallel-group study. • Eligible patients were adults at least 18 years of age with a diagnosis of glaucoma or OHT requiring treatment with IOP-lowering medication. • All patients were treated with latanoprostmonotherapy once daily in the evening for at least 4 weeks prior to the baseline visit. • Patients on IOP-lowering medications at screening underwent a 4-week washout of all medications other than latanoprost. • Patients not on latanoprost at screening were run in on latanoprost for 4 weeks. • At the baseline visit, patients who had IOP ≥ 21 mm Hg in at least 1 eye continued on latanoprost and were randomized to adjunctive treatment with twice-daily Combigan®(n = 102) or timolol (n = 102) for 12 weeks. • IOP was measured at 8 am and 10 am at baseline, week 6, and week 12. • The primary efficacy endpoint was IOP lowering at peak effect (10 am) at week 12. • Safety measures included adverse events (AEs). • Efficacy was evaluated in the worse eye (the eye with higher IOP at baseline) in the per-protocol population of patients with no major protocol violations. • IOP and change from baseline IOP at weeks 6 and 12 were analyzed by ANCOVA with baseline IOP as the covariate.

  4. Results: Patient Population and Disposition Patient Demographics • Study completion rates were similarly high in each treatment group (93.1%, 95/102 in the Combigan®group and 94.1%, 96/102 in the timolol group). • The per-protocol patient population represented 95.6% (195/204) of all randomized patients.

  5. Results: Mean Change From Latanoprost Baseline IOP at 10 am, Week 12 (Primary Endpoint) • There were no statistically significant differences between treatment groups in mean IOP at baseline on latanoprost. • At 10 am, baseline mean IOP was 23.4 mm Hg in the Combigan® group and 23.0 mm Hg in the timolol group (P = .229). • At 10 am, week 12, Combigan®provided 2.1 mm Hg greater IOP lowering compared with timolol when used as adjunctive therapy to latanoprost (P < .001). P < .001 vstimolol. Error bars, SEM.

  6. Results: Percentage of Patients Achieving ≥ 30% Reduction in IOP From Latanoprost Baseline at Week 12 • At week 12, patients treated with adjunctive Combigan®were significantly more likely than patients treated with adjunctive timolol to achieve a ≥ 30% decrease in IOP from latanoprost-treated baseline at both peak and trough effect. Trough Effect (8 am) Peak Effect (10 am) P < .001 vstimolol. P = .006 vstimolol. Combigan® (n = 96) Timolol(n = 94) Combigan® (n = 94) Timolol(n = 94)

  7. Results: Percentage of Patients Achieving IOP < 18 mm Hg at Week 12 Patients With IOP < 18 mm Hg at Both Peak and Trough • At week 12, patients treated with adjunctive Combigan® were significantly more likely than patients treated with adjunctive timolol to consistently achieve IOP < 18 mm Hg at both peak (10 am) and trough (8 am) effect. P = .028 vstimolol. Combigan® (n = 94) Timolol(n = 94)

  8. Safety Assessment Incidence of Adverse Events, n (%) • Both adjunctive study treatments were well tolerated. • The overall incidence of AEs and treatment-related AEs was low in both treatment groups. • The rate of discontinuations due to AEs (not necessarily related to treatment) was 4.9% in the Combigan® group and 2.0% in the timolol group. a Determined to be unrelated to treatment.

  9. Discussion • Achievement of a low target IOP minimizes the risk of vision loss in glaucoma.6,7 • For patients using a PGA who need lower IOP, the addition of a fixed combination provides substantial additional IOP lowering while adding only 1 bottle and 2 drops to the patients’ daily regimen. • In this study, glaucoma and OHT patients on latanoprost who added Combigan®were significantly more likely that patients who added timolol alone to achieve IOP < 18 mm Hg and 30% or larger reductions in IOP. • Adjunctive Combigan® provided an 8.3 mm Hg reduction in IOP at peak effect at week 12, approximately 2 mm Hg larger than the 6.2 mm Hg reduction provided by adjunctive timolol (P < .001). • The results are consistent with a previous study in which Combigan®reduced IOP at least as effectively as fixed dorzolamide-timolol when used as adjunctive therapy to a PGA.8 • In both studies, adjunctive use of Combigan®was well tolerated with few discontinuations due to adverse events. • Adjunctive Combigan®provides the IOP-lowering efficacy of 2 additional medications while minimizing the number of drops used to maintain compliance.

  10. Conclusions • Combigan®reduced IOP significantly more effectively than timolol when used as adjunctive therapy to latanoprost in patients who needed additional IOP lowering. • Adjunctive treatment with Combigan®and timolol was well tolerated.

  11. References • Covert D, Robin AL. Adjunctive glaucoma therapy use associated with travoprost, bimatoprost, and latanoprost. Curr Med Res Opin. 2006;22(5):971-976. • Kass MA, Gordon MO, Gao F, et al; Ocular Hypertension Treatment Study Group. Delaying treatment of ocular hypertension: the ocular hypertension treatment study. Arch Ophthalmol. 2010;128(3):276-287. • Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension an evidence-based review. Ophthalmology. 2005;112(6):953-961. • Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vsmonotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124(9):1230-1238. • Goñi FJ; Brimonidine/Timolol Fixed Combination Study Group. 12-week study comparing the fixed combination of brimonidine and timolol with concomitant use of the individual components in patients with glaucoma and ocular hypertension. Eur J Ophthalmol. 2005;15(5):581-590. • The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429-440. • Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E; Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56. • Nixon DR, Yan DB, Chartrand JP, Piemontesi RL, Simonyi S, Hollander DA. Three-month, randomized, parallel-group comparison of brimonidine-timolol versus dorzolamide-timolol fixed-combination therapy. Curr Med Res Opin. 2009;25(7):1645-1653.

  12. Author Bio ROBERT D. FECHTNER, MD Professor/Director, Glaucoma Division Institute of Ophthalmology and Visual Science New Jersey Medical School, UMDNJ Newark, New Jersey Robert D. Fechtner, MD graduated from the University of Michigan School of Medicine. He completed his residency at Albert Einstein College of Medicine in 1989 and his glaucoma fellowship at University of California, San Diego under a National Research Service Award from the National Institutes of Health. He is now Professor of Ophthalmology and Director of the Glaucoma Division at the Institute of Ophthalmology and Visual Science, New Jersey Medical School in Newark. Dr. Fechtner is an active member of numerous scientific and medical organizations. He has held committee or leadership positions in the American Academy of Ophthalmology, the Association for Research in Vision and Ophthalmology, the American Society of Cataract and Refractive Surgery, the American Glaucoma Society, the International Society for Imaging of the Eye and the Association of International Glaucoma Societies. He has served on the editorial boards of American Journal of Ophthalmology, Journal of Glaucoma, Review of Ophthalmology, Video Journal of Ophthalmology, and Eyenet. In addition to a busy clinical and surgical practice, Dr. Fechtner maintains an active clinical research laboratory concentrating on new technologies and treatments. He has published over 150 peer-reviewed articles, book chapters and abstracts.

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