To compare the ocular hypotensive effect of bimatoprost plus timolol and travoprost plus timolol fixed combinations in glaucoma patients whose disease was controlled but had not reached their target intraocular pressure (IOP) with the fixed combination of latanoprost plus timolol.
A 2 × 3-month, multicenter, prospective, randomized, double-masked, cross-over clinical trial.
Eighty-nine open-angle glaucoma (OAG) patients were included. After a 6-week run-in period with latanoprost plus timolol, patients were randomized to either travoprost plus timolol or bimatoprost plus timolol for 3 months. Patients then switched to the opposite therapy for 3 additional months. The primary end point was the comparison of mean daily IOP after 3 months of each treatment.
At baseline, mean IOP was 16.5 mm Hg (95% confidence interval, 16.0 to 17.0 mm Hg) with treatment with latanoprost plus timolol. Both bimatoprost plus timolol and travoprost plus timolol statistically significantly reduced the mean IOP from baseline ( P < .0001). Mean IOP at month 3 was statistically significantly lower in the bimatoprost plus timolol group compared with the travoprost plus timolol group (14.7 mm Hg [95% confidence interval, 14.3 to 15.3 mm Hg] vs 15.4 mm Hg [95% confidence interval, 15.0 to 15.9 mm Hg]; P = .0041). IOP was lower during bimatoprost plus timolol treatment at all time points and statistical significance was reached at 8 am , 11 am , and 5 pm , but not at 2 pm and 8 pm . Both treatments showed similar tolerability profile.
Bimatoprost plus timolol and travoprost plus timolol can provide additional IOP-lowering effect in patients not fully controlled with latanoprost plus timolol. The observed additional IOP reduction was greater with bimatoprost plus timolol with a similar tolerability profile.
Lowering intraocular pressure (IOP) is the only evidence-based method for treating glaucoma and has been shown to reduce risk of visual field progression from 13% to 19% per 1 mm Hg of IOP lowering. According to the European Glaucoma Society Guidelines, topical monotherapy is the first step in the medical management and prostaglandin analogs are the most widely used ocular hypotensive agents for their IOP-lowering efficacy and safety profile, and if target pressure is not reached, it is recommended to switch drugs or to add another drug.
The use of combination therapy frequently is necessary at any stage of the disease, as it has been reported in the Ocular Hypertension Treatment Study and in the Collaborative Initial Glaucoma Treatment Study, where up to 50% and 75% of patients, respectively, required 2 or more drugs to reach their target pressure. When 2 drugs are required to control the IOP, there are a number of potential advantages in using a fixed combination rather than separate drugs, including no risk of drug washout, reduced exposure to preservatives, and ultimately better patient compliance and quality of life. The first prostaglandin fixed combination available in the market was latanoprost plus timolol followed by the fixed combination of travoprost plus timolol and bimatoprost plus timolol. Although there are several reports comparing the hypotensive effect and tolerability of the different prostaglandin analog monotherapies, fewer studies are available comparing prostaglandin analog fixed combinations. The purpose of this study was to compare the ocular hypotensive effect of bimatoprost plus timolol and travoprost plus timolol in glaucoma patients not fully controlled with latanoprost plus timolol.
This 6-month prospective, multicenter, randomized, double-masked, crossover clinical study was carried out at 5 European centers. Patients of 18 years or older who fulfilled the eligibility requirements detailed below and signed an informed consent at the screening visit were included.
Inclusion criteria included diagnosis of primary open-angle glaucoma based on the European Glaucoma Society Guidelines criteria, treatment with nonfixed combination of latanoprost and timolol for at least 3 months or latanoprost plus timolol fixed combination for at least 6 months, IOP less than 21 mm Hg at the baseline 8 am time point on latanoprost plus timolol fixed combination treatment, and target IOP not reached as set by the treating physician.
Exclusion criteria included contraindications to β-blockers; closed or barely open anterior chamber angles or a history of acute angle closure; ocular surgery or argon laser trabeculoplasty within the previous 3 months; ocular inflammation or infection occurring within 3 months before the pretrial visit; neovascular patients (including diabetic patients with neovascular glaucoma); concomitant topical ocular medications that can interfere with study medications; hypersensitivity to benzalkonium chloride or to any other component of the trial drug solutions; other abnormal condition or symptom preventing the patient from entering the trial, according to the investigator’s judgment; any history of refractive surgery, pregnancy, breastfeeding, or childbearing potential without adequate contraception; inability to adhere to the treatment and visit plan; and participation in any other clinical trials within 3 months before the pretrial visit.
Patients treated with latanoprost plus timolol with an IOP of less than 21 mm Hg but requiring further IOP reduction were enrolled in the study. Patients receiving the nonfixed combination were checked for eligibility and scheduled for a wash-in period of 6 weeks with latanoprost plus timolol fixed combination at the prescreening visit.
At the baseline visit, patients were randomized to either bimatoprost plus timolol or travoprost plus timolol and were treated for 3 months. After 3 months, the patients randomized to bimatoprost plus timolol were switched to travoprost plus timolol and patients randomized to travoprost plus timolol were switched to bimatoprost plus timolol. There was no wash-out between the 2 treatments.
