24-Hour Control with a Latanoprost-Timolol Fixed Combination Vs Timolol Alone

CLINICAL SCIENCES 24-Hour Control With a Latanoprost-Timolol Fixed Combination vs Timolol Alone Anastasios G. P. Konstas, MD, PhD; Symeon Lake, MD; Athanasios I. Economou, MD; Kostantinos Kaltsos, MD; Jessica N. Jenkins, BS; William C. Stewart, MD Objective: To evaluate 24-hour intraocular pressure more than timolol alone at each time point and for the (IOP) control with an evening-dosed latanoprost– 24-hour curve (2.9 mm Hg), and provided a lower ab- timolol maleate fixed combination vs timolol alone in pa- solute IOP at each time point (PϽ.001) and for the range tients with primary open-angle glaucoma. (fluctuation) in IOP (P=.003) and for the 24-hour curve. Several adverse effects were observed more often with the Methods: After a medicine-free period, qualified pa- latanoprost-timolol fixed combination, including ocu- tients were randomized to either placebo dosed in the morn- lar stinging (P=.05), conjunctival hyperemia (P=.02), and ing with a latanoprost-timolol fixed combination dosed in ocular itching (P=.04). the evening or timolol alone dosed twice daily for 8 weeks. Patients were then switched to the opposite treatment for Conclusion: The evening-dosed latanoprost-timolol fixed 8 weeks. At baseline and at the end of each treatment pe- combination may provide better IOP control than timo- riod, patients underwent IOP measurements. lol alone over 24 hours and may demonstrate a nar- rower range of IOP fluctuation in patients with primary Results: Both treatments reduced the IOP from un- open-angle glaucoma. treated baseline at each time point and for the 24-hour curve (PϽ.001). When treatments were compared, the latanoprost-timolol fixed combination decreased the IOP Arch Ophthalmol. 2006;124:1553-1557 HE LATANOPROST–TIMOLOL the difference from the individual com- maleate fixed combina- ponents of the latanoprost-timolol fixed tion (Xalacom; Pfizer, Inc, combination.2 New York, NY) was com- Accordingly, a recent 24-hour study by mercially released in Eu- Konstas and coworkers6 showed that the Trope in 2001. This product, and other fixed latanoprost-timolol fixed combination combinations, has the advantage of dos- compared with latanoprost alone, both ing convenience and, consequently, po- dosed in the evening, provided a wider tentially improved compliance. margin (mean, 2.5 mm Hg) over 24 hours In the regulatory trials of Pfeiffer and as- than the morning dosing used in the regu- sociates1 and Higginbotham and cowork- latory trial. However, little data still exist ers,2 morning dosing of the fixed combi- evaluating 24-hour pressures with the nation further reduced the intraocular evening-dosed fixed combination com- pressure (IOP) compared with latano- pared with timolol dosed twice daily. prost (1.9 and 2.9 mm Hg) or timolol (1.2 This trial evaluates the 24-hour effi- and 1.0 mm Hg) dosed twice daily. cacy and safety of the latanoprost- The reason for the relative lack of effi- timolol fixed combination dosed once each Author Affiliations: Glaucoma cacy has not been explained. However, it evening vs timolol alone dosed twice daily Unit, A University Department may be in part because the fixed combi- in patients with primary open-angle glau- of Ophthalmology, AHEPA nation was instilled in the morning in both coma (POAG). Hospital, Thessaloniki, Greece regulatory trials, whereas latanoprost alone (Drs Konstas, Lake, Economou, was dosed in the evening in the study by METHODS and Kaltsos); Pharmaceutical Higginbotham et al.2 Previously, Alm and Research Network, LLC, coworkers3 and Konstas and associates4,5 Charleston, SC (Ms Jenkins and PATIENTS Dr Stewart); and Carolina Eye have demonstrated that nighttime dosing Institute at the University of of latanoprost provides lower daytime pres- Consecutive patients were recruited for this pro- South Carolina School of sures than morning dosing. Therefore, the spective study from the Glaucoma Unit of the Medicine, Columbia study design of the regulatory trials itself A University Department of Ophthalmology, (Dr Stewart). may have limited the daytime efficacy and AHEPA Hospital. All patients who agreed to par- (REPRINTED) ARCH OPHTHALMOL / VOL 124, NOV 2006 WWW.ARCHOPHTHALMOL.COM 1553 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 ticipate in the study and met the inclusion and exclusion crite- sible within the hospital boundaries. During the study (includ- ria were enrolled. Patients included were older than 29 years; ing during examinations and IOP measurements), the inves- had early to moderate POAG (Ͻ12 mean deviation visual field tigators and staff were masked to the treatment regimen. loss attributed to glaucoma and 0.8 or better vertical cup-disc Medicine labels were removed, and the medicines were kept ratio); at untreated baseline, had a mean IOP at 10 AM (2 con- in an opaque medicine vial. Patients were aware only of the col- secutive readings) higher than 23 mm Hg; had a reliable visual ored bottle cap of the study treatment. field (at least 2 visual fields with Ͻ30% fixation losses, false posi- Patients were instructed regarding correct medication in- tives or negatives); had a best-corrected distance Snellen visual stillation and compliance. In this study, all patients were in- acuity greater than 1/10; had corneal pachymetry results within structed to perform nasolacrimal occlusion for 1 minute after the mean±SD of 550±55 µm range; understood the study in- instillation of each study eyedrop. At each visit, local and sys- structions and were willing to attend all follow-up appoint- temic adverse effects that occurred during the treatment pe- ments; were willing to comply with study medication use; and riod were recorded. Adverse effects were evaluated by asking had open normal-appearing angles. patients a general query about their state of health. Patients also Patients excluded had risk for significant deterioration dur- were queried about their compliance to the study medicine. ing the study; had a known history of lack of response (Ͻ10% reduction) to any topical glaucoma medication; had systemic contraindications to topical ␤-blockers (asthma, bradycardia, STATISTICS or severe congestive heart disease); had known contraindications to prostaglandins, a history of ocular herpetic disease, or The primary efficacy variable was the mean level of the 24- cystoid macular edema; had a history of trauma, inflamma- hour pressure curve (average mean pressures measured through- tion, surgery, or use of corticosteroids (within 2 months); had out the day) between study treatments. This study had an 80% severe dry eyes; used contact lenses; had signs of ocular infec- power to identify a 1.5–mm Hg difference between individual tion, except blepharitis; had a corneal abnormality that may affect time points and between mean diurnal pressures, assuming an IOP measurements; were unwilling to accept the risk for hy- SD of 2.8 mm Hg between treatments.8-15 The data were evalu- perchromia of the iris or development of hypertrichosis; and ated by a repeated measures of analysis. The significance level were females of childbearing potential or lactating mothers. was set at 5%, and a 2-way analysis was used for all tests. The secondary efficacy variables, the level of pressure at each time point, the reduction of pressure from untreated baseline PROCEDURES for each time point and the 24-hour pressure curve, and the maximum, minimum, and mean range of pressure (the aver- All patients signed an informed consent agreement approved age of each patient’s difference between the highest and the low- by an institutional review board before any procedures were est IOP measurement throughout the 24-hour period), were performed. At visit 1, subjects had an ophthalmic and sys- analyzed by a t test within the analysis of variance model. One temic history taken and had dilated ophthalmoscopy and au- eye per patient was randomly chosen to be analyzed for the efficacy analysis. Adverse events were collected from both eyes tomated full-threshold perimetry performed (Humphrey 24-2 16 test, SITA standard). At this visit, and at all other visits, the IOP and were evaluated by a McNemar test. was measured (2 measurements at each time point were aver- aged) and Snellen visual acuity testing and slitlamp biomicros- RESULTS copy were performed. Qualified patients then had their glaucoma medications washed out (6 weeks for prostaglandins and The patient characteristics are shown in Table 1. All pa- 4 weeks for ␤-blockers) and were asked to return in 6 weeks for the baseline visit (visit 2). tients had POAG and all were Greek. One patient was At visit 2, and at all other diurnal curve visits (visits 3 and discontinued from the study early due to intolerance to 4), patients had IOP measurements at 6 AM,10AM,2PM,6PM, the latanoprost-timolol fixed combination. 10 PM, and 2 AM. Patients who met the IOP inclusion require- ments were randomly assigned to receive either the latanoprost- INTRAOCULAR PRESSURE timolol fixed combination once every evening at 8 PM and placebo (Tears Naturale II; Alcon Hellas, Athens, Greece) once every The IOP results and reductions from baseline are shown morning at 8:00 or timolol alone (0.5% Temserin; MSD/ in Table 2 and Table 3. The IOP results are also dia- Vianex, Athens) twice daily at 8 AM and 8 PM for the first 8-week grammed in the Figure. The latanoprost-timolol fixed treatment period. combination and timolol alone showed a significant IOP At the end of period 1, a diurnal curve was again performed (visit 3). Patients were then switched to the second study medi- reduction from untreated baseline at each time point and cine for period 2, and a diurnal curve was performed at the end for the 24-hour curve. of the second 8-week treatment period (visit 4).

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