Assessment of baseline data was conducted before randomization and assessment of IOP and tolerability were carried out at baseline, 1 month, 3 months, 4 months, and 6 months after randomization. The investigator could choose to have a nonscheduled safety visit in between the scheduled visits. At the baseline visit, patients’ ophthalmic and systemic history were recorded and gonioscopy, pachymetry, and standard automated achromatic perimetry were performed. Patients then were randomized to be treated with either bimatoprost plus timolol or travoprost plus timolol, both dosed in the evening at 9 pm . A complete ophthalmologic examination, including visual acuity and refraction and lid and slit-lamp examination, was performed at the baseline, month 3, and month 6 visits. Additionally, IOP was measured at 8 am , 11 am , 2 pm , 5 pm , and 8 pm by Goldmann applanation tonometry. Month 1 and 4 visits were safety visits; IOP was measured at 11 am , and adverse events were recorded.
The primary outcome was to compare the mean diurnal IOP from the daily curve after 3 months of bimatoprost plus timolol and travoprost plus timolol treatment. Secondary outcomes were to compare between groups the diurnal IOP change from baseline 3 months after the start of each treatment (for each time point separately and for the mean IOP), mean morning (8 am , 11 am ), and mean afternoon IOP (2 pm , 5 pm , 8 pm ), IOP change from baseline at 1 month after the start of each treatment, diurnal IOP change from baseline after switch to the other therapy, distribution of IOP reductions from baseline expressed as percentages, and tolerability.
Double masking was performed by relabeling and repackaging the study drugs in identical boxes. Each patient received after randomization an identical masked box containing 4 smaller masked boxes, each containing 1 masked bottle with the first treatment (1 bottle per month of treatment plus 1 extra safety bottle). At the 12-week visit (crossover visit), a second box containing 4 packed bottles of the second treatment were dispensed to each patient. Each patient eligible for the trial was allocated to 1 of the 2 treatment sequences (either first bimatoprost plus timolol for 3 months and thereafter travoprost plus timolol for 3 months or vice versa) according to a per-center computer-generated randomization code list.
Clinical Tolerability Assessments
Best-corrected visual acuity (Snellen chart), biomicroscopy, and ophthalmoscopy were recorded at the pretrial visit and at each follow-up visit. Any kind of adverse event was recorded. Changes of conjunctival hyperemia were recorded at the slit lamp using a standard scale (0 to 3, where 0 is none, 1 is mild, 2 is moderate, and 3 is severe) with the help of a standardized photographic chart. Superficial keratitis, defined as the presence of small circular epithelial erosions in the cornea, was also graded as none, mild, moderate, and severe (none = no staining; mild = rare stained erosions localized close to the lid margins; moderate = rare stained erosions localized in the 4 quadrants; diffuse = diffuse stained erosions involving the 4 quadrants).
Data are presented as mean and 95% confidence intervals for continuous variables and frequencies for categorical variables. For the IOP recordings, the mean value of 2 measurements at each time point (or the median of 3 readings if the first 2 were not within 2 mm Hg) was used in the calculations. In addition, if both eyes fulfilled the eligibility criteria, the worse eye (i.e., with higher IOP) was used in the analysis. An intent-to-treat approach was used to analyze the IOP variables, and in case of missing data, the last observation available was carried forward. A mixed-model analysis of variance model was used to compare the IOP variables between groups, including the following effects: patients as random effect, and drug and interaction between drug and treatment sequence as fixed effects (to explore potential carryover effects). Categorical variables such as proportions and tolerability variables were analyzed using the Pearson chi-square test or Fisher exact test as appropriate.
The sample size estimate was based on a test for superiority for a crossover study. Setting the α error to 5%, 85 patients per group would enable to detect a difference of 1 mm Hg, assuming a standard deviation of 2.3 mm Hg (based on previously published data ) with a power of 80%.
A total of 91 patients were enrolled in this study, and 89 (mean age, 65.9 ± 11.7 years) were included in the analysis. One patient was lost to follow-up after randomization without performing any follow-up visits and was excluded from the IOP and tolerability analysis. One patient had a retinal detachment after randomization and before the first follow-up visit and was discontinued from the intervention and excluded from the IOP analysis, but included in the tolerability analysis, so the IOP analysis was performed on 89 patients who completed both phases of the study.
The Table reports the mean daily IOP at baseline and after 3 months of treatment with either travoprost plus timolol and bimatoprost plus timolol treatment. After 3 months of treatment, mean daily IOP was statistically significantly reduced compared with baseline in both groups (−1.06 mm Hg, 95% confidence interval [CI], −0.62 to −1.49 mm Hg, in the travoprost plus timolol group, P < .001; −1.72 mm Hg, 95% CI, −1.34 to −2.10 mm Hg, in the bimatoprost plus timolol group, P < .001) and was statistically significantly lower in the bimatoprost plus timolol group than in the travoprost plus timolol group ( P = .0041). No interaction between drug and treatment sequence was detected, indicating no carry-over effects between drugs.
|Baseline IOP||3-Month IOP||Mean IOP Change||Mean % IOP Change||P Value a|
|Travoprost plus timolol||16.5 (16.0 to 17.0)||15.4 (15.0 to 15.9)||−1.06 (−0.62 to −1.49)||−5.7%||< .0001|
|Bimatoprost plus timolol||14.7 (14.3 to 15.3)||−1.72 (−1.34 to −2.10)||−10.1%||< .0001|
|P value b||—||.0041||.0041||.0023||—|